Polymorphism of phenylpyrrolehydrazinecarboximidamide compounds.

Abstract

The present disclosure relates to crystalline forms of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide that have high solubility under acidic conditions. The present disclosure also relates to the use of said crystalline forms in medicine.

Description

[Technical Field]

[0001] The present invention relates to polymorphs of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide that have high solubility at low pH, and formulations containing the same. [Background technology]

[0002] The melanocortin system is a collection of neuropeptidergic and immunoendocrine signaling pathways that play essential roles in the homeostatic regulation of diverse physiological functions, including melanogenesis, stress response, inflammation, immunoregulation, and adrenocorticosteroidogenesis. This system consists of multiple components, including five G protein-coupled melanocortin receptors: melanocortin receptor 1 (MC1R)–MC5R; peptide ligands; α, β, γ-melanocyte-stimulating hormone (α, β, γ-MSH); adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary gland; and endogenous antagonists. The biological functions of the melanocortin system are mediated by the five melanocortin receptors (MCRs), which have distinct tissue distributions, differential signal transduction pathways, and diverse biological activities in different organ systems.

[0003] Phenylpyrrolehydrazinecarboximidamide derivatives with activity against melanocortin receptors have been previously described. One example of such a compound is the anti-inflammatory AP11892-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, which was first shown to bind MC1R and subsequently identified as a biased dual agonist at the MC1R and MC3R receptors that does not result in canonical cAMP production (and therefore no MC1R-induced melanin production) but instead appears to induce an alternative pathway involving ERK1 / 2 phosphorylation and Ca2+ mobilization. Summary of the Invention

[0004] The present inventors have discovered a polymorph of AP1189 that has a particularly favorable solubility profile: the present inventors have found that this polymorph of AP1189 is highly soluble in acidic conditions, in contrast to some polymorphic salt forms of AP1189.

[0005] One aspect of the present disclosure is Cu K at 14.5±0.2, 23.9±0.2, and 26.7±0.2. α Provided is a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide (AP1189, free base) that exhibits at least X-ray lines (2-theta values) in a powder diffraction pattern (AP1189 pattern 1) when measured using radioactivity.

[0006] The present disclosure also provides methods for making such crystalline forms.

[0007] One aspect of the present disclosure provides a method for producing a crystalline form of AP1189 of Pattern 1, said method comprising: i. mixing AP1189 and a solvent to form a mixture; ii. isolating the crystalline form of AP1189 of Pattern 1 from said mixture; and Includes.

[0008] One aspect of the present disclosure provides a method for producing a crystalline form of AP1189 of Pattern 1, said method comprising: i. mixing an AP1189 salt and a solvent to form a composition; ii. isolating the Pattern 1 crystalline form of AP1189 from said composition; and Includes.

[0009] One aspect of the present disclosure provides a method for producing a crystalline form of AP1189 of Pattern 1, said method comprising: i. mixing 3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propanal and aminoguanidine or a salt thereof in a solvent to form a composition; ii. isolating the Pattern 1 crystalline form of AP1189 from said composition; and Includes.

[0010] One aspect of the present disclosure provides a method for producing a crystalline form of AP1189 of Pattern 1, said method comprising: i. providing an AP1189 salt comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and a counterion; ii. separating the counterion from 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide using ion exchange; iii. isolating the crystalline form of AP1189 of pattern 1; Includes. Another aspect of the present disclosure provides a pharmaceutical composition comprising a crystalline form of AP1189. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows the XRPD diffractogram for pattern 1 of AP1189 tosylate crystallized from methanol. [Figure 2] Figure 1 shows the XRPD diffractogram for pattern 1 of AP1189 fumarate crystallized from isopropyl alcohol:water 90:10 v / v. [Figure 3] Figure 1 shows the TGA / DSC thermogram of Pattern 1 of AP1189 tosylate salt from 90:10 v / v IPA:water after storage at 40°C. Peak temperature: 239.24°C; Onset: 233.75°C; Enthalpy (normalized): 99.785 J / g. Weight loss: 0.006 mg; Weight loss percentage: 0.330%. [Figure 4] Figure 1 shows the TGA / DSC thermogram of Pattern 1 for fumaric acid from 90:10 2-propanol:water. Peak temperature: 218.27°C; Onset: 214.61°C; Enthalpy (normalized): 68.467 J / g. Weight loss: 0.012 mg; Percent weight loss: 0.319%. [Figure 5] The XRPD diffractogram for pattern 1 of AP1189 free base crystallized from DCM is shown. [Figure 6] The XRPD diffractogram for pattern 1 of AP1189 free base crystallized from DCM is shown. [Figure 7] FIG. 1 shows the XRPD diffractogram for AP1189 free base pattern 3 DMSO solvate. [Figure 8] Figure 1 shows the XRPD diffractogram for AP1189 free base pattern 4 DMF solvate. [Figure 9] Figure 1 shows the XRPD diffractogram for AP1189 free base pattern 5 NMP solvate. [Figure 10] Figure 1 shows the TGA / DSC thermogram of AP1189 Pattern 1 from DCM. Peak temperature: 185.59°C; Onset: 181.20°C; Enthalpy (normalized): 17.549 J / g. First weight loss: 0.092 mg, First weight loss rate: 1.410%, Second weight loss: 0.052 mg, Second weight loss rate: 0.805%, Third weight loss: 0.052 mg, Third weight loss rate: 0.804%. [Figure 11]

[0033] Figure 2 shows the TGA / DSC thermogram of AP1189 Pattern 3 DMSO solvate. Peak temperature: 106.01°C; Onset: 102.89°C; Enthalpy (normalized): 6.6413 J / g. Weight loss: 0.231 mg; Weight loss rate: 2.099%. [Figure 12]

[0033] Figure 2 shows the TGA / DSC thermogram of AP1189 Pattern 5 NMP solvate. Peak temperature: 89.90°C; Onset: 82.69°C; Enthalpy (normalized): 3.6210 J / g. Weight loss: 0.058 mg; Weight loss percentage: 1.069%. DETAILED DESCRIPTION OF THE INVENTION

[0012] definition "Compound of Formula I," "Compound I," and "AP1189" refer to compounds of Formula I: The compound 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide has the chemical structure TIFF2026501257000001.tif53165, and its tautomers and stereoisomers.

[0013] As used herein, the term "AP1189" refers to the free base structure of Formula I. Preferably, the term "AP1189 free base" refers to the structure of Formula I. By "free base" is meant the compound that does not form part of a salt. "AP1189," "AP1189 free base," and "AP1189 free base" are used interchangeably herein.

[0014] 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is also known as N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine. "Resomeragon" has been proposed as the International Nonproprietary Name (INN) for 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0015] With regard to the naming of salts, terms such as "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine," "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium tosylate," and N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine para-toluenesulfonate are intended to be synonymous. That is, when an anion is written immediately after "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine," the protonated form of "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine" means "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium." Similarly, when "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine" is followed by an acid and "salt," it means that it has been protonated from "N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium." These considerations also apply to the name "2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide," in which case the terms "2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide tosylate" and "2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propen-2-ylidene}hydrazine-1-carboximidium tosylate" have the same meaning herein. These considerations also apply to other salts of the disclosed compounds.

[0016] In one embodiment, the compound of the present disclosure is 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including its tautomers and stereoisomers.

[0017] In one embodiment, the compound of the present disclosure is (2E)-2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including its tautomers and stereoisomers.

[0018] In one embodiment, the compound of the present disclosure is 2-{(2E)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propen-2-ylidene}hydrazine-1-carboximidamide, including its tautomers and stereoisomers.

[0019] In one embodiment, the compound of the present disclosure is (2E)-2-{(2E)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propen-2-ylidene}hydrazine-1-carboximidamide (also referred to as (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}aminoguanidine), including its tautomers. These compounds may also appear as salts and the corresponding crystalline forms disclosed herein. In one embodiment, the compounds of the present disclosure are (2Z)-2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, 2-{(2Z)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]propen-2-yllidene}hydrazine-1-carboximidamide, (2Z)-2-{(2Z)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]propen-2-yllidene}hydrazine-1-carboximidamide, The compound of the present disclosure may also be any tautomer of the above structure. As used herein, "tautomer" refers to other structural isomers that exist in equilibrium as a result of the migration of a hydrogen atom.

[0020] When reporting the results of a measurement, such as the measurement of 2-theta values, for example, reading 2-theta values ​​from an XRPD diffractogram, one skilled in the art will understand that the method of measuring this value inherently contains some uncertainty. For example, the measurement of 2-theta values ​​may have an uncertainty of 0.2°.

[0021] "Crystalline form of AP1189" refers to the Cu K crystal corresponding to AP1189 (free base) Pattern 1 as disclosed herein. αIt refers to a crystalline form of AP118 that exhibits X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0022] Unless otherwise specified, 2-theta values ​​are in degrees (°).

[0023] "Onset temperature" refers to the designed intersection of the extrapolated baseline and the tangent to the inflection at the onset of melting.

[0024] As used herein, "seeding" refers to the technique of adding "seed" crystals to a crystallization solution to promote the formation of crystals. Preferably, the composition of the seed crystals is the same as the composition of the crystals that are formed.

[0025] The terms "approximately" and "about" as referred to herein are synonymous. In some embodiments, "approximately" and "about" refer to ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±1% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.1% of the recited amount, value, or duration.

[0026] compound In one embodiment, the present disclosure provides the compound AP1189. One embodiment provides the compound AP1189, including its tautomers and / or isomeric forms, e.g., its enantiomeric and / or diastereomeric forms. In one embodiment, diastereomeric forms include cis and trans forms of the compound, particularly with respect to the alkene moiety. The compound may also exist as either the E or Z form with respect to the C=N double bond of the structure of Formula I. Those skilled in the art will recognize that in certain cases the E configuration is synonymous with the trans configuration, and in certain cases the Z configuration is synonymous with the cis configuration. For example, in certain cases where both atoms forming part of the double bond are each bonded to a hydrogen moiety or exactly one additional moiety that is not a lone pair. In one embodiment, the term "compound of the present disclosure" refers to a crystalline form of AP1189, i.e., a crystalline form of AP1189 free base.

[0027] Crystalline morphology The present disclosure relates to crystalline forms of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide. It is an object of the present disclosure to provide crystalline forms of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide that have high solubility in aqueous media across a range of pH values, particularly low pH values.

[0028] The crystalline forms of AP1189 and its salts may be characterized by X-ray powder diffraction (XRPD) analysis. Such analysis may be performed using a suitable X-ray powder diffractometer, such as a PANalytical X'pert Pro equipped with a PIXcel detector (128 channels). Sample scans may be performed between 3 and 35°2θ. Samples may be gently ground to release aggregates prior to measurement. Samples may be loaded onto a multiwell plate with a Kapton or Mylar polymer film for support. Measurements may be performed by placing the multiwell plate into the diffractometer and subsequently analyzing using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) running in transmission mode (step width 0.0130°2θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA.

[0029] The present disclosure provides crystalline forms of AP1189. The crystalline forms of AP1189 exhibit an XRPD diffractogram as shown in Figure 5. One embodiment of the present disclosure provides crystalline forms of AP1189 with Cu K at 14.5±0.2, 23.9±0.2, and 26.7±0.2. α The present invention provides a crystalline form of AP1189 that exhibits at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactive material. One embodiment provides a Cu K α The present invention provides a crystalline form of AP1189 which further exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. α A crystalline form of AP1189 is provided that exhibits an X-ray pattern (2-theta values) in powder diffraction when measured using radioactivity.

[0030] One embodiment of the present disclosure is a Cu K alloy selected from the group consisting of 8.5, 9.8, 11.6, 11.9, 12.3, 12.9, 13.4, 13.6, 14.1, 14.5, 15.1, 16.9, 17.2, 17.6, 18.2, 19.1, 19.4, 19.7, 20.2, 20.6, 21.2, 21.5, 22.0, 22.8, 23.9, 24.8, 25.4, 25.9, 26.3, 26.7, 27.0, 27.4, 27.8, 28.1, 28.5, 28.8, 29.2, 29.4, and 29.8. α Crystalline forms of AP1189 are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0031] One embodiment of the present disclosure provides the following: 8.5±0.2, 9.8±0.2, 11.6±0.2, 11.9±0.2, 12.3±0.2, 12.9±0.2, 13.4±0.2, 13.6±0.2, 14.1±0.2, 14.5±0.2, 15.1±0.2, 16.9±0.2, 17.2±0.2, 17.6±0.2, 18.2±0.2, 19.1±0.2, 19.4±0.2, 19.7±0.2, 20.2±0.2, 20.6±0.2. 2, 21.2±0.2, 21.5±0.2, 22.0±0.2, 22.8±0.2, 23.9±0.2, 24.8±0.2, 25.4±0.2, 25.9±0.2, 26.3±0.2, 26.7±0.2, 27.0±0.2, 27.4±0.2, 27.8±0.2, 28.1±0.2, 28.5±0.2, 28.8±0.2, 29.2±0.2, 29.4±0.2, and 29.8±0.2. α Crystalline forms of AP1189 are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0032] It may be advantageous to identify the crystalline form of AP1189 by X-ray lines (2-theta values) with relatively high intensity and / or by characteristic X-ray lines. Thus, one embodiment of the present disclosure provides a Cu K crystalline form of AP1189 having a Cu K value selected from the group consisting of 11.6, 12.3, 13.4, 14.5, 16.9, 17.6, 19.1, 19.7, 21.2, 23.9, 26.7, and 27.0. αCrystalline forms of AP1189 are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0033] One embodiment of the present disclosure is a Cu K α Crystalline forms of AP1189 are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0034] One embodiment of the present disclosure provides a Cu K 2-theta value selected from the group consisting of the values ​​listed in Table 3a. α Crystalline forms of AP1189 are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

[0035] The crystalline forms of AP1189 disclosed herein can appear as solvates. One embodiment of the present disclosure provides a crystalline form of AP1189 that is a solvate.

[0036] In one embodiment, the crystalline solvate of AP1189 is a DMSO solvate. One embodiment of the present disclosure provides a crystalline AP1189 with Cu K values ​​of 16.7±0.2, 19.6±0.2, and 21.0±0.2. α Provided is a crystalline form of AP1189 that is a DMSO solvate, which exhibits at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity. In a further embodiment, the crystalline form of AP1189 DMSO solvate has a Cu K value selected from the group consisting of 4.5±0.2, 13.6±0.2, 14.3±0.2, 15.0±0.2, 15.5±0.2, 17.7±0.2, 18.4±0.2, 20.3±0.2, 20.7±0.2, 22.0±0.2, 22.4±0.2, 22.8±0.2, 23.5±0.2, 23.9±0.2, and 24.2±0.2. αOne embodiment of the present disclosure further comprises Cu K selected from the group consisting of 4.5, 12.3, 13.2, 13.4, 13.6, 14.3, 15.0, 15.5, 16.3, 16.7, 17.0, 17.7, 18.4, 18.8, 19.6, 20.3, 20.7, 21.0, 21.4, 22.0, 22.4, 22.8, 23.5, 23.9, 24.2, 24.8, 25.8, 26.3, 26.6, 27.0, 28.9, 29.7, and 30.1, which further exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radiation. α Provided is a crystalline form of AP1189 DMSO solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. One embodiment of the present disclosure includes: 4.5±0.2, 12.3±0.2, 13.2±0.2, 13.4±0.2, 13.6±0.2, 14.3±0.2, 15.0±0.2, 15.5±0.2, 16.3±0.2, 16.7±0.2, 17.0±0.2, 17.7±0.2, 18.4±0.2, 18.8±0.2, 19.6±0.2, 20.3±0.2, 20.7±0.2. 2, 21.0±0.2, 21.4±0.2, 22.0±0.2, 22.4±0.2, 22.8±0.2, 23.5±0.2, 23.9±0.2, 24.2±0.2, 24.8±0.2, 25.8±0.2, 26.3±0.2, 26.6±0.2, 27.0±0.2, 28.9±0.2, 29.7±0.2, and 30.1±0.2. α The present disclosure provides a crystalline form of AP1189 DMSO solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. One embodiment of the present disclosure provides a Cu K solvate having 2-theta values ​​selected from the group consisting of those listed in Table 3b. α The crystalline form of AP1189 DMSO solvate is provided, which exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. α The crystalline form of AP1189 DMSO solvate is provided, which exhibits an X-ray pattern (2-theta values) in powder diffraction when measured using radioactivity.

[0037] In one embodiment, the crystalline solvate of AP1189 is a DMF solvate. One embodiment of the present disclosure has Cu K values ​​of 23.2±0.2, 23.4±0.2, and 25.1±0.2. α Provided is a crystalline form of AP1189 that is a DMF solvate, exhibiting at least X-ray lines (2-theta values) in a powder diffraction pattern as measured using radioactivity. In a further embodiment, the crystalline form of AP1189 DMF solvate has a Cu K value selected from the group consisting of 12.3±0.2, 12.9±0.2, 14.6±0.2, 15.4±0.2, 16.2±0.2, 16.9±0.2, 17.5±0.2, 17.9±0.2, 20.4±0.2, 21.0±0.2, 21.6±0.2, 22.5±0.2, 22.7±0.2, 22.9±0.2, 24.0±0.2, 25.3±0.2, and 26.7±0.2. α One embodiment of the present disclosure further comprises Cu K selected from the group consisting of 4.6, 11.4, 12.3, 12.9, 13.4, 14.0, 14.6, 15.1, 15.4, 16.2, 16.9, 17.5, 17.8, 17.9, 19.0, 19.5, 19.8, 20.4, 21.0, 21.6, 22.5, 22.7, 22.9, 23.2, 23.4, 24.0, 25.1, 25.3, 25.7, 26.0, 26.7, 26.9, 28.1, 28.6, 28.8, 29.2, 30.1, 30.7, 31.7, 32.3, 33.7, and 34.3. αThe present disclosure provides a crystalline form of AP1189 DMF solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. One embodiment of the present disclosure provides crystalline forms of AP1189 DMF solvate that exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. 0.7±0.2, 22.9±0.2, 23.2±0.2, 23.4±0.2, 24.0±0.2, 25.1±0.2, 25.3±0.2, 25.7±0.2, 26.0±0.2, 26.7±0.2, 26.9±0.2, 28.1±0.2, 28.6±0.2, 28.8±0.2, 29.2±0.2, 30.1±0.2, 30.7±0.2, 31.7±0.2, 32.3±0.2, 33.7±0.2, and 34.3±0.2. α The present disclosure provides a crystalline form of AP1189 DMF solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. One embodiment of the present disclosure provides a Cu K solvate having 2-theta values ​​selected from the group consisting of those listed in Table 3c. α The present invention provides a crystalline form of AP1189 DMF solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. α The crystalline form of AP1189 DMF solvate is provided, which exhibits an X-ray pattern (2-theta values) in powder diffraction when measured using radioactivity.

[0038] In one embodiment, the crystalline solvate of AP1189 is an NMP solvate. One embodiment of the present disclosure has Cu K values ​​of 16.2±0.2, 22.8±0.2, and 23.2±0.2. αA crystalline form of AP1189, an NMP solvate, is provided, which exhibits at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity. In a further embodiment, the crystalline form of AP1189 NMP solvate has a Cu K value selected from the group consisting of 12.3±0.2, 14.0±0.2, 14.5±0.2, 15.5±0.2, 17.2±0.2, 17.3±0.2, 17.9±0.2, 18.5±0.2, 19.0±0.2, 19.3±0.2, 20.1±0.2, 20.4±0.2, 20.8±0.2, 21.6±0.2, 22.5±0.2, 23.6±0.2, 24.8±0.2, 25.1±0.2, 28.6±0.2, 29.0±0.2, 29.6±0.2, and 29.9±0.2. α One embodiment of the present disclosure further exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive rays. Cu K selected from the group consisting of .2, 21.6, 22.3, 22.5, 22.8, 23.2, 23.6, 24.5, 24.8, 25.1, 25.7, 26.1, 26.6, 27.1, 27.8, 28.3, 28.6, 29.0, 29.6, 29.9, 30.6, 32.1, 33.2, and 34.1 αCrystalline forms of AP1189 NMP solvate are provided which exhibit one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity. One embodiment of the present disclosure provides the following: 11.7±0.2, 12.1±0.2, 12.3±0.2, 12.6±0.2, 12.8±0.2, 13.0±0.2, 14.0±0.2, 14.5±0.2, 14.9±0.2, 15.5±0.2, 16.2±0.2, 16.4±0.2, 16.7±0.2, 16.9±0.2, 17.2±0.2, 17.3±0.2, 17.9±0.2, 18.5±0.2, 19.0±0.2, 19.3±0.2, 19.6±0.2, 20.1±0.2, 20.4±0.2, 20.8±0.2, 21 0.2±0.2, 21.6±0.2, 22.3±0.2, 22.5±0.2, 22.8±0.2, 23.2±0.2, 23.6±0.2, 24.5±0.2, 24.8±0.2, 25.1±0.2, 25.7±0.2, 26.1±0.2, 26.6±0.2, 27.1±0.2, 27.8±0.2, 28.3±0.2, 28.6±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.6±0.2, 32.1±0.2, 33.2±0.2, and 34.1±0.2. α The present disclosure provides a crystalline form of AP1189 NMP solvate that exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. One embodiment of the present disclosure provides a Cu K solvate having 2-theta values ​​selected from the group consisting of those listed in Table 3d. α 9. The crystalline form of AP1189 NMP solvate is provided, which exhibits one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive materials. α

[0023] Figure 1 provides a crystalline form of AP1189 NMP solvate that exhibits an X-ray pattern (2-theta values) in powder diffraction when measured using radioactivity.

[0039] One embodiment of the present disclosure provides a polymorph of the AP1189 preferred base.

[0040] Further characterization of crystalline morphology The crystalline forms of AP1189 provided herein may be further characterized by the onset temperature they exhibit as assessed by differential scanning calorimetry.

[0041] One embodiment of the present disclosure provides a crystalline form of AP1189 exhibiting an onset temperature in differential scanning calorimetry between 174 and 188°C. A specific embodiment of the present disclosure provides a crystalline form of AP1189 exhibiting an onset temperature in differential scanning calorimetry of substantially 181°C. In a further embodiment, the onset temperature is determined using a heating rate of 10°C / min. One embodiment of the present disclosure provides a crystalline form of AP1189 exhibiting an onset temperature in differential scanning calorimetry as shown in the Examples herein, specifically Example 4, and / or Figures herein, specifically Figure 10. One embodiment of the present disclosure provides a crystalline form of AP1189 exhibiting a differential scanning calorimetry thermogram according to Figure 10. An embodiment of the present disclosure provides a crystalline form of AP1189 which exhibits an onset temperature in differential scanning calorimetry falling within the interval of 181±7°C, such as 181±6°C, for example 181±5°C, such as 181±4°C, for example 181±3°C, such as 181±2°C, for example 181±1°C.

[0042] One embodiment of the present disclosure provides a crystalline form of AP1189 DMSO solvate that exhibits an onset temperature between 96 and 110°C in differential scanning calorimetry. A specific embodiment of the present disclosure provides a crystalline form of AP1189 DMSO solvate that exhibits an onset temperature of substantially 103°C in differential scanning calorimetry. In a further embodiment, the onset temperature is determined using a heating rate of 10°C / min. One embodiment of the present disclosure provides a crystalline form of AP1189 DMSO solvate that exhibits an onset temperature in differential scanning calorimetry as shown in the Examples herein, specifically Example 3, and / or Figures herein, specifically FIG. 11. One embodiment of the present disclosure provides a crystalline form of AP1189 DMSO solvate that exhibits a differential scanning calorimetry thermogram according to FIG. 11. One embodiment of the present disclosure provides a crystalline form of AP1189 DMSO solvate which exhibits an onset temperature in differential scanning calorimetry falling within the interval of 103±7°C, such as 103±6°C, for example 103±5°C, such as 103±4°C, for example 103±3°C, such as 103±2°C, for example 103±1°C.

[0043] One embodiment of the present disclosure provides a crystalline form of AP1189 NMP solvate that exhibits an onset temperature between 76 and 90°C in differential scanning calorimetry. A specific embodiment of the present disclosure provides a crystalline form of AP1189 NMP solvate that exhibits an onset temperature of substantially 83°C in differential scanning calorimetry. In a further embodiment, the onset temperature is determined using a heating rate of 10°C / min. One embodiment of the present disclosure provides a crystalline form of AP1189 NMP solvate that exhibits an onset temperature in differential scanning calorimetry as shown in the Examples herein, specifically Example 3, and / or Figures herein, specifically FIG. 12. One embodiment of the present disclosure provides a crystalline form of AP1189 NMP solvate that exhibits a differential scanning calorimetry thermogram according to FIG. 12. One embodiment of the present disclosure provides a crystalline form of AP1189 NMP solvate which exhibits an onset temperature in differential scanning calorimetry that falls within the interval of 83±7°C, such as 83±6°C, for example 83±5°C, such as 83±4°C, for example 83±3°C, such as 83±2°C, for example 83±1°C.

[0044] Crystalline morphology characteristics The present disclosure provides a polymorph of AP1189 (AP1189 free base) that has high solubility under acidic and weakly acidic conditions. Specifically, as shown in the Examples herein, the crystalline form of AP1189 free base was found to have higher solubility at pH 1.2 compared to the test compound AP1189 fumarate Pattern 1. AP1189 free base Pattern 1 also showed higher solubility at pH 4.5 compared to the test compound AP1189 fumarate Pattern 1.

[0045] An object of the present disclosure is to provide a form of AP1189 that has high solubility at low pH (acidic pH, acidic conditions; pH about 1.2), as this improves the in vivo uptake of AP1189 after administration to a subject, for example, after oral administration to a subject.

[0046] It is also an object of the present disclosure to provide a form of AP1189 that has high solubility in weakly acidic conditions (pH about 4.5), as this improves the in vivo uptake of AP1189 after administration to a subject, for example, after oral administration to a subject.

[0047] As shown in the Examples herein, the solubility of AP1189-derived compounds, particularly AP1189 salts, is not high under acidic conditions. For example, it was found that both AP1189 tosylate and AP1189 fumarate have low solubility at low pH, e.g., pH 1.2-1.3 or pH 4.5.

[0048] One embodiment of the present disclosure provides a crystalline form of AP1189 having a solubility at pH 1.2 of at least 15 mM, such as at least 20 mM, such as at least 25 mM, such as at least 30 mM, such as at least 35 mM.

[0049] One embodiment of the present disclosure provides a crystalline form of AP1189 having a solubility of at least 10 mM, such as at least 15 mM, such as at least 20 mM at pH 4.5.

[0050] The solubility of a compound can be evaluated by adding an excess amount of the compound to a volume of solvent so that a portion of the compound is not dissolved, then isolating and measuring the amount of undissolved compound.Alternatively, the solubility of a compound can be evaluated by adding an excess amount of the compound to a volume of solvent so that a portion of the compound is not dissolved, then measuring the amount of the compound in solution.The amount of the compound in solution can be measured by any suitable method, for example, HPLC, titration or spectroscopic analysis.

[0051] Methods for preparing crystalline forms of AP1189 Crystalline forms of AP1189 may be prepared as disclosed herein.

[0052] One embodiment of the present disclosure provides a method for producing a crystalline form of AP1189 of Pattern 1, said method comprising: i. mixing AP1189 and a solvent to form a mixture; ii. isolating the crystalline form of AP1189 of Pattern 1 from said mixture; and Includes.

[0053] As used herein, a "mixture" can refer to a solution or slurry of one or more solids in a solvent or mixture of solvents. In one embodiment of the present disclosure, the mixture is a solution in which one or more solutes are substantially completely dissolved. In one embodiment, the mixture is a slurry in which one or more solutes are only partially dissolved, with the remaining portion of the solute(s) being undissolved.

[0054] The Pattern 1 AP1189 free base disclosed herein can be obtained from an AP1189 salt using a so-called "salt decomposition" method to produce the AP1189 free base. One embodiment of the present disclosure provides a method for producing a Pattern 1 crystalline form of AP1189, said method comprising: i. mixing an AP1189 salt and a solvent to form a composition; ii. isolating the Pattern 1 crystalline form of AP1189 from said composition; and Includes.

[0055] As used herein, a "composition" can refer to a solution or slurry of one solid in a solvent or mixture of solvents. In one embodiment of the present disclosure, the composition is a solution in which the solute is substantially completely dissolved. In one embodiment, the composition is a slurry in which the solute is only partially dissolved and the remainder of the solute is undissolved. The composition may further include one or more other agents or reagents that may be dissolved or only partially dissolved. Such other agents include, but are not limited to, surfactants, detergents, acids, bases, sugars, salts, biomolecules, bioactive agents, and other excipients, such as pharmaceutical excipients.

[0056] The present disclosure also relates to non-solid compositions, such as liquid compositions, gel compositions, pastes, creams, or ointments, prepared from the crystalline forms disclosed herein. One embodiment provides a liquid composition, gel composition, paste, cream, or ointment prepared from the crystalline forms disclosed herein. A specific embodiment provides a liquid composition prepared from the crystalline forms disclosed herein and a solvent. In a specific embodiment, the solvent is aqueous. In one embodiment, the present disclosure provides a method for preparing a liquid composition, gel composition, paste, cream, or ointment, the method comprising mixing the crystalline forms disclosed herein with one or more additional agents. A specific embodiment provides a method for preparing a liquid composition, the method comprising mixing the crystalline forms disclosed herein with a solvent. In a further embodiment, the solvent is aqueous.

[0057] The crystalline form of AP1189 of Pattern 1 can be obtained directly from the reaction of one or more precursors to produce AP1189. AP1189 can be produced from the condensation reaction of 3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propanal with aminoguanidine. Thus, one embodiment of the present disclosure provides a method for producing the crystalline form of AP1189 of Pattern 1, said method comprising: i. mixing 3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propanal and aminoguanidine or a salt thereof in a solvent to form a composition; ii. isolating the Pattern 1 crystalline form of AP1189 from said composition; and Includes.

[0058] Any one of the above reagents in step i may be generated in situ from a precursor.

[0059] The crystalline forms of AP1189 of Pattern 1 can be obtained from the salt decomposition of an AP1189 salt using ion exchange. Thus, one embodiment of the present disclosure provides a method for producing the crystalline forms of AP1189 of Pattern 1, said method comprising: i. providing an AP1189 salt comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and a counterion; ii. separating the counterion from 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide using ion exchange; iii. isolating the crystalline form of AP1189 of pattern 1; Includes.

[0060] In one embodiment of the present disclosure, the solvent is a protic solvent or a polar aprotic solvent. In one embodiment, the solvent is selected from the group consisting of 2-methyltetrahydrofuran, 2-propanol, ethanol, water, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, heptane, methanol, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), and toluene. In one embodiment, the solvent is a mixture of two or more solvents, such as a mixture of 2-propanol and water or a mixture of ethanol and water.

[0061] In one embodiment of the present disclosure, the mixture or composition is heated at least once before the isolation step. In one embodiment, the mixture or composition is heated and cooled in cycles before the isolation step. In one embodiment, the mixture or composition is heated and cooled in cycles for up to 72 hours before the isolation step. In one embodiment, the mixture or composition is heated and cooled in cycles for 15 minutes to 72 hours before the isolation step. In one embodiment, one cycle comprises heating the mixture or composition to at least a first threshold temperature, maintaining the temperature above the first threshold temperature for a first duration, then cooling the mixture or composition to a temperature below a second threshold temperature, and maintaining the temperature below the second threshold temperature for a second duration. In one embodiment of the present disclosure, the cycle is performed 1 to 200 times. In one embodiment of the present disclosure, the first threshold temperature is 30°C, e.g., 35°C, e.g., 40°C, e.g., 45°C, e.g., 50°C, e.g., 55°C, e.g., 60°C, e.g., 65°C, e.g., 70°C, e.g., 75°C, e.g., 80°C. In one embodiment of the present disclosure, the second threshold temperature is 30°C, e.g., 25°C, e.g., 20°C, e.g., 15°C, e.g., 10°C, e.g., 7°C, e.g., 5°C. In one embodiment of the present disclosure, the first and / or second duration is 1 to 2 minutes, e.g., 2 to 5 minutes, e.g., 5 to 10 minutes, e.g., 10 to 20 minutes, e.g., 20 to 30 minutes, e.g., 30 to 40 minutes, e.g., 40 to 50 minutes, e.g., 50 to 60 minutes, e.g., 1 to 1.5 hours, e.g., 1.5 to 2 hours, e.g., 2 to 3 hours, e.g., 3 to 4 hours, e.g., 4 to 5 hours, e.g., 5 to 6 hours, e.g., 6 to 7 hours, e.g., 7 to 8 hours. In one embodiment, the first duration and the second duration are the same. In one embodiment, the first duration and the second duration are different. In one embodiment, the first duration is different or the same for each cycle. In one embodiment, the second duration is different or the same for each cycle.

[0062] In one embodiment, the heating is to about 40°C.

[0063] In one embodiment, the cooling is to about 20°C.

[0064] In one embodiment, the method further comprises adding an anti-solvent to the mixture or composition prior to the isolating step. In one embodiment, the anti-solvent is a non-polar aprotic solvent. In one embodiment, the anti-solvent is selected from the group consisting of tert-butyl methyl ether, THF, and acetone, and mixtures comprising tert-butyl methyl ether, THF, or acetone. In one embodiment of the present disclosure, the anti-solvent is water. In one embodiment, the anti-solvent is a mixture of two or more solvents.

[0065] Isolation of the crystals may be carried out using any suitable means. In one embodiment of the present disclosure, isolation is carried out using filtration, centrifugation, and / or evaporation of one or more solvents. In one embodiment, a slow evaporation method is utilized. In one embodiment, a fast evaporation method is utilized. In one embodiment, evaporation is carried out using spray drying. In one embodiment, evaporation is carried out using fluidized bed drying, freeze drying, vacuum drying, tumble drying, rotary evaporation, and / or thin film evaporation. In one embodiment, drying is carried out using conductive (contact) dryers, including tray dryers, rotary cone dryers, tumble dryers, and paddle dryers. In a further embodiment, drying is carried out using a carrier gas.

[0066] One embodiment provides a method disclosed herein, the method further comprising the step of seeding with Pattern 1 crystalline form of AP1189.

[0067] One embodiment provides a crystalline form of AP1189 of Pattern 1 produced by the methods disclosed herein.

[0068] One embodiment provides a method for preparing an amorphous form of AP1189, the method comprising converting a crystalline form of AP1189 of Pattern 1 into the amorphous form of AP1189.

[0069] Pharmaceutical composition (crystalline form) One embodiment of the present disclosure provides a pharmaceutical composition comprising the crystalline form of AP1189 free base disclosed herein.

[0070] One embodiment of the present disclosure provides a pharmaceutical composition comprising a crystalline form of AP1189 free base disclosed herein and a pharmaceutically acceptable excipient.

[0071] In some embodiments, there is provided an oral formulation, pharmaceutical composition, or unit dosage form comprising a crystalline form of AP1189 free base disclosed herein.

[0072] One embodiment provides a pharmaceutical composition as disclosed herein, wherein the pharmaceutical composition is formulated for oral administration, and such a composition may be in the form of a tablet or capsule.

[0073] One embodiment of the present disclosure provides a method for preparing a pharmaceutical composition comprising mixing a crystalline form of AP1189 free base with a pharmaceutically acceptable excipient.

[0074] One embodiment of the present disclosure provides a crystalline form of AP1189 free base or a pharmaceutical composition disclosed herein for use in medicine.One embodiment of the present disclosure provides a crystalline form of AP1189 free base or a pharmaceutical composition disclosed herein for use in treating kidney diseases such as proteinuria, cardiovascular diseases, arthritic diseases, or viral infections.

[0075] One embodiment of the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, said method comprising administering to the subject in need thereof a crystalline form of AP1189 free base, or a pharmaceutical composition disclosed herein. In a further embodiment, the disease or disorder is selected from the list consisting of a renal disease such as proteinuria, a cardiovascular disease, an arthritic disease, or a viral infection.

[0076] One embodiment of the present disclosure provides the use of a crystalline form of AP1189 free base, or a pharmaceutical composition disclosed herein, for the manufacture of a medicament for treating a disease or disorder.

[0077] Pharmaceutical Composition (Gastric Release) It is an aspect of the present disclosure to provide pharmaceutical compositions comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide (AP1189 free base), including its tautomers and stereoisomers, that have high solubility at low pH.

[0078] Reference to a pharmaceutical composition comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is meant to encompass any form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including crystalline and amorphous forms.

[0079] Some embodiments of the present disclosure provide pharmaceutical compositions comprising a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0080] Some embodiments of the present disclosure provide pharmaceutical compositions comprising an amorphous form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0081] Some embodiments of the present disclosure provide a unit dosage form of a pharmaceutical composition comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0082] Some embodiments of the present disclosure provide oral formulations comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0083] Some embodiments of the present disclosure provide oral formulations comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and at least one pharmaceutically acceptable excipient.

[0084] Some embodiments of the present disclosure provide an oral formulation comprising AP1189 (free base), wherein the AP1189 has a solubility of at least 15 mM, such as at least 20 mM, for example at least 25 mM, for example at least 30 mM, for example at least 35 mM at pH 1.2, for example at about pH 1.2.

[0085] Some embodiments of the present disclosure provide oral formulations comprising AP1189 (free base), wherein said AP1189 has a solubility of at least 10 mM, such as at least 15 nM, such as at least 20 mM, at pH 4.5, such as at about pH 4.5.

[0086] In some embodiments, the oral formulation delivers the AP1189 free base to the gastric compartment (or stomach). In some embodiments, the oral formulation delivers the AP1189 free base primarily or preferentially to the gastric compartment (or stomach).

[0087] In some embodiments, the oral formulation releases the AP1189 free base in the stomach compartment. In some embodiments, the oral formulation releases the AP1189 free base primarily or preferentially in the stomach compartment.

[0088] In some embodiments, the oral formulation releases the AP1189 free base in the stomach compartment by immediate release, by delayed release, by burst release, or by any means that releases the AP1189 free base primarily or preferentially in the stomach compartment.

[0089] In some embodiments, the oral formulation delivers and / or releases about 65% to about 80% or more of the AP1189 free base in the gastric compartment.

[0090] In some embodiments, the oral formulation delivers and / or releases about 65% or more of the AP1189 free base, such as about 70% or more, for example about 75% or more, such as about 80% or more, for example about 85% or more, such as about 90% or more, for example about 95% or more of the AP1189 free base in the gastric compartment.

[0091] In some embodiments, the oral formulation provides immediate release of the AP1189 free base into the gastric compartment.

[0092] In some embodiments, the oral formulation releases the AP1189 free base into the stomach compartment for gastric absorption of the AP1189.

[0093] In some embodiments, the oral formulation releases the AP1189 free base into the stomach compartment for absorption of the AP1189 on the gastric mucus layer.

[0094] In some embodiments, the oral formulation is designed for gastric delivery.

[0095] In some embodiments, the oral formulation is designed for gastric release.

[0096] In some embodiments, the oral formulation is designed for gastric absorption.

[0097] In some embodiments, the oral dosage form is a solid oral dosage form.

[0098] It is an aspect of the present disclosure to provide solid oral formulations comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including its tautomers and stereoisomers. Some embodiments of the present disclosure provide solid oral formulations comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0099] Some embodiments of the present disclosure provide a solid oral formulation comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and at least one pharmaceutically acceptable excipient.

[0100] It is an aspect of the present disclosure to provide solid oral dosage forms comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including its tautomers and stereoisomers. Some embodiments of the present disclosure provide solid oral dosage forms comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

[0101] Some embodiments of the present disclosure provide a solid oral dosage form comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and at least one pharmaceutically acceptable excipient.

[0102] In some embodiments, the oral formulation is a tablet. In some embodiments, the solid oral formulation is a tablet. In some embodiments, the solid oral dosage form is a tablet.

[0103] Some embodiments of the present disclosure provide a tablet comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and at least one pharmaceutically acceptable excipient.

[0104] In some embodiments, an oral formulation is provided comprising AP1189 free base, wherein greater than about 65% to about 80% of said AP1189 free base dissolves in the solution of the gastric compartment.

[0105] In some embodiments, a solid oral dosage form or tablet is provided comprising AP1189 free base, wherein greater than about 65% to about 80% of said AP1189 free base dissolves in the solution of the gastric compartment.

[0106] In some embodiments there is provided a solid oral formulation, solid oral dosage form or tablet comprising AP1189 free base, wherein about 65% or more, such as about 70% or more, for example about 75% or more, such as about 80% or more, for example about 85% or more, such as about 90% or more, for example about 95% or more of said AP1189 free base dissolves in solution in the stomach compartment.

[0107] In some embodiments, the oral formulation is a delayed-release tablet comprising AP1189 free base that is targeted for release in the gastric compartment.

[0108] In some embodiments, the solid oral formulation is a delayed-release solid oral formulation comprising AP1189 free base that is targeted for release in the gastric compartment.

[0109] In some embodiments, the oral formulation is a gastroretentive delayed-release formulation. In some embodiments, the oral formulation is a gastroretentive tablet. In some embodiments, the gastroretentive tablet is a gastroretentive bilayer tablet formulation. In some embodiments, the gastroretentive bilayer tablet formulation is a gastric swelling system (GSS), such as a GSS consisting of a swelling layer and a drug-releasing layer.

[0110] It is an aspect of the present disclosure to provide a gastroretentive delayed release solid oral formulation, solid oral dosage form, or tablet comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including its tautomers and stereoisomers.

[0111] In some embodiments, the oral formulation is an immediate release oral formulation.

[0112] In some embodiments, the solid oral dosage form is an immediate release solid oral dosage form. In some embodiments, the solid oral dosage form is an immediate release tablet.

[0113] In some embodiments, the solid oral formulation is an immediate release tablet comprising AP1189 free base targeted for release in the gastric compartment.

[0114] It is an aspect of the present disclosure to provide immediate release solid oral formulations, such as immediate release solid oral dosage forms, such as immediate release tablets, comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including tautomers and stereoisomers thereof.

[0115] In some embodiments, there is provided an immediate release solid oral formulation, such as an immediate release solid oral dosage form, such as an immediate release tablet, comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, including tautomers and stereoisomers thereof, and at least one pharmaceutically acceptable excipient.

[0116] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP1189 free base is provided, wherein about 65% to about 80% or more of the AP1189 free base dissolves in solution in about 5 minutes.

[0117] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP118 free base is provided, wherein about 65 to about 80% or more of the AP118 free base goes into solution in about 5 minutes at a pH of about 1 to 3, e.g., about pH 0.5 to 3.5; for example, about pH 0.5 to 1, such as about pH 1 to 1.5, for example, about pH 1.5 to 2, such as about pH 2 to 2.5, for example, about pH 2.5 to 3, for example, about pH 3 to 3.5.

[0118] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP1189 free base is provided, wherein about 65 to about 80% or more of the AP1189 free base dissolves in a solution having a pH of about 1.2 in about 5 minutes.

[0119] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP1189 free base is provided, wherein about 80% or more of the AP1189 free base dissolves in solution in about 10 minutes, e.g., about 15 minutes.

[0120] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP118 free base, wherein about 80% or more of the AP118 free base goes into solution in about 10 minutes at a pH of about 1 to 3, e.g., about pH 0.5 to 3.5; such as about pH 0.5 to 1, for example, about pH 1 to 1.5, for example, about pH 1.5 to 2, such as about pH 2 to 2.5, for example, about pH 2.5 to 3, for example, about pH 3 to 3.5.

[0121] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate-release solid oral formulation, comprising AP1189 free base is provided, wherein about 80% or more of the AP1189 free base dissolves in solution at a pH of about 1.2 in about 10 minutes, e.g., at a pH of about 1.2 in about 15 minutes.

[0122] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 free base, wherein the disintegration time of the solid oral formulation is between ½ minute and 10 minutes, such as between ½ minute and 1 minute, for example, between 1 and 2 minutes, for example, between 2 and 3 minutes, such as between 3 and 4 minutes, for example, between 4 and 5 minutes, for example, between 5 and 6 minutes, for example, between 6 and 7 minutes, for example, between 7 and 8 minutes, for example, between 8 and 9 minutes, for example, between 9 and 10 minutes.

[0123] In some embodiments, the solid oral dosage form comprises AP1189 free base at a dose of about 25 mg to about 650 mg, e.g., about 25 mg, for example, about 50 mg, for example, about 100 mg, for example, about 150 mg, for example, about 200 mg, for example, about 250 mg, for example, about 300 mg, for example, about 350 mg, for example, about 400 mg, for example, about 450 mg, for example, about 500 mg, for example, about 550 mg, for example, about 600 mg, for example, about 650 mg, of AP1189 free base per tablet.

[0124] In some embodiments, the solid oral dosage form comprises AP1189 free base at a dosage of about 25 mg per tablet, such as about 50 mg, for example about 100 mg, for example about 150 mg, for example about 200 mg per tablet.

[0125] The solid oral dosage forms of the present disclosure can be formulated by any means known to one of skill in the art to provide release of the AP1189 free base in the gastric compartment.

[0126] Dosage According to the present disclosure, oral formulations containing the compounds of the present disclosure are administered to individuals in need of treatment in pharmaceutically effective doses. A therapeutically effective amount of a compound is an amount sufficient to cure, prevent, reduce the risk of, alleviate, or partially arrest the clinical symptoms of a given disease and its complications. The amount effective for a particular therapeutic purpose will depend on the severity and type of disorder, as well as the weight and general condition of the subject. The compound may be administered once or several times daily, for example, 1 to 8 times per day, for example, 1 to 6 times per day, for example, 1 to 5 times per day, for example, 1 to 4 times per day, for example, 1 to 3 times per day, for example, 1 to 2 times per day, for example, 2 to 4 times per day, for example, 2 to 3 times per day. Alternatively, the compound may be administered less than once per day, for example, once per day, once every two days, for example, once every three days, once every four days, for example, once every five days, once every six days, for example, once every week.

[0127] In some embodiments, oral formulations comprising compounds of the present disclosure are administered in therapeutically effective amounts, for example, 1 mg to 1000 mg of AP1189 free base per day.

[0128] In some embodiments, AP1189 free base is administered in an amount of 1 mg to 1000 mg per day, e.g., 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 20 to 25 mg, 25 to 50 mg, 50 to 75 mg, 75 to 100 mg, 100 to 125 mg, 125 to 150 mg, 150 to 175 mg, 175 to 200 mg, 200 to 250 mg, 250 to 300 mg, 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, 450 to 500 mg, 500 to 600 mg, 600 to 700 mg, 700 to 800 mg, 800 to 900 mg, or 900 to 1000 mg.

[0129] In some embodiments, "per day" means that the dose is given in a single dose or in multiple doses per day, such as once daily (QD), twice daily (BID), and / or three times daily (TID).

[0130] In some embodiments, the oral formulation of the present disclosure is administered once daily.

[0131] In some embodiments, AP1189 free base is administered in an amount of 1 mg to 1000 mg per dose, e.g., 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 15 to 20 mg, 20 to 25 mg, 25 to 50 mg, 50 to 75 mg, 75 to 100 mg, 100 to 125 mg, 125 to 150 mg, 150 to 175 mg, 175 to 200 mg, 200 to 250 mg, 250 to 300 mg, 300 to 350 mg, 350 to 400 mg, 400 to 450 mg, 450 to 500 mg, 500 to 600 mg, 600 to 700 mg, 700 to 800 mg, 800 to 900 mg, or 900 to 1000 mg of AP1189.

[0132] In some embodiments, AP1189 free base is administered in an amount of 25 mg once daily, 50 mg once daily, 100 mg once daily, 200 mg once daily, 300 mg once daily, 400 mg once daily, 500 mg once daily, 600 mg once daily, 700 mg once daily, 800 mg once daily, 900 mg once daily, or 1000 mg once daily.

[0133] In some embodiments, AP1189 free base is administered in an amount of 50 mg once daily, 50 mg twice daily (BID), or 50 mg three times daily (TID).

[0134] In some embodiments, AP1189 free base is administered in an amount of 100 mg once daily, 100 mg twice daily (BID), or 100 mg three times daily (TID).

[0135] In some embodiments, AP1189 free base is administered in an amount of 200 mg once daily, 200 mg twice daily (BID), or 200 mg three times daily (TID).

[0136] In some embodiments, AP1189 free base is administered in an amount of 400 mg once daily, 400 mg twice daily (BID), or 200 mg three times daily (TID).

[0137] In some embodiments, the daily dose of AP1189 free base is divided into multiple dosage forms and / or administrations.

[0138] In another embodiment, AP1189 free base is administered in an amount of 0.1 to 0.5 mg / kg body weight, such as 0.5 mg to 1 mg / kg body weight, for example, 1 to 2 mg / kg body weight, for example, 2 to 3 mg / kg body weight, for example, 3 to 5 mg / kg body weight, for example, 5 to 10 mg / kg body weight, for example, 10 to 15 mg / kg body weight, for example, 15 to 20 mg / kg body weight, for example, 20 to 25 mg / kg body weight, for example, 25 to 30 mg / kg body weight.

[0139] Medical uses One aspect of the present disclosure is to provide a pharmaceutical formulation, e.g., an oral formulation, comprising AP1189 free base, such as the crystalline forms of AP1189 free base disclosed herein, for use in treating a disease or disorder.

[0140] In some embodiments, the disease or disorder is selected from the group consisting of a kidney disease, an arthritic disease, a viral disease or disorder, and a cardiovascular disease and / or atherosclerosis.

[0141] kidney disease One aspect of the present disclosure is to provide a pharmaceutical composition according to the present disclosure for use in treating or preventing kidney disease.

[0142] Also disclosed are methods of treating or preventing kidney disease in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0143] Also disclosed is the use of a pharmaceutical composition according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of kidney disease.

[0144] In some embodiments, the kidney disease is manifested by proteinuria. In some embodiments, the kidney disease is proteinuric kidney disease.

[0145] In some embodiments, the kidney disease is a glomerular disease.

[0146] In some embodiments, the kidney disease is nephrotic syndrome (glomerular nephropathy).

[0147] In some embodiments, the kidney disease is primary nephrotic syndrome (primary glomerular nephropathy).

[0148] In some embodiments, the primary nephrotic syndrome is membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)).

[0149] In some embodiments, the primary nephrotic syndrome is focal segmental glomerulosclerosis (FSGS).

[0150] In some embodiments, the primary nephrotic syndrome is membranoproliferative glomerulonephritis (MPGN).

[0151] In some embodiments, the membranoproliferative glomerulonephritis (MPGN) is selected from type 1 MPGN and type 2 MPGN.

[0152] In some embodiments, the primary nephrotic syndrome is rapidly progressive glomerulonephritis (RPGN) (crescentic GN).

[0153] In some embodiments, the primary nephrotic syndrome is minimal change disease (MCD).

[0154] In some embodiments, the kidney disease is secondary nephrotic syndrome (secondary glomerular nephropathy).

[0155] In some embodiments, the secondary nephrotic syndrome is caused by an underlying autoimmune disease, an underlying cancer disease, an underlying genetic disease, or an underlying disease selected from the group consisting of systemic lupus erythematosus (SLE), diabetic nephropathy, sarcoidosis, Sjogren's syndrome, amyloidosis, multiple myeloma, vasculitis, cancer, and a genetic disease (e.g., congenital nephrotic syndrome).

[0156] In some embodiments, the secondary nephrotic syndrome is caused by diabetic nephropathy, an infection such as, for example, a urinary tract infection, such as an infection selected from the group consisting of HIV, syphilis, hepatitis, such as hepatitis A, B, and C, post-streptococcal infection, bladder schistosomiasis, and Ebola. In some embodiments, the secondary nephrotic syndrome is drug-induced.

[0157] In some embodiments, the kidney disease is an inflammatory kidney disease.

[0158] In some embodiments, the kidney disease is glomerulonephritis (GN), hi some embodiments, the glomerulonephritis is selected from the group consisting of IgA nephropathy (Berger's disease), IgM nephropathy, post-infectious glomerulonephritis, and thin basement membrane disease.

[0159] In some embodiments, the kidney disease is idiopathic membranous nephropathy (iMN).

[0160] In some embodiments, there is provided a pharmaceutical composition according to the present disclosure for use in treating or preventing idiopathic membranous nephropathy (iMN).

[0161] Arthritic diseases One aspect of the present disclosure is to provide a pharmaceutical composition according to the present disclosure for use in treating or preventing arthritic diseases.

[0162] Also disclosed is a method of treating or preventing an arthritic disease in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0163] Also disclosed is the use of a pharmaceutical composition according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of arthritic diseases.

[0164] In one embodiment, the arthritic disease is an autoimmune and / or inflammatory disease that presents with inflammation of the joints.

[0165] In one embodiment, the arthritic disease is selected from the group consisting of inflammatory arthritis, degenerative arthritis, metabolic arthritis, reactive arthritis and infectious arthritis.

[0166] In one embodiment, the arthritic disease is inflammatory arthritis.

[0167] In one embodiment, the inflammatory arthritis is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis.

[0168] In one embodiment, the inflammatory arthritis is rheumatoid arthritis (RA).

[0169] In one embodiment, the rheumatoid arthritis is severely active RA (CDAI>22). In one embodiment, the rheumatoid arthritis is RA with a CDAI>22.

[0170] In one embodiment, the rheumatoid arthritis is RA with a DAS28 score greater than 5.1.

[0171] In one embodiment, the rheumatoid arthritis is juvenile rheumatoid arthritis (JRA).

[0172] In one embodiment, the degenerative arthritis is osteoarthritis.

[0173] In one embodiment, the metabolic arthritis is gouty arthritis.

[0174] In one embodiment, the reactive arthritis and / or infectious arthritis is arthritis associated with infection with one or more of Hepatitis C, Chlamydia, Gonorrhea, Salmonella or Shigella.

[0175] In one embodiment, the arthritic disease is arthritis as part of a systemic inflammatory disease.

[0176] In one embodiment, the systemic inflammatory disease, for example, arthritis as part of an inflammatory disease selected from the group consisting of systemic lupus erythematosus, mixed connective tissue disease, Still's disease, and polymyalgia rheumatica.

[0177] In some embodiments, there is provided a pharmaceutical composition according to the present disclosure for use in treating or preventing rheumatoid arthritis.

[0178] Viral diseases or disorders One aspect of the present disclosure is to provide a pharmaceutical composition according to the present disclosure for use in treating or preventing a viral disease or disorder.

[0179] Also disclosed are methods of treating or preventing a viral disease or disorder in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0180] Also disclosed is the use of a pharmaceutical composition according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of a viral disease or disorder.

[0181] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder.

[0182] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder associated with inflammation, eg, hyperinflammation.

[0183] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder involving inflammation, e.g., hyperinflammation, in one or more organs, which may also be referred to as local inflammation.

[0184] In some embodiments, the one or more organs are selected from the group consisting of lungs, respiratory tract, kidneys, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscle, bone marrow, skin, skeleton, bladder, reproductive organs including fallopian tubes, eyes, ears, vascular system, digestive tract including small intestine, colon, rectum, anal canal, and prostate.

[0185] In some embodiments, the viral disease or disorder is an inflammatory viral disease or disorder.

[0186] In some embodiments, the viral disease or disorder is a viral respiratory infection, such as a viral lower respiratory tract infection.

[0187] In some embodiments, the viral disease or disorder is a viral respiratory disease or disorder.

[0188] In some embodiments, the viral disease or disorder is a pulmonary viral disease or disorder.

[0189] In some embodiments, the viral disease or disorder is a viral disease or disorder involving inflammation in the respiratory system, eg, in the lungs and / or airways.

[0190] In some embodiments, the viral disease or disorder is a viral disease or disorder accompanied by one or more respiratory symptoms, hi one embodiment, the one or more respiratory symptoms are selected from the group consisting of cough, dry cough, dyspnea, impaired oxygenation, respiratory disease, respiratory insufficiency, respiratory failure, respiratory syndrome, and acute respiratory disease (ARD).

[0191] In some embodiments, the viral disease or disorder is severe, manifested by difficulty breathing, increased respiratory rate, decreased blood oxygen saturation, and / or pulmonary infiltrates.

[0192] In some embodiments, the viral disease or disorder is a critical illness manifesting as respiratory failure, septic shock, and / or multiple organ dysfunction (MOD) or multiple organ failure (MOF).

[0193] In some embodiments, the viral disease or disorder is viral pneumonia.

[0194] In some embodiments, the viral disease or disorder is viral bronchiolitis.

[0195] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with respiratory failure.

[0196] In some embodiments, the viral disease or disorder is acute respiratory distress syndrome (ARDS).

[0197] In some embodiments, the viral disease or disorder is viral acute respiratory distress syndrome (ARDS).

[0198] In some embodiments, the viral disease or disorder is symptomatic COVID-19 with acute respiratory distress syndrome (ARDS).

[0199] In some embodiments, there is provided an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in treating or preventing ARDS, e.g., viral ARDS.

[0200] In some embodiments, the viral disease or disorder is systemic inflammatory distress syndrome (SIDS) and / or viral diseases and disorders associated with sepsis.

[0201] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with pulmonary dysfunction.

[0202] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with cytokine release syndrome (CRS) and / or cytokine storm (hypercytokinemia).

[0203] In some embodiments, the viral disease or disorder is caused by a viral infection selected from the group consisting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often referred to as COVID-19 virus; SARS-CoV, MERS-CoV, dengue virus, and influenza virus (including types A, B, and C).

[0204] cardiovascular disease and / or atherosclerosis One aspect of the present disclosure is to provide a pharmaceutical composition according to the present disclosure for use in the treatment or prevention of cardiovascular disease or atherosclerosis.

[0205] Also disclosed are methods of treating or preventing cardiovascular disease or atherosclerosis in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0206] Also disclosed is the use of a pharmaceutical composition according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of cardiovascular disease and / or atherosclerosis.

[0207] In some embodiments, the cardiovascular disease is selected from the group consisting of coronary artery disease (CAD), such as angina pectoris and myocardial infarction (commonly known as a heart attack); stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, cardiac rhythm disorders, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, vascular disease, thromboembolic disease, and venous thrombosis.

[0208] In some embodiments, the cardiovascular disease is atherosclerotic cardiovascular disease.

[0209] In some embodiments, the atherosclerotic cardiovascular disease is selected from the group consisting of coronary artery disease, stroke (cerebrovascular disease), and peripheral artery disease.

[0210] In some embodiments, the cardiovascular disease is vascular inflammation.

[0211] systemic inflammatory diseases One aspect of the present disclosure is to provide a pharmaceutical composition according to the present disclosure for use in treating or preventing a systemic inflammatory disease.

[0212] Also disclosed is a method of treating or preventing a systemic inflammatory disease in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0213] Also disclosed is the use of a pharmaceutical composition according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of systemic inflammatory disease.

[0214] Systemic diseases that can affect the nervous system include a variety of diseases with presumed inflammatory and autoimmune pathomechanisms, such as Behçet's disease, sarcoidosis, systemic lupus erythematosus, juvenile idiopathic arthritis, scleroderma, and Sjögren's syndrome. This group of diseases includes systemic inflammatory diseases with genetically defined dysregulation of the innate immune system, as well as systemic autoimmune diseases characterized by alterations in adaptive immunity, such as autoantibodies and autoreactive T cells.

[0215] In some embodiments, the systemic inflammatory disease is an autoimmune disease.

[0216] In some embodiments, the systemic inflammatory disease is selected from the group consisting of Behcet's disease, sarcoidosis, systemic lupus erythematosus, juvenile idiopathic arthritis, scleroderma, Sjogren's syndrome, myositis, including dermatomyositis and polymyositis, vasculitis, giant cell arteritis, ankylosing spondylitis, polymyalgic rheumatoid arthritis, and psoriatic arthritis. [Example]

[0217] Example 1: AP1189 Free Base Preparation Method 1 A salt digestion for the preparation of the free base from the acetate starting material was carried out using extraction into ethyl acetate as follows: 35 mL of ethyl acetate and 35 mL of 1 M sodium bicarbonate were added to approximately 500 mg of AP1189 acetate. The mixture was transferred to a separatory funnel to remove the aqueous layer, and 15 mL of water was added to wash the organic layer. The phases were separated, sodium sulfate was added to the organic phase, and after allowing to stand for approximately 10 minutes, the slurry was filtered through a Buchner funnel using grade 1 filter paper. The solution was transferred to a round-bottom flask, and the solvent was removed by rotary evaporation. 15 mL of DCM was added to the prepared free base to dissolve it, and the solution was evaporated at ambient temperature and pressure for approximately 18 hours. The solid was dried under vacuum for approximately 1 hour. The solid was analyzed by XRPD, HPLC (purity), and KF to determine water content.

[0218] Results of Method 1 Figures 5 and 6 show the XRPD analysis of the material received, designated as Free Base Pattern 1. KF analysis measured 0.3% w / w water for Free Base Pattern 1.

[0219] Method 2 A 2 g salt digestion was performed as follows: 140 mL of ethyl acetate and 140 mL of 1 M sodium bicarbonate were added to approximately 2 mg of AP1189 acetate salt. The mixture was transferred to a separatory funnel, and the organic layer was washed with 50 mL of water. The organic phase was dried over sodium sulfate for approximately 10 minutes, and the solids were removed using grade 1 filter paper. The solvent was removed by rotary evaporation. The residue was dissolved in 60 mL of DCM, and the solvent was evaporated at ambient temperature and pressure for approximately 17 hours. The solid was then dried under vacuum at ambient temperature for approximately 1 hour. The solid was then analyzed by XRPD.

[0220] Results of Method 2 Figure 6 shows the XRPD analysis of the material obtained, which corresponded to the free base pattern 1.

[0221] Method 3 Using a method similar to Method 2 above, AP1189 free base was prepared starting with 2.8 g of AP1189 acetate using 196 mL of ethyl acetate and 196 mL of 1 M sodium bicarbonate, washing with 84 mL of water, and recrystallization in 70 mL of DMC.

[0222] Results of Method 3 Figure 6 shows the XRPD analysis of the material obtained, which corresponded to the free base pattern 1.

[0223] Example 2: Polymorphism investigation for AP1189 free base method An initial polymorphic investigation was performed to identify any possible alternative forms. Approximately 7 mg of free base Pattern 1, obtained from DCM evaporation, was added in 50 μL aliquots of the appropriate solvent system. If solids remained in the vial, the mixture was gently heated to approximately 40°C to promote dissolution. Solvent addition was continued until the material was completely dissolved or until the appropriate solvent system was added (<10 mg / mL). The anti-solvent (t-BME) was added dropwise (with stirring) at ambient temperature. The volume of t-BME used is listed in Table 1. If the solution was already present as a slurry before the anti-solvent addition, no anti-solvent was added. The experiment was temperature cycled between ambient and 40°C in 4-hour cycles with stirring for approximately 24 hours. The slurry was separated by centrifugation, and the solution was allowed to evaporate at ambient temperature. XRPD analysis of the resulting solid was performed.

[0224] result Table 1 shows the volumes of antisolvent used in the additions. TIFF2026501257000002.tif87160

[0225] Table 2 shows the results of the polymorphism survey. TIFF2026501257000003.tif211165

[0226] AP1189 free base pattern 3 DMSO solvate was prepared as follows: dimethyl sulfoxide (25 μL) was added to approximately 100 mg of amorphous free base in a 20 mL scintillation vial equipped with a magnetic stir bar. The resulting slurry was thermally cycled between 40° C. and 20° C. for 3 days (ramp rate: 0.1° C. / min with 1 hour isothermal holds at 40° C. and 20° C.). The solid was analyzed by XRPD.

[0227] AP1189 free base pattern 4 DMF solvate was prepared as follows: Dimethylformamide (25 μL) was added to approximately 100 mg of amorphous free base in a 20 mL scintillation vial equipped with a magnetic stir bar. The resulting slurry was thermally cycled between 40° C. and 20° C. for 3 days (ramp rate: 0.1° C. / min with 1 hour isothermal holds at 40° C. and 20° C.). The solid was analyzed by XRPD.

[0228] AP1189 free base pattern 5 NMP solvate was prepared as follows: N-methylpyrrolidone (25 μL) was added to approximately 100 mg of amorphous free base in a 20 mL scintillation vial equipped with a magnetic stir bar. The resulting slurry was thermally cycled between 40° C. and 20° C. for 3 days (ramp rate: 0.1° C. / min with 1 hour isothermal holds at 40° C. and 20° C.). The solid was analyzed by XRPD.

[0229] Example 3: X-ray powder diffraction method XRPD analysis was performed on a PANalytical X'pert pro equipped with a PIXcel detector (128 channels) scanning the sample between 3 and 35° 2θ. The material was gently ground (if necessary) to release aggregates and loaded into a multiwell plate with a Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in the diffractometer and analyzed using Cu K radiation (α1 λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) operating in transmission mode (step width 0.0130° 2θ, step time 18.87 s) using a generator setting of 40 kV / 40 mA.

[0230] result The XRPD diffractogram of AP1189 free base 1 crystallized from DCM is shown in Figure 5. The corresponding XRPD diffractogram peak list for free base pattern 1 is shown in Table 3a. TIFF2026501257000004.tif131169TIFF2026501257000005.tif210160

[0231] The XRPD diffractogram of AP1189 free base 3 DMSO solvate is shown in Figure 7. The corresponding XRPD diffractogram peak list for free base pattern 3 is shown in Table 3b. TIFF2026501257000006.tif243160TIFF2026501257000007.tif11160

[0232] The XRPD diffractogram of AP1189 free base 4 DMF solvate is shown in Figure 8. The corresponding XRPD diffractogram peak list for free base pattern 4 is shown in Table 3c. TIFF2026501257000008.tif212160TIFF2026501257000009.tif108160

[0233] The XRPD diffractogram of AP1189 free base 5 NMP solvate is shown in Figure 9. The corresponding XRPD diffractogram peak list for free base pattern 5 is shown in Table 3d. TIFF2026501257000010.tif114159TIFF2026501257000011.tif222163

[0234] The XRPD diffractogram for AP1189 tosylate salt pattern 1 crystallized from methanol is shown in Figure 1. The corresponding XRPD diffractogram peak list for tosylate salt pattern 1 is shown in Table 4. TIFF2026501257000012.tif210158TIFF2026501257000013.tif148164

[0235] The XRPD diffractogram for AP1189 fumarate salt pattern 1 crystallized from isopropyl alcohol:water 90:10 v / v is shown in Figure 2. The corresponding XRPD diffractogram peak list for fumarate salt pattern 1 from isopropyl alcohol:water 90:10 v / v is shown in Table 5. TIFF2026501257000014.tif51161TIFF2026501257000015.tif238162TIFF2026501257000016.tif99162

[0236] A sample of AP1189 free base lyophilized from a 1,4-dioxane solution was amorphous as evidenced by the absence of any peaks in the XRPD spectrum.

[0237] conclusion X-ray powder diffraction data was collected for a selection of various AP1189 salts and AP1189 free base.

[0238] Example 4: Thermogravimetry / Differential Scanning Calorimetry and Differential Scanning Calorimetry method For TGA / DSC evaluation, approximately 5-10 mg of material was added to a pre-tared open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC. The sample was then heated from 30 to 400 °C at a rate of 10 °C / min, during which the change in sample weight was recorded along with the heat flow response (DSC). A 200 cm³ sample purge gas was used. 3 Nitrogen was used at a flow rate of 1 / min.

[0239] For DSC evaluation, approximately 1-5 mg of material was weighed into an aluminum DSC pan and sealed, but not hermetically, with an aluminum lid. The sample pan was then loaded into a TA Instruments Discovery DSC 2500 differential scanning calorimeter equipped with an RC90 condenser. The sample and reference were heated to 230 or 240 °C at a scan rate of 10 °C / min, and the resulting heat flow response was monitored. The sample was recooled to 20 °C and then reheated again to 230 or 240 °C, all at 10 °C / min. 50 cm was used as a purge gas. 3 Nitrogen was used at a flow rate of 1 / min.

[0240] result The results of the TGA / DSC evaluation and the DSC evaluation are shown in Table 6. TIFF2026501257000017.tif78165

[0241] Example 5: Nuclear Magnetic Resonance method NMR experiments were performed on a Bruker AVIIHD spectrometer equipped with a DCH or PRODIGY cryoprobe operating at 500.12 MHz or 500.23 MHz for protons. Experiments were performed in deuterated DMSO, and each sample was prepared to a concentration of approximately 10 mM.

[0242] result AP1189 from salt 1 The chemical shifts and integrals of the 1 H-NMR signals are shown in Table 7. TIFF2026501257000018.tif110165TIFF2026501257000019.tif244165TIFF2026501257000020.tif146163

[0243] conclusion The chemical shift values ​​and peak integrations correspond to the expected salts or free base of AP1189.

[0244] Example 6: Solubility of AP1189 and salts method The solubility of AP1189 free base, tosylate, and fumarate salts was investigated in buffer solutions: the amount of compound was suspended in the buffer and stirred at ambient temperature for 24 hours, after which the supernatant was sampled and analyzed for AP1189 content by HPLC.

[0245] result The results of the test are shown in Table 8. TIFF2026501257000021.tif96165

[0246] conclusion The test compounds exhibited significantly different solubilities at low pH, specifically the high solubility of the free base at pH 1.2, indicating the potential use of the compounds in applications where high solubility at low pH is desirable.

Claims

1. Cu K at 14.5±0.2, 23.9±0.2, and 26.7±0.2 α A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, which exhibits at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity.

2. Cu K selected from the group consisting of 11.6±0.2, 12.3±0.2, 13.4±0.2, 16.9±0.2, 17.6±0.2, 19.1±0.2, 19.7±0.2, 21.2±0.2, and 27.0±0.2 α 2. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to claim 1, further exhibiting one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactive rays.

3. Cu K according to FIG. α 10. A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of the preceding claims, which exhibits an X-ray pattern (2-theta values) in powder diffraction when measured using radioactive rays.

4. A process for producing crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, said process comprising the steps of: i. combining 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and a solvent to form a mixture; ii. isolating from the mixture the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide of any one of claims 1 to 3; The method comprising:

5. A process for producing crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, said process comprising the steps of: i. combining 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propen-2-ylidene}hydrazine-1-carboxyimidamidium salt and a solvent to form a composition; ii. isolating from said composition the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide of any one of claims 1 to 3; The method comprising:

6. A process for producing crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, said process comprising the steps of: i. mixing 3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-propanal and aminoguanidine or a salt thereof in a solvent to form a composition; ii. isolating from said composition the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide of any one of claims 1 to 3; The method comprising:

7. A process for producing crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, said process comprising the steps of: i. providing a 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide salt comprising a 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide and a counterion; ii. Separating the counterion from 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide using ion exchange; iii. Isolating the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3; The method comprising:

8. The method according to any one of claims 4 to 7, wherein the solvent is a protic or polar aprotic solvent.

9. 9. The method of claim 4, wherein the solvent is selected from the group consisting of 2-methyltetrahydrofuran, 2-propanol, ethanol, water, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide, ethyl acetate, heptane, methanol, methyl ethyl ketone, methyl isobutyl ketone, tert-butyl methyl ether, tetrahydrofuran, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), and toluene.

10. The method of any one of claims 4 to 9, wherein the mixture or composition is heated at least once before the isolating step.

11. 11. The method of any one of claims 4 to 10, wherein the mixture or composition is heated and cooled in cycles for 15 minutes to 72 hours before the isolation step.

12. 12. The method of claim 11, wherein the heating is to about 40°C, to about 60°C, or to about 80°C.

13. 12. The method of claim 11, wherein the cooling is to about 20°C.

14. The method of any one of claims 4 to 13, further comprising the step of adding an anti-solvent to the mixture or composition prior to the isolation step.

15. 15. The method of claim 14, wherein the anti-solvent is a non-polar aprotic solvent.

16. The method of claim 14, wherein the anti-solvent is water.

17. 15. The method of any one of claims 14, wherein the anti-solvent is selected from the group consisting of tert-butyl methyl ether, THF, and acetone.

18. The method of any one of claims 4 to 17, wherein the isolation is carried out using filtration, centrifugation, and / or evaporation of the solvent or solvents.

19. 20. The method of claim 18, wherein the evaporation is carried out using spray drying, fluidized bed drying, freeze drying, vacuum drying, tumble drying, rotary evaporation, and / or thin film drying.

20. 20. The method of any one of claims 4 to 19, further comprising the step of seeding with a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

21. A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide produced by the method of any one of claims 4 to 20.

22. Cu K at 16.7±0.2, 19.6±0.2, and 21.0±0.2 α A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, which is a DMSO solvate, exhibiting at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity.

23. Cu K selected from the group consisting of 14.3±0.2, 15.5±0.2, 18.4±0.2, and 23.5±0.2 α 23. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMSO solvate of claim 22, further exhibiting one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

24. Cu K at 23.2±0.2, 23.4±0.2, and 25.1±0.2 α A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, which is a DMF solvate, exhibiting at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity.

25. Cu K selected from the group consisting of 16.2±0.2, 21.0±0.2, and 22.9±0.2 α 25. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMF solvate of claim 24, further exhibiting one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

26. Cu K at 16.2±0.2, 22.8±0.2, and 23.2±0.2 α A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, which is an NMP solvate, exhibiting at least an X-ray line (2-theta value) in a powder diffraction pattern when measured using radioactivity.

27. Cu K selected from the group consisting of 12.3±0.2, 15.5±0.2, 19.3±0.2, 20.1±0.2, and 20.8±0.2 α 27. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide NMP solvate of claim 26, further exhibiting one or more X-ray lines (2-theta values) in a powder diffraction pattern when measured using radioactivity.

28. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, which exhibits an onset temperature of 174 to 188°C in a differential scanning calorimeter using a heating rate of 10°C / min.

29. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to claim 28, which exhibits an onset temperature of substantially 181°C in a differential scanning calorimeter using a heating rate of 10°C / min.

30. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMSO solvate according to any one of claims 22 to 23, which exhibits an onset temperature of 96 to 110°C in a differential scanning calorimeter using a heating rate of 10°C / min.

31. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMSO solvate according to claim 30, which exhibits an onset temperature of substantially 103°C in a differential scanning calorimeter using a heating rate of 10°C / min.

32. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide NMP solvate solvate according to any one of claims 26 to 27, which exhibits an onset temperature of 76 to 90°C in a differential scanning calorimeter using a heating rate of 10°C / min.

33. 33. The crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide NMP solvate according to claim 32, which exhibits an onset temperature of substantially 83°C in a differential scanning calorimeter using a heating rate of 10°C / min.

34. A pharmaceutical composition comprising the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29.

35. 32. A pharmaceutical composition comprising a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMSO solvate according to any one of claims 22 to 23 and 30 to 31, a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide DMF solvate according to any one of claims 24 to 25, or a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide NMP solvate according to any one of claims 26 to 27 and 32 to 33, and optionally further comprising a pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29, and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition prepared by mixing the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29 in a pharmaceutically acceptable solvent.

38. The pharmaceutical composition according to any one of claims 34 to 37, wherein the pharmaceutical composition is for oral administration.

39. 30. A method for preparing a pharmaceutical composition, the method comprising mixing a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29, and a pharmaceutically acceptable excipient.

40. A liquid formulation prepared by mixing the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29 with a solvent.

41. A liquid formulation comprising the crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29, and a solvent.

42. 30. A method for preparing a liquid formulation, the method comprising mixing a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21, and 28 to 29, with a solvent.

43. 30. A process for preparing an amorphous form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide, the process comprising converting a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21 and 28 to 29 to the amorphous form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

44. 44. An amorphous form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide obtained by the method of claim 43.

45. A pharmaceutical composition comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide in the form described in any one of claims 1 to 3, 21 to 33, and 44.

46. 10. A unit dosage form of the pharmaceutical composition according to any one of the preceding claims.

47. An oral formulation comprising 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide in the form of any one of claims 1 to 3, 21 to 33, and 44.

48. 48. The oral formulation of claim 47, further comprising at least one pharmaceutically acceptable excipient.

49. 49. The oral formulation of any one of claims 47 and 48, wherein the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide has a solubility of at least 15 mM at a pH of about 1.2, such as at least 20 mM at a pH of about 1.2, for example at least 25 mM at a pH of about 1.2, such as at least 30 mM at a pH of about 1.2, for example at least 35 mM at a pH of about 1.2, such as at least 40 mM at a pH of about 1.

2.

50. 50. The oral formulation of any one of claims 47 to 49, wherein the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide has a solubility of at least 10 mM at a pH of about 4.5, such as at least 15 mM at a pH of about 4.5, for example at least 20 mM at a pH of about 4.

5.

51. 51. The oral formulation of any one of claims 47 to 50, wherein the oral formulation delivers and / or releases the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide to the gastric compartment (or stomach), e.g., delivers and / or releases the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide primarily or preferentially to the gastric compartment (or stomach).

52. 52. The oral dosage form of any one of claims 47-51, wherein greater than about 65% to about 80% of the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is released in the stomach compartment.

53. 53. The oral dosage form of any one of claims 47 to 52, wherein the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is released into the stomach compartment for gastric absorption.

54. The oral formulation according to any one of claims 47 to 53, wherein the oral formulation is a solid oral formulation.

55. The oral formulation of any one of claims 47 to 54, wherein the oral formulation is a solid oral dosage form.

56. The oral formulation according to any one of claims 47 to 55, wherein the oral formulation is a tablet.

57. 56. The oral formulation of any one of claims 47 to 55, wherein about 65% or more to about 80% of the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is dissolved in solution in the stomach compartment; such as about 65% or more, such as about 70% or more, such as about 75% or more, such as about 80% or more, such as about 85% or more, such as about 90% or more, such as about 95% or more of the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide is dissolved in solution in the stomach compartment.

58. 58. The oral formulation of any one of claims 47 to 57, wherein the oral formulation is a delayed release formulation comprising the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide that targets release in the gastric compartment.

59. The oral formulation according to any one of claims 47 to 58, wherein the oral formulation is a gastric retention-type delayed-release formulation comprising the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide.

60. 60. The oral formulation of any one of claims 47 to 59, wherein the oral formulation is an immediate release formulation comprising the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide targeted for immediate release in the gastric compartment.

61. 61. The oral formulation of any one of claims 47-60, wherein greater than about 65% to about 80% of the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide dissolves in solution at a pH of about 1 to about 3, e.g., about 1.2, for about 10 minutes.

62. 62. The oral formulation of any one of claims 47-61, wherein about 80% or more of the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide dissolves in solution at a pH of about 1 to about 3, e.g., about 1.2, for about 5 minutes.

63. 63. An oral formulation according to any one of claims 47 to 62, wherein the solid oral formulation has a disintegration time of from ½ minute to 10 minutes, such as from ½ minute to 1 minute, for example from 1 to 2 minutes, such as from 2 to 3 minutes, for example from 3 to 4 minutes, such as from 4 to 5 minutes, for example from 5 to 6 minutes, such as from 6 to 7 minutes, for example from 7 to 8 minutes, such as from 8 to 9 minutes, for example from 9 to 10 minutes.

64. 64. The oral formulation of any one of claims 47 to 63, wherein the oral formulation comprises the 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide in a dosage of about 25 mg to about 650 mg, such as about 25 mg of AP1189 free base, for example about 50 mg, such as about 100 mg, for example about 150 mg, such as about 200 mg, for example about 250 mg, such as about 300 mg, for example about 350 mg, such as about 400 mg, for example about 450 mg, such as about 500 mg, for example about 550 mg, such as about 600 mg, for example about 650 mg of AP1189.

65. A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide in the form of any one of claims 1 to 3, 21 to 33 and 44, or a pharmaceutical composition of any one of claims 34 to 43 and 45 to 64, for use in medicine.

66. 65. A crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21 to 33, and 44, or a pharmaceutical composition according to any one of claims 34 to 43, and 45 to 64, for use in the treatment of kidney disease, arthritic disease, cardiovascular disease, atherosclerosis, viral disease or disorder, or systemic inflammatory disease.

67. The kidney disease is i. Renal disease presenting with proteinuria, ii. Kidney disease with proteinuria, iii. glomerular disease, iv. Nephrotic syndrome (glomerular nephropathy), v. Primary nephrotic syndrome (primary glomerular nephropathy) vi. Secondary nephrotic syndrome (secondary glomerulonephropathy), vii. inflammatory kidney disease, viii. glomerulonephritis (GN), and ix. Idiopathic Membranous Nephropathy (iMN) 67. The use of claim 66, selected from the group consisting of:

68. 68. The use of claim 67, wherein the primary nephrotic syndrome is membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN) (membranocapillaris glomerulonephritis), rapidly progressive glomerulonephritis (RPGN) (crescentic GN), or minimal change disease (MCD).

69. 68. The use of claim 67, wherein the secondary nephrotic syndrome is caused by an underlying autoimmune disease, an underlying cancer disease, an underlying genetic disease, or an underlying disease selected from the group consisting of systemic lupus erythematosus (SLE), diabetic nephropathy, sarcoidosis, Sjogren's syndrome, amyloidosis, multiple myeloma, vasculitis, cancer, and a genetic disease (e.g., congenital nephrotic syndrome).

70. 68. The use of claim 67, wherein the secondary nephrotic syndrome is caused by an infection, such as a urinary tract infection, e.g. an infection selected from the group consisting of HIV, syphilis, hepatitis such as hepatitis A, B and C, post-streptococcal infection, bladder schistosomiasis and Ebola. In some embodiments, the secondary nephrotic syndrome is drug-induced.

71. 68. The use of claim 67, wherein the glomerulonephritis is selected from the group consisting of IgA nephropathy (Berger's disease), IgM nephropathy, post-infectious glomerulonephritis and thin basement membrane disease.

72. The arthritis disease is i. Autoimmune and / or inflammatory diseases presenting with joint inflammation, ii. inflammatory arthritis, iii. Degenerative arthritis iv. metabolic arthritis, v. reactive arthritis, vi. infectious arthritis, and vii. Arthritis as part of a systemic inflammatory disease 67. The use of claim 66, selected from the group consisting of:

73. 73. The use of claim 72, wherein the inflammatory arthritis is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis.

74. 74. The use of claim 73, wherein the rheumatoid arthritis is juvenile rheumatoid arthritis (JRA).

75. 73. The use of claim 72, wherein the degenerative arthritis is osteoarthritis.

76. 73. The use of claim 72, wherein the metabolic arthritis is gouty arthritis.

77. 73. The use of claim 72, wherein the reactive arthritis and / or infectious arthritis is arthritis associated with infection with one or more of Hepatitis C, Chlamydia, Gonorrhea, Salmonella or Shigella.

78. The inflammatory diseases include systemic lupus erythematosus, mixed connective tissue disease, Still's disease, and polymyalgia rheumatica.

73. The use of claim 72, selected from the group consisting of:

79. The viral disease or disorder is i. a symptomatic viral disease or disorder; ii. A symptomatic viral disease or disorder accompanied by inflammation; iii. Inflammatory viral diseases or disorders; iv. viral respiratory infections, v. viral respiratory disease or disorder; vi. Viral diseases or disorders of the lungs; vii. viral diseases or disorders involving inflammation of the respiratory system; viii. A viral disease or disorder with one or more respiratory symptoms; ix. Serious illness, x. serious illness, xi. viral pneumonia, xii. viral bronchiolitis, xiii. Viral diseases or disorders associated with respiratory failure; xiv. acute respiratory distress syndrome (ARDS), xv. viral acute respiratory distress syndrome (ARDS); xvi. Symptomatic COVID-19 with acute respiratory distress syndrome (ARDS), xvii. viral diseases or disorders associated with systemic inflammatory distress syndrome (SIDS) and / or sepsis; xviii. Viral diseases or disorders associated with pulmonary dysfunction; xix. Viral diseases or disorders associated with cytokine release syndrome (CRS) and / or cytokine storm (hypercytokinemia); xx. A viral disease or disorder caused by infection with a virus selected from the group consisting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); SARS-CoV, MERS-CoV, dengue virus, and influenza virus (including types A, B, and C).

73. The use of claim 72, selected from the group consisting of:

80. 80. The use of claim 79, wherein the inflammation is excessive inflammation, e.g., inflammation or hyperinflammation in one or more organs; e.g., the one or more organs are selected from the group consisting of lung, respiratory tract, kidney, liver, pancreas, spleen, exocrine glands, endocrine glands, lymph nodes, brain, heart, muscle, bone marrow, skin, skeleton, bladder, reproductive organs including fallopian tubes, eye, ear, vascular system, gastrointestinal tract including small intestine, colon, rectum, anal canal, and prostate.

81. 80. The use of claim 79, wherein the viral respiratory infection is a viral lower respiratory tract infection.

82. 80. The use of claim 79, wherein the viral disease or disorder associated with inflammation in the respiratory system is a viral disease or disorder associated with inflammation in the respiratory system of the lungs and / or airways.

83. 80. The use of claim 79, wherein the one or more respiratory symptoms are selected from the group consisting of cough, dry cough, dyspnea, impaired oxygenation, respiratory disease, respiratory insufficiency, respiratory failure, respiratory syndrome, and acute respiratory disease (ARD).

84. 80. The use of claim 79, wherein the severe disease is manifested by dyspnea, increased respiratory frequency, decreased blood oxygen saturation and / or pulmonary infiltrates.

85. 80. The use of claim 79, wherein the critical illness manifests as respiratory failure, septic shock, and / or multiple organ dysfunction (MOD) or multiple organ failure (MOF).

86. The cardiovascular disease is i. coronary artery disease (CAD), ii. stroke, iii. heart failure, iv. hypertensive heart disease, v. rheumatic heart disease, vi. cardiomyopathy, vii. abnormal heart rhythm; viii. congenital heart disease, ix. valvular heart disease, x. Carditis, xi. aortic aneurysm, xii. peripheral arterial disease, xiii. Vascular disease, xiv. thromboembolic disease, xv. venous thrombosis, xvi. Vascular inflammation, and xvii. The use of claim 66, wherein the anti-inflammatory agent is selected from the group consisting of atherosclerotic.

87. 87. The use of claim 86, wherein the coronary artery disease (CAD) is selected from the group consisting of angina pectoris and myocardial infarction.

88. 87. The use of claim 86, wherein the atherosclerotic condition is selected from the group consisting of coronary artery disease, stroke (cerebrovascular disease), and peripheral artery disease.

89. 87. The use of claim 86, wherein the systemic inflammatory disease is an autoimmune disease.

90. 87. The use of claim 86, wherein the systemic inflammatory disease is selected from the group consisting of Behcet's disease, sarcoidosis, systemic lupus erythematosus, juvenile idiopathic arthritis, scleroderma, Sjogren's syndrome, myositis including dermatomyositis and polymyositis, vasculitis, giant cell arteritis, ankylosing spondylitis, polymyalgia rheumatica, and psoriatic arthritis.

91. 64. A method for treating a disease or disorder in a subject in need thereof, said method comprising administering to a subject in need thereof a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21 to 33, and 44, or a pharmaceutical composition according to any one of claims 34 to 43, and 45 to 64.

92. Use of a crystalline form of 2-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-ene-1-pyridine}hydrazine-1-carboximidamide according to any one of claims 1 to 3, 21 to 33, and 44, or a pharmaceutical composition according to any one of claims 34 to 43, and 45 to 64, in the manufacture of a medicament for the treatment of a disease or disorder.

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