Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • 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
• • 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
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the immune system in mammals regulates the activation and inactivation of lymphocytes through various mechanisms during and after an immune response.
• these mechanisms there are mechanisms that specifically modulate the immune response as and when required.
• 3-substituted 1,2,4-oxadiazole compounds act as immunomodulators.
• 3- substituted 1,2,4-oxadiazole compounds can be used in the treatment of cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
• One aspect of the invention relates to a crystalline compound having the structure of formula (I),
• Another aspect of the invention relates to methods for preparing the crystalline compounds of formula (I).
• the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising a crystalline compound of formula (I), and one or more pharmaceutically acceptable excipients.
• the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described here BRIEF DESCRIPTION OF THE DRAWINGS
• Figure 1 shows the XRPD patterns of formula (I) Form 1.
• Figure 2 shows overlay XRPD patterns of formula (I) Form 2 from example 2D and Example 2E
• Figure 3 shows the thermogravimetric analysis and differential scanning
• Figure 4 shows the thermogravimetric analysis and differential scanning calorimetry thermogram of Form 2.
• Figure 5 shows a comparison of XRPD patterns of formula (I) Form 2 at 25 °C, 60% relative humidity (RH); 40 °C, 75% RH; and 30 °C, 56% RH after 7-8 days compared to a Form 2 reference sample in solid form.
• Figure 6 shows a comparison of XRPD patterns of formula (I) Form 2 in water at 20 °C; in water at 30 °C; and Form 2 after solubility testing.
• Figure 7 A shows the asymmetric unit of the formula (I) Form 2 single crystal.
• Figure 7B shows a proposed proton transfer to form a zwitterion in the formula (I) Form 2 crystal.
• Figure 8 shows the XRPD patterns of amorphous formula (I).
• the invention provides a crystalline compound having the structure of formula (I),
• the invention provides a crystalline compound having the structure of formula (I) could also be written by showing all of the atoms,
• a crystalline compound of formula (I) is solvated.
• the crystalline compound of formula (I) is a hydrate (e.g., a monohydrate or a dihydrate).
• the crystalline compound of formula (I) is a monohydrate.
• the crystalline compound of formula (I) is a dihydrate.
• Any crystalline compound described herein may be used in the manufacture of a medicament for the treatment of any diseases or conditions disclosed herein.
• the compounds of the present invention can assemble into more than one crystal formation.
• the crystalline compound having the structure of formula (I) exists as "Form 1", “Form 2", or a mixture thereof, as described in detail below. These different forms are understood as “polymorphs" herein.
• the polymorph of the crystalline compound is characterized by powder X-ray diffraction (XRD).
• ⁇ represents the diffraction angle, measured in degrees.
• the diffractometer used in XRD measures the diffraction angle as two times the diffraction angle ⁇ .
• the diffraction patterns described herein refer to X-ray intensity measured against angle 2 ⁇ .
• a crystalline compound of formula (I) is solvated.
• a crystalline compound of formula (I) is solvated with water and is a hydrate.
• the crystalline hydrate of the compound of formula (I) is a monohydrate or a dihydrate.
• the crystalline hydrate of the compound of formula (I) is a monohydrate.
• the crystalline hydrate of the compound of formula (I) is a dihydrate.
• a crystalline hydrate of the compound of formula (I) has 2 ⁇ values 8.4 + 0.2, 13.6 + 0.2, 16.5 + 0.2, 16.8 + 0.2, 21.4 + 0.2, and 28.4 + 0.2.
• the crystalline hydrate has 2 ⁇ values 8.4 + 0.2, 13.6 + 0.2, 16.5 + 0.2, 16.8 + 0.2, 19.3 + 0.2, 20.4 + 0.2, 21.4 + 0.2, and 28.4 + 0.2.
• the crystalline hydrate has 2 ⁇ values 8.4 + 0.2, 13.6 + 0.2, 16.5 + 0.2, 16.8 + 0.2, 19.3 + 0.2, 19.9 + 0.2, 20.4 + 0.2, 21.4 + 0.2, 24.5 + 0.2, 26.5 + 0.2, and 28.4 + 0.2.
• the crystalline hydrate has 2 ⁇ values 8.4 + 0.2, 11.5 + 0.2, 13.6 + 0.2, 16.5 + 0.2, 16.8 + 0.2, 19.3 + 0.2, 19.9 + 0.2, 20.4 + 0.2, 21.4 + 0.2, 21.8 + 0.2, 24.5 + 0.2, 26.5 + 0.2, 27.5 + 0.2, 28.0 + 0.2, 28.4 + 0.2, 30.0 + 0.2, and 32.4 + 0.2.
• the crystalline hydrate has 2 ⁇ values selected from the following peaks listed Table 1 + 0.2.
• a crystalline hydrate of the compound of formula (I) has an XRD pattern substantially as shown in FIG. 1, labeled Form 1.
• the crystalline hydrate has 2 ⁇ values 12.9 + 0.2, 13.5 + 0.2, 15.7 + 0.2, 17.0 + 0.2, 29.7 + 0.2, and 33.7 + 0.2. In further embodiments, the crystalline hydrate has 2 ⁇ values 12.9 + 0.2, 13.5 + 0.2, 15.7 + 0.2, 17.0 + 0.2, 20.3 + 0.2, 28.9 + 0.2, 29.7 + 0.2, and 33.7 + 0.2.
• the crystalline hydrate has 2 ⁇ values 12.9 + 0.2, 13.5 + 0.2, 15.7 + 0.2, 17.0 + 0.2, 19.6 + 0.2, 20.3 + 0.2, 26.2 + 0.2, 28.9 + 0.2, 29.7 + 0.2, and 33.7 + 0.2.
• the crystalline hydrate has 2 ⁇ values 12.9 + 0.2, 13.5 + 0.2, 15.7 + 0.2, 17.0 + 0.2, 19.1 + 0.2, 19.6 + 0.2, 20.3 + 0.2, 21.1 + 0.2, 21.4 + 0.2, 26.2 + 0.2, 27.2 + 0.2, 28.9 + 0.2, 29.7 + 0.2, 32.2 + 0.2, and 33.7 + 0.2.
• the crystalline hydrate has 2 ⁇ values selected from the following peaks listed Table 2 + 0.2.
• a crystalline hydrate of the compound of formula (I) has an XRD pattern substantially as shown in FIG. 2, labeled Form 2.
• the crystalline hydrate of the compound of formula (I) is a monohydrate. In certain embodiments, the crystalline hydrate of the compound of formula (I) contains about 0.9, about 1.0, about 1.1, or about 1.2 molecules of water to one molecule of the compound of formula (I). In certain embodiments, the crystalline hydrate of the compound of formula (I) by differential scanning calorimetry (DSC) shows one or two overlapping endotherms with a peak temperature from about 115 °C to about 145 °C before melting/decomposition.
• DSC differential scanning calorimetry
• the crystalline hydrate of the compound of formula (I) shows one or two overlapping endotherms with a peak temperature in the range selected from about 116 °C to about 140 °C before melting/decomposition. In some embodiments, the crystalline hydrate of the compound of formula (I) shows one or two overlapping endotherms with a peak temperature in the range selected from about 120 °C to about 140 °C, about 125 °C to about 135 °C, and about 126 °C to about 133 °C by DSC before melting/decomposition. See FIG. 3, labeled Form 1.
• the crystalline hydrate of the compound of formula (I) is a dihydrate. In certain embodiments, the crystalline hydrate of the compound of formula (I) contains about 1.8, about 1.9, about 2.0, about 2.1, or about 2.2 molecules of water to one molecule of the compound of formula (I).
• the crystalline hydrate of the compound of formula (I) by differential scanning calorimetry shows two endotherms with a peak temperature of the first endotherm in the range selected from about 25 °C to about 65 °C, 30 °C to about 60 °C, about 40 °C to about 55 °C, and about 45 °C to about 50 °C; and a peak temperature of the second endotherm in the range selected from about 60 °C to about 85 °C, about 65 °C to about 80 °C, and about 70 °C to about 75 °C before melting/decomposition. See FIG. 4, labeled Form 2.
• the crystalline hydrate of the compound of formula (I) shows melting/decomposition with an onset temperature in the range selected from about 178 °C to about 190 °C, about 182 °C to about 186 °C, and about 183 °C to about 185 °C by DSC.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a crystalline compound of formula (I) and one or more pharmaceutically acceptable excipients.
• the pharmaceutical composition is selected from tablets, capsules, and suspensions.
• the pharmaceutical composition comprises the salt of the compound of formula (I) and one or more pharmaceutically acceptable excipients.
• hydrate refers to a complex formed by the combining of Compound of formula (I) and water.
• the term includes stoichiometric as well as non- stoichiometric hydrates.
• solvate refers to a complex formed by the combining of Compound of formula (I) and a solvent.
• therapeutically effective amount refers to an amount that is sufficient to effect treatment, when administered to a mammal in need of such treatment.
• the therapeutically effective amount will vary depending upon the subject being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
• substantially pure refers to a crystalline polymorph that is greater than 90% pure, meaning that it contains less than 10% of any other compound, or an alternative polymorph of the crystalline form.
• the crystalline polymorph is greater than 95% pure, or even greater than 98% pure.
• substantially as shown in Fig. refers to an X-ray powder diffraction pattern with at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% or at least 99% of its peak appears in FIG.
• the term "about" when referring to a number or a numerical range means that the number or numerical range referred to, is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range.
• the invention relates to a method for preparing a crystalline compound having the structure of formula (I), comprising:
• the mixture comprising the compound of formula (I) and the solvent is a reaction mixture.
• the mixture comprising the compound of formula (I) is a solution.
• the solution comprises a compound of formula (I) dissolved in a solvent.
• the solution comprises a crude solid material comprising the compound of formula (I) dissolved in a solvent.
• the solution comprises a reaction mixture.
• the mixture is a slurry or a suspension.
• the slurry or the suspension comprises crude solid material comprising the compound of formula (I).
• the crude solid material comprising the compound of formula (I) is less than 70% pure, less than 75% pure, less than 80% pure, less than 85% pure, or less than 90% pure with respect to the compound of formula (I). In certain embodiments, the crude solid material comprising the compound of formula (I) is less than 90% pure with respect to the compound of formula (I). In certain embodiments, the crude solid material comprises about 70% to about 90% compound of formula (I). In some embodiments, the purity of the crude solid material is about 70% to about 90% with respect to the compound of formula (I).
• the compound of formula (I) is substantially pure.
• the crystalline form of the compound of formula (I) is greater than 90% pure.
• the purity of the crystalline form of the compound of formula (I) is selected from greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%.
• the purity of the crystalline form of the compound of formula (I) is greater than 95%.
• the purity of the crystalline form of the compound of formula (I) is greater than 98%.
• the purity of the crystalline form of the compound of formula (I) is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%.
• the crystalline compound made by the methods of the invention is a solvate, e.g., a hydrate.
• the crystalline compound made by the methods of the invention is a monohydrate.
• the crystalline compound made by the methods of the invention is a dihydrate.
• solvent vapor slowly diffuses into a solid sample.
• the solvent vapor is water vapor.
• the solid sample is Form 1
• solvent is water.
• the crystalline Form 1 of compound of formula (I) can be substantially free of other crystalline forms of compound of formula (I). In certain embodiments, the crystalline Form 1 of compound of formula (I), can be substantially free of crystalline Form 2 of compound of formula (I).
• the crystalline Form 2 of compound of formula (I) can be substantially free of other crystalline forms of compound of formula (I). In certain embodiments, the crystalline Form 2 of compound of formula (I), can be substantially free of crystalline Form 1 of compound of formula (I).
• the mixture comprising the compound of formula (I) is a solution
• the step of crystallizing the compound from the mixture comprises bringing the solution to supersaturation to cause the compound of formula (I) to precipitate out of solution.
• bringing the mixture comprising the compound of formula (I) to supersaturation comprises the slow addition of an anti-solvent, such as heptanes, hexanes, ethanol, or another polar or non-polar liquid miscible with an aqueous solution, allowing the solution to cool (with or without seeding the solution), reducing the volume of the solution, or any combination thereof.
• the anti-solvent is ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, methyl tert-butyl ether, isopropyl acetate and acetone.
• the anti-solvent is ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and acetone. In certain embodiments, the anti-solvent is ethanol. In certain embodiments, bringing the mixture comprising the compound of formula (I) to supersaturation comprises adding an anti- solvent, cooling the solution to ambient temperature or lower, and reducing the volume of the solution, e.g., by evaporating solvent from the solution. In certain embodiments, allowing the solution to cool may be passive (e.g., allowing the solution to stand at ambient temperature) or active (e.g., cooling the solution in an ice bath or freezer).
• the preparation method further comprises isolating the crystals, e.g., by filtering the crystals, by decanting fluid from the crystals, or by any other suitable separation technique. In further embodiments, the preparation method further comprises washing the crystals.
• the preparation method further comprises inducing crystallization.
• the method can also comprise drying the crystals, for example under reduced pressure.
• inducing precipitation or crystallization comprises secondary nucleation, wherein nucleation occurs in the presence of seed crystals or interactions with the environment (crystallizer walls, stirring impellers, sonication, etc.).
• the solvent is acetonitrile, diethyl ether, N,N- dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane, ethanol, ethyl acetate, heptanes, hexanes, isopropyl acetate, methanol, methylethyl ketone, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, toluene, 2-propanol (isopropanol), 1-butanol, water, or any combination thereof.
• the solvent is dichloromethane.
• the solvent is tetrahydrofuran.
• the anti- solvent is selected from tetrahydrofuran, methanol, isopropanol, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, and acetone.
• an aqueous solution comprising the compound of formula (I) is slowly added an anti-solvent.
• an aqueous solution comprising Form 1 is combined with an anti-solvent selected from tetrahydrofuran, methanol, isopropanol, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, and acetone.
• the anti- solvent is selected from tetrahydrofuran, methanol, isopropanol, 1,4-dioxane, acetonitrile, and acetone.
• an anti-solvent slowly diffuses into an aqueous solution comprising the compound of formula (I).
• an aqueous solution comprising Form 1 is diffused with an anti-solvent selected from tetrahydrofuran, methanol, isopropanol, 1,4-dioxane, acetonitrile, and acetone.
• a slurry comprising the compound of formula (I) and a solvent were mixed before isolating the solids.
• the isolation of the solids is by filtration or centrifugation.
• the slurry comprising Form 1 was mixed with a solvent selected from acetonitrile, anisole, dichloromethane, ethanol, isopropyl acetate, methyl tert-butyl ether (MTBE), n-heptane, tetrahydrofuran, water, and mixtures thereof.
• a solvent selected from acetonitrile, anisole, dichloromethane, ethanol, isopropyl acetate, methyl tert-butyl ether (MTBE), n-heptane, tetrahydrofuran, water, and mixtures thereof.
• the slurry comprising Form 1 was mixed with a solvent selected from acetonitrile, ethanol, methyl tert-butyl ether (MTBE), water, and mixtures thereof.
• a solvent selected from acetonitrile, ethanol, methyl tert-butyl ether (MTBE), water, and mixtures thereof.
• the slurry comprising compound was mixed with a solvent selected from acetonitrile, methyl tert-butyl ether (MTBE), water, and mixtures thereof.
• a solvent selected from acetonitrile, methyl tert-butyl ether (MTBE), water, and mixtures thereof.
• the solvent is a mixture comprising water. In some preferred embodiments, the solvent is a mixture comprising water and ethanol, isopropanol, methanol, or tetrahydrofuran. In certain preferred embodiments, for example to achieve Form 2, the solvent is a mixture comprising water and tetrahydrofuran. In other embodiments the solvent is a mixture comprising water, and other solvents selected from ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, and acetone.
• the solvent mixture is selected from water/ tetrahydrofuran (H 2 0/THF), water/methanol (H 2 0/MeOH), water/ isopropanol (H 2 0/IPA), water/ethanol (H 2 0/EtOH), water/ 1,4-dioxane (H 2 0/ 1,4-dioxane), water/acetonitrile (H 2 0/ACN), or water/ Acetone (H 2 0/Acetone).
• H 2 0/THF water/ tetrahydrofuran
• H 2 0/MeOH water/methanol
• H 2 0/IPA water/ isopropanol
• H 2 0/EtOH water/ethanol
• H 2 0/EtOH water/ 1,4-dioxane
• H 2 0/ACN water/acetonitrile
• Acetone H 2 0/Acetone
• the solvent is a mixture comprising EtOH:H 2 0 in a volume- to-volume ratio selected from 19:2, 5: 1, 2: 1, 1: 1, and 1:9.
• the solvent is a mixture comprising ethanol and water to which additional ethanol or a mixture of ethanol and water is added.
• the mixture comprises the compound of formula (I) and a solvent of 2: 1 EtOH:H 2 0 (v/v), then a mixture of 19:2 EtOH:H 2 0 is added for crystallization.
• crystallization is aided by seeding or seed loading, that is adding seed crystals to the mixture.
• the seed crystals are added at a weight percentage of the total mixture selected from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, and about 10 wt%.
• the seed crystals are added at a weight percentage of the total mixture selected from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, and about 6 wt%.
• the seed crystals are added at a weight percentage of the total mixture selected from 3 wt%, 4 wt%, and 5 wt%.
• the seed crystals are formula (I) Form 2 seed crystals. In certain embodiments, the seed crystals are milled.
• washing the crystals comprises washing with a liquid selected from anti-solvent, acetonitrile, ethanol, heptanes, hexanes, methanol,
• anti- solvent means a solvent in which the compound crystals are insoluble, minimally soluble, or partially soluble.
• an anti- solvent to a solution in which the salt crystals are dissolved reduces the solubility of the salt crystals in solution, thereby stimulating precipitation of the salt.
• the crystals are washed with a combination of anti- solvent and the organic solvent.
• the anti-solvent is water, while in other embodiments it is an alkane solvent, such as hexane or pentane, or an aromatic hydrocarbon solvent, such as benzene, toluene, or xylene.
• the anti-solvent is methanol.
• washing the crystals comprises washing the crystalline compound of formula (I) with a solvent or a mixture of one or more solvents, which are described above.
• the solvent or mixture of solvents is cooled prior to washing.
• the methods of making the crystalline forms of the compound of formula (I) are used to remove one or more impurities from a sample of the compound of formula (I).
• the crystallization methods described herein are used for purifying the compound of formula (I), e.g., as a final purification step in the manufacture of the compound.
• the compound of formula (I) is purified by crystallization.
• purification of the compound of formula (I) does not use high- performance liquid chromatography (HPLC), including preparative HPLC.
• HPLC high- performance liquid chromatography
• purification of the compound of formula (I) by crystallization is scalable. Advantages of purification by crystallization include, but are not limited to, removal of soluble impurities, ease of purification process, applicability to large scale synthesis, acceptable yields, and high product purity.
• the crystalline formula (I) Form 2 was the form with greater stability.
• the crystalline formula (I) Form 2 is more stable than the crystalline formula (I) Form 1 in water.
• the temperature was below about 20 °C, below about 15 °C, below about 10 °C, below about 5 °C, or below about 0 °C. In some embodiments, the temperature was about 20 °C, about 15 °C, about 10 °C, about 5 °C, or about 0 °C. In some embodiments, the temperature was about 10 °C, about 9 °C, about 8 °C, about 7 °C, about 6 °C, about 5 °C, about 4 °C, about 3 °C, about 2 °C, about 1 °C, about 0 °C, about -1 °C, or about -2 °C. In some embodiments, the temperature was about 10 °C.
• the conversion to crystalline formula (I) Form 2 was complete in about 4 h, in about 8 h, in about 12 h, in about 16 h, in about 20 h, in about 1 day, in about 2 days, in about 3 days, in about 4 days, in about 5 days, in about 6 days, in about 7 days.
• the conversion to crystalline formula (I) Form 2 was complete in about 2 h, in about 3 h, in about 4 h, in about 5 h, in about 6 h, in about 7 h, in about 8 h, in about 9 h, in about 10 h, in about 11 h, in about 12 h, in about 13 h, in about 14 h, in about 15 h, in about 16 h, in about 17 h, in about 18 h, in about 19 h, in about 20 h, in about 21 h, in about 22 h, in about 23 h, in about 24 h, in about 25 h, or in about 26 h.
• the compound of formula (I) is a 3-substituted 1,2,4-oxadiazole compound having the following structure,
• T cell exhaustion was initially described for CD8 T cells in mice chronically infected with lymphocytic choriomeningitis virus clone 13.
• lymphocytic choriomeningitis virus mouse model repeated antigen stimulation through the T cell antigen receptor drives the sustained expression of T cell inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte activationgene-3 (LAG-3), on virus- specific CD8 T cells (J. Illingworth et al., J. Immunol. 2013, 190(3): 1038-1047).
• PD-1 programmed cell death-1
• LAG-3 lymphocyte activationgene-3
• diseases modulated by an immune response including, but not limited to, cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection, can be treated by administering an immunomodulator, such as the compound of formula (I), and compositions disclosed herein.
• an immunomodulator such as the compound of formula (I), and compositions disclosed herein.
• 3-substituted 1,2,4-oxadiazole compounds act as immunomodulators.
• the compound of formula (I) modulates an immune response in a cell.
• the present disclosure provides a method of modulating an immune response in a cell, comprising contacting the cell with a composition comprising a crystalline form of the compound of formula (I), according to any of the above embodiments. In some embodiments, the present disclosure provides a method of modulating an immune response in a cell, comprising contacting the cell with a composition comprising a crystalline form of the compound of formula (I), according to any of the above embodiments.
• the present disclosure provides uses of a crystalline form of the compound of formula (I) for the preparation of a medicament, e.g., for the treatment of cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
• contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder selected from cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.
• the present disclosure provides methods for treating cancer, wherein the method comprises administration of a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) the subject in need thereof.
• the present disclosure provides methods for inhibiting growth of tumor cells and/or metastasis by administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) to the subject in need thereof.
• tumor cells include cells of a cancer such as, but not limited to, blastoma (e.g., glioblastoma), breast cancer (e.g., breast carcinoma, primary ductal carcinoma, triple negative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (PR+), and/or human epidermal growth factor receptor 2 positive (HER2+)), epithelial cancer (e.g., carcinomas), colon cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), melanoma (e.g., cutaneous melanoma, ocular melanoma, cutaneous or intraocular malignant melanoma,and lymph node-associated melanoma), prostate cancer (e.g., prostate adenocarcinoma), renal cancer (e.g., renal cell cancer (RCC) and kidney cancer), bone cancer (e.g., osteosar
• the tumor cells may include cells of a cancer selected from prostate cancer, melanoma, breast cancer, colon cancer, prostate cancer, lung cancer,renal cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, thyroid cancer, thymic carcinoma, sarcoma, glioblastoma, chronic or acute leukemia, lymphoma, myeloma, Merkel cell carcinoma, epithelial cancer, colorectal cancer, vaginal cancer, cervical cancer, ovarian cancer, and cancer of the head and neck.
• a cancer selected from prostate cancer, melanoma, breast cancer, colon cancer, prostate cancer, lung cancer,renal cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, thyroid cancer, thymic carcinoma, sarcoma, glioblastoma, chronic or acute leukemia, lymphoma, myeloma, Merkel cell carcinoma, epit
• the tumor cells may include cells of a cancer selected from melanoma, triple negative breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma, Hodgkins's lymphoma, cervical cancer, ovarian cancer, and head and neck squamous cell carcinoma.
• a cancer selected from melanoma, triple negative breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric carcinoma, bladder cancer, mesothelioma, Hodgkins's lymphoma, cervical cancer, ovarian cancer, and head and neck squamous cell carcinoma.
• the tumor cells are cells of a cancer selected from small cell lung cancer, multiple myeloma, bladder carcinoma, primary ductal carcinoma, ovarian carcinoma, Hodgkin's lymphoma, gastric carcinoma, acute myeloid leukemia, and pancreatic cancer.
• the tumor cells are cells of a cancer selected from carcinoma of the endometrium, ovarian cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, and multiple myeloma.
• a cancer selected from carcinoma of the endometrium, ovarian cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, and multiple myeloma.
• the tumor cells are cells of a cancer selected from prostate adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, breast cancer and colorectal adenocarcinoma.
• tumor cells are from breast cancer.
• the tumor cells are from a breast cancer selected from triple negative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (PR+), and/or human epidermal growth factor receptor 2 (HER2+).
• the tumor cells are from a PAM50+ breast cancer assay panel (Parker, J.S., et al., J. Clin. Oncol., 2009, 27(8): 1160-1167), breast cancer selected from luminal A, luminal B, HER2-enriched, basal-like and normal-like.
• the tumor cells are cells of a cancer selected from triple negative breast cancer, micro satellite instability high colorectal cancer, gastric carcinoma, mesothelioma, pancreatic cancer, and cervical cancer.
• an immunooncology therapy includes, but is not limited to, atezolizumab (human monoclonal antibody that targets PD-L1), avelumab (human monoclonal antibody that targets PD-L1), brentuximab vedotin (antibody-drug conjugate that targets CD30), durvalamab (human monoclonal antibody that targets PD-L1), ipilimumab (human monoclonal antibody that targets CTLA-4), nivolumab (human monoclonal antibody that targets PD-L1), pembrolizumab (also referred to as lambrolizumab, human monoclonal antibody that targets PD-L1), tremelimumab (human monoclonal antibody that targets CTLA-4), CT-011 (antibody that targets PD
• the immunooncology therapy is selected from an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti-PD-L2 antibody, an anti-TIGIT antibody (e.g., antibodies disclosed in WO 2015/009856).
• the tumor cells are, and/or the subject is responsive to immune checkpoint therapy.
• the cancer has shown response to anti- PD1 therapy.
• the cancer may include non-small cell lung cancer (NSCLC), melanoma, renal cell cancer (RCC), cancer of the bladder, Hodgkin's lymphoma, and head and neck squamous cell carcinoma.
• Still other embodiments of the present disclosure provide a method of treatment of infection comprising administration of a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) to the subject in need thereof.
• the present disclosure provides uses of a crystalline form of the compound of formula (I) for the preparation of a medicament for the treatment of infectious disease, as well as methods of administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) for the treatment of infectious disease.
• the infectious disease is bacterial infection, viral infection, fungal infection, or parasitic infection, as well as methods of administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) for the treatment of bacterial infection, viral infection, fungal infection, or parasitic infection.
• bacterial infection may be caused by at least one bacterium selected from anthrax, Bacilli, Bordetella, Borrelia, botulism, Brucella, Burkholderia, Campylobacter, Chlamydia, cholera, Clostridium, Conococcus, Corynebacterium, diptheria, Enterobacter, Enterococcus, Erwinia, Escherichia, Francisella, Haemophilus, Heliobacter, Klebsiella, Legionella, Leptospira, leptospirosis, Listeria, Lyme's disease, meningococcus, Mycobacterium, Mycoplasma, Neisseria, Pasteurella, Pelobacter, plague, Pneumonococcus, Proteus, Pseudomonas, Rickettsia, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus, tetanus, Trepone
• bacterium selected from
• viral infection may be caused by at least one virus selected from Adenoviridae, Papillomaviridae, Polyomaviridae, Herpesviridae, Poxviridae, Hepadnaviridae, Parvoviridae, Astroviridae, Caliciviridae, Picornaviridae, Coronoviridae, Flaviviridae, Retroviridae, Togaviridae, Arenaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, and Reoviridae.
• the virus may be arboviral encephalitis virus, adenovirus, herpes simplex type I, herpes simplex type 2, Varicella-zoster virus, Epstein-barr virus, cytomegalovirus, herpesvirus type 8, papillomavirus, BK virus, coronavirus, echovirus, JC virus, smallpox, Hepatitis B, bocavirus, parvovirus B 19, astrovirus, Norwalk virus, coxsackievirus, Hepatitis A, poliovirus, rhinovirus, severe acute respiratory syndrome virus, Hepatitis C, yellow fever, dengue virus, West Nile virus, rubella, Hepatitis E, human immunodeficiency virus (HIV), human T-cell lymphotropic virus (HTLV), influenza, guanarito virus, Junin virus, Lassa virus, Machupo virus, Sabia virus, Crimean- Congo hemorrhagic fever virus, ebola virus, Marburg virus, measles virus
• fungal infection may be selected from thrush, Aspergillus (fumigatus, niger, etc.), Blastomyces dermatitidis, Candida ⁇ albicans, krusei, glabrata, tropicalis, etc.), Coccidioides immitis, Cryptococcus (neoformans, etc.), Histoplasma capsulatum, Mucorales (mucor, absidia, rhizophus), Paracoccidioides brasiliensis,, sporotrichosis, Sporothrix schenkii, zygomycosis, chromoblastomycosis, lobomycosis, mycetoma, onychomycosis, piedra pityriasis versicolor, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea favosa, tinea nigra, tinea pedis, o
• parasitic infection may be caused by at least one parasite selected from Acanthamoeba, Babesia microti, Balantidium coli, Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodesiense, Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Pneumocystis carinii, Trichomonas vaginalis, Histomonas meleagridis, Secementea, Trichuris trichiura, Ascaris lumbricoides, Enterobius ver
• subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
• domestic animals e.g., household pets including cats and dogs
• non-domestic animals such as wildlife.
• a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence or frequency of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
• prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
• Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
• Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population.
• treating includes prophylactic and/or therapeutic treatments.
• prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a crystalline form of the compound of formula (I) as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent.
• the present disclosure also provides methods for formulating the disclosed crystalline forms of the compound of formula (I) for pharmaceutical administration.
• compositions and methods of the present disclosure may be utilized to treat an individual in need thereof.
• the individual is a mammal such as a human, or a non-human mammal.
• the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a crystalline form of the compound of formula (I) of the disclosure and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
• the aqueous solution is pyrogen-free, or substantially pyrogen-free.
• the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
• the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
• the composition can also be present in a transdermal delivery system, e.g., a skin patch.
• the composition can also be present in a solution suitable for topical administration, such as an eye drop.
• a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a crystalline form of the compound of formula (I) of the disclosure.
• physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
• the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
• the preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a self- microemulsifying drug delivery system.
• the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a crystalline form of the compound of formula (I) of the disclosure.
• Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
• a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop).
• routes of administration including, for example, orally (for example, drenches as in aqueous or
• the compound may also be formulated for inhalation.
• a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
• the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
• Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a crystalline form of the compound of formula (I) of the disclosure, with the carrier and, optionally, one or more accessory ingredients.
• an active compound such as a crystalline form of the compound of formula (I) of the disclosure
• the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
• Formulations of the disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient.
• Compositions or compounds may also be administered as a bolus, electuary or paste.
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
• pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
• compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
• compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions that can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
• Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
• compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
• Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
• Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
• the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body.
• dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
• Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure.
• Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference in its entirety.
• liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
• a preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).
• a suppository also is contemplated as being within the scope of this disclosure.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• injectable organic esters such as ethyl oleate.
• Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
• the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
• active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• Methods of introduction may also be provided by rechargeable or biodegradable devices.
• Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
• a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
• the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject.
• the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the crystalline form of the compound of formula (I) of the disclosure.
• a larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
• a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
• the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
• the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
• the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
• wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
• antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
• water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
• oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
• X-Ray Powder Diffraction patterns were collected on an Empyrean diffractometer or an X'Pert3 diffractometer using Cu Ka radiation (45 kV, 40 mA).
• TGA Thermogravimetric analysis
• Formula (I) Form 1 exists at ambient conditions upon short term storage (i.e., less than 8 d).
• a mixture of formula (I) Forms 1 and 2 (16 mg) was weighed into a glass vial, and tetrahydrofuran (THF, 0.5 mL) was added. The resulting slurry was stirred at room temperature for about 4 d.
• the wet solids were analyzed by XRPD in transmission mode and confirmed to be crystalline formula (I) Form 1, as shown by XRPD analysis (FIG. 1).
• Formula (I) Form 1 (approximately 15.3 mg) was weighed into a 3-mL vial, which was then placed into a 20-mL vial with 4.0 mL of water. The 20-mL vial was sealed with a cap and kept at RT for a week allowing solvent vapor to interact with the sample. The obtained solid was shown by XRPD analysis to be crystalline formula (I) Form 2.
• Example 3 Thermo gravimetric analysis and differential scanning calorimetry of formula (I) Thermogravimetric analysis (TGA) of formula (I) Form 1 showed a weight loss of 5.2% up to 80 °C, which is consistent with a monohydrate form. Differential scanning calorimetry (DSC) showed two overlapped endotherms at 125.6 °C and 133.1 °C (peak temperature) before melting/decomposition with an onset at 184.1 °C (FIG. 3).
• TGA of formula (I) Form 2 showed a two-step weight loss of 9.6% up to 80 °C, which is consistent with a dihydrate form.
• DSC showed two endotherms at 47.2 °C and 72.9 °C (peak temperature) before melting/decomposition with an onset at 184.3 °C (FIG. 4).
• Samples of formula (I) crystalline Form 2 were stored as solids at 25 °C/60% Relative Humidity (RH), 30 °C/ ⁇ 56%, and 40 °C/75% RH for 7-8 days. The samples were prepared in duplicate with an offset of 2 weeks. Each replicate was stored in a different container.
• Formula (I) crystalline Form 2 remained unchanged in terms of solid form and particle morphology after storage for 7-8 days at 25 °C/60% RH, 30 °C/ ⁇ 56% RH, and 40 °C/75% RH. See FIG. 5.
• a single crystal for X-ray diffraction was obtained via a liquid vapor diffusion method from H 2 0/l,4-dioxane as described in Example 2F.
• X-ray diffraction data was collected using a PANalytical instrument. The structural information and refinement parameters are given in Table 10.

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