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WO2025137345A1 - Crystalline forms of an imidazopyridine derivative - Google Patents

Crystalline forms of an imidazopyridine derivative Download PDF

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Publication number
WO2025137345A1
WO2025137345A1 PCT/US2024/061121 US2024061121W WO2025137345A1 WO 2025137345 A1 WO2025137345 A1 WO 2025137345A1 US 2024061121 W US2024061121 W US 2024061121W WO 2025137345 A1 WO2025137345 A1 WO 2025137345A1
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Prior art keywords
compound
polymorphic form
tablet
pharmaceutically acceptable
crystalline
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French (fr)
Inventor
Vidyasagar Reddy Gantla
Eric Brown
Nadezda V. SOKOLOVA
Kenneth Mccormack
Gregory Henkel
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Arisan Therapeutics Inc
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Arisan Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to crystalline forms of 3-(4-(tert-butoxy)phenyl)-6-(4- isopropoxyphenyl)-7-methylimidazo[1 ,2-a]py ridine (alternatively named 3-[4-(1 ,1-dimethylethoxy)phenyl]- 7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-tert-butoxyphenyl)-7-methyl-6-(4- (propan-2-yloxy)phenyl)imidazo[1 ,2-a]pyridine), to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to
  • the invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(fert-butoxy)phenyl)-6-(4- isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
  • the present invention relates to methods of modulating cannabinoid receptor 1 (CB1 R) in humans, other mammals, or in cell culture, to methods of treating diseases or conditions mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, and other diseases or conditions associated with or influenced by the CB1 R.
  • metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control
  • hepatic diseases fibrotic disorders
  • This invention related to crystalline forms of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7- methylimidazo[1 ,2-a]pyridine (alternatively named 3-[4-(1 ,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1- methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-terf-butoxyphenyl)-7-methyl-6-(4-(propan-2- yloxy)phenyl)imidazo[1 ,2-a]pyridine) (hereinafter referred to as “Compound 1”) as shown below to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers,
  • the invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
  • Compound 1 is a potent and broad-spectrum arenavirus inhibitor, which is useful in the treatment of arenavirus infections such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers (HF) that are mediated by arenavirus glycoproteins.
  • arenavirus infections such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers (HF) that are mediated by arenavirus glycoproteins.
  • Arenaviridae comprise a diverse family of 29 (and growing) negative stranded enveloped RNA viruses. Arenaviruses are divided into two groups, Old and New World, based on serological, genetic and geographical data. Old World viruses are found primarily throughout South and West Africa and include the prototypic lymphocytic choriomeningitis virus (LCMV), along with Lassa (LASV), Lujo (LUJV), Mopeia (MOPV), Ippy and Mobala (MOBV) viruses. Both LASV and LUJV can cause lethal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis.
  • LCMV prototypic lymphocytic choriomeningitis virus
  • LASV Lassa
  • LJV Lujo
  • MOPV Mopeia
  • Ippy and Mobala MOBV
  • Lassa alone is estimated to cause over 300,000 disease cases each year in West Africa, of which 15-20% of hospitalized patients die and survivors often suffer sequelae, including permanent bilateral hearing damage.
  • Clade B HF viruses include, Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV) and Chapare, along with non-HF viruses such as Tacaribe (TCRV) and Amapari (AMPV).
  • Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane, and the NP contains two ambisense RNA genome segments L and S that direct the synthesis of two polypeptides.
  • the L segment encodes the RNA-dependent-RNA polymerase (RdRp) and a small Ring Finger protein Z.
  • the S segment encodes for nucleoprotein and a glycoprotein precursor GPC that is cleaved by host proteases and undergoes post-translational modification into a mature complex composed of glycoproteins GP1 (binds host protein at the cell surface), GP2 (directs pH dependent membrane fusion and release of genomic material in the cytoplasm) and a stable signal peptide (SSP1).
  • GP1 binds host protein at the cell surface
  • GP2 directs pH dependent membrane fusion and release of genomic material in the cytoplasm
  • SSP1 stable signal peptide
  • the mature glycoprotein complex (GP, or referred to as glycoprotein) is formed in the viral envelope and is responsible for mediating viral entry.
  • the Old World arenaviruses bind to host a-dystroglycan while New World arenaviruses bind to transferrin receptor 1 for entry/endocytosis into cells.
  • the virus Upon binding to cell surface receptors, the virus is endocytosed and directed to acidic late endosomes whereby, GP2 mediates pH dependent membrane fusion and release of genomic material into the cytoplasm for viral replication and transcription. Therefore, viral entry inhibitors (e.g. small molecules) that target virus GP complex or host factors are a potential therapeutic/prophylactic approach in treating patients infected with arenavirus infection.
  • VSV vesicular stomatitis virus
  • GP pseudotype VSV viruses The cell entry and infectivity properties of GP pseudotype VSV viruses have been shown for multiple viruses including HIV, Hepatitis B and C, Ebola, Lassa, Hanta and others [Ogino, M., et al. Use of vesicular stomatitis virus pseudotypes bearing hantaan or seoul virus envelope proteins in a rapid and safe neutralization test. Clin. Diagn. Lab. Immunol. (2003) 10(1):154-60; Saha, M.N., et al. Formation of vesicular stomatitis virus pseudotypes bearing surface proteins of hepatitis B virus. J. Virol. (2005) 79(19):12566-74; Takada, A., et al.
  • the invention also relates to methods of modulating cannabinoid receptor 1 (CB1 R) in humans, other mammals, or in cell culture, to methods of treating diseases or conditions mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, and other diseases or conditions associated with or influenced by the CB1 R.
  • metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control
  • hepatic diseases fibrotic disorders
  • Cannabinoid receptor 1 (CB1 R) is a G-protein coupled receptor responsible for mediating both natural endocannabinoids and synthetic cannabinoid ligand signaling regulating physio-pathologies as potential targets of pharmacotherapy.
  • Agonists of CB1 R regulate appetite promoting orexigenic factors [Di Marzo, V., Goparaju, S. K.,Wang, L., Liu, J., Batkai, S., Jarai, Z., Kunos, G. (2001).
  • Leptin regulated endocannabinoids are involved in maintaining food intake.
  • CB1 R are also expressed at low functional levels in peripheral organs including liver, skeletal muscle, adipose tissue and pancreas.
  • selective CB-R antagonists for peripheral CB1 R demonstrated similar metabolic benefits as Rimonabant in rodent models of obesity and diabetes without the neuropsychiatric side-effects.
  • An increasing number of studies endorsed peripheral CB1 R as an emerging therapeutic target for multiple disease conditions in which increased CB1 R expression/activity in peripheral organs (liver, kidney, heart, pancreas, adipose tissue, muscle, lung) and immune cells (monocytes, macrophages) was found to have a pathogenic function.
  • adipocyte CB1 R contributes to hyperleptinemia [Tam, J., Cinar, R., Liu, J., Godlewski, G., esley, D., Jourdan, T., Kunos, G. (2012).
  • Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism 16, 167-179] and increased lipolysis [Muller, T., Demizieux, L., Troy-Fioramonti, S., Gresti, J., Pais de Barros, J. P., Berger, H., Degrace, P. (2017).
  • Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142, 1218-1228]), alcoholic fatty liver disease [Choi,W.M., Kim, H. H., Kim, M. H., Cinar, R., Yi, H. S., Eun, H. S., Jeong, . I. (2019). Glutamate signaling in hepatic stellate cells drives alcoholic steatosis. Cell Metabolism 30 (877-889), e877; Jeong, W.
  • CB1 R antagonists of CB1 R have potential use for the treatment of the various liver disorders mentioned above.
  • Activation of CB1 R in skeletal muscle inhibits insulin-induced glucose uptake contributing to peripheral insulin resistance [Eckardt, K., Sell, H., Taube, A., Koenen, M., Platzbecker, B., Cramer, A., Eckel, J. (2009).
  • Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 52, 664-674; Liu, Y. L., Connoley, I. P., ilson, C. A., & Stock, M. J. (2005).
  • CB1 R is expressed in p-cells of pancreatic islets where its activation negatively regulates insulin receptor signaling and p-cell proliferation [Kim, W., Doyle, M. E., Liu, Z., Lao, Q., Shin, Y. K., Carlson, O. D., Egan, J. M. (201 1). Cannabinoids inhibit insulin receptor signaling in pancreatic beta-cells.
  • Diabetes 60, 1198-1209 leading to p-cell death [Kim,W., Lao, Q., Shin, Y. K., Carlson, O. D., Lee, E. K., Gorospe, M., Egan, J.M. (2012). Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. Science Signaling 5, ra23. Gonzalez-Mariscal, L, Krzysik-Walker, S. M., Kim, W., Rouse, M., & Egan, J. M. (2016). Blockade of cannabinoid 1 receptor improves GLP-1 R mediated insulin secretion in mice.
  • Compound 1 of the present invention is CB1 R modulator that may be useful in treating a number of diseases, conditions and disorders mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, including the above-mentioned indications.
  • metabolic diseases such as obesity, diabetes, eating disorders, weight loss and control
  • hepatic diseases fibrotic disorders
  • crystalline or amorphous forms that possess physical properties amenable to reliable formulation and manufacture.
  • properties for example, include filterability, hygroscopicity, density and flowability, as well as stability.
  • Polymorphs are different crystalline forms of the same compound which differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) as described in guideline Q6A of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). Such forms may have different pharmaceutically relevant properties, in particular, as oral formulations, including solubility, stability, processability, hygroscopicity, density, flowability, dissolution rate, and bioavailability.
  • the previously known method of preparing Compound 1 has produced an amorphous material.
  • the present invention provides six crystalline forms of Compound I, namely, polymorphic Form A, polymorphic Form B, polymorphic Form C, polymorphic Form D, polymorphic Form E, and polymorphic Form F and the methods for making these crystalline forms.
  • Polymorph Form A was found to be the most stable of the forms identified. It is anhydrous, crystalline, stable and has acceptable solid-state properties for solid dosage form development.
  • the present invention also relates to the use of these crystalline forms in therapeutics methods and in the preparation of pharmaceutical compositions comprising such crystalline forms.
  • the present invention relates to crystalline forms of Compound 1 , shown below, and named 3-(4- (te/Y-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a] py ridi ne (alternatively named 3-[4- (1 ,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-tert- butoxyphenyl)-7-methyl-6-(4-(propan-2-yloxy)phenyl)imidazo[1 ,2-a]pyridine), to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers,
  • the invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]py ridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
  • the invention relates to crystalline forms of Compound 1 , wherein Compound
  • the invention relates to crystalline forms of Compound 1 , wherein the crystalline form is selected from the group consisting of: polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1, polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable carrier, diluent, or vehicle.
  • the invention relates to methods of treating infections associated with viruses of the Arenaviridae enveloped virus family, or any virus expressing Arenavirus glycoproteins to mediate cell entry comprising administering a pharmaceutically effective dose of a crystalline form of Compound 1 with a pharmaceutically acceptable carrier, dilutant or vehicle thereof.
  • the present invention also relates to methods of modulating cannabinoid receptor 1 (CB1 R) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a Compound 1 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof.
  • CBD1 R cannabinoid receptor 1
  • Figure 1 shows the XRPD diffraction pattern of polymorphic Form A of Compound 1 .
  • Figure 2 shows the TGA/DSC overlay of polymorphic Form A of Compound 1 .
  • Figure 3 shows the XRPD diffraction pattern of polymorphic Form B of Compound 1 .
  • Figure 4 shows the TGA/DSC overlay of polymorphic Form B of Compound 1 .
  • Figure 5 shows the XRPD diffraction pattern of polymorphic Form C of Compound 1 .
  • Figure 6 shows the TGA/DSC overlay of polymorphic Form C of Compound 1 .
  • Figure 7 shows the XRPD diffraction pattern of polymorphic Form D of Compound 1 .
  • Figure 8 shows the TGA/DSC overlay of polymorphic Form D of Compound 1 .
  • Figure 9 shows the XRPD diffraction pattern of polymorphic Form E of Compound 1 .
  • Figure 10 shows the TGA/DSC overlay of polymorphic Form E of Compound 1 .
  • Figure 11 shows the XRPD diffraction pattern of polymorphic Form F of Compound 1 .
  • Figure 12 shows the TGA/DSC overlay of polymorphic Form F of Compound 1 .
  • Figure 13 shows the Phase map of crystal Forms A-F of Compound 1 .
  • Figure 14 shows the DVS Isotherm of polymorphic Form A of Compound 1 .
  • Figure 16 shows the Mean Fasting Glucose in Mouse Obesity Model.
  • the invention relates to crystalline forms of Compound 1 , wherein Compound 1 is represented by the following structural formula:
  • the invention relates to crystalline forms of Compound 1 , wherein the crystalline form is selected from the group consisting of: polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1 , polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 1 .
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein said crystalline form displays a small endotherm at about 70 °C, followed by melting at about 120 °C in DSC.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein Form B is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 9.9, and 14.9 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 3.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein said crystalline form displays endotherms at about 67 and 120 °C in DSC.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein Form C is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 10.7, and 18.8 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 5.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein said crystalline form displays endotherms at about 65, 116, 120, and 137 °C in DSC.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein Form D is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.2, 14.4, and 21 .7 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 7.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein said crystalline form displays endotherms at about 61 , 72, and 1 18 °C in DSC.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein Form E is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 10.7, and 15.1 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 9.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein said crystalline form displays endotherms at about 68, 118, and 120 °C in DSC.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein Form F is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 11 .9, and 17.0 degrees 2-theta.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 11.
  • the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein said crystalline form displays endotherms at about 62, 73, and 93 °C in DSC.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable carrier, diluent, or vehicle.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form B.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form C.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form D.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form E.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form F.
  • the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, poly
  • the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbon
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
  • the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises from about 0.5 wt% to about 60 wt% of polymorphic form A of Compound 1 by weight of the composition, wherein a pharmaceutical composition is a tablet or a capsule.
  • the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises from about 0.5 wt% to about 60 wt% of polymorphic form A of Compound 1 by weight of the composition and wherein preferred composition being a tablet.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises from about 20 mg to about 350 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises from about 50 mg to about 250 mg of crystalline Compound 1 per tablet, which may be associated with an acute or severe therapeutic treatment, and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 50 mg of crystalline Compound 1 per tablet, which may be associated with a chronic therapeutic treatment, and wherein the polymorphic form of Compound 1 is Form A.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per capsule.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 20 mg to about 350 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 25 mg to about 300 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 50 mg to about 250 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 50 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
  • the invention in another embodiment, relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising a polymorphic form selected from the group consisting of polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1 , polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1 described as Examples 2 to 22 with a pharmaceutically acceptable carrier, dilutant, or vehicle.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition
  • a pharmaceutical composition comprising approximately 34.03 %w/w of polymorphic Form A of Compound 1 , 31 .03 %w/w microcrystalline cellulose, 6.67% hydroxypropyl cellulose, 4.76 %w/w croscarmellose sodium, 1.49 %w/w magnesium stearate, 17.28 %w/w silicified microcrystalline cellulose, 3.78 %w/w Opadry Green, and 0.95% Opadry Clear, with a pharmaceutically acceptable carrier, dilutant, or vehicle.
  • the method comprises administering a pharmaceutically effective amount of a pharmaceutical composition comprising polymorphic forms of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with an additional therapeutically effective amount of a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.
  • a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with a therapeutically effective amount of Favipiravir.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, po
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium,
  • the method comprises of administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
  • the method comprises of administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, wherein Compound 1 is represented by the following structural formula:
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, wherein the polymorphic form of Compound 1 is Form A and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, with a therapeutically effective amount of Favipiravir.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K- alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir.
  • the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
  • Compound 1 of the invention in development for arenavirus treatment and in particular for Lassa fever, exhibited interesting CB1 R antagonist pharmacological activity and properties.
  • Compound 1 of the invention and their therapeutically acceptable salts, esters, tautomeric forms are CB1 R antagonists.
  • Compound 1 ofthe invention and their therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of diseases and conditions amenable by treatment by CB1 R antagonist.
  • Compound 1 ofthe invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of metabolic diseases, fibrotic disorders, pain, nervous system disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, and osteoporosis.
  • Compound 1 ofthe invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of metabolic diseases, which include, but are not limited to, obesity, diabetes, eating disorders, anorexia, bulimia, weight loss and control, and hepatic diseases, such as nonalcoholic steatohepatitis (NASH).
  • metabolic diseases include, but are not limited to, obesity, diabetes, eating disorders, anorexia, bulimia, weight loss and control
  • hepatic diseases such as nonalcoholic steatohepatitis (NASH).
  • NASH nonalcoholic steatohepatitis
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of fibrotic disorders, which include, but are not limited to, liver fibrosis, pulmonary fibrosis, chronic kidney diseases and renal fibrosis.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of pain, such as acute, chronic, inflammatory and neuropathic pain.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of nervous system disorders, which include, but are not limited to, seizures, epilepsy, migraine, anxiety, depression, bipolar disorders, psychoses, schizophrenia, cognitive disorders, such as learning and memory impairment, withdrawal syndrome, neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spasticity in multiple sclerosis, and substance abuse/dependence disorders, such as opioid addiction, psychostimulant addiction, alcohol addiction, and nicotine addiction.
  • nervous system disorders include, but are not limited to, seizures, epilepsy, migraine, anxiety, depression, bipolar disorders, psychoses, schizophrenia, cognitive disorders, such as learning and memory impairment, withdrawal syndrome, neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spasticity in multiple sclerosis, and substance abuse
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of cardiovascular diseases, which include, but are not limited to, hypertension and atherosclerosis.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of various types of cancer, which include, but are not limited to, cancers of the breast, prostate, and colon.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of inflammatory and autoimmune diseases, which include, but are not limited to, systemic sclerosis and rheumatoid arthritis.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of respiratory disorders, which include, but are not limited to, asthma.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of gastrointestinal diseases, which include, but are not limited to, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), constipation, emesis and nausea.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of genetic disorders, which include, but are not limited to, Duchenne muscular dystrophy and Down syndrome.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of reproductive system disorders, which include, but are not limited to, endometriosis and erectile dysfunction.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of sleep disorders, which include, but are not limited to, narcolepsy and insomnia.
  • Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of osteoporosis.
  • crystalline refers to any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with sharply defined peaks.
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
  • amorphous refers to any solid, oil, or liquid substance which (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, order only over short distances (e.g., less than 10 A), or both.
  • amorphous substances include partially crystalline materials and crystalline mesophases with, e.g. one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals).
  • solvate is used to describe a molecular complex between compounds of the present invention and solvent molecules.
  • examples of solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • DMSO dimethylsulfoxide
  • hydrate can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
  • Powder X-ray diffraction pattern or "XRPD pattern” or “PXRD pattern” refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-Ray diffraction patterns are characterized by peak position (abscissa) and peak intensities (ordinate).
  • 2 theta value or “2-theta” or “20” refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns.
  • cannabinoid receptor 1 refers to a G protein-coupled type 1 cannabinoid receptor that in humans is encoded by the CNR1 gene.
  • pharmaceutically acceptable formulation means a combination of a compound of the invention, or solvate thereof, and an excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
  • Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art.
  • the compounds of the present invention can be formulated with common excipients and formed into tablets, capsules, and the like.
  • excipients that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate.
  • fillers and extenders such as starch, sugars, mannitol, and silicic derivatives
  • binding agents
  • Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, dragees, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain one compound of the present invention and one or more additional agents that inhibit arenavirus. Alternatively, such formulations may contain Compound 1 of the present invention and one or more additional agents that modulate CB1 R activity.
  • pharmaceutically acceptable formulation and “pharmaceutical composition” are synonyms and can be used interchangeably.
  • excipient is defined as: An excipient is any ingredient or substance intentionally added to a drug that is not part of the active pharmaceutical substance.
  • active pharmaceutical substance is defined as: An active pharmaceutical substance mean any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
  • excipients examples include but are not limited to bulking agents, fillers, carriers, diluents, disintegrants, lubricants, solubility enhancers, glidants, sweeteners, coatings, and colorants.
  • a “bulking agent” is defined as an agent that provides a matrix that carries the active pharmaceutical substance when the active pharmaceutical substance is in a low concentration.
  • Bulking agents include, but are not limited to, mannitol, lactose sucrose, dextran, trehalose, and glycine.
  • a “filler” is defined as: An inactive substance used to make the active pharmaceutical substance easier to measure in tablet or capsule formation. Fillers add volume to the formulation while conferring mechanical properties that increase flowability and compressibility which facilitates manufacture and increases the robustness and content uniformity of the final formulation. Examples of fillers include but are not limited to lactose, mannitol, microcrystalline cellulose, dibasic calcium phosphate, and calcium hydrogen phosphate dihydrate.
  • a “binder” is defined as: A material used in formulations to bind ingredients together. Binders are used in tablets and granules to hold active pharmaceutical ingredients (APIs) and excipients together. Binders are added to improve tablet’s mechanical properties and can also improve flowability and the distribution of APIs. Examples of binders include but are not limited to povidone, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, gelatin, starch, carbomers, and sodium carboxymethyl cellulose.
  • a “carrier” is defined as: A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of the active pharmaceutical substance.
  • Carrier types include but are not limited to liposomes, polymeric micelles, microspheres, and dextrans.
  • a “diluent” is defined as: Diluents act as fillers in pharmaceutical tablets to increase weight and improve content uniformity. Diluents include but are not limited to substances such as natural diluents which include starches, hydrolyzed starches, and partially pregelatinized starches. Common diluents include anhydrous lactose, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol. Diluents provide better tablet properties such as improved cohesion or to promote flow in tablet or capsule formation.
  • Disintegrants are agents added to tablet formulations to promote the break-up of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical substance.
  • Disintegrants include but are not limited to alginic acid, bentonite, microcrystalline cellulose, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, low substituted sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.
  • Glidants are substances that are used to enhance the flowability of a powder by reducing the interparticle friction, surface charge, and cohesion, which in turn decreases the angle of repose. They are often incorporated as a dry powder just prior to direct compression of the tablet. Glidants include but are not limited to ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, colloidal silicon dioxide, starch and talc.
  • a “solubility enhancer” or a “solubility enhancement excipient” is defined as a substance that is used to enhance the solubility and increase the bioavailability of the active pharmaceutical ingredient (API).
  • Solubility enhancers include but are not limited to meglumine, cyclodextrins, polymers, for example, polyacrylic acid and poly(amino acid), copolymers, for example, copolymers derived from methacrylic acid/ethyl acrylate, liposomes, and polymeric micelles.
  • Colorant or coloring agents are defined as: A colorant or coloring agent is any dye, pigment or substance which when added to a food, drug or cosmetic, or to the human body will impart a color.
  • modulator in relation to the CB1 R as used herein, refers to the use of a compound of the present invention, or a salt or solvate thereof, as a CB1 R antagonist.
  • modulating amount in relation to the CB1 R as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit or enhance CB1 R activity in vivo, such as in a mammal or in vitro.
  • the amount of such compounds required to cause such modulation can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
  • inhibitorting amount in relation to the CB1 R as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit or enhance CB1 R activity in vivo, such as in a mammal, or in vitro.
  • the amount of such compounds required to cause such inhibition or enhancement can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
  • a therapeutically effective amount in relation to the CB1 R as used herein, means an amount of a compound of the present invention, or a salt or solvate thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the present invention, or a salt or solvate thereof is a quantity sufficient to inhibit or enhance CB1 R activity, such that the condition that may be influenced by CB1 R activity is reduced or alleviated.
  • treat include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition.
  • a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., a CB1 R modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of Compound 1 of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compound into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., a CB1 R modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one or more pharmaceutically suitable carriers which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compound into the final pharmaceutical preparations.
  • a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable excipients, which may be selected, for example, from diluents, carriers and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one compound of the present invention as an active ingredient
  • pharmaceutically suitable excipients which may be selected, for example, from diluents, carriers and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • the pharmaceutical carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropyl methylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
  • the agent may be dissolved in a suitable co-solvent or combinations of co-solvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the compounds can be formulated by combining at least one polymorph with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the polymorphs of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • the pharmaceutically acceptable formulations of the present invention may contain a polymorph of the present invention, or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 10 mg to about 50 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 50 mg to about 250 mg, or from about 100 mg to about 500 mg, or from about 25 mg to about 300 mg, or from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a polymorph of the present invention, or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w% .
  • the polymorphs of the present invention, or solvates thereof, may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus in combination with at least one other agent used for treatment of arenavirus selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors as shown by Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156, incorporated herein by reference in its entirety, Favipiravir , a broadspectrum inhibitor of viral RNA-Dependent RNA Polymerases, Triazavirin, a broad-spectrum inhibitor of viral RNA-Dependent RNA Polymerases, small interfering RNAs (siRNAs) and microRNAs as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms ofmiRNAs and
  • polymorphs of the present invention are useful for modulating or inhibiting arenavirus glycoprotein (GP) both in vitro and in vivo.
  • GP arenavirus glycoprotein
  • these polymorphs are useful for the prevention and/or treatment of disease states associated with arenavirus infection or treating viruses expressing the arenavirus glycoprotein.
  • This invention also relates to a method for the treatment of arenavirus infection in mammals including a human comprising administering to said mammal an amount of a polymorph of Compound 1 , as defined above, or a solvate thereof, that is effective in treating disease states associated with Arenavirus infection or viruses expressing the arenavirus glycoprotein.
  • the compound of the present invention may be administered to a mammal, such as a human, suffering from a condition or disease mediated by CB1 R activity, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
  • the compound of the present invention may be administered to a mammal, such as a human, suffering from CB1 R-mediated diseases or conditions in combination with at least one other agent used in the treatment/prevention/suppression or amelioration of CB1 R-mediated diseases or conditions selected from the group consisting of, but not limited to anti-obesity agents, antidiabetic agents, lipid lowering agents, antihypertensive agents, anorectic agents, anti-epileptics, anxiolytics, anti-depressant agents, anti-inflammatory agents, anti-asthmatic agents, anti-migraine agents, cognition enhancing agents, antipsychotic agents, nicotine receptor partial agonists, opioid antagonists, dopamine receptor agonists, alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
  • a mammal such as a human
  • the compound of the present invention is useful for modulating CB1 R. Accordingly, this compound is useful for the prevention and/or treatment of CB1 R-mediated diseases or conditions.
  • This invention also relates to a method for the treatment of CB1 R-mediated diseases or conditions including a human comprising administering to said mammal an amount of Compound 1 , as defined above, or a salt or solvate thereof, that is effective in treating CB1 R-mediated diseases or conditions.
  • XRPD analyses were performed with a Panalytical X’Pert 3 Powder XRPD on a Si zerobackground holder. The 20 position was calibrated against a Panalytical Si reference standard disc. The parameters used are listed in Table 1 . Table 1. Parameters for XRPD Test.
  • TGA Thermogravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • TGA data were collected using a TA Discovery 550 TGA from TA Instrument.
  • DSC analyses were performed using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 2. Table 2. Parameters for TGA and DSC test. Examples
  • Amorphous Compound 1 used to prepare the polymorphs of this invention may be synthesized using the methods described in WO 2020/117794 A1 patent application.
  • Step 1 6-bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1 ,2-a]pyridine
  • Step 2 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine (Amorphous
  • amorphous Compound 1 of this invention may be prepared by standard manipulations of methods known to those skilled in the art.
  • Polymorphic Form A can be prepared by recrystallization of Compound 1 from hot ethanol, followed by powdering the obtained solid material and drying at 60 °C under vacuum using the following method:
  • Amorphous Compound 1 was dissolved in a minimal volume ( ⁇ 2.8 volumes) of hot (near boiling) ethanol to become a homogeneous solution.
  • the hot solution was allowed to cool to room temperature and then placed in a freezer. Precipitation occurred while keeping the ethanol solution in the freezer at about -20 °C.
  • the precipitate was filtered under vacuum and solid material was collected which was polymorphic Form F.
  • the obtained solid material was grounded to a powder with a mortar and pestle and dried at 60 °C under vacuum for about 2 days to provide polymorphic Form A as a white solid.
  • Form A can be prepared by crystallization of amorphous Compound 1 from hexanes using the following method:
  • Example 3 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form A
  • Amorphous Compound 1 which was isolated as a colorless oil by rotary evaporation from a mixture of hexanes and ethyl acetate, was treated with a small amount of hexanes. After shaking the resulting mixture, the solidification began to occur. The resulting mixture was kept in a freezer until all oil crystallized into a hard solid, then hexanes was decanted and the residue was dried on a rotary evaporator at about 50 °C to afford polymorphic Form A as a white solid.
  • polymorphic Form A can be prepared by recrystallization of Compound 1 from a heptanes solution.
  • the XRPD and a TGA/DSC overlay of Form A are shown in Figs 1 and 2, respectively.
  • the XRPD pattern of Form A expressed in terms of the degree (2-theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 3.
  • Polymorphic Form B can be prepared by slurrying polymorphic Form A at room temperature in a mixture of DMF:H2 ⁇ D (3:7).
  • the XRPD and a TGA/DSC overlay of Form B are shown in Figs 3 and 4, respectively.
  • the XRPD pattern of Form B expressed in terms of the degree (2 -theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 4.
  • Polymorphic Form C can be prepared by slurrying polymorphic Form A at room temperature in a mixture of EtOH:n-heptane (2:8).
  • the XRPD and a TGA/DSC overlay of Form C are shown in Figs 5 and 6, respectively.
  • the XRPD pattern of Form C expressed in terms of the degree (2-theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 5.
  • Polymorphic Form D can be prepared by slurrying polymorphic Form A at room temperature in a mixture of MTBE:n-heptane (3:7).
  • Polymorphic Form E can be prepared by slurrying polymorpich Form A at 50 °C in a mixture of EtOH:H 2 O (1 :1).
  • the XRPD and a TGA/DSC overlay of Form E are shown in Figs 9 and 10, respectively.
  • polymorphic Form F may be obtained from polymorphic Form A by solid vapor diffusion in ethanol vapor.
  • polymorphic Form A may be prepared by conversion of polymorphic Form F using the following method:
  • Form A after vacuum drying or heating shows absence of both peak at -7.5° 20 and/or ⁇ 21 ° 20 (very small peak).
  • polymorphic Form A of Compound 1 multiple polymorph screening experiments were conducted to evaluate the formation of different polymorphs using various solvents and multiple formation processes, including slurry at room temperature, slurry at 50 °C, solid vapor diffusion, liquid vapor diffusion, anti-solvent addition, cooling crystallization, polymer induced crystallization, and slow evaporation.
  • Solid vapor diffusion experiments were conducted using various solvents. Approximately 11 mg of polymorphic Form A of Compound 1 was weighed and placed into a 3-mL vial, which was then placed into a 20-mL vial containing 4 mL of volatile solvent. The 20-mL vial was then sealed with a cap and kept at RT for seven days allowing solvent vapor to interact with sample. The remaining solids were isolated for XRPD analysis (Table 16). Table 16. Summary of solid vapor diffusion experiments.
  • Liquid vapor diffusion experiments were conducted using various solvents. Approximately 11 mg of polymorphic Form A of Compound 1 was dissolved in about 0.2-0.5 mL of appropriate solvent to obtain a clear solution in a 1 .5-mL vial. This solution was then placed into a 20-mL vial containing 4 mL of volatile solvents. The 20-mL vial was sealed with a cap and kept at RT allowing organic vapor to interact with the solution. The precipitates were isolated for XRPD analysis (Table 17).
  • Anti-Solvent Addition Anti-Solvent addition experiments were carried out using various solvents. About 10 mg of polymorphic Form A of Compound 1 was dissolved in about 0.3-0.6 mL solvent to obtain a clear solution. The solution was magnetically stirred followed by addition of about 0.5-0.8 mL anti-solvent stepwise until a precipitate appeared, or the total amount of anti-solvent reached 15.0 mL. The obtained precipitate was isolated for XRPD analysis (Table 18). Table 18. Summary of anti-solvent addition experiments.
  • PVP polyvinyl pyrrolidone
  • PVA polyvinyl alcohol
  • PVC polyvinylchloride
  • HPMC hypromellose
  • MC methyl cellulose
  • PMMA poly(methyl methacrylate)
  • SA sodium alginate
  • HEC hydroxyethyl cellulose
  • Cooling crystallization experiments data are shown in Table 21 .
  • Approximately ⁇ 30 mg of polymorphic Form A of Compound 1 was dissolved in corresponding solvents in a 1 .5-mL glass vial at 50 °C.
  • the suspension was then filtered at 50 °C, with the vial cap being closed immediately after filtration.
  • the samples were then heated to 50 °C for 30 minutes, and then cooled from 50 °C to 5 °C over a period of 8 hours.
  • the samples were then kept at 5 °C until removed. Solids were then isolated and analyzed by XRPD (Table 21).
  • Polymorphic Form A of Compound 1 was screened against a variety of excipients to evaluate compatibility (Table 22). The mixtures were placed in open containers and stored at 50°C and 75% Relative Humidity (RH) for 4 weeks. The compound was compatible with all excipients and blends in Table 22 and maintained polymorph form and thermal stability as neat powder.
  • a batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 23 using the procedure below.
  • Polymorphic Form A of Compound 1 40.0% w/w
  • silicified microcrystalline cellulose 40.0% w/w
  • colloidal silicon dioxide (1 .0% w/w
  • croscarmellose sodium 2.5% w/w
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .59 - 1 .94 mm. Ribbons were granulated using 20 mesh screen.
  • Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 24).
  • Example 11 Prototype-1 Capsule Formulation (100 mg dose capsules)
  • HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 10, for a dose of 100 mg of polymorphic Form A of Compound 1 per capsule.
  • Capsules were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a spiral capsule sinker and a paddle speed of 75-rpm. Dissolution data are provided in Table 26.
  • Example 13 Prototype-1 Tablet Formulation (25 mg and 300 mg dose tablets)
  • a batch of tablet blend was formulated and used to make oval tablet cores containing 25 mg and 300 mg of polymorphic Form A of Compound 1 per tablet using the procedure described below.
  • Prototype-1 Tablet Formulation compositions for 25 and 300 mg dose tablets are shown in Table 29.
  • Polymorphic Form A of Compound 1 (40.2% w/w), silicified microcrystalline cellulose (39.8% w/w), fumed silica (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend.
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .59 - 1 .94 mm. Ribbons were granulated using 20 mesh screen.
  • Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend.
  • the obtained tablet blend was split and part of it was pressed using tablet press machine to produce 25 mg dose tablet cores. Tablet cores were characterized for weight, thickness, hardness, and friability (Table 30).
  • Tablet cores were characterized for weight, thickness, and hardness (Table 31).
  • a batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 32 using the procedure below.
  • Polymorphic Form A of Compound 1 40.0% w/w
  • dibasic calcium phosphate 10.0% w/w
  • microcrystalline cellulose 30.0% w/w
  • colloidal silicon dioxide (1.0% w/w
  • croscarmellose sodium (2.5% w/w
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1.80 - 1 .86 mm.
  • Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 33).
  • a batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 34 using the procedure below.
  • Polymorphic Form A of Compound 1 40.9% w/w
  • mannitol (16.0% w/w)
  • silicified microcrystalline cellulose 23.1% w/w
  • colloidal silicon dioxide (1 .0% w/w
  • croscarmellose sodium (2.5% w/w
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .63 - 1 .86 mm.
  • Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 35).
  • Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 36. Table 34. Prototype-3 Tablet Formulation to produce 100 mg dose tablets.
  • HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 15, for a dose of 100 mg of polymorphic Form A of Compound 1 per capsule.
  • Capsules were analyzed in 900 ml_ of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a spiral capsule sinker and a paddle speed of 75-rpm. Dissolution data are provided in Table 37.
  • Example 17 Prototype-4 Tablet Formulation (100 mg dose tablets)
  • a batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 38 using the procedure below.
  • Polymorphic Form A of Compound 1 40.9% w/w
  • mannitol (16.0% w/w)
  • microcrystalline cellulose (23.1 % w/w)
  • colloidal silicon dioxide (1 .0% w/w
  • croscarmellose sodium (2.5% w/w
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .65 - 1 .86 mm.
  • Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 39).
  • Example 18 Prototype-5 Tablet Formulation (300 mg dose tablets)
  • a batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 40 using the procedure below.
  • Polymorphic Form A of Compound 1 35.4% w/w
  • silicified microcrystalline cellulose 35.2% w/w
  • colloidal silicon dioxide (1 .0% w/w
  • croscarmellose sodium 2.5% w/w
  • Intragranular blend was dry granulated using roller compactor to produce intact ribbons. Ribbons were granulated using 20 mesh screen.
  • Dry granulation blend was further mixed with silicified microcrystalline cellulose (20.4% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (2.0% w/w) for 2 min to produce tablet blend.
  • the obtained tablet blend was pressed using tablet press machine to produce 300 mg dose tablet cores. Tablet cores were characterized for weight, thickness, and hardness (Table 41).
  • the tablet cores were coated with Opadry Green, which was prepared by dispersing the film coat in treated water (250 g (20% w/w) of Opadry Green and 1000 g (80% w/w) of water).
  • the tablet cores (850 mg/tablet, 96.2% w/w) were coated with the suspension (34 mg/tablet) to a weight gain of 3.8%.
  • the second layer of coating was done with Opadry II Clear, which was prepared by dispersing the film coat in treated water (160 g/batch (8% w/w) of Opadry II Clear and 1840 g/batch (92% w/w) of water).
  • the tablets (884 mg/tablet, 99% w/w) were coated with the suspension (8.84 mg/tablet) to a weight gain of 1 %.
  • Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 42. Table 40. Prototype-5 Tablet Formulation composition for 300 mg dose tablets.
  • Example 19 Prototype-5 Tablet Formulation (25 mg and 150 mg dose tablets)
  • a batch of tablet blend was formulated and used to make oval tablet cores containing 25 mg and 150 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 43 in the same manner as described in Example 18.
  • Tablet cores were characterized for weight, thickness, hardness, disintegration time, and friability (Tables 44 and 45).
  • the tablet cores were coated with 20% solids suspension of Opadry Green in water, followed by a second layer of 8% solids suspension of Opadry II Clear in water using the amounts of ingredients recited in Table 43.
  • Tablets containing 25 mg of polymorphic Form A of Compound 1 per tablet were analyzed in 900 ml_ of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 46.
  • a batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 47 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, hardness, and friability (Table 48). The tablet cores were coated with Opadry Green, followed by Opadry II Clear using the amounts of ingredients recited in Table 47.
  • Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 49.
  • Table 47 Prototype-5 Tablet Formulation composition for 100 mg dose tablets. a. Film coat suspension was prepared in excess of the theoretical required quantity. b. Water is removed during processing and is not present in the final product.
  • mice dosed with Compound 1 at both 10 and 30 mg/kg/day demonstrated significant decreases in body weight relative to obese mice dosed with vehicle.
  • food intake was significantly lower at 30 mg/kg/day compared vehicle dosed obese mice.
  • cholesterol levels were significantly reduced at all doses tested including 10, 30 and 50 mg/kg/day.

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Abstract

Polymorphic forms A, B, C, D, E, and F of Compound 1, as shown below, have been discovered and formulated with pharmaceutically acceptable excipients to form tablets and capsules.

Description

PATENT APPLICATION
Crystalline Forms Of An Imidazopyridine Derivative
Inventors: Vidyasagar Reddy Gantla, Eric Brown, Nadezda V. Sokolova, Kenneth McCormack, Gregory
Henkel
Entity: Small
Ken McCormack
Arisan Therapeutics
5825 Avenida Encinas, Suite 101
Carlsbad, CA 92008
858-766-0495 kenm@arisanthera.com Crystalline Forms Of An Imidazopyridine Derivative
CROSS REFERENCES TO RELATED APPLICATIONS
This patent application is a continuation in part of and claims the benefit of priority to United States Provisional Patent Application serial number 63/612,863, filed December 20, 2023 herein incorporated by reference in its entirety for all purposes.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
This invention was made with government support under R44 AI112097 awarded by U.S. National Institutes of Health. The government has certain rights in the invention.
REFERENCE TO A “SEQUENCE LISTING, A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK
NOT APPLICABLE FIELD OF THE INVENTION
The present invention relates to crystalline forms of 3-(4-(tert-butoxy)phenyl)-6-(4- isopropoxyphenyl)-7-methylimidazo[1 ,2-a]py ridine (alternatively named 3-[4-(1 ,1-dimethylethoxy)phenyl]- 7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-tert-butoxyphenyl)-7-methyl-6-(4- (propan-2-yloxy)phenyl)imidazo[1 ,2-a]pyridine), to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Bolivian, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to pharmaceutical compositions comprising such crystalline forms that can be employed for such methods. The invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(fert-butoxy)phenyl)-6-(4- isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
Additionally, the present invention relates to methods of modulating cannabinoid receptor 1 (CB1 R) in humans, other mammals, or in cell culture, to methods of treating diseases or conditions mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, and other diseases or conditions associated with or influenced by the CB1 R.
BACKGROUND OF THE INVENTION
This invention related to crystalline forms of 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7- methylimidazo[1 ,2-a]pyridine (alternatively named 3-[4-(1 ,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1- methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-terf-butoxyphenyl)-7-methyl-6-(4-(propan-2- yloxy)phenyl)imidazo[1 ,2-a]pyridine) (hereinafter referred to as “Compound 1”) as shown below
Figure imgf000005_0001
to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Bolivian, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to pharmaceutical compositions comprising such crystalline forms that can be employed for such methods. The invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
The preparation of Compound 1 is described in WO 2020/117794 A1 , the entire disclosure whereof is incorporated herein by reference.
Compound 1 is a potent and broad-spectrum arenavirus inhibitor, which is useful in the treatment of arenavirus infections such as Lassa, Bolivian, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers (HF) that are mediated by arenavirus glycoproteins.
Arenaviridae comprise a diverse family of 29 (and growing) negative stranded enveloped RNA viruses. Arenaviruses are divided into two groups, Old and New World, based on serological, genetic and geographical data. Old World viruses are found primarily throughout South and West Africa and include the prototypic lymphocytic choriomeningitis virus (LCMV), along with Lassa (LASV), Lujo (LUJV), Mopeia (MOPV), Ippy and Mobala (MOBV) viruses. Both LASV and LUJV can cause lethal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis. Lassa (LASV) alone is estimated to cause over 300,000 disease cases each year in West Africa, of which 15-20% of hospitalized patients die and survivors often suffer sequelae, including permanent bilateral hearing damage. The larger New World complex primarily located in the South American continent, is divided into 3 clades, A, B, and C, with clade B being important as many of the viruses in this group can cause lethal HF. Clade B HF viruses include, Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV) and Chapare, along with non-HF viruses such as Tacaribe (TCRV) and Amapari (AMPV). Human infection occurs through contact with the excretions of an infected rodent or by inhalation of tiny particles soiled with rodent urine or saliva (aerosol transmission). There is also evidence of human-to-human spread primarily in nosocomial settings (e.g. hospitals). The incubation period of virus is 1 -2 weeks followed by fever, general malaise, weakness, sore throat, headache, cough, diarrhea, and vomiting. These general symptoms make it difficult to differentially diagnose arenavirus infection. Poor prognosis is indicated as symptoms worsen to include pleural effusions, facial edema, neurological complications and bleeding from mucosal surfaces. Current arenavirus treatment is limited to the use of ribavirin, which is only partially effective if given early and associated with significant side effects. Although a vaccine has been developed for Junin virus its usage is primarily restricted to the most at risk populations of farm workers in Argentina and there are no approved vaccines for any other arenaviruses. Although highly desirable, prophylactic vaccines may not always be effective countermeasures against rapidly emerging, antigenically distinct new virus strains and the existing vaccine development and production strategies cannot adequately respond to the diverse family of current or emergent arenaviruses. Novel broad-spectrum antiviral drugs could therefore, provide a first line therapy and/or prophylactic not only for endemic regions of arenavirus infection but also as a safeguard against potential biological warfare agents.
Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane, and the NP contains two ambisense RNA genome segments L and S that direct the synthesis of two polypeptides. The L segment encodes the RNA-dependent-RNA polymerase (RdRp) and a small Ring Finger protein Z. The S segment encodes for nucleoprotein and a glycoprotein precursor GPC that is cleaved by host proteases and undergoes post-translational modification into a mature complex composed of glycoproteins GP1 (binds host protein at the cell surface), GP2 (directs pH dependent membrane fusion and release of genomic material in the cytoplasm) and a stable signal peptide (SSP1). The mature glycoprotein complex (GP, or referred to as glycoprotein) is formed in the viral envelope and is responsible for mediating viral entry. The Old World arenaviruses bind to host a-dystroglycan while New World arenaviruses bind to transferrin receptor 1 for entry/endocytosis into cells. Upon binding to cell surface receptors, the virus is endocytosed and directed to acidic late endosomes whereby, GP2 mediates pH dependent membrane fusion and release of genomic material into the cytoplasm for viral replication and transcription. Therefore, viral entry inhibitors (e.g. small molecules) that target virus GP complex or host factors are a potential therapeutic/prophylactic approach in treating patients infected with arenavirus infection.
Because the HF arenavirus species are classified as BSL-4, alternative approaches are needed to identify viral entry inhibitors. To facilitate the identification of arenavirus entry inhibitors one may express arenavirus GP complex in nonpathogenic BSL-2 envelope viruses to produce single round infectious pseudoviruses whose viral entry functions are determined by the heterogeneous glycoprotein of interest. One viral expression system that may be utilized is the vesicular stomatitis virus (VSV) system, whereby the envelope protein of VSV is substituted with an envelope glycoprotein from another virus, e.g., LASV, to mediate entry of the pseudotype virion. The cell entry and infectivity properties of GP pseudotype VSV viruses have been shown for multiple viruses including HIV, Hepatitis B and C, Ebola, Lassa, Hanta and others [Ogino, M., et al. Use of vesicular stomatitis virus pseudotypes bearing hantaan or seoul virus envelope proteins in a rapid and safe neutralization test. Clin. Diagn. Lab. Immunol. (2003) 10(1):154-60; Saha, M.N., et al. Formation of vesicular stomatitis virus pseudotypes bearing surface proteins of hepatitis B virus. J. Virol. (2005) 79(19):12566-74; Takada, A., et al. A system for functional analysis of Ebola virus glycoprotein, Proc. Natl. Acad. Sci. (1997) 94:14764-69; Garbutt, M., et al. Properties of replication- competent vesicular stomatitis virus vectors expressing glycoproteins of filoviruses and arenaviruses. J. Virol, (2004) 78(10):5458-65]. The above papers are herein incorporated by reference in their entirety for all purposes. To monitor pseudovirus infection, a reporter gene such as green fluorescent protein (GFP) or luciferase can be engineered into the pseudovirus genome, and virus infectivity in mammalian cell lines (e.g. Vero or Hek293) can be monitored using optical detection methods (e.g. plate reader) [Cote, M.; Misasi, J.; Ren, T.; Bruchez, A., Lee, K., Filone, C. M.; Hensley, L.; Li, Q.; Ory, D.; Chandran, K.; Cunningham, J., Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection, Nature (2011) 477: 344-348, Elshabrawy, H. A., et al. Identification of a broad-spectrum antiviral amall molecule against severe scute respiratory syndrome Coronavirus and Ebola, Hendra, and Nipah Viruses by using a novel high-throughput screening assay. J. Virol. (2014) 88: 4353-4365]. The above papers are herein incorporated by reference in their entirety for all purposes. The “pseudoviruses” may therefore be used to screen chemical compound libraries to identify inhibitors of arenavirus cell entry while avoiding the complications of working with highly pathogenic BSL-4 agents.
The invention also relates to methods of modulating cannabinoid receptor 1 (CB1 R) in humans, other mammals, or in cell culture, to methods of treating diseases or conditions mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, and other diseases or conditions associated with or influenced by the CB1 R.
Cannabinoid receptor 1 (CB1 R) is a G-protein coupled receptor responsible for mediating both natural endocannabinoids and synthetic cannabinoid ligand signaling regulating physio-pathologies as potential targets of pharmacotherapy. Agonists of CB1 R regulate appetite promoting orexigenic factors [Di Marzo, V., Goparaju, S. K.,Wang, L., Liu, J., Batkai, S., Jarai, Z., Kunos, G. (2001). Leptin regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822-825] via the hypothalamic CB1 R providing the rationale to develop CB1 R antagonists for the treatment of obesity and metabolic complications associated with obesity. The above paper is herein incorporated by reference in their entirety for all purposes. Rimonabant, a first in class CB1 R antagonist/inverse agonist in clinical trials demonstrated weight loss in obese people and also improved multiple cardiometabolic parameters altered in obese people including waist circumference, hemoglobin A1c, high density lipoprotein (HDL), plasma cholesterol and triglycerides [Despres, J. P., Golay, A., Sjostrom, L., & Rimonabant in Obesity- Lipids Study G (2005). Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. The New England Journal of Medicine 353, 2121-2134; Van Gaal, L. F., Scheen, A. J., Rissanen, A. M., Rossner, S., Hanotin, C., & Ziegler, O. (2008). Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. European Heart Journal 29(14), 1761-1771], The above papers are herein incorporated by reference in their entirety for all purposes. Unfortunately, Rimonabant was withdrawn from clinical use due to it's neuropsychiatric sideeffects.
CB1 R are also expressed at low functional levels in peripheral organs including liver, skeletal muscle, adipose tissue and pancreas. Interestingly, selective CB-R antagonists for peripheral CB1 R demonstrated similar metabolic benefits as Rimonabant in rodent models of obesity and diabetes without the neuropsychiatric side-effects. An increasing number of studies endorsed peripheral CB1 R as an emerging therapeutic target for multiple disease conditions in which increased CB1 R expression/activity in peripheral organs (liver, kidney, heart, pancreas, adipose tissue, muscle, lung) and immune cells (monocytes, macrophages) was found to have a pathogenic function. Subsequent studies demonstrated that activation of adipocyte CB1 R contributes to hyperleptinemia [Tam, J., Cinar, R., Liu, J., Godlewski, G., esley, D., Jourdan, T., Kunos, G. (2012). Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metabolism 16, 167-179] and increased lipolysis [Muller, T., Demizieux, L., Troy-Fioramonti, S., Gresti, J., Pais de Barros, J. P., Berger, H., Degrace, P. (2017). Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue. American Journal of Physiology. Endocrinology and Metabolism 313, E26-E36; Sidibeh, C. O., Pereira, M. J., Lau Borjesson, J., Kamble, P. G., Skrtic, S., Katsogiannos, P., Eriksson, J.W. (2017). Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance. Endocrine 55, 839-852]. The above papers are herein incorporated by reference in their entirety for all purposes. Selective genetic deletion was later found to be sufficient to prevent diet-induced obesity (DIO) through reprogramming of adipose tissue resulting in browning of white fat and increased thermogenesis. The CB1 R was also identified in hepatocytes where their activation promotes de novo lipogenesis and hepatic insulin resistance [Osei-Hyiaman, D., DePetrillo, M., Pacher, P., Liu, J., Radaeva, S., Batkai, S., Kunos, G. (2005). Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet- induced obesity. The Journal of Clinical Investigation 115, 1298-1305; Osei-Hyiaman, D., Liu, J., Zhou, L., Godlewski, G., Harvey-White, J., Jeong, . I., Kunos, G. (2008). Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. The Journal of Clinical Investigation 118, 3160-3169]. The above papers are herein incorporated by reference in their entirety for all purposes. CB1 R expression and activity are increased in the liver under various pathologic conditions of different etiologies, such as non-alcoholic fatty liver disease [Jourdan, T., Demizieux, L., Gresti, J., Djaouti, L., Gaba, L., Verges, B., & Degrace, P. (2012). Antagonismof peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants. Hepatology 55, 790-799; Liu, J., Zhou, L., Xiong, K., Godlewski, G., Mukhopadhyay, B., Tam, J., Kunos, G. (2012). Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 142, 1218-1228]), alcoholic fatty liver disease [Choi,W.M., Kim, H. H., Kim, M. H., Cinar, R., Yi, H. S., Eun, H. S., Jeong, . I. (2019). Glutamate signaling in hepatic stellate cells drives alcoholic steatosis. Cell Metabolism 30 (877-889), e877; Jeong, W. L, Osei- Hyiaman, D., Park, O., Liu, J., Batkai, S., Mukhopadhyay, P., Kunos, G. (2008). Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metabolism 7, 227-235], viral hepatitis [van der Poorten, D., Shahidi, M., Tay, E., Sesha, J., Tran, K., McLeod, D., George, J. (2010). Hepatitis C virus induces the cannabinoid receptor 1. PLoS One 5] and hepatocellular carcinoma [Mukhopadhyay, B., Schuebel, K., Mukhopadhyay, P., Cinar, R., Godlewski, G., Xiong, K., Kunos, G. (2015). Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms. Hepatology 61 , 1615-1626], The above papers are herein incorporated by reference in their entirety for all purposes. Selective deletion of CB1 R in hepatocytes attenuated diet-induced hepatic lipogenesis, dyslipidemia, insulin and leptin resistance but not adiposity. Therefore, antagonists of CB1 R have potential use for the treatment of the various liver disorders mentioned above. Activation of CB1 R in skeletal muscle inhibits insulin-induced glucose uptake contributing to peripheral insulin resistance [Eckardt, K., Sell, H., Taube, A., Koenen, M., Platzbecker, B., Cramer, A., Eckel, J. (2009). Cannabinoid type 1 receptors in human skeletal muscle cells participate in the negative crosstalk between fat and muscle. Diabetologia 52, 664-674; Liu, Y. L., Connoley, I. P., ilson, C. A., & Stock, M. J. (2005). Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice. International Journal of Obesity 29, 183-187], The above papers are herein incorporated by reference in their entirety for all purposes. Skeletal musclespecific deletion of CB1 R prevented diet-induced insulin resistance and increased whole body energy expenditure [Gonzalez-Mariscal, l.,Montoro, R. A., O’Connell, J. F., Kim, Y., Gonzalez-Freire, M., Liu, Q. R.,... Egan, J. M. (2019). Muscle cannabinoid 1 receptor regulates 11-6 and myostatin expression, governing physical performance and whole-body metabolism. The FASEB Journal 33, 5850-5863]. The above paper is herein incorporated by reference in their entirety for all purposes. CB1 R is expressed in p-cells of pancreatic islets where its activation negatively regulates insulin receptor signaling and p-cell proliferation [Kim, W., Doyle, M. E., Liu, Z., Lao, Q., Shin, Y. K., Carlson, O. D., Egan, J. M. (201 1). Cannabinoids inhibit insulin receptor signaling in pancreatic beta-cells. Diabetes 60, 1198-1209] leading to p-cell death [Kim,W., Lao, Q., Shin, Y. K., Carlson, O. D., Lee, E. K., Gorospe, M., Egan, J.M. (2012). Cannabinoids induce pancreatic beta-cell death by directly inhibiting insulin receptor activation. Science Signaling 5, ra23. Gonzalez-Mariscal, L, Krzysik-Walker, S. M., Kim, W., Rouse, M., & Egan, J. M. (2016). Blockade of cannabinoid 1 receptor improves GLP-1 R mediated insulin secretion in mice. Molecular and Cellular Endocrinology 423, 1-10], The above papers are herein incorporated by reference in their entirety for all purposes. Pharmacological blockade of CB1 R in p-cells improved incretin-induced insulin secretion [Gonzalez-Mariscal, L, Montoro, R. A., Doyle, M. E., Liu, Q. R., Rouse, M., O’Connell, J. F., Egan, J. M. (2018). Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets. Diabetologia 61 , 1470-1483] and glucose responsiveness [Shin, H., Han, J. H., Yoon, J., Sim, H. J., Park, T. J., Yang, S., Kim, W. (2018). Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. Journal of Cellular and MolecularMedicine 22, 2337-2345], whereas selective deletion of CB1 R in p-cells protects from dietary induced p-cell dysfunction [Gonzalez-Mariscal, L, Montoro, R. A., Doyle, M. E., Liu, Q. R., Rouse, M., O’Connell, J. F., Egan, J. M. (2018). Absence of cannabinoid 1 receptor in beta cells protects against high- fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets. Diabetologia 61 , 1470- 1483], The above papers are herein incorporated by reference in their entirety for all purposes. Therefore, antagonism of peripheral CB1 R has the potential to treat multiple metabolic disorders.
Similar to a number of pharmaceutical compounds Compound 1 of the present invention is CB1 R modulator that may be useful in treating a number of diseases, conditions and disorders mediated by the CB1 R, including metabolic diseases, such as obesity, diabetes, eating disorders, weight loss and control, and hepatic diseases, fibrotic disorders, pain, nervous system disorders, including substance abuse/dependence disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, osteoporosis, including the above-mentioned indications.
As understood by those skilled in the art, once a compound has been selected for development as a clinical candidate, it is desirable to have crystalline or amorphous forms, that possess physical properties amenable to reliable formulation and manufacture. Such properties, for example, include filterability, hygroscopicity, density and flowability, as well as stability.
Polymorphs are different crystalline forms of the same compound which differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopolymorphs) as described in guideline Q6A of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). Such forms may have different pharmaceutically relevant properties, in particular, as oral formulations, including solubility, stability, processability, hygroscopicity, density, flowability, dissolution rate, and bioavailability. It may be desirable to identify improved forms that display improved properties, such as increased aqueous solubility and stability, better processability, lack of hygroscopic tendencies, enhanced rates of dissolution, and increase of the bioavailability of orally-administered compositions. By varying the forms, it may be possible to alter the properties discussed above in a way that is beneficial for a desired therapeutic effect.
The previously known method of preparing Compound 1 , described in WO 2020/117794 A1 , has produced an amorphous material. The present invention provides six crystalline forms of Compound I, namely, polymorphic Form A, polymorphic Form B, polymorphic Form C, polymorphic Form D, polymorphic Form E, and polymorphic Form F and the methods for making these crystalline forms. Polymorph Form A was found to be the most stable of the forms identified. It is anhydrous, crystalline, stable and has acceptable solid-state properties for solid dosage form development.
The present invention also relates to the use of these crystalline forms in therapeutics methods and in the preparation of pharmaceutical compositions comprising such crystalline forms.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to crystalline forms of Compound 1 , shown below, and named 3-(4- (te/Y-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a] py ridi ne (alternatively named 3-[4- (1 ,1-dimethylethoxy)phenyl]-7-methyl-6-[4-(1-methylethoxy)phenyl]-imidazo[1 ,2-a]pyridine or 3-(4-tert- butoxyphenyl)-7-methyl-6-(4-(propan-2-yloxy)phenyl)imidazo[1 ,2-a]pyridine), to methods for the preparation of such crystalline forms, to the use of such crystalline forms for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Bolivian, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to pharmaceutical compositions comprising such crystalline forms that can be employed for such methods. The invention is also directed to pharmaceutical compositions comprising at least one crystalline form of the compound 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]py ridine and to the therapeutic or prophylactic use of such crystalline forms and compositions.
In one embodiment, the invention relates to crystalline forms of Compound 1 , wherein Compound
1 is represented by the following structural formula:
Figure imgf000012_0001
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the crystalline form is selected from the group consisting of: polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1, polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable carrier, diluent, or vehicle.
In another embodiment, the invention relates to methods of treating infections associated with viruses of the Arenaviridae enveloped virus family, or any virus expressing Arenavirus glycoproteins to mediate cell entry comprising administering a pharmaceutically effective dose of a crystalline form of Compound 1 with a pharmaceutically acceptable carrier, dilutant or vehicle thereof.
The present invention also relates to methods of modulating cannabinoid receptor 1 (CB1 R) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a Compound 1 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the XRPD diffraction pattern of polymorphic Form A of Compound 1 .
Figure 2 shows the TGA/DSC overlay of polymorphic Form A of Compound 1 .
Figure 3 shows the XRPD diffraction pattern of polymorphic Form B of Compound 1 .
Figure 4 shows the TGA/DSC overlay of polymorphic Form B of Compound 1 .
Figure 5 shows the XRPD diffraction pattern of polymorphic Form C of Compound 1 .
Figure 6 shows the TGA/DSC overlay of polymorphic Form C of Compound 1 .
Figure 7 shows the XRPD diffraction pattern of polymorphic Form D of Compound 1 .
Figure 8 shows the TGA/DSC overlay of polymorphic Form D of Compound 1 .
Figure 9 shows the XRPD diffraction pattern of polymorphic Form E of Compound 1 .
Figure 10 shows the TGA/DSC overlay of polymorphic Form E of Compound 1 .
Figure 11 shows the XRPD diffraction pattern of polymorphic Form F of Compound 1 .
Figure 12 shows the TGA/DSC overlay of polymorphic Form F of Compound 1 .
Figure 13 shows the Phase map of crystal Forms A-F of Compound 1 .
Figure 14 shows the DVS Isotherm of polymorphic Form A of Compound 1 .
Figure 15 shows A) Mean % Weight Change and B) Mean Food Intake in Mouse DIO Obesity Study.
Figure 16 shows the Mean Fasting Glucose in Mouse Obesity Model.
Figure 17 shows the Mean Cholesterol Measurement at End of 28-Day GLP Rat Toxicity Study.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the invention relates to crystalline forms of Compound 1 , wherein Compound 1 is represented by the following structural formula:
Figure imgf000013_0001
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the crystalline form is selected from the group consisting of: polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1 , polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 1 .
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form A of Compound 1 and wherein said crystalline form displays a small endotherm at about 70 °C, followed by melting at about 120 °C in DSC.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein Form B is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 9.9, and 14.9 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 3.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form B of Compound 1 and wherein said crystalline form displays endotherms at about 67 and 120 °C in DSC.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein Form C is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 10.7, and 18.8 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 5. In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form C of Compound 1 and wherein said crystalline form displays endotherms at about 65, 116, 120, and 137 °C in DSC.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein Form D is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.2, 14.4, and 21 .7 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 7.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form D of Compound 1 and wherein said crystalline form displays endotherms at about 61 , 72, and 1 18 °C in DSC.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein Form E is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 5.0, 10.7, and 15.1 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 9.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form E of Compound 1 and wherein said crystalline form displays endotherms at about 68, 118, and 120 °C in DSC.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein Form F is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 11 .9, and 17.0 degrees 2-theta.
In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein said crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2-theta) essentially and approximately the same as shown in Figure 11. In another embodiment, the invention relates to crystalline forms of Compound 1 , wherein the polymorphic form is Form F of Compound 1 and wherein said crystalline form displays endotherms at about 62, 73, and 93 °C in DSC.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable carrier, diluent, or vehicle.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form B.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form C.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form D.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form E.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form F.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a pharmaceutically acceptable formulation comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate. In another embodiment, the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises from about 0.5 wt% to about 60 wt% of polymorphic form A of Compound 1 by weight of the composition, wherein a pharmaceutical composition is a tablet or a capsule.
In another embodiment, the invention relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises from about 0.5 wt% to about 60 wt% of polymorphic form A of Compound 1 by weight of the composition and wherein preferred composition being a tablet.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 20 mg to about 350 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 25 mg to about 300 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 50 mg to about 250 mg of crystalline Compound 1 per tablet, which may be associated with an acute or severe therapeutic treatment, and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 50 mg of crystalline Compound 1 per tablet, which may be associated with a chronic therapeutic treatment, and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate. In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A. In another embodiment, the invention relates to a tablet formulation, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per capsule.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 20 mg to about 350 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 25 mg to about 300 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 50 mg to about 250 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises from about 10 mg to about 50 mg of crystalline Compound 1 per capsule and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the capsules are HPMC capsules. In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate, and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, fumed silica, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , dibasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the invention relates to a capsule formulation, wherein the capsule formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate, and wherein the polymorphic form of Compound 1 is Form A and wherein the capsules are HPMC capsules.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising a polymorphic form selected from the group consisting of polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1 , polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1 described as Examples 2 to 22 with a pharmaceutically acceptable carrier, dilutant, or vehicle.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising approximately 34.03 %w/w of polymorphic Form A of Compound 1 , 31 .03 %w/w microcrystalline cellulose, 6.67% hydroxypropyl cellulose, 4.76 %w/w croscarmellose sodium, 1.49 %w/w magnesium stearate, 17.28 %w/w silicified microcrystalline cellulose, 3.78 %w/w Opadry Green, and 0.95% Opadry Clear, with a pharmaceutically acceptable carrier, dilutant, or vehicle.
In another embodiment the method comprises administering a pharmaceutically effective amount of a pharmaceutical composition comprising polymorphic forms of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with an additional therapeutically effective amount of a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.
In another embodiment the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with a therapeutically effective amount of Favipiravir.
In another embodiment the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 with a pharmaceutically acceptable carrier, dilutant, or vehicle, with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A.
In another embodiment the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir.
In another embodiment the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings. In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the method comprises of administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
In another embodiment, the method comprises of administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of the tablet formulation with a therapeutically effective amount of Favipiravir, wherein the tablet formulation comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate and wherein the polymorphic form of Compound 1 is Form A.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, wherein Compound 1 is represented by the following structural formula:
Figure imgf000028_0001
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, wherein the polymorphic form of Compound 1 is Form A and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, with a therapeutically effective amount of Favipiravir.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant or vehicle thereof, with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K- alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K- alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly(amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
In another embodiment, the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of at least one polymorphic form of Compound 1 or a pharmaceutically acceptable solvate thereof and at least one pharmaceutically acceptable excipient with a therapeutically effective amount of Favipiravir, wherein the polymorphic form of Compound 1 is Form A and wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and magnesium stearate.
It was unexpectedly discovered that Compound 1 of the invention, in development for arenavirus treatment and in particular for Lassa fever, exhibited interesting CB1 R antagonist pharmacological activity and properties.
One can treat a disease or condition in a mammal or human that is amenable to treatment by a CB1 R modulator by administering a pharmaceutically effective amount of a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, dilutant, or vehicle.
In another embodiment, Compound 1 ofthe invention and their therapeutically acceptable salts, esters, tautomeric forms are CB1 R antagonists.
In another embodiment, Compound 1 ofthe invention and their therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of diseases and conditions amenable by treatment by CB1 R antagonist.
In another embodiment, Compound 1 ofthe invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of metabolic diseases, fibrotic disorders, pain, nervous system disorders, cardiovascular diseases, cancer, inflammatory and autoimmune diseases, respiratory disorders, gastrointestinal diseases, genetic disorders, reproductive system disorders, sleep disorders, and osteoporosis.
In another embodiment, Compound 1 ofthe invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of metabolic diseases, which include, but are not limited to, obesity, diabetes, eating disorders, anorexia, bulimia, weight loss and control, and hepatic diseases, such as nonalcoholic steatohepatitis (NASH). In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of fibrotic disorders, which include, but are not limited to, liver fibrosis, pulmonary fibrosis, chronic kidney diseases and renal fibrosis.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of pain, such as acute, chronic, inflammatory and neuropathic pain.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of nervous system disorders, which include, but are not limited to, seizures, epilepsy, migraine, anxiety, depression, bipolar disorders, psychoses, schizophrenia, cognitive disorders, such as learning and memory impairment, withdrawal syndrome, neurodegenerative disorders, such as Alzheimer’s and Huntington’s diseases, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, spasticity in multiple sclerosis, and substance abuse/dependence disorders, such as opioid addiction, psychostimulant addiction, alcohol addiction, and nicotine addiction.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of cardiovascular diseases, which include, but are not limited to, hypertension and atherosclerosis.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of various types of cancer, which include, but are not limited to, cancers of the breast, prostate, and colon.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of inflammatory and autoimmune diseases, which include, but are not limited to, systemic sclerosis and rheumatoid arthritis.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of respiratory disorders, which include, but are not limited to, asthma.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of gastrointestinal diseases, which include, but are not limited to, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), constipation, emesis and nausea. In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of genetic disorders, which include, but are not limited to, Duchenne muscular dystrophy and Down syndrome.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of reproductive system disorders, which include, but are not limited to, endometriosis and erectile dysfunction.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of sleep disorders, which include, but are not limited to, narcolepsy and insomnia.
In another embodiment, Compound 1 of the invention and its therapeutically acceptable salts, esters, tautomeric forms are potentially of use as medicaments for the treatment of osteoporosis.
DEFINITIONS
As used herein, the terms “comprising” and “including” are used in their open, non-limiting sense.
The term "crystalline" refers to any solid substance exhibiting three-dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with sharply defined peaks.
The term "polymorph" refers to different crystalline forms of the same compound and includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
The term "amorphous" refers to any solid, oil, or liquid substance which (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, order only over short distances (e.g., less than 10 A), or both. Thus, amorphous substances include partially crystalline materials and crystalline mesophases with, e.g. one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals).
The term "solvate," is used to describe a molecular complex between compounds of the present invention and solvent molecules. Examples of solvates include, but are not limited to, compounds of the invention in combination with water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term “hydrate” can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
The term "powder X-ray diffraction pattern" or "XRPD pattern" or “PXRD pattern” refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-Ray diffraction patterns are characterized by peak position (abscissa) and peak intensities (ordinate).
The term "2 theta value" or "2-theta" or “20” refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns.
The term “cannabinoid receptor 1 ” or “CB1 receptor” or “CB1 R” or “CB1” as used herein, refers to a G protein-coupled type 1 cannabinoid receptor that in humans is encoded by the CNR1 gene.
The term “pharmaceutically acceptable formulation,” as used herein, means a combination of a compound of the invention, or solvate thereof, and an excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art. For example, the compounds of the present invention can be formulated with common excipients and formed into tablets, capsules, and the like. Examples of excipients that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate. Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, dragees, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain one compound of the present invention and one or more additional agents that inhibit arenavirus. Alternatively, such formulations may contain Compound 1 of the present invention and one or more additional agents that modulate CB1 R activity.
The terms “pharmaceutically acceptable formulation” and “pharmaceutical composition” are synonyms and can be used interchangeably.
The term "excipient" is defined as: An excipient is any ingredient or substance intentionally added to a drug that is not part of the active pharmaceutical substance.
The term "active pharmaceutical substance" is defined as: An active pharmaceutical substance mean any substance that is intended for incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
Examples of types of excipients include but are not limited to bulking agents, fillers, carriers, diluents, disintegrants, lubricants, solubility enhancers, glidants, sweeteners, coatings, and colorants.
A “bulking agent” is defined as an agent that provides a matrix that carries the active pharmaceutical substance when the active pharmaceutical substance is in a low concentration. Bulking agents include, but are not limited to, mannitol, lactose sucrose, dextran, trehalose, and glycine.
A “filler” is defined as: An inactive substance used to make the active pharmaceutical substance easier to measure in tablet or capsule formation. Fillers add volume to the formulation while conferring mechanical properties that increase flowability and compressibility which facilitates manufacture and increases the robustness and content uniformity of the final formulation. Examples of fillers include but are not limited to lactose, mannitol, microcrystalline cellulose, dibasic calcium phosphate, and calcium hydrogen phosphate dihydrate.
A “binder” is defined as: A material used in formulations to bind ingredients together. Binders are used in tablets and granules to hold active pharmaceutical ingredients (APIs) and excipients together. Binders are added to improve tablet’s mechanical properties and can also improve flowability and the distribution of APIs. Examples of binders include but are not limited to povidone, hydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol, gelatin, starch, carbomers, and sodium carboxymethyl cellulose.
A “carrier” is defined as: A drug carrier or drug vehicle is a substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of the active pharmaceutical substance. Carrier types include but are not limited to liposomes, polymeric micelles, microspheres, and dextrans.
A “dilutent” is defined as: Diluents act as fillers in pharmaceutical tablets to increase weight and improve content uniformity. Diluents include but are not limited to substances such as natural diluents which include starches, hydrolyzed starches, and partially pregelatinized starches. Common diluents include anhydrous lactose, lactose monohydrate, and sugar alcohols such as sorbitol, xylitol and mannitol. Diluents provide better tablet properties such as improved cohesion or to promote flow in tablet or capsule formation.
A “disintegrant” is defined as: Disintegrants are agents added to tablet formulations to promote the break-up of the tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical substance. Disintegrants include but are not limited to alginic acid, bentonite, microcrystalline cellulose, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, low substituted sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.
A “lubricant” is defined as: Lubricants are the agents added to tablet and capsule formulations in small to improve the powder processing properties of formulations. Lubricants include but are not limited to magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silicon dioxide, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, and sodium stearyl fumarate.
A “glidant” is defined as: Glidants are substances that are used to enhance the flowability of a powder by reducing the interparticle friction, surface charge, and cohesion, which in turn decreases the angle of repose. They are often incorporated as a dry powder just prior to direct compression of the tablet. Glidants include but are not limited to ascorbyl palmitate, calcium palmitate, magnesium stearate, fumed silica, colloidal silicon dioxide, starch and talc.
A “solubility enhancer” or a “solubility enhancement excipient” is defined as a substance that is used to enhance the solubility and increase the bioavailability of the active pharmaceutical ingredient (API). Solubility enhancers include but are not limited to meglumine, cyclodextrins, polymers, for example, polyacrylic acid and poly(amino acid), copolymers, for example, copolymers derived from methacrylic acid/ethyl acrylate, liposomes, and polymeric micelles.
A “sweetener” is defined as: A sweetener masks the taste of the medication to make it palatable to the patient. For example, a spoonful of sugar helps the medicine go down. Sweeteners would include sugar, sorbitol, xylitol, and artificial sweeteners.
A “coating” is defined as the film formed by the coating procedure. For example, the coating is defined as a procedure in which the desired dosage form may be a granule or tablet coated with an outer dry film to obtain specific objectives such as masking taste or protecting against environmental conditions. The coating material may be composed of coloring materials, flavorants, gums, resins, waxes, plasticizers, and a polyhydric alcohol. In the modern era, polymers and polysaccharides were principally used as coating materials along with other materials like plasticizers and pigments. Many precautions must be considered during the coating process to make the coating durable and steady.
“Colorants” or “coloring agents” are defined as: A colorant or coloring agent is any dye, pigment or substance which when added to a food, drug or cosmetic, or to the human body will impart a color.
Examples of types of excipients also include surfactants, emulsifying agents, solubilizing agents, dispersing agents, and in vivo absorbance enhancers, for example, poloxamers.
The term “Arenavirus GP-inhibiting amount” as used herein, refers to the amount of a compound of the present invention, or solvate thereof, required to inhibit the cell entry of Arenaviruses in vivo, such as in a mammal, birds or in vitro. The amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
The term "therapeutically effective amount," as used herein, means an amount of a compound of the present invention that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, a therapeutically effective amount of a compound of the present invention is a quantity sufficient to modulate or inhibit the activity of the Arenavirus GP protein such that cell entry and replication of arenaviruses that is mediated by activity of the Arenavirus GP protein is reduced or alleviated.
The terms "treat", "treating", and "treatment" with reference to arenavirus infection, in mammals, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition.
The term “modulating” in relation to the CB1 R as used herein, refers to inhibiting or enhancing the CB1 R activity, by a measurable amount and by inhibiting we mean that the CB1 R activity is decreased and by enhancing we mean that the CB1 R activity is increased; such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or may be manifest only in particular cell types.
The term “modulator” in relation to the CB1 R as used herein, refers to the use of a compound of the present invention, or a salt or solvate thereof, as a CB1 R antagonist.
The term “antagonist” in relation to the CB1 R as used herein, refers to a compound, devoid of intrinsic regulatory activity, which produces effects by interfering with the binding of an agonist (for example, the endogenous endocannabinoid ligands anandamide (N-arachidonoylethanolamide) and 2- AG (2-arachidonoylglycerol) or inhibiting the action of an agonist or decreases basal activity in the absence of an agonist.
The term “modulating amount” in relation to the CB1 R as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit or enhance CB1 R activity in vivo, such as in a mammal or in vitro. The amount of such compounds required to cause such modulation can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
The term “inhibiting amount” in relation to the CB1 R as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit or enhance CB1 R activity in vivo, such as in a mammal, or in vitro. The amount of such compounds required to cause such inhibition or enhancement can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
The term "therapeutically effective amount," in relation to the CB1 R as used herein, means an amount of a compound of the present invention, or a salt or solvate thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, a therapeutically effective amount of a compound of the present invention, or a salt or solvate thereof, is a quantity sufficient to inhibit or enhance CB1 R activity, such that the condition that may be influenced by CB1 R activity is reduced or alleviated.
The terms "treat", "treating", and "treatment" with reference to CB1 R activity, in mammals, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition.
To treat or prevent diseases or conditions mediated in part or whole by CB1 R activity, a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., a CB1 R modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of Compound 1 of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compound into the final pharmaceutical preparations.
The polymorphs of the present invention may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one polymorph of the present invention and an inert, pharmaceutically acceptable excipient.
To treat or prevent diseases or conditions mediated in part or whole by arenavirus infection or viruses expressing the arenavirus glycoprotein, a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable excipients, which may be selected, for example, from diluents, carriers and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropyl methylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
The agent may be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
For oral administration, the compounds can be formulated by combining at least one polymorph with pharmaceutically acceptable carriers known in the art. Such carriers enable the polymorphs of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers. These carriers may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol®, Transcutol®, and the like may be used.
It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage determination tests in view of the experimental data may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Furthermore, the pharmaceutically acceptable formulations of the present invention may contain a polymorph of the present invention, or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 10 mg to about 50 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 50 mg to about 250 mg, or from about 100 mg to about 500 mg, or from about 25 mg to about 300 mg, or from about 50 mg to about 300 mg, or from about 100 mg to about 300 mg.
Additionally, the pharmaceutically acceptable formulations of the present invention may contain a polymorph of the present invention, or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w% .
The polymorphs of the present invention, or solvates thereof, may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus or any virus expressing arenavirus glycoprotein, either alone or in combination with one or more compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors as part of a pharmaceutically acceptable formulation and administered once a day, twice a day, three times a day, four times a day, or even more frequently.
The polymorphs of the present invention, or solvates thereof, may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus in combination with at least one other agent used for treatment of arenavirus selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors as shown by Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156, incorporated herein by reference in its entirety, Favipiravir , a broadspectrum inhibitor of viral RNA-Dependent RNA Polymerases, Triazavirin, a broad-spectrum inhibitor of viral RNA-Dependent RNA Polymerases, small interfering RNAs (siRNAs) and microRNAs as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms ofmiRNAs and siRNAs, Nature, 2009; 136: 642-655, incorporated herein by reference in its entirety, vaccines as shown by Nablel GJ, Designing Tomorrow’s Vaccines, NEJM, 2013; 368: 551-560, incorporated herein by reference in its entirety, and immunomodulators as shown by Patil US, Jaydeokar AV and Bandawane DD, Immunomodulators: A Pharmacological Review, Internatl J Pharmacy and Pharmaceutical Sci, 2012; 4: 30-36, incorporated herein by reference in its entirety], alone or as part of a pharmaceutically acceptable formulation containing other arenavirus inhibitors, once a day, twice a day, three times a day, four times a day, or even more frequently.
Those of ordinary skill in the art will understand that with respect to the polymorphs of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.
The polymorphs of the present invention are useful for modulating or inhibiting arenavirus glycoprotein (GP) both in vitro and in vivo.
Accordingly, these polymorphs are useful for the prevention and/or treatment of disease states associated with arenavirus infection or treating viruses expressing the arenavirus glycoprotein.
This invention also relates to a method for the treatment of arenavirus infection in mammals including a human comprising administering to said mammal an amount of a polymorph of Compound 1 , as defined above, or a solvate thereof, that is effective in treating disease states associated with Arenavirus infection or viruses expressing the arenavirus glycoprotein.
The compound of the present invention, or salts or solvates thereof, may be administered to a mammal, such as a human, suffering from a condition or disease mediated by CB1 R activity, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
The compound of the present invention, or salts or solvates thereof, may be administered to a mammal, such as a human, suffering from CB1 R-mediated diseases or conditions in combination with at least one other agent used in the treatment/prevention/suppression or amelioration of CB1 R-mediated diseases or conditions selected from the group consisting of, but not limited to anti-obesity agents, antidiabetic agents, lipid lowering agents, antihypertensive agents, anorectic agents, anti-epileptics, anxiolytics, anti-depressant agents, anti-inflammatory agents, anti-asthmatic agents, anti-migraine agents, cognition enhancing agents, antipsychotic agents, nicotine receptor partial agonists, opioid antagonists, dopamine receptor agonists, alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
Those of ordinary skill in the art will understand that with respect to the compound of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.
The compound of the present invention is useful for modulating CB1 R. Accordingly, this compound is useful for the prevention and/or treatment of CB1 R-mediated diseases or conditions.
This invention also relates to a method for the treatment of CB1 R-mediated diseases or conditions including a human comprising administering to said mammal an amount of Compound 1 , as defined above, or a salt or solvate thereof, that is effective in treating CB1 R-mediated diseases or conditions.
In the following Preparations and Examples, “Ac” means acetyl, “Me” means methyl, “Et” means ethyl, “DCM” (CH2CI2) means dichloromethane or methylene chloride, "DMF" means N-N-dimethyl formamide, “DMSO" means dimethylsulfoxide, “IPA” means isopropyl alcohol, “EtOAc” means ethyl acetate, “Na2SO4” means sodium sulphate, “MeOH” means methanol, “EtOH” means ethanol, “H2O” means water, “K2CO3” means potassium carbonate, “THF” means tetra hydrofuran, “TBME” or "MTBE" means terf-butyl methyl ether, “dppf’ means 1 ,1 ’-bis(diphenylphosphino)ferrocene, “ACN” means acetonitrile, “MIBK” means methyl isobutyl ketone, “IPAc” means isopropyl acetate, “CPME” means cyclopentyl methyl ether, “MEK” means methyl ethyl ketone, “2-MeTHF” means 2-methyltetrahydrofuran, “N” means Normal, “M” means molar, “ml_” means millilitre, “mmol” means millimoles, “pmol” means micromoles, “eq.” means equivalent, “°C” means degrees Celsius, “RT” means room temperature, “RH” means relative humidity, “XRPD” means X-Ray Powder Diffraction, “DSC” means Differential Scanning Calorimetry, “TGA” means Thermogravimetric Analysis, “DVS” means Dynamic Vapor Sorption, “HPLC” means high-performance liquid chromatography, “HPMC” means hydroxypropyl methylcellulose, “MCC” means microcrystaline cellulose, “HPC” means hydroxypropylcellulose, “PVP” means polyvinylpyrrolidone, “Mann” means mannitol, “Lact” means lactose, “CPV” means crospovidone, “CCS” means croscarmellose sodium, “SLS” means sodium lauryl sulfate, “FS” means fumed silica, “SSF” means sodium stearyl fumarate, “MS” means magnesium stearate.
Experimental Methods
X-Ray Powder Diffraction (XRPD)
XRPD analyses were performed with a Panalytical X’Pert3 Powder XRPD on a Si zerobackground holder. The 20 position was calibrated against a Panalytical Si reference standard disc. The parameters used are listed in Table 1 . Table 1. Parameters for XRPD Test.
Figure imgf000044_0001
Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)
TGA data were collected using a TA Discovery 550 TGA from TA Instrument. DSC analyses were performed using a TA Q2000 DSC from TA Instrument. DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 2. Table 2. Parameters for TGA and DSC test.
Figure imgf000044_0002
Examples
Amorphous Compound 1 used to prepare the polymorphs of this invention may be synthesized using the methods described in WO 2020/117794 A1 patent application.
Example 1 : 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a] pyridine (Amorphous Compound 1)
Step 1 : 6-bromo-3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1 ,2-a]pyridine
Figure imgf000045_0001
To a solution of 6-bromo-3-iodo-7-methylimidazo[1 ,2-a]pyridine (0.033 g, 0.1 mmol) in dioxane (1 ml_) and water (0.5 ml_) was added 4-(tert-butoxy)phenylboronic acid (0.020 g, 0.1 mmol) and sodium carbonate (0.032 g, 0.3 mmol). The reaction mixture was purged with nitrogen, then Pd(dppf)Cl2 (0.05 g, 0.06 mmol) was added. The resulting reaction mixture was heated to 90°C for 12h, brought to room temperature and was extracted with ethyl acetate. Dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (hexanes I EtOAc from 4:1 to 1 :2) to give 0.026 g of the title compound. Yield: 72%. LC/MS m/z: calculated for CiaHigBrIShO [M+H]+ 359.08, found 359.22.
Step 2: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine (Amorphous
Compound 1)
Figure imgf000045_0002
To a solution of 6-bromo-3-(4-(te/Y-butoxy)phenyl)-7-methylimidazo[1 ,2-a]pyridine (0.026 g, 0.072 mmol) in dioxane (1 mL) and water (0.5 mL) was added 4-(isopropoxy)phenylboronic acid (0.015 g, 0.083 mmol) and sodium carbonate (0.022 g, 0.216 mmol). The reaction mixture was purged with nitrogen, then Pd(dppf)Cl2 (0.025 g, 0.03 mmol) was added. The resulting reaction mixture was heated to 90°C for 12h, brought to room temperature and was extracted with ethyl acetate. Dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by SiO2 column chromatography (hexanes / EtOAc from 4:1 to 1 :2) to give 0.009 g of the title compound as an amorphous solid. Yield: 31 %. LC/MS m/z: calculated for C27H30N2O2 [M+H]+ 415.24, found 415.36. 1H NMR (500 MHz, DMSO-c/6) 6 8.13 (s, 1 H), 7.65 (s, 1 H), 7.57 (d, 2H), 7.54 (s, 1 H), 7.33 (d, 2H), 7.11 (d, 2H), 6.97 (d, 2H), 4.62- 4.67 (m, 1 H), 2.24 (s, 3H), 1.33 (s, 9H), 1.28 (d, 6H). 13C NMR: (300 MHz, CDCI3) 6 157.56, 155.34, 145.81 , 134.59, 132.26, 130.72, 129.57, 128.71 , 129.54, 124.93, 124.55, 124.31 , 121.83, 116.88, 1 15.49, 78.93, 69.91 , 28.8, 22.05, 20.68.
In addition, amorphous Compound 1 of this invention may be prepared by standard manipulations of methods known to those skilled in the art.
Polymorphic Form A can be prepared by recrystallization of Compound 1 from hot ethanol, followed by powdering the obtained solid material and drying at 60 °C under vacuum using the following method:
Example 2: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form A
Amorphous Compound 1 was dissolved in a minimal volume (~2.8 volumes) of hot (near boiling) ethanol to become a homogeneous solution. The hot solution was allowed to cool to room temperature and then placed in a freezer. Precipitation occurred while keeping the ethanol solution in the freezer at about -20 °C. The precipitate was filtered under vacuum and solid material was collected which was polymorphic Form F. The obtained solid material was grounded to a powder with a mortar and pestle and dried at 60 °C under vacuum for about 2 days to provide polymorphic Form A as a white solid.
Alternatively, Form A can be prepared by crystallization of amorphous Compound 1 from hexanes using the following method:
Example 3: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form A Amorphous Compound 1 , which was isolated as a colorless oil by rotary evaporation from a mixture of hexanes and ethyl acetate, was treated with a small amount of hexanes. After shaking the resulting mixture, the solidification began to occur. The resulting mixture was kept in a freezer until all oil crystallized into a hard solid, then hexanes was decanted and the residue was dried on a rotary evaporator at about 50 °C to afford polymorphic Form A as a white solid.
Alternatively, polymorphic Form A can be prepared by recrystallization of Compound 1 from a heptanes solution.
The XRPD and a TGA/DSC overlay of Form A are shown in Figs 1 and 2, respectively. The XRPD pattern of Form A, expressed in terms of the degree (2-theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 3.
Table 3. Form A XRPD peak list.
Figure imgf000047_0001
Figure imgf000048_0001
*The relative intensities may vary depending on the morphology and particle size of a sample.
Example 4: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form B
Polymorphic Form B can be prepared by slurrying polymorphic Form A at room temperature in a mixture of DMF:H2<D (3:7).
The XRPD and a TGA/DSC overlay of Form B are shown in Figs 3 and 4, respectively. The XRPD pattern of Form B, expressed in terms of the degree (2 -theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 4.
Table 4. Form B XRPD peak list.
Figure imgf000048_0002
Figure imgf000049_0001
Example 5: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form C
Polymorphic Form C can be prepared by slurrying polymorphic Form A at room temperature in a mixture of EtOH:n-heptane (2:8).
The XRPD and a TGA/DSC overlay of Form C are shown in Figs 5 and 6, respectively. The XRPD pattern of Form C, expressed in terms of the degree (2-theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 5.
Table s. Form C XRPD peak list.
Figure imgf000049_0002
Figure imgf000050_0001
Example 6: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a] pyridine polymorphic Form D
Polymorphic Form D can be prepared by slurrying polymorphic Form A at room temperature in a mixture of MTBE:n-heptane (3:7).
The XRPD and a TGA/DSC overlay of Form D are shown in Figs 7 and 8, respectively. The XRPD pattern of Form D, expressed in terms of the degree (2 -theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 6.
Table 6. Form D XRPD peak list.
Figure imgf000050_0002
Figure imgf000051_0001
Example 7: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a] pyridine polymorphic Form E
Polymorphic Form E can be prepared by slurrying polymorpich Form A at 50 °C in a mixture of EtOH:H2O (1 :1). The XRPD and a TGA/DSC overlay of Form E are shown in Figs 9 and 10, respectively. The XRPD pattern of Form E, expressed in terms of the degree (2 -theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 7.
Table 7. Form E XRPD peak list.
Figure imgf000052_0001
Example 8: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]py ridi ne polymorphic Form F
Polymorphic Form F can be prepared by recrystallization of amorphous Compound 1 from hot ethanol. Compound 1 was dissolved in a minimal volume (~2.8 volumes) of boiling ethanol to become homogeneous solution. The hot solution was slowly cooled. The formed crystals were filtered from the solution, subsequently washed with cold ethanol and hexanes, and dried under high vacuum to provide Form F as an off-white solid.
The XRPD and a TGA/DSC overlay of Form F are shown in Figs 11 and 12, respectively. The XRPD pattern of Form F, expressed in terms of the degree (2 -theta) and relative intensities, measured on a diffractometer with Cu K-alpha radiation, is shown in Table 8.
Table 8. Form F XRPD peak list.
Figure imgf000053_0001
Figure imgf000054_0001
Alternatively, polymorphic Form F may be obtained from polymorphic Form A by solid vapor diffusion in ethanol vapor.
Alternatively, polymorphic Form A may be prepared by conversion of polymorphic Form F using the following method:
Example 9: 3-(4-(tert-butoxy)phenyl)-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyridine polymorphic Form A
Polymorphic Form F of Compound 1 was dissolved in a minimal volume (~2.8 volumes) of hot (near boiling) ethanol to become a homogeneous solution. The hot solution was allowed to cool to room temperature and then placed in a freezer. Precipitation occurred while keeping the ethanol solution in the freezer at about -20 °C. The precipitate was filtered under vacuum and solid material was collected which was polymorph Form F. The obtained solid material was grounded to a powder with a mortar and pestle and dried at 60 °C under vacuum for about 2 days. The obtained solids were analyzed by XRPD. The XRPD pattern was consistent with Form A. Characterization of polymorphic forms A-F of Compound 1 is listed in Table 9.
Table 9. Characterization of polymorphic forms of Compound 1.
Figure imgf000054_0002
Figure imgf000055_0001
‘Form A after vacuum drying or heating shows absence of both peak at -7.5° 20 and/or ~21 ° 20 (very small peak).
The relationships of the polymorphic forms A-F of Compound 1 are displayed in an interconversion diagram in Figure 13. The hygroscopicity and the sorption properties of polymorphic Form A of Compound 1 were assessed using DVS. The isotherm diagram was obtained at 25°C and showed that Form A of Compound 1 is slightly hygroscopic with a weight increase of -0.28% at 80% RH and less than 0.5% at 95% RH (Figure 14).
Water activity experiments conducted on polymorphic Form A of Compound 1 using an IPA/H2O system at varying water concentrations to identify possible hydrates are shown in Table 10.
Table 10. Concentrations of water and isopropyl alcohol (IPA) used in water activity screening.
Figure imgf000055_0002
To investigate the stability relationship among the anhydrate polymorphic Forms A and E and ethanol solvate polymorphic Form F, slurry competition experiments were performed in ACN at room temperature and 60 °C. The results of this study indicate that all polymorphic forms converted to Form A, which indicates that Form A is the most stable anhydrous form among the currently known anhydrate forms of Compound 1 (Table 11).
Table 11 . Summary of interconversion study for anhydrates/solvates.
Figure imgf000056_0001
The approximate solubility of polymorphic Form A of Compound 1 was determined at room temperature in the various solvents indicated in Table 12.
Table 12. Approximate solubility (S) of polymorphic Form A of Compound 1 at room temperature.
Figure imgf000056_0002
The solubility properties of polymorphic Form A of Compound 1 were evaluated in water and three biorelevant media at room temperature at 24 hours. The results are summarized in Table 13. Table 13. Solubility of polymorphic Form A of Compound 1 in water and Biorelevant Media.
Figure imgf000057_0001
Using polymorphic Form A of Compound 1 multiple polymorph screening experiments were conducted to evaluate the formation of different polymorphs using various solvents and multiple formation processes, including slurry at room temperature, slurry at 50 °C, solid vapor diffusion, liquid vapor diffusion, anti-solvent addition, cooling crystallization, polymer induced crystallization, and slow evaporation.
Slurry at room temperature Slurry experiments were conducted at room temperature in various solvent systems. About -11 mg of polymorphic Form A of Compound 1 was suspended in about 0.2-0.5 ml_ of solvent in a 1 .5-mL glass vial. After the suspension was stirred magnetically for three days at room temperature, the remaining solids were isolated for XRPD analysis (Table 14). Table 14. Summary of slurry experiments at RT.
Figure imgf000057_0002
Figure imgf000058_0001
Slurry at 50 °C
Slurry experiments were conducted at 50 °C in various solvent systems. About ~10 mg of polymorphic Form A of Compound 1 was suspended in a range of about 0.2 - 0.4 ml_ of solvent in a 1 .5-mL glass vial. After the suspension was stirred magnetically for two days at 50 °C, the remaining solids were isolated for XRPD analysis (Table 15).
Table 15. Summary of slurry experiments at 50 °C.
Figure imgf000058_0002
Figure imgf000059_0001
Solid Vapor Diffusion
Solid vapor diffusion experiments were conducted using various solvents. Approximately 11 mg of polymorphic Form A of Compound 1 was weighed and placed into a 3-mL vial, which was then placed into a 20-mL vial containing 4 mL of volatile solvent. The 20-mL vial was then sealed with a cap and kept at RT for seven days allowing solvent vapor to interact with sample. The remaining solids were isolated for XRPD analysis (Table 16). Table 16. Summary of solid vapor diffusion experiments.
Figure imgf000059_0002
Liquid Vapor Diffusion
Liquid vapor diffusion experiments were conducted using various solvents. Approximately 11 mg of polymorphic Form A of Compound 1 was dissolved in about 0.2-0.5 mL of appropriate solvent to obtain a clear solution in a 1 .5-mL vial. This solution was then placed into a 20-mL vial containing 4 mL of volatile solvents. The 20-mL vial was sealed with a cap and kept at RT allowing organic vapor to interact with the solution. The precipitates were isolated for XRPD analysis (Table 17).
Table 17. Summary of liquid vapor diffusion experiments.
Figure imgf000060_0001
Anti-Solvent Addition Anti-solvent addition experiments were carried out using various solvents. About 10 mg of polymorphic Form A of Compound 1 was dissolved in about 0.3-0.6 mL solvent to obtain a clear solution. The solution was magnetically stirred followed by addition of about 0.5-0.8 mL anti-solvent stepwise until a precipitate appeared, or the total amount of anti-solvent reached 15.0 mL. The obtained precipitate was isolated for XRPD analysis (Table 18). Table 18. Summary of anti-solvent addition experiments.
Figure imgf000060_0002
Figure imgf000061_0001
Slow Evaporation
Slow evaporation experiments were performed using various solvents. Approximately 10 mg of polymorphic Form A of Compound 1 was dissolved in about 1 -1 .5 mL of solvent in a 3-mL glass vial. The vial was then covered with parafilm, and the solutions were allowed to evaporate at room temperature via needle-sized holes poked through the parafilm. The solids were then isolated for XRPD analysis (Table 19).
Table 19. Summary of slow evaporation experiments.
Figure imgf000061_0002
Figure imgf000062_0001
Polymer Induced Crystallization
Polymer Induced Crystallization experiments were conducted in various solvent systems. About 15 mg of polymorphic Form A of Compound 1 was suspended in 0.4 mL of solvent in a 3-mL glass vial at RT. About 4 mg of Polymer mixture was added to each vial and stirred at 800 RPM at RT to induce precipitation. Solids were then isolated for XRPD analysis (Table 20).
Table 20. Summary of polymer induced crystallization experiments.
Figure imgf000062_0002
*A: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinylchloride (PVC), hypromellose (HPMC), methyl cellulose (MC) (mass ratio of 1 :1 :1 :1 :1). **B: poly(methyl methacrylate) (PMMA), sodium alginate (SA), and hydroxyethyl cellulose (HEC) (mass ratio of 1 :1 :1).
Cooling Crystallization
Cooling crystallization experiments data are shown in Table 21 . Approximately ~30 mg of polymorphic Form A of Compound 1 was dissolved in corresponding solvents in a 1 .5-mL glass vial at 50 °C. The suspension was then filtered at 50 °C, with the vial cap being closed immediately after filtration. The samples were then heated to 50 °C for 30 minutes, and then cooled from 50 °C to 5 °C over a period of 8 hours. The samples were then kept at 5 °C until removed. Solids were then isolated and analyzed by XRPD (Table 21).
Table 21. Summary of cooling crystallization experiments.
Figure imgf000063_0001
Excipient Compatibility Study
Polymorphic Form A of Compound 1 was screened against a variety of excipients to evaluate compatibility (Table 22). The mixtures were placed in open containers and stored at 50°C and 75% Relative Humidity (RH) for 4 weeks. The compound was compatible with all excipients and blends in Table 22 and maintained polymorph form and thermal stability as neat powder.
Table 22. Excipient compatibility study of polymorphic Form A of Compound 1 with various excipients.
Figure imgf000063_0002
Figure imgf000064_0001
Example 10: Prototype-1 Tablet Formulation (100 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 23 using the procedure below. Polymorphic Form A of Compound 1 (40.0% w/w), silicified microcrystalline cellulose (40.0% w/w), colloidal silicon dioxide (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .59 - 1 .94 mm. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 24).
Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 25.
Table 23. Prototype-1 Tablet Formulation to produce 100 mg dose tablets.
Figure imgf000065_0001
‘Adjusted for purity value of Compound 1 of 97.7%. Table 24. Prototype-1 Tablet Formulation tableting results (100 mg dose tablets).
Figure imgf000066_0001
Table 25. Dissolution of Prototype-1 tablets (100 mg dose) in 0.1 N HCI.
Figure imgf000066_0002
Example 11 : Prototype-1 Capsule Formulation (100 mg dose capsules)
HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 10, for a dose of 100 mg of polymorphic Form A of Compound 1 per capsule. Capsules were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a spiral capsule sinker and a paddle speed of 75-rpm. Dissolution data are provided in Table 26.
Table 26. Dissolution of Prototype- 1 capsules (100 mg dose) in 0.1 N HCI.
Figure imgf000066_0003
Example 12: Prototype-1 Tablet Formulation (300 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 27 in the same manner as described in Example 10. Tablet cores were characterized for weight, thickness, hardness, disintegration time, and friability (Table 28). The tablet cores were coated with Opadry White, which was prepared by dispersing the film coat in treated water (375 g (25% w/w) of Opadry White and 1125 g (75% w/w) of water). The tablet cores (750 mg/tablet, 96.2% w/w) were coated with the suspension (30 mg/tablet) to a weight gain of 3.8%.
Table 27. Prototype-1 Tablet Formulation to produce 300 mg dose tablets.
Figure imgf000067_0001
‘Adjusted for purity value of Compound 1 of 99.42%. Table 28. Prototype-1 Tablet Formulation tableting results (300 mg dose tablets).
Figure imgf000067_0002
Example 13: Prototype-1 Tablet Formulation (25 mg and 300 mg dose tablets)
A batch of tablet blend was formulated and used to make oval tablet cores containing 25 mg and 300 mg of polymorphic Form A of Compound 1 per tablet using the procedure described below. Prototype-1 Tablet Formulation compositions for 25 and 300 mg dose tablets are shown in Table 29.
Polymorphic Form A of Compound 1 (40.2% w/w), silicified microcrystalline cellulose (39.8% w/w), fumed silica (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .59 - 1 .94 mm. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. The obtained tablet blend was split and part of it was pressed using tablet press machine to produce 25 mg dose tablet cores. Tablet cores were characterized for weight, thickness, hardness, and friability (Table 30).
Part of the tablet blend was mixed with additional magnesium stearate (1 .0% w/w) for 2 min and the resulting tablet bled was pressed using tablet press machine to produce 300 mg dose tablet cores. Tablet cores were characterized for weight, thickness, and hardness (Table 31).
Table 29. Prototype-1 Tablet Formulation compositions for 25 and 300 mg dose tablets.
Figure imgf000068_0001
‘Adjusted for purity value of Compound 1 of 99.42%.
** Applies only for 300 mg dose tablet cores. Table 30. Prototype-1 Tablet Formulation tableting results (25 mg dose tablets).
Figure imgf000069_0001
Table 31. Prototype-1 Tablet Formulation (with additional 1 % magnesium stearate) tableting results (300 mg dose tablets).
Figure imgf000069_0002
Example 14: Prototype-2 Tablet Formulation (100 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 32 using the procedure below. Polymorphic Form A of Compound 1 (40.0% w/w), dibasic calcium phosphate (10.0% w/w), microcrystalline cellulose (30.0% w/w), colloidal silicon dioxide (1.0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1.80 - 1 .86 mm. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 33).
Table 32. Prototype-2 Tablet Formulation to produce 100 mg dose tablets.
Figure imgf000069_0003
Figure imgf000070_0001
‘Adjusted for purity value of Compound 1 of 97.7%.
Table 33. Prototype-2 Tablet Formulation tableting results (100 mg dose tablets).
Figure imgf000070_0002
Example 15: Prototype-3 Tablet Formulation (100 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 34 using the procedure below. Polymorphic Form A of Compound 1 (40.9% w/w), mannitol (16.0% w/w), silicified microcrystalline cellulose (23.1% w/w), colloidal silicon dioxide (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .63 - 1 .86 mm. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 35).
Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 36. Table 34. Prototype-3 Tablet Formulation to produce 100 mg dose tablets.
Figure imgf000071_0001
‘Adjusted for purity value of Compound 1 of 97.7%.
Table 35. Prototype-3 Tablet Formulation tableting results (100 mg dose tablets).
Figure imgf000071_0002
Table 36. Dissolution of Prototype-3 tablets (100 mg dose) in 0.1 N HCI.
Figure imgf000072_0001
Example 16: Prototype-3 Capsule Formulation (100 mg dose capsules)
HPMC capsules (size 1) were manually filled with approximately 250 mg of the tablet blend described in Example 15, for a dose of 100 mg of polymorphic Form A of Compound 1 per capsule. Capsules were analyzed in 900 ml_ of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a spiral capsule sinker and a paddle speed of 75-rpm. Dissolution data are provided in Table 37.
Table 37. Dissolution of Prototype-3 capsules (100 mg dose) in 0.1 N HCI.
Figure imgf000072_0002
Example 17: Prototype-4 Tablet Formulation (100 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 38 using the procedure below. Polymorphic Form A of Compound 1 (40.9% w/w), mannitol (16.0% w/w), microcrystalline cellulose (23.1 % w/w), colloidal silicon dioxide (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons with thickness at an average of 1 .65 - 1 .86 mm. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (12.0% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce tablet blend. Tablet blend was pressed using hand press to produce 100 mg dose tablets. Tablet cores were characterized for weight, thickness, hardness, and disintegration time (Table 39).
Table 38. Prototype-4 Tablet Formulation to produce 100 mg dose tablets.
Figure imgf000073_0001
‘Adjusted for purity value of Compound 1 of 97.7%. Table 39. Prototype-4 Tablet Formulation tableting results (100 mg dose tablets).
Figure imgf000073_0002
Example 18: Prototype-5 Tablet Formulation (300 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 40 using the procedure below. Polymorphic Form A of Compound 1 (35.4% w/w), silicified microcrystalline cellulose (35.2% w/w), colloidal silicon dioxide (1 .0% w/w), and croscarmellose sodium (2.5% w/w) were blended for 10 min, followed by mixing with magnesium stearate (1 .0% w/w) for 2 min to produce intragranular blend. Intragranular blend was dry granulated using roller compactor to produce intact ribbons. Ribbons were granulated using 20 mesh screen. Dry granulation blend was further mixed with silicified microcrystalline cellulose (20.4% w/w) and croscarmellose sodium (2.5% w/w) for 10 min, followed by mixing with magnesium stearate (2.0% w/w) for 2 min to produce tablet blend. The obtained tablet blend was pressed using tablet press machine to produce 300 mg dose tablet cores. Tablet cores were characterized for weight, thickness, and hardness (Table 41). The tablet cores were coated with Opadry Green, which was prepared by dispersing the film coat in treated water (250 g (20% w/w) of Opadry Green and 1000 g (80% w/w) of water). The tablet cores (850 mg/tablet, 96.2% w/w) were coated with the suspension (34 mg/tablet) to a weight gain of 3.8%. The second layer of coating was done with Opadry II Clear, which was prepared by dispersing the film coat in treated water (160 g/batch (8% w/w) of Opadry II Clear and 1840 g/batch (92% w/w) of water). The tablets (884 mg/tablet, 99% w/w) were coated with the suspension (8.84 mg/tablet) to a weight gain of 1 %.
Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 42. Table 40. Prototype-5 Tablet Formulation composition for 300 mg dose tablets.
Figure imgf000074_0001
‘Adjusted for purity value of Compound 1 of 99.6%. Table 41. Prototype-5 Tablet Formulation tableting results (300 mg dose tablets).
Figure imgf000075_0001
Table 42. Dissolution of Prototype-5 tablets (300 mg dose) in 0.1 N HCI.
Figure imgf000075_0002
*Average of 6 vessels.
Example 19: Prototype-5 Tablet Formulation (25 mg and 150 mg dose tablets)
A batch of tablet blend was formulated and used to make oval tablet cores containing 25 mg and 150 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 43 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, hardness, disintegration time, and friability (Tables 44 and 45). The tablet cores were coated with 20% solids suspension of Opadry Green in water, followed by a second layer of 8% solids suspension of Opadry II Clear in water using the amounts of ingredients recited in Table 43.
Tablets containing 25 mg of polymorphic Form A of Compound 1 per tablet were analyzed in 900 ml_ of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 46.
Table 43. Prototype-5 Tablet Formulation compositions for 25 and 150 mg dose tablets.
Figure imgf000075_0003
Figure imgf000076_0001
‘Adjusted for purity value of Compound 1 of 99.6%.
Table 44. Prototype-5 Tablet Formulation tableting results (25 mg dose tablets).
Figure imgf000076_0002
Table 45. Prototype-5 Tablet Formulation tableting results (150 mg dose tablets).
Figure imgf000076_0003
Table 46. Dissolution of Prototype-5 tablets (25 mg dose) in 0.1 N HCL
Figure imgf000076_0004
‘Average of 6 vessels. Example 19: Prototype-5 Tablet Formulation (100 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 100 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 47 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, hardness, and friability (Table 48). The tablet cores were coated with Opadry Green, followed by Opadry II Clear using the amounts of ingredients recited in Table 47.
Tablets were analyzed in 900 mL of 0.1 N HCI dissolution media using USP Apparatus 2 (Paddles) with a paddle speed of 75-rpm. Dissolution data are provided in Table 49.
Table 47. Prototype-5 Tablet Formulation composition for 100 mg dose tablets.
Figure imgf000077_0001
Figure imgf000078_0001
a. Film coat suspension was prepared in excess of the theoretical required quantity. b. Water is removed during processing and is not present in the final product.
Table 48. Prototype-5 Tablet Formulation tableting results (100 mg dose tablets).
Figure imgf000078_0002
* Average of 10 tablets
Table 49. Dissolution of Prototype-5 tablets (100 mg dose) in 0.1 N HCI.
Figure imgf000078_0003
‘Average of 6 vessels.
Example 20: Prototype-6 Tablet Formulation (300 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 50 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, and hardness (Table 51). The tablet cores were coated with Opadry Green, which was prepared by dispersing the film coat in treated water (250 g (20% w/w) of Opadry Green and 1000 g (80% w/w) of water). The tablet cores (850 mg/tablet, 96.2% w/w) were coated with the suspension (34 mg/tablet) to a weight gain of 3.8%. The second layer of coating was done with Opadry II Clear, which was prepared by dispersing the film coat in treated water (160 g/batch (8% w/w) of Opadry II Clear and 1840 g/batch (92% w/w) of water). The tablets (884 mg/tablet, 99% w/w) were coated with the suspension (8.84 mg/tablet) to a weight gain of 1 %.
Table 50. Prototype-6 Tablet Formulation to produce 300 mg dose tablets.
Figure imgf000078_0004
Figure imgf000079_0001
‘Adjusted for purity value of Compound 1 of 99.6%.
Table 51. Prototype-6 Tablet Formulation tableting results (300 mg dose tablets).
Figure imgf000079_0002
Example 21 : Prototype-7 Tablet Formulation (300 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 52 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, hardness, friability, and disintegration (Table 53).
Table 52. Prototype-7 Tablet Formulation to produce 300 mg dose tablets.
Figure imgf000079_0003
Figure imgf000080_0001
Table 53. Prototype-7 Tablet Formulation tableting results (300 mg dose tablets).
Figure imgf000080_0002
Example 22: Prototype-8 Tablet Formulation (300 mg dose tablets)
A batch of oval tablet cores was formulated to have approximately 300 mg of polymorphic Form A of Compound 1 per tablet using the amounts of ingredients recited in Table 54 in the same manner as described in Example 18. Tablet cores were characterized for weight, thickness, hardness, friability, and disintegration (Table 55). Table 54. Prototype-8 Tablet Formulation to produce 300 mg dose tablets.
Figure imgf000081_0001
Table 55. Prototype-8 Tablet Formulation tableting results (300 mg dose tablets).
Figure imgf000081_0002
Following procedure described in Example 18 the following tablets can be made using the amounts of ingredients recited in Table 56. Table 56. Example Tablet Formulation to produce 25, 100, 150, and 300 mg dose tablets.
Figure imgf000082_0001
CB1R Human Cannabinoid GPCR Cell Based Antagonist cAMP Assay
Evaluation of the potency (IC50) of Compound 1 for the human CB1 R in stably transfected CHO- K1 cells was determined in a cAMP cell based assay using HTRF detection method. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C overnight prior to testing. Prior to testing cell plating media was exchanged with 10 pL of Assay buffer (HBSS + 10 mM HEPES). Briefly, intermediate dilution of sample stocks was performed in assay buffer to generate a sample at 4X the final testing concentration. 5 pL of 4X sample was added to cells and incubated at 37°C for 30 minutes. 5uL of CP55940 at 4X the final ECao concentration in 4X forskolin reagent (at 80 uM) was added and cells incubated for 37°C for 30 minutes. The final concentration of forskolin in the assay was 20 uM. Final assay vehicle concentration was 1 %. The results are expressed as a percent inhibition of CP55940 in antagonist mode.
Compound 1 was screened for functional activity of CB1 R and the IC50 was 3.8 uM.
Mouse DIO Obesity Study
To determine if Compound 1 might have anti-obesity activity through CB1 R antagonism a four week in vivo study in obese C57BL/6J DIO mice was initiated to investigate weight gain, food intake and fasting blood glucose levels (see Table 57 for experimental design). A GMP lot of Compound 1 at different doses was evaluated and compared to DIO mice dosed with vehicle alone. The compound was formulated as a homogenous suspension with Vitamin-E-TPGS, PEG400, Glycerol, Methylcellulose, 10 mM Sodium Citrate buffer pH6 and water. Animals were orally gavaged once-a-day with either test article or vehicle for 4 weeks.
Table 57. Experimental Design for Evaluating Compound 1 in DIO Mouse Obesity Model.
Figure imgf000083_0001
Figure imgf000084_0001
There was a significant dose-dependent drop in percent weight gain in group 4 and 5 Compound 1 treated obese mice compared to obese mice treated with vehicle. The % weight loss correlated with significant reduced food intake (Figure 15) in group 5. On the other hand there was no significant effect on fasting blood glucose in Compound 1 treated obese mice compared to obese mice dosed with vehicle (Figure 16).
In addition to the ob DIO mouse obesity model, significant dose-dependent decreases in mean cholesterol was observed in rats dosed with Compound 1 compared to rats dosed with vehicle in a 28- day GLP toxicity study (Figure 17). The same suspension formulation used in the mouse obesity model was used for the rat GLP toxicity study.
In conclusion, mice dosed with Compound 1 at both 10 and 30 mg/kg/day demonstrated significant decreases in body weight relative to obese mice dosed with vehicle. In addition, food intake was significantly lower at 30 mg/kg/day compared vehicle dosed obese mice. Finally, in a rat 28-day GLP toxicity study, cholesterol levels were significantly reduced at all doses tested including 10, 30 and 50 mg/kg/day. In the same rat toxicity study, there was no evidence of CNS effect as measured by functional observational battery. Therefore, Compound 1 exhibits the potential for therapeutic treatment of metabolic disorders as well as other therapeutic applications via peripheral CB1 R antagonism.

Claims

WHAT IS CLAIMED IS:
1 . A crystalline form of Compound 1 , wherein Compound 1 is represented by the following structural formula:
Figure imgf000085_0001
2. The crystalline form of claim 1 , wherein the crystalline form is selected from the polymorphs consisting of polymorphic Form A of Compound 1 , polymorphic Form B of Compound 1 , polymorphic Form C of Compound 1 , polymorphic Form D of Compound 1 , polymorphic Form E of Compound 1 , and polymorphic Form F of Compound 1.
3. The polymorphic form of claim 2, wherein the polymorphic form is Form A of Compound 1 and wherein Form A is characterized by a powder X-ray diffraction pattern measured using Cu K-alpha radiation comprising at least 3 characteristic peaks selected from about 7.3, 14.5, and 16.8 degrees 2-theta.
4. A pharmaceutical composition comprising a crystalline form of compound 1 and a pharmaceutically acceptable excipient.
5. The pharmaceutical composition of claim 4 comprising polymorphic form A and at least one pharmaceutically acceptable excipient.
6. The pharmaceutical composition of claim 4, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate, calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly (amino acid), 96 copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
57. The pharmaceutical composition of claim 5, wherein the excipients are chosen from the group consisting of mannitol, lactose, sucrose, dextran, trehalose, glycine, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, calcium hydrogen phosphate dihydrate, starch, sugars, lactose monohydrate, sorbitol, xylitol, alginic acid, bentonite, powdered cellulose, guar galactomannan, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl
10 cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, crospovidone, carboxymethyl cellulose, povidone, sodium starch glycolate, agar, calcium carbonate, sodium bicarbonate, alginates, gelatin, polyvinylpyrrolidone, glycerol, magnesium stearate, calcium stearate, polyethylene glycols, colloidal silicon dioxide, fumed silica, fatty acid esters, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, ascorbyl palmitate,
15 calcium palmitate, talc, meglumine, cyclodextrins, polymers, polyacrylic acid, poly (amino acid), copolymers, methacrylic acid/ethyl acrylate copolymer, liposomes, polymeric micelles, microspheres, paraffin, quaternary ammonium compounds, cetyl alcohol, kaolin, solid polyethylene glycols, sodium lauryl sulfate, coloring materials, flavorants, gums, resins, waxes, plasticizers, polyhydric alcohol, pigments, polysaccharides, dyes, poloxamers, and film coatings.
208. The pharmaceutical composition of claim 7, wherein the excipients are chosen from the group consisting of silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
9. The pharmaceutical composition of claim 7, wherein the excipients are chosen from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline
25 cellulose, and magnesium stearate.
10. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises from about 0.5 wt% to about 60 wt% of polymorphic form A of Compound 1 by weight of the composition, wherein a pharmaceutical composition is a tablet or a capsule.
11. The pharmaceutical composition of claim 10, wherein preferred composition being a tablet.
3012. A tablet formulation, wherein the tablet formulation comprises from about 10 mg to about 500 mg of crystalline Compound 1 per tablet.
13. The tablet formulation of claim 12, wherein the crystalline Compound 1 is polymorphic form A. 97
14. The tablet formulation of claim 13, wherein the tablet formulation comprises from about 50 mg to about 250 mg of crystalline Compound 1 per tablet, which may be associated with an acute or severe therapeutic treatment.
15. The tablet formulation of claim 13, wherein the tablet formulation comprises from about 10 mg to about 50 5 mg of crystalline Compound 1 per tablet, which may be associated with a chronic therapeutic treatment.
16. The tablet formulation of claim 13, wherein the tablet comprises crystalline Compound 1 , silicified microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate.
17. The tablet formulation of claim 13, wherein the tablet comprises crystalline Compound 1 , microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, and
10 magnesium stearate.
18. The crystalline form of claim 1 wherein a therapeutically effective amount of the crystalline form of claim 1 is administered with a therapeutically effective amount of at least one of the compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, and immunomodulators.
1519. The pharmaceutical composition of claim 4 wherein a pharmaceutically effective amount of the pharmaceutical composition comprising crystalline Compound 1 is administered with a therapeutically effective amount of at least one of the compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, and immunomodulators.
2020. A method of treating infections associated with viruses of the Arenaviridae enveloped virus family, or any virus expressing Arenavirus glycoproteins to mediate cell entry comprising administering a pharmaceutically effective dose of a crystalline form of Compound 1 with a pharmaceutically acceptable carrier, dilutant or vehicle thereof, wherein Compound 1 is represented by the following structural formula:
Figure imgf000087_0001
2521 . The method of claim 20 wherein a pharmaceutically acceptable dose of the crystalline form of Compound
1 of claim 20 is administered with a pharmaceutically acceptable dose of at least one of the compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, and immunomodulators.
22. A method of modulating cannabinoid receptor 1 (CB1 R) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a Compound 1 or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein Compound 1 is represented by the following structural formula:
Figure imgf000088_0001
23. The method of treating a disease state in a mammal that is amenable to treatment by a cannabinoid receptor 1 (CB1 R) modulator, comprising administration of a therapeutically effective amount of a compound of Claim 22.
24. The method of claim 23, wherein the disease state is selected from metabolic disease, fibrotic disorder, pain, nervous system disorder, substance abuse/dependence disorder, cardiovascular disease, cancer, inflammatory and autoimmune disease, respiratory disorder, gastrointestinal disease, genetic disorder, reproductive system disorder, sleep disorder, and osteoporosis.
PCT/US2024/061121 2023-12-20 2024-12-19 Crystalline forms of an imidazopyridine derivative Pending WO2025137345A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020117794A1 (en) * 2018-12-06 2020-06-11 Arisan Therapeutics, Inc. Compounds for the treatment of arenavirus infection
WO2022108849A1 (en) * 2020-11-17 2022-05-27 Arisan Therapeutics Inc. Heterocyclic compounds as therapeutic agents
US20220193038A1 (en) * 2018-12-06 2022-06-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection

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Publication number Priority date Publication date Assignee Title
WO2020117794A1 (en) * 2018-12-06 2020-06-11 Arisan Therapeutics, Inc. Compounds for the treatment of arenavirus infection
US20220193038A1 (en) * 2018-12-06 2022-06-23 Arisan Therapeutics Inc. Compounds for the treatment of arenavirus infection
WO2022108849A1 (en) * 2020-11-17 2022-05-27 Arisan Therapeutics Inc. Heterocyclic compounds as therapeutic agents

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