Phenylpyrrole aminoguanidine salts and preparations

Abstract

The present disclosure relates to oral formulations for intragastric delivery of pharma- ceutically acceptable salts of phenylpyrrole aminoguanidine compounds.

Description

[Technical field]

[0001] The present invention relates to a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine) that is highly soluble at low pH, e.g., has a solubility of more than 10 mM at pH 1.2, a pharmaceutical composition comprising the same, and a solid oral formulation comprising the pharma-ceutically acceptable salt of AP1189. [Background technology]

[0002] Melanocortin (MC) receptors (MC1R-MC5R) are a family of class A G protein-coupled receptors (GPCRs) that, due to their wide distribution and the diversity of physiological processes they regulate, are attractive therapeutic targets for multiple conditions. MC1R is expressed on leukocytes and therefore regulates UV light-induced sunburn and other immune responses. MC2R regulates adrenal cortisol production and MC5R is involved in exocrine gland secretion. MC3R and MC4R exert non-redundant functions on energy homeostasis in addition to specific anti-inflammatory roles, whereas MC3R activation is particularly protective in joint inflammation such as arthritis and MC4R provides neuroprotection in brain inflammation. Thus, MCR drugs can target multiple pathological situations such as skin conditions, cardiovascular pathologies, joint inflammation, obesity and cachexia.

[0003] Peripheral MC1R and MC3R can be pharmacologically activated to induce anti-inflammation. The endogenous agonist α-melanocyte-stimulating hormone (αMSH), as well as other protective mediators, are released by immune cells to balance proinflammatory signals and thus prevent excessive tissue damage. In parallel with the elucidation of the inflammation concept, therapeutics targeting MC1R and MC3R could act by mimicking the body's own sources of protection and feature a lighter burden of side effects.

[0004] The use of corticotropin or adrenocorticotropin hormone (ACTH) has been shown to be effective in rheumatic diseases since the early 1950s, but this use declined when synthetic glucocorticoids became available. However, the discovery of an alternative anti-inflammatory mechanism of ACTH that involves the activation of peripheral MC receptors in immune cells has generated interest in the development of novel ACTH-like molecules without steroidogenic effects for the treatment of arthritic diseases such as gout or RA (rheumatoid arthritis). In addition to commercially available ACTH preparations, translational delivery of novel MC drugs is limited by the lack of receptor selectivity that has been achieved so far.

[0005] Innovative approaches in G protein-coupled receptor drug discovery may help overcome this limitation. Allosteric modulation consists in the ability of a molecule to enhance (positive regulation) or reduce (negative regulation) the effect of an endogenous ligand by binding to a distinct site on the receptor protein called the allosteric site. Among the five MCRs, the allosteric region is less conserved and therefore higher selectivity is expected, and indeed, allosteric modulators in MC4R are currently under development for the treatment of obesity.

[0006] Another novel concept that shows great therapeutic interest is that of biased agonism. The previous concept that receptors can exist in two specific conformations (i.e., active and inactive conformations) has been replaced by the concept that multiple active conformations can exist, each of which generates a different signal that leads to multiple functional outcomes. Receptor activation is not linear and static, but occurs as a highly dynamic and multidimensional process, in which a diversity of active conformations can be induced by different molecules, which can lead to distinct effects.

[0007] Melanocortin therapy with adrenocorticotropic hormone (ACTH) or nonsteroidal melanocortin peptides reduces proteinuria and glomerular damage in experimental glomerular diseases and induces remission of the nephrotic syndrome in patients with a variety of glomerulopathies, even in steroid-resistant patients.

[0008] Phenylpyrrole aminoguanidine compounds having activity against MCR are disclosed in WO2007 / 141343.

[0009] The small molecule AP1189 ((E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-arylidene}-aminoguanidine) (or specifically N''-[(E)-[(2E)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-en-1-ylidene]amino]guanidine) has been characterized as a biased agonist at the receptors MC1R and MC3R, where it does not induce canonical cAMP production but causes ERK1 / 2 phosphorylation, a signaling pathway involved in the proefferocytic effects elicited in primary macrophages. AP1189 was shown to reduce cytokine release in macrophages, whereas melanogenesis was not induced by AP1189 in melanocytes. In vivo, AP1189 has been shown to induce anti-inflammatory effects in peritonitis, accelerate the degradative phase, and significantly reduce gross and histological parameters of joint destruction in experimental inflammatory arthritis. Thus, AP1189 is a biased dual agonist at MC1R and MC3R with anti-inflammatory properties combined with a lack of effect on melanin production.

[0010] Because the stomach has a small surface area and drugs do not usually remain in the stomach for long, the absorption of drugs in the stomach is usually not a significant factor in the total absorption of a drug dose.In addition, some drugs are ionized by the pH of the stomach and are not absorbed very well.Some drugs are decomposed by the pH of the stomach, which reduces their absorption.Therefore, the pH of the stomach and the rate of disappearance from the stomach can affect the availability and exposure of all oral drugs.

[0011] AP1189 is currently being investigated in clinical trials for efficacy in the kidney disease iMN (idiopathic membranous nephropathy), rheumatoid arthritis in combination with methotrexate (MTX), and acute respiratory distress syndrome (ARDS) in COVID19 patients. The formulation currently used in the clinic is a suspension with alkaline excipients, following a previous enteric-coated tablet formulation (targeting the small intestine). The enteric-coated tablet showed suboptimal absorption and low bioavailability. Summary of the Invention

[0012] To avoid degradation at low pH (such as the low pH of the gastric compartment), AP1189 is formulated as an enteric coated tablet and then as an alkaline suspension. A subset of pharma-ceutically acceptable salts of AP1189 have now been shown to be highly soluble at low pH, such as pH 1.2, which mimics gastric pH. For example, the acetate and succinate forms of AP1189 are surprisingly soluble at low pH, whereas other salt forms do not show such high solubility at low pH (e.g., the tosylate form of AP1189).

[0013] Therefore, based on this knowledge, it is shown that certain pharma- ceutical acceptable salts of AP1189, such as acetate and succinate forms of AP1189, do not require protection from low pH, such as low pH of the stomach compartment, as attempted in previous enteric-coated tablets and current alkaline suspensions.In contrast, it is now shown that immediate release solid oral formulations have superior bioavailability compared to enteric-coated tablets and superior or equivalent to alkaline suspensions of AP1189 and its pharma- ceutical acceptable salts, which are highly soluble at low pH.High solubility at low pH, e.g. pH 1.2, promotes rapid release and absorption in the stomach compartment after oral ingestion.

[0014] Formulating AP1189 and its pharma- ceutically acceptable salts into a solid oral dosage form that targets the gastric compartment offers advantages over currently available formulations in terms of improved bioavailability and exposure, and ease of administration.

[0015] One aspect of the present disclosure provides pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and stereoisomeric forms, wherein said pharma-ceutically acceptable salts have high solubility at low pH.

[0016] In some embodiments, a pharma- ceutically acceptable salt of AP1189 has high solubility at gastric pH, for example at a pH of about 0.5 to 3.5, for example at a pH of about 1.2.

[0017] In some embodiments, the solubility of the pharma- ceutically acceptable salt of AP1189 is at least 10 mM at pH 1.2, e.g., at least 12 mM at pH 1.2, e.g., at least 15 mM at pH 1.2, e.g., at least 20 mM at pH 1.2, or higher. In some embodiments, the solubility of the pharma- ceutically acceptable salt of AP1189 is at least 10 mM at pH 1.2. In some embodiments, the solubility of the pharma- ceutically acceptable salt of AP1189 is at least 15 mM at pH 1.2. In some embodiments, the solubility of the pharma- ceutically acceptable salt of AP1189 is at least 50 mM at pH 1.2.

[0018] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is selected from the group consisting of: Acetate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate; "AP1189 acetate"); AP1189 succinate salt ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate salt; "AP1189 succinate salt"); DL-mandelic acid salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelate, "AP1189 DL-mandelate"); AP1189 hippuric acid salt ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippurate; "AP1189 hippurate"); A salt of L-lactic acid of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactate; "AP1189 L-lactate"); AP1189 besylate salt ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate, "AP1189 besylate salt"); AP1189 oxoglutarate ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate; "AP1189 oxoglutarate"); The formic acid salt of AP1189 (the formic acid salt of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine, "AP1189 formate"); A salt of DL-lactic acid of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactate; "AP1189 DL-lactate"); AP1189 glutaric acid salt ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutarate; "AP1189 glutarate"); Adipic acid salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid salt, "AP1189 adipic acid salt"); and The nitrate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate; "AP1189 nitrate salt").

[0019] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is selected from the acetate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate salt) and the succinate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate salt).

[0020] It is also an aspect of the present disclosure to provide an oral formulation comprising the pharma- ceutically acceptable salt of AP1189 disclosed herein.In some embodiments, the oral formulation delivers the pharma- ceutically acceptable salt of AP1189 primarily to the stomach compartment, thereby allowing gastric absorption of the AP1189.

[0021] In some embodiments, the oral formulation comprising a pharma- ceutically acceptable salt of AP1189 is a solid oral dosage form. In some embodiments, the oral formulation comprising a pharma- ceutically acceptable salt of AP1189 is an immediate release solid oral dosage form.

[0022] It is also an aspect of the present disclosure to provide an oral formulation comprising a pharma- ceutically acceptable salt of AP1189 for use in the treatment of a disease or disorder, such as a renal disease, an arthritic disease, a viral disease or disorder, a cardiovascular disease and / or atherosclerosis, and a systemic inflammatory disorder. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the mean AP1189 plasma concentration versus time by treatment. Treatment A (squares): AP1189 acetate powder in suspension. Treatment B (triangles): AP1189 acetate enteric coated tablet formulation, fasting. Treatment C (circles): AP1189 acetate enteric coated tablet formulation, postprandial. See Example 5. [Diagram 2] Mean AP1189 plasma concentrations (ng / mL) versus time: Day 1 (circles); Day 7 (triangles); Day 14 (squares) (enteric coated tablets). See Example 6. [Diagram 3] Figure 1 shows the AUC0-24 (plasma concentration of AP1189) shown for formulations (AP1189 acetate oral suspension, alkaline; AP1189 acetate immediate release tablets "AP1189" and AP1189 succinate immediate release tablets "SP1189"). Data was pooled on days 1 and 5. See Example 8. [Figure 4] Figure 1 shows the Cmax (plasma concentration of AP1189) shown for formulations (AP1189 acetate oral suspension, alkaline; AP1189 acetate immediate release tablets "AP1189" and AP1189 succinate immediate release tablets "SP1189"). Data was pooled on days 1 and 5. See Example 8. [Diagram 5]1 shows the plasma concentration of AP1189 for time 0 to 24 hours. Data is shown for AP1189 acetate oral suspension, alkaline agent; AP1189 acetate immediate release tablet "AP1189", and AP1189 succinate immediate release tablet "SP1189". See Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] definition The term "pharmaceutically acceptable derivatives" in this context includes pharmaceutically acceptable salts, which refer to salts that are not harmful to the subject. Such salts include pharmaceutically acceptable base or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Pharmaceutically acceptable derivatives further include esters and prodrugs of a compound, or other precursors that can be metabolized to a biologically active compound, or crystalline forms of a compound.

[0025] A pharma- ceutically acceptable salt of AP1189 is considered to be highly soluble at low pH according to the present disclosure if the solubility of the pharma- ceutically acceptable salt of AP1189 is at least 10 mM at pH 1.2, such as at least 12 mM at pH 1.2, such as at least 15 mM at pH 1.2, such as at least 20 mM at pH 1.2.

[0026] Reference to pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, is meant to embrace amorphous forms and all polymorphic (crystalline) forms of such salts. A person skilled in the art knows how to prepare polymorphic forms of AP1189 salts. Polymorphic forms of pharma- ceutically acceptable salts of AP1189 are disclosed in PCT / EP2022 / 066884.

[0027] The term "pharmacologically effective amount" of a compound as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the clinical symptoms of a given disease or disorder and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount". The amount effective for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that the determination of the appropriate dosage can be achieved using routine experimental methods by constructing a matrix of values ​​and testing different points within the matrix, all of which are within the ordinary skill of a trained physician or veterinarian.

[0028] The terms "treatment" and "treating" as used herein refer to the management and care of a subject for the purpose of combating a condition, disease or disorder. The term is intended to include all therapies for a given condition suffered by the subject. The subject to be treated is preferably a mammal, in particular a human. However, treatment of animals such as mice, rats, dogs, cats, horses, cows, sheep and pigs is also within the scope of the present invention. The subject to be treated can be of various ages.

[0029] An "arthritic disease" as referred to herein is an inflammatory disease manifested by inflammation of the joints, also known as arthritis.

[0030] pH is a measurement of a solution's acidity or alkalinity, or a negative logarithmic scale of the hydrogen ion concentration in a solution. The higher the hydrogen ion concentration, the more acidic the solution, represented by a lower pH. The lower the hydrogen ion concentration, the more alkaline the solution, represented by a higher pH. The pH scale runs from 1 (strongly acidic) to 7 (neutral) to 14 (strongly alkaline).

[0031] The terms "approximately" and "about" 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.

[0032] Detailed Description Compounds of the Disclosure The present disclosure provides certain salt forms of phenylpyrrole aminoguanidine compounds. By "compounds of the present disclosure" is meant compounds as defined herein below.

[0033] AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine), including its tautomeric and isomeric forms, has the chemical structure of Formula I: [ka]

[0034] In some embodiments, the compound is N''-[(E)-[(2E)-3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]prop-2-en-1-ylidene]amino]guanidine or a pharma- ceutically acceptable salt thereof, as identified throughout this specification.

[0035] In some embodiments of the present disclosure, the compounds of the present disclosure are pharma- ceutically acceptable salts of AP1189.

[0036] In some embodiments of the disclosure, a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine) of formula I: [ka] (including tautomeric and isomeric forms thereof) are provided which are soluble at low pH, e.g., highly soluble at low pH.

[0037] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 are provided that are soluble at low pH (eg, acidic pH).

[0038] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 that are highly soluble at low pH (eg, acidic pH), eg, pharma- ceutically acceptable salts of AP1189 that have high solubility at low pH, are provided.

[0039] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including tautomeric and isomeric forms thereof, are provided, wherein the pharma- ceutically acceptable salts have high solubility at low pH.

[0040] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility at low pH.

[0041] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility at gastric pH.

[0042] References to "high solubility" in some embodiments refer to "highly soluble."

[0043] Gastric pH in this specification refers to the pH of the stomach (gastric juice, gastric acid), which has a pH of about 1-3. Hydrochloric acid is secreted by the gastric parietal cells to kill or reduce the growth of certain bacteria and promote the denaturation of proteins as they enter the gastrointestinal tract. Gastric acid is controlled in a feedback system to increase production when needed, for example after a meal. Other cells in the stomach produce bicarbonate, a base, to buffer the fluid, thus ensuring control of the pH value. These cells also produce mucus, a viscous barrier, to prevent gastric acid from damaging the stomach. The pH of gastric acid is 1.5-3.5 in the human gastric lumen, which is controlled by the proton pump H + / K + This is the level maintained by ATPase. When food enters the stomach, the pH level rises (to as high as pH 6), but as gastric acid is secreted, the pH level drops again throughout digestion.

[0044] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is soluble at a pH of 1 to 3, for example, at a pH of 0.5 to 3.5. In some embodiments, the pharma- ceutically acceptable salt of AP1189 is soluble at a pH of about 1.2.

[0045] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility at a pH of 1 to 3, for example at a pH of 0.5 to 3.5.

[0046] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility at a pH of about 1.2.

[0047] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility at pH 1.2.

[0048] In some embodiments, the pharma- ceutically acceptable salt of AP1189 has high solubility in acidic conditions. In some embodiments, the pharma- ceutically acceptable salt of AP1189 is highly soluble in acidic conditions.

[0049] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, are provided, which are highly soluble at low pH.

[0050] In some embodiments, pharma- ceutically acceptable salts of AP1189 are considered to be soluble or highly soluble at low pH if they have a solubility at a particular concentration (mM) or higher at low pH, e.g., an acidic pH, e.g., a pH of about 1.2.

[0051] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, are provided, which have the following solubilities: at least 10 mM at pH 1.2, at least 11 mM at pH 1.2, at least 12 mM at pH 1.2, at least 13 mM at pH 1.2, at least 14 mM at pH 1.2, at least 15 mM at pH 1.2, at least 16 mM at pH 1.2, at least 17 mM at pH 1.2, at least 18 mM at pH 1.2, at least 19 mM at pH 1.2, at least 20 mM at pH 1.2, at least 21 mM at pH 1.2, at least 22 mM at pH 1.2, at least 23 mM at pH 1.2, at least 24 mM at pH 1.2, at least 25 mM at pH 1.2, at least 26 mM at pH 1.2, at least 27 mM at pH 1.2, at least 28 mM at pH 1.2, at least 29 mM at pH 1.2, at least 30 mM at pH 1.2, at least 31 mM at pH 1.2, at least 32 mM at pH 1.2, at least 33 mM at pH 1.2, at least 34 mM at pH 1.2, at least 35 mM at pH 1.2, at least 36 mM at pH 1.2, at least 37 mM at pH 1.2, at least 38 mM at pH 1.2, at least 39 mM at pH 1.2, at least 40 mM at pH 1.2, at least 41 mM at pH 1.2, at least 42 mM at At least 14 mM at pH 1.2, at least 15 mM at pH 1.2, at least 16 mM at pH 1.2, at least 17 mM at pH 1.2, at least 18 mM at pH 1.2, at least 19 mM at pH 1.2, at least 20 mM at pH 1.2, at least 25 mM at pH 1.2, at least 30 mM at pH 1.2, at least 35 mM at pH 1.2, at least 40 mM at pH 1.2, At least 45 mM at pH 1.2, at least 50 mM at pH 1.2, at least 60 mM at pH 1.2, at least 70 mM at pH 1.2, at least 80 mM at pH 1.2, at least 90 mM at pH 1.2, at least 100 mM at pH 1.2, at least 110 mM at pH 1.2, at least 120 mM at pH 1.2, at least 130 mM at pH 1.2 140 mM, at least 150 mM at pH 1.2, at least 175 mM at pH 1.2, at least 200 mM at pH 1.2, at least 250 mM at pH 1.2, at least 300 mM at pH 1.2, at least 350 mM at pH 1.2, at least 400 mM at pH 1.2, at least 450 mM at pH 1.2, at least 500 mM at pH 1.2, at least 550 mM.

[0052] In some embodiments of the present disclosure, there is provided a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which has a solubility of at least 10 mM at pH 1-3, e.g., pH 0.5-3.5.

[0053] In some embodiments of the present disclosure, there are provided pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which have a solubility of at least 10 mM at pH 1.2.

[0054] In some embodiments of the present disclosure, there is provided a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which has a solubility of at least 15 mM at pH 1-3, e.g., pH 0.5-3.5.

[0055] In some embodiments of the present disclosure, there are provided pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which have a solubility of at least 15 mM at pH 1.2.

[0056] In some embodiments of the present disclosure, there is provided a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which has a solubility of 15 mM or more and less than 50 mM at pH 1-3, e.g., pH 0.5-3.5.

[0057] In some embodiments of the present disclosure, there are provided pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which have a solubility of 15 mM or more and less than 50 mM at pH 1.2.

[0058] In some embodiments of the present disclosure, there is provided a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which has a solubility of 50 mM or greater at pH 1-3, e.g., pH 0.5-3.5.

[0059] In some embodiments of the present disclosure, there are provided pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, which have a solubility of 50 mM or greater at pH 1.2.

[0060] In some embodiments of the present disclosure, pharma- ceutically acceptable salts of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and isomeric forms, are provided, which have the following solubilities: at least 25 mg / mL at pH 1.2, at least 50 mg / mL at pH 1.2, at least 75 mg / mL at pH 1.2, at least 100 mg / mL at pH 1.2, at least 125 mg / mL at pH 1.2, at least 150 mg / mL at pH 1.2, at least 175 mg / mL at pH 1.2, at least 200 mg / mL at pH 1.2.

[0061] The present inventors have surprisingly found that a subset of pharma-ceutically acceptable salts of AP1189 are highly soluble at low pH.

[0062] In particular, the present inventors have surprisingly found that the acetate, succinate, DL-mandelic acid, hippuric acid, L-lactic acid, besylate, oxoglutarate, formic acid, DL-lactic acid, glutaric acid, and adipic acid salts of AP1189 are highly soluble at low pH, e.g., at pH 1.2. In contrast, for example, the tosylate salt of AP1189 is significantly less soluble at low pH.

[0063] In some embodiments of the present disclosure, the pharma- ceutically acceptable salts of AP1189 have a higher solubility at low pH, such as pH 1.2, than AP1189 fumarate and / or AP1189 tosylate and / or AP1189 napadisylate and / or AP1189 esylate and / or AP1189 edisylate and / or AP1189 cyclamate and / or AP1189 oxalate and / or AP1189 (+)-camphor-10-sulfonate.

[0064] In some embodiments of the present disclosure, a pharma- ceutically acceptable salt of AP1189 has a higher solubility at low pH, for example pH 1.2, than AP1189 tosylate.

[0065] AP1189 soluble salt In some embodiments, the pharma- ceutically acceptable salt of AP1189 is selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate, including its tautomeric and stereoisomeric forms.

[0066] In some embodiments of the present disclosure, the solubility of the AP1189 salt is at least 15 mM at low pH, such as pH 1-3, such as pH 0.5-3.5, such as pH 1.2.

[0067] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including their tautomeric and stereoisomeric forms; and Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including its tautomeric and stereoisomeric forms.

[0068] In some embodiments of the present disclosure, the solubility of the AP1189 salt is at least 50 mM at low pH, such as pH 1-3, such as pH 0.5-3.5, such as pH 1.2.

[0069] In some embodiments, the pharma- ceutically acceptable salt of AP1189 according to the present disclosure is a crystalline or polymorphic form of a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate salt. Polymorphic forms have been prepared and disclosed in PCT / EP2022 / 066884, the disclosure of which is incorporated herein by reference.

[0070] AP1189 Acetate In some embodiments, the pharma- ceutically acceptable salt of AP1189 is (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate).

[0071] In some embodiments of the present disclosure, the acetate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine) of formula II; [ka] (including tautomeric and stereoisomeric forms thereof) are provided.

[0072] In some embodiments, the AP1189 acetate has high solubility at low pH, such as high solubility at a pH of about 0.5 to 3.5, such as high solubility at a pH of about 1 to 3, such as high solubility at a pH of about 1.2.

[0073] In some embodiments of the present disclosure, the solubility of AP1189 acetate is at least 50 mM at pH 1.2, such as at least 60 mM at pH 1.2, such as at least 70 mM at pH 1.2, such as at least 80 mM at pH 1.2, such as at least 90 mM at pH 1.2, such as at least 100 mM at pH 1.2, such as at least 110 mM at pH 1.2, such as at least 120 mM at pH 1.2, such as at least 130 mM at pH 1.2, such as at least 140 mM at pH 1.2, such as at least 150 mM at pH 1.2, such as at least 160 mM at pH 1.2, such as at least 170 mM at pH 1.2, such as at least 180 mM at pH 1.2, such as at least 190 mM at pH 1.2, such as at least 200 mM at pH 1.2, such as at least 210 mM at pH 1.2, such as at least 220 mM at pH 1.2, such as at least 230 mM at pH 1.2, such as at least 240 mM at pH 1.2, such as at least 250 mM at pH 1.2, such as at least 260 mM at pH 1.2, such as at least 270 mM at pH 1.2, such as at least 280 mM at pH 1.2, such as at least 290 mM at pH 1.2, such as at least 300 mM at pH 1.2, such as at least 310 mM at pH 1.2, such as at least 320 mM at pH 1.2, such as at least 330 mM at pH 1.2, such as at least 340 mM at pH 1.2, such as at least 350 mM at pH 1.2, such at least 150 mM at pH 1.2, such as at least 175 mM at pH 1.2, for example, at least 200 mM at pH 1.2, such as at least 250 mM at pH 1.2, for example, at least 300 mM at pH 1.2, such as at least 350 mM at pH 1.2, for example, at least 400 mM at pH 1.2, such as at least 450 mM at pH 1.2, for example, at least 500 mM at pH 1.2, such as at least 550 mM at pH 1.2, for example, at least 600 mM at pH 1.2.

[0074] In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 617 mM ± 200 mM at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 617 mM ± 100 mM at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 617 mM ± 50 mM at pH 1.2.

[0075] In some embodiments of the present disclosure, the solubility of AP1189 acetate is at least 25 mg / mL at pH 1.2, such as at least 50 mg / mL at pH 1.2, such as at least 75 mg / mL at pH 1.2, such as at least 100 mg / mL at pH 1.2, such as at least 125 mg / mL at pH 1.2, such as at least 150 mg / mL at pH 1.2, such as at least 175 mg / mL at pH 1.2, such as at least 200 mg / mL at pH 1.2.

[0076] In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 223 mg / mL ± 100 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 223 mg / mL ± 75 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 223 mg / mL ± 50 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 acetate is approximately 223 mg / mL ± 25 mg / mL at pH 1.2.

[0077] AP1189 Succinate In some embodiments, the pharma- ceutically acceptable salt of AP1189 is (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189).

[0078] In some embodiments of the present disclosure, the succinate salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine) of formula III; [ka] (including tautomeric and stereoisomeric forms thereof) are provided.

[0079] In some embodiments, the AP1189 succinate salt has high solubility at low pH, for example high solubility at a pH of about 0.5 to 3.5, for example high solubility at a pH of about 1 to 3, for example high solubility at a pH of about 1.2.

[0080] In some embodiments of the present disclosure, the solubility of AP1189 succinate is at least 20 mM at pH 1.2, such as at least 30 mM at pH 1.2, such as at least 35 mM at pH 1.2, such as at least 40 mM at pH 1.2, such as at least 50 mM at pH 1.2, such as at least 60 mM at pH 1.2, such as at least 70 mM at pH 1.2, such as at least 80 mM at pH 1.2, such as at least 90 mM at pH 1.2, such as at least 100 mM at pH 1.2, such as at least 110 mM at pH 1.2, such as at least 100 mM at pH 1.2, at least 120 mM, for example at pH 1.2, at least 130 mM, for example at pH 1.2, at least 140 mM, for example at pH 1.2, at least 150 mM, for example at pH 1.2, at least 175 mM, for example at pH 1.2, at least 200 mM, for example at least 250 mM, for example at pH 1.2, at least 300 mM, for example at least 350 mM, for example at pH 1.2, at least 400 mM, for example at pH 1.2, at least 450 mM, for example at pH 1.2, at least 500 mM, for example at least 550 mM, for example at pH 1.2.

[0081] In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 593 mM ± 200 mM at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 593 mM ± 100 mM at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 593 mM ± 50 mM at pH 1.2.

[0082] In some embodiments of the present disclosure, the solubility of AP1189 succinate is at least 25 mg / mL at pH 1.2, such as at least 50 mg / mL at pH 1.2, such as at least 75 mg / mL at pH 1.2, such as at least 100 mg / mL at pH 1.2, such as at least 125 mg / mL at pH 1.2, such as at least 150 mg / mL at pH 1.2, such as at least 175 mg / mL at pH 1.2, such as at least 200 mg / mL at pH 1.2.

[0083] In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 245 mg / mL ± 100 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 245 mg / mL ± 75 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 245 mg / mL ± 50 mg / mL at pH 1.2. In some embodiments of the present disclosure, the solubility of AP1189 succinate is approximately 245 mg / mL ± 25 mg / mL at pH 1.2.

[0084] Pharmaceutical Compositions Also, an aspect of the present disclosure is to provide a pharmaceutical composition comprising a pharma- ceutically acceptable salt of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine, including its tautomeric and stereoisomeric forms (AP1189).

[0085] In some embodiments, the pharmaceutical composition comprises a compound selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate, including its tautomeric and stereoisomeric forms.

[0086] In some embodiments, the pharmaceutical composition comprises a compound selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including their tautomeric and stereoisomeric forms; and Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including its tautomeric and stereoisomeric forms.

[0087] In some embodiments, the pharmaceutical composition comprises (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate).

[0088] In some embodiments, the pharmaceutical composition comprises (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms) (AP1189 succinate, "SP1189").

[0089] The terms "composition" and "pharmaceutical composition" may be used interchangeably herein.

[0090] It is also an aspect of the present disclosure to provide a unit dosage form of a pharmaceutical composition comprising a pharma- ceutically acceptable salt of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine (AP1189).

[0091] In some embodiments, the unit dosage form comprises a pharmaceutical composition comprising a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: acetate salt of AP1189, succinate salt of AP1189, DL-mandelic acid salt of AP1189, hippuric acid salt of AP1189, L-lactic acid salt of AP1189, besylate salt of AP1189, oxoglutarate salt of AP1189, formic acid salt of AP1189, DL-lactic acid salt of AP1189, glutaric acid salt of AP1189, adipic acid salt of AP1189, and nitrate salt of AP1189.

[0092] In some embodiments, the unit dosage form comprises a pharmaceutical composition comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate).

[0093] In some embodiments, the unit dosage form comprises a pharmaceutical composition comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189).

[0094] Oral Formulations One aspect of the present disclosure is to provide an oral formulation comprising a soluble form of AP1189 or a pharma- ceutically acceptable salt thereof that is soluble at low pH, e.g., has high solubility at low pH.

[0095] One aspect of the disclosure is a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine) of formula I: [ka] (including tautomeric and stereoisomeric forms thereof), wherein the pharma- ceutically acceptable salt is soluble at low pH, e.g., has high solubility at low pH.

[0096] Also disclosed is an oral formulation comprising a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and stereoisomeric forms, that is soluble at low pH, e.g., has high solubility at low pH, and at least one pharma-ceutically acceptable excipient.

[0097] In some embodiments, the oral formulation comprises a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and stereoisomeric forms, wherein the pharma- ceutically acceptable salt has the following solubility: at least 10 mM at pH 1.2, such as at least 11 mM at pH 1.2, such as at least 12 mM at pH 1.2, such as at least 13 mM at pH 1.2, such as at least 15 mM at pH 1.2, at least 14 mM, for example at pH 1.2, at least 15 mM, for example at pH 1.2, at least 16 mM, for example at pH 1.2, at least 17 mM, for example at pH 1.2, at least 18 mM, for example at pH 1.2, at least 19 mM, for example at pH 1.2, at least 20 mM, for example at pH 1.2, at least 25 mM, for example at pH 1.2, at least 30 mM, for example at pH 1.2, at least 35 mM, for example at least 40 mM, , for example at least 50 mM at pH 1.2, for example at least 60 mM at pH 1.2, for example at least 70 mM at pH 1.2, for example at least 80 mM at pH 1.2, for example at least 90 mM at pH 1.2, for example at least 100 mM at pH 1.2, for example at least 110 mM at pH 1.2, for example at least 120 mM at pH 1.2, for example at least 130 mM at pH 1.2, for example at least 140 mM at pH 1.2, for example For example, at least 150 mM at pH 1.2, such as at least 175 mM at pH 1.2, for example, at least 200 mM at pH 1.2, such as at least 250 mM at pH 1.2, for example, at least 300 mM at pH 1.2, such as at least 350 mM at pH 1.2, for example, at least 400 mM at pH 1.2, such as at least 450 mM at pH 1.2, for example, at least 500 mM at pH 1.2, for example, at least 550 mM at pH 1.2.

[0098] In some embodiments, the oral formulation comprises a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and stereoisomeric forms, wherein the pharma- ceutically acceptable salt has a solubility of at least 10 mM at pH 1.2; e.g., at least 15 mM at pH 1.2, e.g., a solubility of 15 mM or more and less than 50 mM at pH 1.2, e.g., a solubility of 50 mM or more.

[0099] In some embodiments, the oral formulation comprises a pharma- ceutically acceptable salt of AP1189 ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine), including its tautomeric and stereoisomeric forms, wherein the pharma- ceutically acceptable salt has the following solubility: at least 25 mg / mL at pH 1.2, such as at least 50 mg / mL at pH 1.2, such as at least 75 mg / mL at pH 1.2, such as at least 100 mg / mL at pH 1.2, such as at least 125 mg / mL at pH 1.2, such as at least 150 mg / mL at pH 1.2, such as at least 175 mg / mL at pH 1.2, such as at least 200 mg / mL at pH 1.2.

[0100] An embodiment of the present disclosure also includes a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate (including its tautomeric and stereoisomeric forms); and optionally at least one pharma- ceutically acceptable excipient.

[0101] An embodiment of the present disclosure also includes a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including their tautomeric and stereoisomeric forms; and Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; and at least one pharma- ceutically acceptable excipient.

[0102] An aspect of the present disclosure is also to provide an oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate) and at least one pharma- ceutically acceptable excipient.

[0103] An aspect of the present disclosure is also to provide an oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189), and at least one pharma- ceutically acceptable excipient.

[0104] In some embodiments, the oral formulation delivers the pharmaceutically acceptable salt of AP1189 to the gastric compartment (or stomach). In some embodiments, the oral formulation delivers primarily or predominantly the pharmaceutically acceptable salt of AP1189 to the gastric compartment (or stomach).

[0105] In some embodiments, the oral formulation releases the pharma- ceutically acceptable salt of AP1189 in the gastric compartment.In some embodiments, the oral formulation releases primarily or predominantly the pharma- ceutically acceptable salt of AP1189 in the gastric compartment (or stomach).

[0106] In some embodiments, the oral formulation releases said pharma- ceutically acceptable salt of AP1189 in the stomach compartment by immediate release, by delayed release, by burst release, or by any means that releases said pharma- ceutically acceptable salt of AP1189 primarily or predominantly in the stomach compartment.

[0107] In some embodiments, the oral formulation delivers and / or releases about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 in the gastric compartment.

[0108] In some embodiments, the oral formulation delivers and / or releases about 65% or more of the pharma- ceutically acceptable salt of AP1189 in the gastric compartment, e.g., about 70% or more, such as about 75% or more, for example, about 80% or more, such as about 85% or more, for example, about 90% or more, for example, about 95% or more of the pharma- ceutically acceptable salt of AP1189.

[0109] In some embodiments, the oral formulation provides immediate release of the pharma- ceutically acceptable salt of AP1189 in the gastric compartment.

[0110] In some embodiments, the oral formulation releases the pharma- ceutically acceptable salt of AP1189 in the stomach compartment for gastric absorption of the AP1189.

[0111] In some embodiments, the oral formulation releases the pharma- ceutically acceptable salt of AP1189 in the stomach compartment due to absorption of the AP1189 on the gastric mucus layer.

[0112] In some embodiments, the oral formulation is designed for gastric delivery. In some embodiments, the oral formulation is designed for gastric release. In some embodiments, the oral formulation is designed for gastric absorption.

[0113] In some embodiments, the oral formulation is non-alkaline. In some embodiments, the oral formulation is not a suspension. In some embodiments, the oral formulation is not an alkaline suspension. In some embodiments, the oral formulation is not an enteric coated tablet.

[0114] In some embodiments, the oral formulation is a solid oral formulation. In a preferred embodiment, the oral dosage form is a solid oral dosage form.

[0115] One aspect of the present disclosure is to provide a solid oral formulation comprising a pharma- ceutically acceptable salt of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium, including its tautomeric and stereoisomeric forms, and at least one pharma- ceutically acceptable excipient, wherein the pharma- ceutically acceptable salt is soluble or highly soluble at low pH; For example, a pharma- ceutically acceptable salt of AP1189 has the following solubility: at least 10 mM at pH 1.2, such as at least 11 mM at pH 1.2, such as at least 12 mM at pH 1.2, such as at least 13 mM at pH 1.2, such as at least 14 mM at pH 1.2, such as at least 15 mM at pH 1.2, such as at least 16 mM at pH 1.2, such as at least 17 mM at pH 1.2. , for example at least 18 mM at pH 1.2, for example at least 19 mM at pH 1.2, for example at least 20 mM at pH 1.2, for example at least 25 mM at pH 1.2, for example at least 30 mM at pH 1.2, for example at least 35 mM at pH 1.2, for example at least 40 mM at pH 1.2, for example at least 50 mM at pH 1.2, for example at least 60 mM at pH 1.2, for example At least 70 mM at pH 1.2, such as at least 80 mM at pH 1.2, for example at least 90 mM at pH 1.2, for example at least 100 mM at pH 1.2, for example at least 110 mM at pH 1.2, for example at least 120 mM at pH 1.2, for example at least 130 mM at pH 1.2, for example at least 140 mM at pH 1.2, for example at least 150 mM at pH 1.2, for example , at least 175 mM at pH 1.2, such as at least 200 mM at pH 1.2, for example at least 250 mM at pH 1.2, for example at least 300 mM at pH 1.2, for example at least 350 mM at pH 1.2, for example at least 400 mM at pH 1.2, for example at least 450 mM at pH 1.2, for example at least 500 mM at pH 1.2, for example at least 550 mM at pH 1.2; Or, for example, a pharma- ceutically acceptable salt of AP1189 has the following solubility: at least 25 mg / mL at pH 1.2, for example at least 50 mg / mL at pH 1.2, for example at least 75 mg / mL at pH 1.2, for example at least 100 mg / mL at pH 1.2, for example at least 125 mg / mL at pH 1.2, for example at least 150 mg / mL at pH 1.2, for example at least 175 mg / mL at pH 1.2, for example at least 200 mg / mL at pH 1.2.

[0116] One aspect of the present disclosure provides a solid oral formulation comprising a pharma- ceutically acceptable salt of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium (including its tautomeric and stereoisomeric forms) and at least one pharma- ceutically acceptable excipient, wherein the pharma- ceutically acceptable salt has a solubility of at least 10 mM at pH 1.2; e.g., at least 15 mM at pH 1.2, e.g., a solubility of 15 to less than 50 mM at pH 1.2, e.g., a solubility of 50 mM or more.

[0117] In some embodiments of the disclosure, a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate, including its tautomeric and stereoisomeric forms; and optionally at least one pharma- ceutically acceptable excipient.

[0118] One aspect of the present disclosure is to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms (AP1189 acetate), and at least one pharma- ceutically acceptable excipient.

[0119] An aspect of the present disclosure is also to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189), and at least one pharma- ceutically acceptable excipient.

[0120] In some embodiments, the solid oral formulation is a solid oral dosage form.

[0121] In some embodiments, said solid oral formulation is a delayed release solid oral formulation comprising a pharma- ceutically acceptable salt of AP1189 that targets release in the gastric compartment.

[0122] In some embodiments, the solid oral dosage form is an immediate release solid oral dosage form.

[0123] In some embodiments, the solid oral dosage form is an immediate release solid oral dosage form.

[0124] 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.

[0125] An embodiment of the present disclosure also includes a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate (including its tautomeric and stereoisomeric forms); and at least one pharma- ceutically acceptable excipient.

[0126] In a preferred embodiment, the present disclosure provides a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including their tautomeric and stereoisomeric forms; and Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; and at least one pharma- ceutically acceptable excipient.

[0127] One aspect of the present disclosure is to provide a solid oral dosage form, such as a tablet, comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate) and at least one pharma- ceutically acceptable excipient.

[0128] One aspect of the present disclosure is to provide a solid oral dosage form, such as a tablet, comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189), and at least one pharma- ceutically acceptable excipient.

[0129] In some embodiments, a solid oral formulation, solid oral dosage form or tablet is provided comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution in the gastric compartment.

[0130] In some embodiments, there is provided a solid oral formulation, solid oral dosage form or tablet comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein 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 pharma- ceutically acceptable salt of AP1189 dissolves in solution in the gastric compartment.

[0131] In some embodiments, the oral formulation is a delayed release tablet comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein that targets release in the gastric compartment.

[0132] 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 distension system (GSS), such as a gastric distension system consisting of a swelling layer and a drug-releasing layer.

[0133] One aspect of the disclosure is a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate (including its tautomeric and stereoisomeric forms); and at least one pharma- ceutically acceptable excipient.

[0134] One aspect of the present disclosure is to provide a gastroretentive delayed release solid oral formulation, dosage form or tablet comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate) and at least one pharma- ceutically acceptable excipient.

[0135] One aspect of the present disclosure is to provide a gastroretentive delayed release solid oral formulation, dosage form or tablet comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189), and at least one pharma- ceutically acceptable excipient.

[0136] In some embodiments, the oral formulation is an immediate release tablet.In some embodiments, the solid oral formulation is an immediate release tablet.

[0137] One aspect of the disclosure is a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium besylate (including its tautomeric and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium oxoglutarate, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine formic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-lactic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine glutaric acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine adipic acid, including their tautomeric and stereoisomeric forms; and (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium nitrate (including its tautomeric and stereoisomeric forms); and at least one pharma- ceutically acceptable excipient.

[0138] One aspect of the disclosure is a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of: (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate, including its tautomeric and stereoisomeric forms; (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric and stereoisomeric forms); Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine DL-mandelic acid, including their tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine hippuric acid, including its tautomeric and stereoisomeric forms; Salts of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidine L-lactic acid, including their tautomeric and stereoisomeric forms; and at least one pharma- ceutically acceptable excipient.

[0139] One aspect of the present disclosure is to provide an immediate release solid oral formulation, such as an immediate release solid oral dosage form, such as an immediate release tablet, comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium acetate (including its tautomeric and stereoisomeric forms) (AP1189 acetate) and at least one pharmaceutically acceptable excipient.

[0140] One aspect of the present disclosure is to provide an immediate release solid oral formulation, such as an immediate release solid oral dosage form, such as an immediate release tablet, comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate, including its tautomeric and stereoisomeric forms (AP1189 succinate, SP1189), and at least one pharma- ceutically acceptable excipient.

[0141] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution in about 5 minutes.

[0142] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate, AP1189 succinate, DL-mandelate of AP1189, hippuric acid salt of AP1189, L-lactic acid salt of AP1189, besylate of AP1189, oxoglutarate of AP1189, formic acid salt of AP1189, DL-lactic acid salt of AP1189, glutaric acid salt of AP1189, adipic acid salt of AP1189, or nitrate of AP1189 is provided, wherein about 65% to about 80% or more of the AP1189 acetate or succinate is dissolved in solution in about 5 minutes.

[0143] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate, AP1189 succinate, a salt of AP1189 DL-mandelic acid, a salt of AP1189 hippuric acid, or a salt of AP1189 L-lactic acid is provided, wherein about 65% to about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 5 minutes.

[0144] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 65% to about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 5 minutes.

[0145] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution in about 5 minutes at a pH of about 1 to 3, e.g., about pH 0.5 to 3.5; e.g., about pH 0.5 to 1, e.g., about pH 1 to 1.5, e.g., about pH 1.5 to 2, e.g., about pH 2 to 2.5, e.g., about pH 2.5 to 3, e.g., about pH 3 to 3.5.

[0146] In some embodiments, AP1189 is selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate. An oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 is provided, wherein about 65 to about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution in about 5 minutes at a pH of about 1 to 3, e.g., about pH 0.5 to 3.5; e.g., about pH 0.5 to 1, e.g., about pH 1 to 1.5, e.g., about pH 1.5 to 2, e.g., about pH 2 to 2.5, e.g., about pH 2.5 to 3, e.g., about pH 3 to 3.5.

[0147] 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 acetate or AP1189 succinate, wherein about 65 to about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 5 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, such as about pH 1.5 to 2, for example about pH 2 to 2.5, for example about pH 2.5 to 3, for example about pH 3 to 3.5.

[0148] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution in about 5 minutes at a pH of about 1.2.

[0149] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of AP1189 DL-mandelic acid, the salt of AP1189 hippuric acid, the salt of AP1189 L-lactic acid, the salt of AP1189 besylate, the salt of AP1189 oxoglutarate, the salt of AP1189 formic acid, the salt of AP1189 DL-lactic acid, the salt of AP1189 glutaric acid, the salt of AP1189 adipic acid, and the salt of AP1189 nitrate, wherein about 65 to about 80% or more of the pharmaceutically acceptable salt of AP1189 is dissolved in solution in about 5 minutes at a pH of about 1.2.

[0150] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 65 to about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 5 minutes at a pH of about 1.2.

[0151] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, wherein about 65% to about 80% or more of the nominal dose of AP1189 is released in about 5 minutes in a monograph dissolution test.

[0152] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelate, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate, wherein about 65% to about 80% or more of the nominal dose of AP1189 is released in about 5 minutes in the monograph dissolution test.

[0153] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 65% to about 80% or more of the nominal dose of AP1189 is released in about 5 minutes in a monograph dissolution test.

[0154] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution at pH 1 (0.1 N HCl) in about 5 minutes.

[0155] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 65% to about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution at pH 1 in about 5 minutes.

[0156] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of AP1189 DL-mandelic acid, the salt of AP1189 hippuric acid, the salt of AP1189 L-lactic acid, the salt of AP1189 besylate, the salt of AP1189 oxoglutarate, the salt of AP1189 formic acid, the salt of AP1189 DL-lactic acid, the salt of AP1189 glutaric acid, the salt of AP1189 adipic acid, and the salt of AP1189 nitrate, wherein about 65 to about 80% or more of the pharmaceutically acceptable salt of AP1189 is dissolved in solution at pH 1 in about 5 minutes.

[0157] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 65 to about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution at pH 1 in about 5 minutes.

[0158] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution in about 10 minutes.

[0159] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 dissolves in solution in about 15 minutes.

[0160] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of AP1189 DL-mandelic acid, the salt of AP1189 hippuric acid, the salt of AP1189 L-lactic acid, the salt of AP1189 besylate, the salt of AP1189 oxoglutarate, the salt of AP1189 formic acid, the salt of AP1189 DL-lactic acid, the salt of AP1189 glutaric acid, the salt of AP1189 adipic acid, and the salt of AP1189 nitrate, wherein about 80% or more of the pharmaceutically acceptable salt of AP1189 is dissolved in solution in about 10 minutes, e.g., in about 15 minutes.

[0161] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 10 minutes.

[0162] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 15 minutes.

[0163] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution at about pH 1-3, e.g., about pH 0.5-3.5; e.g., about pH 0.5-1, e.g., about pH 1-1.5, e.g., about pH 1.5-2, e.g., about pH 2-2.5, e.g., about pH 2.5-3, e.g., about pH 3-3.5, in about 10 minutes; For example, at a pH of about 1 to 3, for example, about pH 0.5 to 3.5; for example, at a pH of about 0.5 to 1, for example, at a pH of about 1 to 1.5, for example, at a pH of about 1.5 to 2, for example, at a pH of about 2 to 2.5, for example, at a pH of about 2.5 to 3, for example, at a pH of about 3 to 3.5, it is dissolved into the solution in about 15 minutes.

[0164] In some embodiments, AP1189 is selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate. and an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution at about pH 1 to 3, e.g., about pH 0.5 to 3.5; e.g., about pH 0.5 to 1, e.g., about pH 1 to 1.5, e.g., about pH 1.5 to 2, e.g., about pH 2 to 2.5, e.g., about pH 2.5 to 3, e.g., about pH 3 to 3.5, in about 10 minutes; For example, at a pH of about 1 to 3, for example, about pH 0.5 to 3.5; for example, at a pH of about 0.5 to 1, for example, at a pH of about 1 to 1.5, for example, at a pH of about 1.5 to 2, for example, at a pH of about 2 to 2.5, for example, at a pH of about 2.5 to 3, for example, at a pH of about 3 to 3.5, it is dissolved into the solution in about 15 minutes.

[0165] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution in about 10 minutes at a pH of about 1 to 3, e.g., about pH 0.5 to 3.5; e.g., about pH 0.5 to 1, e.g., about pH 1 to 1.5, e.g., about pH 1.5 to 2, e.g., about pH 2 to 2.5, e.g., about pH 2.5 to 3, e.g., about pH 3 to 3.5.

[0166] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution at about pH 1.2 in about 10 minutes, at about pH 1.2 in about 15 minutes.

[0167] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of DL-mandelic acid of AP1189, the salt of hippuric acid of AP1189, the salt of L-lactic acid of AP1189, the salt of besylate of AP1189, the salt of oxoglutarate of AP1189, the salt of formic acid of AP1189, the salt of DL-lactic acid of AP1189, the salt of glutaric acid of AP1189, the salt of adipic acid of AP1189, and the salt of nitrate of AP1189, wherein about 80% or more of the pharmaceutically acceptable salt of AP1189 is dissolved in a 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.

[0168] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution at a pH of about 1.2 in about 10 minutes.

[0169] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein, wherein about 80% or more of the nominal dose of AP1189 is released in about 10 minutes in a monograph dissolution test.

[0170] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelate, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate, wherein about 80% or more of the nominal dose of AP1189 is released in about 10 minutes in the monograph dissolution test.

[0171] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the nominal dose of AP1189 is released in about 10 minutes in a monograph dissolution test.

[0172] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 disclosed herein is provided, wherein about 80% or more of the pharma- ceutically acceptable salt of AP1189 is dissolved in solution at a pH of about 1 in about 10 minutes, e.g., at a pH of about 1 in about 15 minutes.

[0173] In some embodiments, there is provided an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of DL-mandelic acid of AP1189, the salt of hippuric acid of AP1189, the salt of L-lactic acid of AP1189, the salt of besylate of AP1189, the salt of oxoglutarate of AP1189, the salt of formic acid of AP1189, the salt of DL-lactic acid of AP1189, the salt of glutaric acid of AP1189, the salt of adipic acid of AP1189, and the salt of nitrate of AP1189, wherein about 80% or more of the pharmaceutically acceptable salt of AP1189 is dissolved in a solution at a pH of about 1 in about 10 minutes, e.g., at a pH of about 1 in about 15 minutes.

[0174] In some embodiments, an oral formulation, e.g., a solid oral formulation, e.g., an immediate release solid oral formulation, comprising AP1189 acetate or AP1189 succinate is provided, wherein about 80% or more of the AP1189 acetate or AP1189 succinate is dissolved in solution at a pH of about 1 in about 10 minutes.

[0175] In some embodiments there is provided an oral formulation, e.g. a solid oral formulation, e.g. an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, wherein the disintegration time of said oral formulation, e.g. the solid oral formulation, is 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, for example, from 4 to 5 minutes, for example, from 5 to 6 minutes, for example, from 6 to 7 minutes, for example, from 7 to 8 minutes, for example, from 8 to 9 minutes, for example, from 9 to 10 minutes.

[0176] In some embodiments, the hydroxyl group is selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate salt. There is provided an oral formulation, e.g. a solid oral formulation, e.g. an immediate release solid oral formulation, comprising a pharma- ceutically acceptable salt of AP1189, wherein the disintegration time of said oral formulation, e.g. the solid oral formulation, is ½ minute to 10 minutes, such as ½ minute to 1 minute, for example, 1 to 2 minutes, for example, 2 to 3 minutes, for example, 3 to 4 minutes, for example, 4 to 5 minutes, for example, 5 to 6 minutes, for example, 6 to 7 minutes, for example, 7 to 8 minutes, for example, 8 to 9 minutes, for example, 9 to 10 minutes.

[0177] 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 acetate or AP1189 succinate, wherein the oral formulation, e.g. the solid oral formulation, has a disintegration time of ½ minute to 10 minutes, such as ½ minute to 1 minute, for example, 1 to 2 minutes, such as 2 to 3 minutes, for example, 3 to 4 minutes, for example, 4 to 5 minutes, such as 5 to 6 minutes, for example, 6 to 7 minutes, for example, 7 to 8 minutes, for example, 8 to 9 minutes, for example, 9 to 10 minutes.

[0178] In some embodiments, the oral formulation, e.g., the solid oral formulation, has a T of about 1-6 hours after administration, e.g., about 1-4 hours after administration, e.g., about 1-3 hours after administration, e.g., about 1-2 hours after administration. max to provide.

[0179] In some embodiments, the oral formulation, e.g., the solid oral formulation, has a T of about 6 hours after administration, such as about 5 hours after administration, such as about 4 hours after administration, such as about 3 hours after administration, such as about 2.5 hours after administration, such as about 2 hours after administration, such as about 1 hour after administration. max to provide.

[0180] In some embodiments, an oral formulation, e.g., a solid oral formulation, is provided comprising a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate, wherein T max is about 1 to 4 hours after administration, for example, about 1 to 3 hours after administration, for example, about 1 to 2 hours after administration.

[0181] In some embodiments, an oral formulation, e.g., a solid oral formulation, is provided comprising AP1189 acetate or AP1189 succinate, wherein T max is about 1 to 4 hours after administration, for example, about 1 to 3 hours after administration, for example, about 1 to 2 hours after administration.

[0182] In some embodiments, the elimination half-life of the oral formulation, eg, a solid oral formulation, is about 5 to 25 hours, such as 5 to 10 hours, such as 10 to 15 hours, such as 15 to 20 hours, such as 20 to 25 hours.

[0183] In some embodiments, the elimination half-life of the oral formulation, for example, a solid oral formulation, is about 4 to about 5 hours.

[0184] In some embodiments, the elimination half-life of the oral formulation, e.g., the solid oral formulation, is about 15 hours, such as about 16 hours, for example about 17 hours, such as about 18 hours, for example about 19 hours, such as about 20 hours, for example about 21 hours, such as about 22 hours, for example about 23 hours, such as about 24 hours, for example about 25 hours.

[0185] In some embodiments, the exposure dose (C max and / or AUC) is higher for a solid oral formulation containing AP1189 or a pharma- ceutical acceptable salt thereof than for an enteric coated tablet and / or an alkaline suspension containing AP1189 or a pharma-ceutical acceptable salt thereof.

[0186] In some embodiments, the exposure of a solid oral formulation comprising AP1189 or a pharma- ceutical acceptable salt thereof (C max and / or AUC) is equivalent to the exposure of an alkaline suspension containing AP1189 or a pharma- ceutical acceptable salt thereof.

[0187] In some embodiments, the exposure dose (C max and / or AUC) are higher for solid oral formulations containing AP1189 acetate or AP1189 succinate than the exposure for enteric coated tablets and / or alkaline suspensions containing AP1189 acetate or AP1189 succinate.

[0188] In some embodiments, the exposure (C) of a solid oral formulation comprising AP1189 acetate or AP1189 succinate ismax and / or AUC) are equivalent to the exposure of alkaline suspensions containing AP1189 acetate or AP1189 succinate.

[0189] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate salt. The relative bioavailability of a solid oral formulation containing a pharma- ceutically acceptable salt of AP1189 disclosed herein is about 0.7 to 1.8, for example, about 0.7, for example, about 0.8, for example, about 0.9, for example, about 1.0, for example, about 1.1, for example, about 1.2, for example, about 1.3, for example, about 1.4, for example, about 1.5, for example, about 1.6, for example, about 1.7, for example, about 1.8, compared to an alkaline suspension containing the above-mentioned pharma- ceutically acceptable salt of AP1189.

[0190] In some embodiments, the relative bioavailability of a solid oral formulation comprising AP1189 acetate or AP1189 succinate compared to an alkaline suspension comprising AP1189 acetate or AP1189 succinate is about 0.7 to 1.8, such as about 0.7, for example about 0.8, such as about 0.9, for example about 1.0, such as about 1.1, for example about 1.2, for example about 1.3, such as about 1.4, for example about 1.5, for example about 1.6, such as about 1.7, for example about 1.8.

[0191] In some embodiments, the AUC 0-24after administration of a single dose of a pharma- ceutically acceptable salt of AP1189, for example selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate; For example, after administration of a single dose of AP1189 acetate or AP1189 succinate: 1000hr*ng / mL or more, for example, 1200hr*ng / mL or more, for example, 1400hr*ng / mL or more, for example, 1600hr*ng / mL or more, for example, 1800hr*ng / mL or more, for example, 2000hr*ng / mL or more, for example, 2500hr*ng / mL or more, for example, 3000hr*ng / mL or more, for example, 3500hr*ng / mL or more, for example, 4000hr*ng / mL or more, for example, 4500hr*ng / mL or more, for example, 5000hr*ng / mL or more, for example, 5500hr*ng / mL or more, for example, 6000hr*ng / mL or more, for example, 6500hr*ng / mL or more, for example, 7000hr*ng / mL or more, for example, 7500hr*ng / mL or more, for example, 8000hr*ng / mL or more.

[0192] AUC 0-t is defined herein as the area under the concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration and was calculated using the linear trapezoidal method.

[0193] In some embodiments, the geometric mean AUC of solid oral formulations comprising AP1189 acetate 0-t had an AUC of 4423.40 (CV 20.8%) h*ng / mL after a single dose 0-t is within about 80.00% to about 125.00% of the above.

[0194] In some embodiments, the geometric mean AUC of solid oral formulations comprising AP1189 succinate 0-t had an AUC of 3526.23 (CV 23.0%) h*ng / mL after a single dose 0-t is within about 80.00% to about 125.00% of the above.

[0195] In some embodiments, the dose-normalized geometric mean AUC of a solid oral formulation comprising AP1189 acetate 0-t / D had an AUC of 44.23 (CV 20.8%) h*ng / mL after single dose administration. 0-t is within about 80.00% to about 125.00% of the above.

[0196] In some embodiments, the dose-normalized geometric mean AUC of a solid oral formulation comprising AP1189 succinate 0-t / D had an AUC of 35.26 (CV 23.0%) h*ng / mL after single dose administration. 0-t is within about 80.00% to about 125.00% of the above.

[0197] In some embodiments, the AUC 0-t is 0 to 24 hours.

[0198] AUC 0-infinity AUC 0-∞ is herein referred to as AUC 0-t +AUC t-∞ where AUC is the average of the mean squared mean squared mean squared. t-∞ =Ct / k e where Ct is the measured concentration at the last quantifiable concentration t, k e is the terminal plasma elimination rate constant.

[0199] In some embodiments, the geometric mean AUC of solid oral formulations comprising AP1189 acetate 0-infinity had an AUC of 4840.61 (CV 18.2%) h*ng / mL after a single dose 0-infinity is within about 80.00% to about 125.00% of the above.

[0200] In some embodiments, the geometric mean AUC of solid oral formulations comprising AP1189 succinate 0-infinity had an AUC of 4013.18 (CV 20.2%) h*ng / mL after a single dose 0-infinity is within about 80.00% to about 125.00% of the above.

[0201] In some embodiments, the dose-normalized geometric mean AUC of a solid oral formulation comprising AP1189 acetate 0-infinity / D had an AUC of 48.41 (CV 18.2%) h*ng / mL after single dose administration. 0-infinity is within about 80.00% to about 125.00% of the above.

[0202] In some embodiments, the dose-normalized geometric mean AUC of a solid oral formulation comprising AP1189 succinate 0-infinity / D had an AUC of 40.13 (CV 20.2%) h*ng / mL after single dose administration. 0-infinity is within about 80.00% to about 125.00% of the above.

[0203] In some embodiments, the AUC is measured after administration of a single dose of 100 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 50 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 200 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 83 mg of AP1189 acetate (calculated as free base).

[0204] In some embodiments, the AUC is measured after administration of a single dose of 100 mg AP1189 succinate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 50 mg AP1189 succinate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 200 mg AP1189 succinate (calculated as free base).

[0205] In some embodiments, the AUC is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject.

[0206] In some embodiments, the AUC is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject, in the fasted state.

[0207] In some embodiments, the fasting state comprises a minimum of 10 hours of overnight fasting.

[0208] In some embodiments, the AUC is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject, in the postprandial state.

[0209] In some embodiments, the postprandial state involves a high fat standard breakfast consumed 30 minutes prior to dosing and after collection of a pre-dose blood sample for PK.

[0210] In some embodiments, after administration of a single dose of a pharma- ceutically acceptable salt of AP1189: For example, after administration of a single dose of a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate; For example, after administration of a single dose of AP1189 acetate or AP1189 succinate, the C maxis 180ng / mL or more, for example, 200ng / mL or more, for example, 225ng / mL or more, for example, 250ng / mL or more, for example, 275ng / mL or more, for example, 300ng / mL or more, for example, 350ng / mL or more, for example, 400ng / mL or more, for example, 450ng / mL or more, for example, 500ng / mL or more, for example, 600ng / mL or more, for example, 700ng / mL or more, for example, 800ng / mL or more, for example, 900ng / mL or more, for example, 1000ng / mL or more, g / mL or more, for example, 1200 ng / mL or more, for example, 1400 ng / mL or more, for example, 1600 ng / mL or more, for example, 1800 ng / mL or more, for example, 2000 ng / mL or more, for example, 2200 ng / mL or more, for example, 2400 ng / mL or more, for example, 2600 ng / mL or more, for example, 2800 ng / mL or more, for example, 3000 ng / mL or more, for example, 3200 ng / mL or more, for example, 3400 ng / mL or more, for example, 3600 ng / mL or more.

[0211] In some embodiments, the geometric mean C of the solid oral formulation comprising AP1189 acetate is max had a C of 302.70 (CV 31.1%) ng / mL after a single dose. max is within about 80.00% to about 125.00% of the above.

[0212] In some embodiments, the geometric mean C of the solid oral formulation comprising AP1189 succinate max had a C of 255.93 (CV 18.6%) ng / mL after a single dose. max is within about 80.00% to about 125.00% of the above.

[0213] In some embodiments, the dose-normalized geometric mean C of a solid oral formulation comprising AP1189 acetate is max / D had a C of 3.03 (CV 31.1%) ng / mL / mg after single dose administration. max / D is within about 80.00% to about 125.00%.

[0214] In some embodiments, the dose-normalized geometric mean C of a solid oral formulation comprising AP1189 succinatemax / D had a C of 2.56 (CV 18.6%) ng / mL / mg after single dose administration. max / D is within about 80.00% to about 125.00%.

[0215] In some embodiments, the AUC is measured after administration of a single dose of 100 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 50 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 200 mg of AP1189 acetate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 83 mg of AP1189 acetate (calculated as free base).

[0216] In some embodiments, the AUC is measured after administration of a single dose of 100 mg AP1189 succinate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 50 mg AP1189 succinate (calculated as free base). In some embodiments, the AUC is measured after administration of a single dose of 200 mg AP1189 succinate (calculated as free base).

[0217] In some embodiments, the above C max is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject.

[0218] In some embodiments, the above C max is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject, in the fasting state.

[0219] In some embodiments, the above C max is measured after administration of a single dose to a human subject, e.g., a healthy male Caucasian subject, in the postprandial state.

[0220] In some embodiments, the solid oral dosage form comprises a pharma- ceutically acceptable salt of AP1189 (calculated as the free base of AP1189) at a dosage 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 per tablet.

[0221] In some embodiments, the solid oral dosage form contains an AP1189 dosage of about 25 mg to about 650 mg per tablet, such as 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. The present invention includes a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 nitrate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formate, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate (calculated as AP1189 free base).

[0222] In some embodiments, the solid oral dosage form comprises AP1189 acetate at a dosage of about 25 mg to about 650 mg, e.g., about 25 mg, e.g., about 50 mg, e.g., about 100 mg, e.g., about 150 mg, e.g., about 200 mg, e.g., about 250 mg, e.g., about 300 mg, e.g., about 350 mg, e.g., about 400 mg, e.g., about 450 mg, e.g., about 500 mg, e.g., about 550 mg, e.g., about 600 mg, e.g., about 650 mg, of AP1189 per tablet (calculated as the free base of AP1189). For clarity, a tablet containing about 100 mg of AP1189 contains about 120 mg of AP1189 acetate.

[0223] In some embodiments, the solid oral dosage form comprises AP1189 acetate in a dosage of about 25 mg per tablet, such as about 50 mg, such as about 100 mg, such as about 150 mg, such as about 200 mg per tablet.

[0224] In some embodiments, the solid oral dosage form comprises AP1189 succinate at a dosage of about 25 mg to about 650 mg, e.g., about 25 mg, e.g., about 50 mg, e.g., about 100 mg, e.g., about 150 mg, e.g., about 200 mg, e.g., about 250 mg, e.g., about 300 mg, e.g., about 350 mg, e.g., about 400 mg, e.g., about 450 mg, e.g., about 500 mg, e.g., about 550 mg, e.g., about 600 mg, e.g., about 650 mg, of AP1189 per tablet (calculated as the free base of AP1189). For clarity, a tablet containing about 100 mg of AP1189 contains about 140 mg of AP1189 succinate.

[0225] In some embodiments, the solid oral dosage form comprises AP1189 succinate in a dosage of about 25 mg per tablet, such as about 50 mg, such as about 100 mg, such as about 150 mg, such as about 200 mg per tablet.

[0226] One aspect of the present disclosure is directed to a pharmaceutical composition comprising a pharmaceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate salt, and at least one pharmaceutically acceptable excipient; For example, to provide a solid oral dosage form comprising one or more gastroretentive excipients, such as one or more immediate release excipients.

[0227] One aspect of the present disclosure is to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (AP1189 acetate) and at least one pharma- ceutically acceptable excipient.

[0228] One aspect of the present disclosure is to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (AP1189 acetate) and at least one pharma- ceutically acceptable excipient, such as one or more gastroretentive excipients.

[0229] One aspect of the present disclosure is to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (AP1189 acetate) and at least one pharma- ceutically acceptable excipient, such as one or more immediate release excipients.

[0230] One aspect of the present disclosure is to provide a solid oral formulation comprising (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (AP1189 succinate) and at least one pharma- ceutically acceptable excipient, such as one or more immediate release excipients.

[0231] The solid oral formulations, such as the immediate release solid oral formulations of the present disclosure, can be formulated by any means known to one of skill in the art to provide immediate release of the pharma- ceutically acceptable salt of AP1189 described above.

[0232] A solid oral formulation, such as the immediate release solid oral formulation of the present disclosure, can be formulated by any means known to one of skill in the art to provide immediate release of the pharma- ceutically acceptable salt of AP1189 in the gastric compartment.

[0233] In some embodiments, oral formulations of the present disclosure, such as solid oral formulations, comprise at least one pharma- ceutically acceptable excipient as described above.

[0234] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises a bulking agent. In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more bulking agents.

[0235] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises a filler that is microcrystalline cellulose (MCC).

[0236] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises a filler selected from the group consisting of microcrystalline cellulose (MCC), silicified microcrystalline cellulose, and mannitol.

[0237] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more binders.

[0238] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more binders that are maltodextrin.

[0239] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more disintegrants.

[0240] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more intergranular disintegrants.

[0241] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more disintegrants that are sodium starch glycolate.

[0242] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more wetting agents.

[0243] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more wetting agents that is polysorbate 80.

[0244] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more flow agents or lubricants.

[0245] In some embodiments, the at least one pharma- ceutically acceptable excipient comprises one or more flow agents or lubricants that is magnesium stearate.

[0246] In some embodiments, the oral formulation is first prepared as granules containing the pharma- ceutically acceptable salt of AP1189, which are then compressed into tablets.

[0247] In some embodiments, the granules are wet granules.

[0248] In some embodiments, the oral formulation is first prepared as granules comprising the pharma- ceutically acceptable salt of AP1189 and one or more pharma- ceutically acceptable excipients, which are then compressed into tablets.

[0249] In some embodiments, the oral formulation is first prepared as a granule comprising the pharma- ceutically acceptable salt of AP1189 and one or more pharma- ceutically acceptable excipients, which is further mixed with one or more pharma- ceutically acceptable excipients (or fillers) and then compressed into tablets.

[0250] In some embodiments the granules comprise about 30% to about 70% w / w AP1189 (free base); such as about 30-35% w / w, for example about 35-40% w / w, such as about 40-45% w / w, for example about 45-50% w / w, such as about 50-55% w / w, for example about 55-60% w / w, such as about 60-65% w / w, for example about 65-70% w / w, such as about 60-65% w / w, for example about 65-70% w / w AP1189 (free base).

[0251] In some embodiments the granules comprise about 50% w / w, such as about 55% w / w, for example about 60% w / w, such as about 65% w / w, for example about 70% w / w, such as about 75% w / w of AP1189 (free base).

[0252] In some embodiments, the granules comprise a pharma- ceutically acceptable salt of AP1189; for example, an AP1189 salt selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate. 189; for example, about 60% to about 90% w / w of a pharma- ceutically acceptable salt of AP1189, such as AP1189 acetate or AP1189 succinate, for example, about 65% to about 85% w / w; for example, about 60-65% w / w, for example, about 65-70% w / w, for example, about 70-75% w / w, for example, about 70-75% w / w, for example, about 75-80% w / w, for example, about 80-85% w / w, for example, about 85-90% w / w of a pharma-ceutically acceptable salt of AP1189.

[0253] In some embodiments, the granules comprise a pharma- ceutically acceptable salt of AP1189; for example, AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formate salt, AP1189 DL-lactic acid salt, AP1189 glutarate, AP1189 acetone salt ... A pharma- ceutically acceptable salt of AP1189 selected from the group consisting of an acid salt, an adipic acid salt of AP1189, and a nitrate salt of AP1189; for example comprising about 60% w / w, such as about 65% w / w, for example about 70% w / w, such as about 75% w / w, for example about 80% w / w, for example about 85% w / w, for example about 90% w / w of an acetate or a succinate salt of AP1189.

[0254] In some embodiments, the granules comprise about 75% w / w of a pharma- ceutically acceptable salt of AP1189, e.g., selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate salt.

[0255] In some embodiments, the granules comprise about 75% w / w AP1189 acetate.

[0256] In some embodiments, the granules comprise about 75% w / w AP1189 succinate.

[0257] In some embodiments, the granules comprise about 62.4% w / w AP1189 (free base).

[0258] In some embodiments, the granules comprise at least one pharma- ceutically acceptable excipient.

[0259] In some embodiments, the granules comprise at least one pharma- ceutically acceptable excipient selected from the group consisting of fillers, binders, disintegrants, and wetting agents.

[0260] In some embodiments, the granules comprise a pharma- ceutically acceptable salt of AP1189, such as a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, the salt of AP1189 DL-mandelic acid, the salt of AP1189 hippuric acid, the salt of AP1189 L-lactic acid, the salt of AP1189 besylate, AP1189 oxoglutarate, the salt of AP1189 formic acid, the salt of AP1189 DL-lactic acid, the salt of AP1189 glutaric acid, the salt of AP1189 adipic acid, and the salt of AP1189 nitrate, and at least one pharma- ceutically acceptable excipient selected from the group consisting of a filler, a binder, a disintegrant, and a wetting agent.

[0261] In some embodiments, the granules comprise AP1189 acetate or succinate and at least one pharma- ceutically acceptable excipient selected from the group consisting of fillers, binders, disintegrants and wetting agents.

[0262] In some embodiments, the granules comprise a filler, a binder, a disintegrant, and a wetting agent.

[0263] In some embodiments, the granules are mixed with one or more additional fillers.

[0264] In some embodiments, the granules are mixed with one or more additional fillers before being compressed into a tablet.

[0265] In some embodiments, the granules are mixed with one or more additional fillers and one or more flow agents or lubricants.

[0266] In some embodiments, the granules are mixed with one or more additional fillers and one or more flow agents or lubricants prior to compression into tablets.

[0267] In some embodiments, the one or more additional fillers are selected from the group consisting of silicified microcrystalline cellulose and mannitol.

[0268] In some embodiments, the granules are mixed with the fillers silicified microcrystalline cellulose and mannitol in a ratio of about 3:1.

[0269] In some embodiments, the one or more flow agents or lubricants is magnesium stearate.

[0270] In some embodiments, the granules are compressed into a tablet.

[0271] In some embodiments, the tablet thickness is about 1 to 20 mm, such as about 1 to 2 mm, for example about 2 to 3 mm, for example about 3 to 4 mm, for example about 4 to 5 mm, for example about 5 to 6 mm, for example about 6 to 7 mm, for example about 7 to 8 mm, for example about 8 to 9 mm, for example about 9 to 10 mm, for example about 10 to 11 mm, for example about 11 to 12 mm, for example about 12 to 13 mm, for example about 13 to 14 mm, for example about 14 to 15 mm, for example about 15 to 16 mm, for example about 16 to 17 mm, for example about 17 to 18 mm, for example about 18 to 19 mm, for example about 19 to 20 mm.

[0272] In some embodiments the tablet thickness is about 2 mm, such as about 2.5 mm, for example about 3 mm, such as about 3.5 mm, for example about 4 mm, such as about 4.5 mm, for example about 5 mm, such as about 5.5 mm, for example about 6 mm, such as about 6.5 mm, for example about 7 mm, such as about 7.5 mm, for example about 8 mm, such as about 8.5 mm, for example about 9 mm.

[0273] In some embodiments, the tablet thickness is about 5.5 mm.

[0274] In some embodiments, the tablet is oval in shape.

[0275] In some embodiments, the tablets are compressed into an oval shape. In some embodiments, the tablets are oval shaped.

[0276] In some embodiments, the tablet is about 15.5x7.1 mm. In some embodiments, the tablet is about 10-20 mmx5-10 mm.

[0277] In some embodiments, the tablets are coated, hi some embodiments, the tablets are film coated.

[0278] In some embodiments, the tablets are coated with hypromellose.

[0279] In some embodiments, the tablets are coated to achieve a weight gain of about 4%, hi some embodiments, the tablets are coated to achieve a weight gain of about 2-6%, such as 2-3%, for example 3-4%, such as 4-5%, for example 5-6%.

[0280] In some embodiments the tablets are coated to achieve a weight gain of about 1%, such as about 2%, for example about 3%, such as about 4%, for example about 5%, such as about 6%, for example about 7%, such as about 8%, for example about 9%, for example about 10%.

[0281] Dosage According to the present disclosure, oral formulations containing the compounds of the present disclosure are administered in a pharma- ceutically effective dose to an individual in need of treatment. A therapeutically effective amount of a compound is an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially prevent 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 compounds may be administered once or several times per day, for example, 1-8 times / day, for example, 1-6 times / day, for example, 1-5 times / day, for example, 1-4 times / day, for example, 1-3 times / day, for example, 1-2 times / day, for example, 2-4 times / day, for example, 2-3 times / day. Alternatively, the compounds may be administered less than once per day, for example, once per day, once every 2 days, for example, once every 3 days, once every 4 days, for example, once every 5 days, once every 6 days, for example, once every week.

[0282] In some embodiments, oral formulations containing compounds of the disclosure are administered in a therapeutically effective amount, for example, between 1 mg and 1000 mg of AP1189 per day (calculated as the free base).

[0283] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 1 mg to 1000 mg, 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 per day. All dosages of pharma- ceutically acceptable salts of AP1189 presented herein are calculated as the free base, unless otherwise indicated.

[0284] In some embodiments, "daily" means that the dosage 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).

[0285] In some embodiments, the oral formulations of the present disclosure are administered once daily.

[0286] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 1 mg to 1000 mg, 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, per dose.

[0287] In some embodiments, the pharma- ceutically acceptable salt of AP1189 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.

[0288] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is administered in an amount of 50 mg once daily.

[0289] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 50 mg twice daily (BID) or 50 mg three times daily (TID).

[0290] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is administered in an amount of 100 mg once daily.

[0291] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 100 mg twice daily (BID) or 100 mg three times daily (TID).

[0292] In some embodiments, the pharma- ceutically acceptable salt of AP1189 is administered in an amount of 200 mg once daily.

[0293] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 200 mg twice daily (BID) or 200 mg three times daily (TID).

[0294] In some embodiments, AP1189 or a pharma- ceutically acceptable salt thereof is administered in an amount of 400 mg once daily.

[0295] In some embodiments, a pharma- ceutically acceptable salt of AP1189 is administered in an amount of 400 mg twice daily (BID) or 200 mg three times daily (TID).

[0296] In some embodiments, the daily dosage of a pharma- ceutically acceptable salt of AP1189 is divided into multiple dosage forms and / or administrations.

[0297] In another embodiment, the pharma- ceutically acceptable salt of AP1189 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.

[0298] Medical Use One aspect of the present disclosure is to provide an oral formulation as disclosed herein comprising a pharma- ceutically acceptable salt of AP1189 that is soluble or highly soluble at pH 1.2 as disclosed herein, for example a pharma- ceutically acceptable salt of AP1189 selected from the group consisting of AP1189 acetate, AP1189 succinate, AP1189 DL-mandelic acid salt, AP1189 hippuric acid salt, AP1189 L-lactic acid salt, AP1189 besylate, AP1189 oxoglutarate, AP1189 formic acid salt, AP1189 DL-lactic acid salt, AP1189 glutaric acid salt, AP1189 adipic acid salt, and AP1189 nitrate, in particular AP1189 acetate or AP1189 succinate, for use in the treatment of a disease or disorder.

[0299] One aspect of the present disclosure is to provide an oral formulation as disclosed herein comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, which is soluble or highly soluble at pH 1.2, for use in treating a disease or disorder in a subject, wherein the subject to be treated is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a livestock animal. In some embodiments, the mammal is selected from the group consisting of a mouse, a rat, a dog, a cat, a horse, a cow, a sheep, and a pig.

[0300] In some embodiments, the disease or disorder is selected from the group consisting of a renal disease, an arthritic disease, a viral disease or disorder, a cardiovascular disease and / or atherosclerosis, and a systemic inflammatory disorder.

[0301] kidney disease An aspect of the present disclosure is to provide an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in treating or preventing renal disease.

[0302] Also disclosed is a method of treating or preventing renal disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oral formulation, pharmaceutical composition, or unit dosage form of the present disclosure.

[0303] Also disclosed is the use of an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of renal disease.

[0304] In some embodiments of the present disclosure, there is provided an oral formulation, e.g., a solid oral formulation, for use in the treatment or prevention of renal disease, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, e.g., AP1189 acetate or AP1189 succinate, and at least one pharma- ceutically acceptable excipient as disclosed herein.

[0305] In some embodiments, the renal disease is manifested by proteinuria, hi some embodiments, the renal disease is proteinuric renal disease.

[0306] In some embodiments, the renal disease is a glomerular disease.

[0307] In some embodiments, the kidney disease is nephrotic syndrome (glomerular nephropathy).

[0308] In some embodiments, the kidney disease is primary nephrotic syndrome (primary glomerular nephropathy).

[0309] In some embodiments, the primary nephrotic syndrome is membranous glomerulonephritis (MGN) (or membranous nephropathy (MN)).

[0310] In some embodiments, the primary nephrotic syndrome is focal segmental glomerulosclerosis (FSGS).

[0311] In some embodiments, the primary nephrotic syndrome is membranoproliferative glomerulonephritis (MPGN) (mesangiocapillary glomerulonephritis).

[0312] In some embodiments, the membranoproliferative glomerulonephritis (MPGN) is selected from type 1 MPGN and type 2 MPGN.

[0313] In some embodiments, the primary nephrotic syndrome is rapidly progressive glomerulonephritis (RPGN) (crescentic GN).

[0314] In some embodiments, the primary nephrotic syndrome is minimal change disease (MCD).

[0315] In some embodiments, the kidney disease is secondary nephrotic syndrome (secondary glomerular nephropathy).

[0316] In some embodiments, the secondary nephrotic syndrome is caused by an underlying autoimmune disease, an underlying cancer disease, an underlying genetic disorder, 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 genetic disorders (such as congenital nephrotic syndrome).

[0317] In some embodiments, the secondary nephrotic syndrome is caused by diabetic nephropathy, an infection, e.g., 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, urinary schistosomiasis, and Ebola. In some embodiments, the secondary nephrotic syndrome is drug-induced.

[0318] In some embodiments, the kidney disease is an inflammatory kidney disease.

[0319] 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.

[0320] In some embodiments, the renal disease is idiopathic membranous nephropathy (iMN).

[0321] 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 idiopathic membranous nephropathy (iMN).

[0322] Arthritic diseases An aspect of the present disclosure is to provide an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in treating or preventing an arthritic disease.

[0323] Also disclosed is a method of treating or preventing an arthritic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oral formulation, pharmaceutical composition, or unit dosage form of the present disclosure.

[0324] Also disclosed is the use of an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of arthritic diseases.

[0325] In some embodiments, an oral formulation as disclosed herein is provided, comprising a soluble or highly soluble pharmacologic salt of AP1189 as disclosed herein, for use in treating an arthritic disease in a subject, wherein the subject being treated is a mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a livestock animal. In some embodiments, the mammal is selected from the group consisting of a mouse, a rat, a dog, a cat, a horse, a cow, a sheep, and a pig.

[0326] In some embodiments of the present disclosure, there is provided an oral formulation, e.g., a solid oral formulation, for use in the treatment or prevention of arthritic diseases, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, e.g., AP1189 acetate or AP1189 succinate, and optionally at least one pharma- ceutically acceptable excipient as disclosed herein.

[0327] In one embodiment, the arthritic disease is an autoimmune and / or inflammatory disease with inflammation of the joints.

[0328] In one embodiment, the arthritic disease is selected from the group consisting of inflammatory arthritis, osteoarthritis, metabolic arthritis, reactive arthritis and infectious arthritis.

[0329] In one embodiment, the arthritic disease is inflammatory arthritis.

[0330] In one embodiment, the inflammatory arthritis is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis.

[0331] In one embodiment, the inflammatory arthritis is rheumatoid arthritis (RA).

[0332] In one embodiment, the rheumatoid arthritis is severely active RA (CDAI>22). In one embodiment, the rheumatoid arthritis is RA with a CDAI>22.

[0333] In one embodiment, the rheumatoid arthritis is RA with a DAS28 score of greater than 5.1.

[0334] In one embodiment, the rheumatoid arthritis is juvenile rheumatoid arthritis (JRA).

[0335] In one embodiment, the osteoarthritis is osteoarthritis.

[0336] In one embodiment, the metabolic arthritis is gouty arthritis.

[0337] 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.

[0338] In one embodiment, the arthritic disease is arthritis as part of a systemic inflammatory disease.

[0339] In one embodiment, arthritis as part of a systemic inflammatory disease, for example an inflammatory disease selected from the group consisting of systemic lupus erythematosus, mixed connective tissue disease, Still's disease, and polymyalgia rheumatica.

[0340] 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 rheumatoid arthritis.

[0341] In some embodiments, there is provided an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure in combination with MTX (methotrexate) for use in the treatment or prevention of rheumatoid arthritis.

[0342] In some embodiments, there is provided an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure, alone or in combination with MTX (methotrexate), for use in the treatment or prevention of rheumatoid arthritis in patients who have an inadequate response to MTX (e.g., patients who have a reduced response to MTX treatment, e.g., MTX non-responders).

[0343] Viral diseases or disorders It is an aspect of the present disclosure to provide an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in treating or preventing a viral disease or disorder.

[0344] Also disclosed is a method of treating or preventing a viral disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oral formulation, pharmaceutical composition, or unit dosage form of the present disclosure.

[0345] Also disclosed is the use of an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of a viral disease or disorder.

[0346] In some embodiments of the present disclosure, there is provided an oral formulation, e.g., a solid oral formulation, for use in the treatment or prevention of a viral disease or disorder, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, e.g., AP1189 acetate or AP1189 succinate, and at least one pharma- ceutically acceptable excipient as disclosed herein.

[0347] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder.

[0348] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder associated with inflammation, eg, hyperinflammation.

[0349] In some embodiments, the viral disease or disorder is a symptomatic viral disease or disorder with inflammation, such as hyperinflammation, in one or more organs. Inflammation in one or more organs can also be referred to as local inflammation.

[0350] In some embodiments, 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 (such as the phallopian tubes), eye, ear, vascular system, gastrointestinal tract (such as the small intestine, colon, rectum, anal canal), and prostate.

[0351] In some embodiments, the viral disease or disorder is an inflammatory viral disease or disorder.

[0352] In some embodiments, the viral disease or disorder is a viral respiratory infection, such as a viral lower respiratory tract infection.

[0353] In some embodiments, the viral disease or disorder is a viral respiratory disease or disorder.

[0354] In some embodiments, the viral disease or disorder is a pulmonary viral disease or disorder.

[0355] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with inflammation in the respiratory system, for example in the lungs and / or airways.

[0356] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with 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, oxygen impairment, respiratory disease, respiratory insufficiency, respiratory failure, respiratory syndrome, and acute respiratory disease (ARD).

[0357] In some embodiments, the viral disease or disorder is a severe disease manifested by difficulty breathing, increased respiratory rate, decreased blood oxygen saturation, and / or pulmonary infiltrates.

[0358] 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).

[0359] In some embodiments, the viral disease or disorder is viral pneumonia.

[0360] In some embodiments, the viral disease or disorder is viral bronchiolitis.

[0361] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with respiratory failure.

[0362] In some embodiments, the viral disease or disorder is acute respiratory distress syndrome (ARDS).

[0363] In some embodiments, the viral disease or disorder is viral acute respiratory distress syndrome (ARDS), such as viral-induced ARDS.

[0364] In some embodiments, the viral disease or disorder is symptomatic COVID-19 with acute respiratory distress syndrome (ARDS).

[0365] 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.

[0366] In some embodiments, the viral disease or disorder is systemic inflammatory distress syndrome (SIDS) and / or a viral disease or disorder associated with sepsis.

[0367] In some embodiments, the viral disease or disorder is a viral disease or disorder associated with pulmonary dysfunction.

[0368] 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).

[0369] 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 (such as types A, B, and C).

[0370] Cardiovascular disease and / or atherosclerosis It is an aspect of the present disclosure to provide an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the treatment or prevention of cardiovascular disease and / or atherosclerosis.

[0371] Also disclosed is a method of treating or preventing cardiovascular disease and / or atherosclerosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oral formulation, pharmaceutical composition, or unit dosage form of the present disclosure.

[0372] Also disclosed is the use of an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of cardiovascular disease and / or atherosclerosis.

[0373] In some embodiments of the present disclosure, there is provided an oral formulation, e.g., a solid oral formulation, for use in the treatment or prevention of cardiovascular disease and / or atherosclerosis comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, e.g., AP1189 acetate or AP1189 succinate, and at least one pharma- ceutically acceptable excipient as disclosed herein.

[0374] In some embodiments, the cardiovascular disease is selected from the group consisting of coronary artery disease (CAD), e.g., angina pectoris and myocardial infarction (commonly known as heart attack); stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathies, heart rhythm disorders, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, vascular disease, thromboembolic disease, and venous thrombosis.

[0375] In some embodiments, the cardiovascular disease is atherosclerotic cardiovascular disease.

[0376] In some embodiments, the atherosclerotic cardiovascular disease is selected from the group consisting of coronary artery disease, stroke (cerebrovascular disease), and peripheral artery disease.

[0377] In some embodiments, the cardiovascular disease is vascular inflammation.

[0378] Systemic inflammatory disorders An aspect of the present disclosure is to provide an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in treating or preventing a systemic inflammatory disorder.

[0379] Also disclosed is a method of treating or preventing a systemic inflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an oral formulation, pharmaceutical composition, or unit dosage form of the disclosure.

[0380] Also disclosed is the use of an oral formulation, pharmaceutical composition, or unit dosage form according to the present disclosure for use in the manufacture of a medicament for the treatment or prevention of a systemic inflammatory disorder.

[0381] In some embodiments of the present disclosure, there is provided an oral formulation, e.g., a solid oral formulation, for use in the treatment or prevention of a systemic inflammatory disorder, comprising a pharma- ceutically acceptable salt of AP1189 as disclosed herein, e.g., AP1189 acetate or AP1189 succinate, and at least one pharma- ceutically acceptable excipient as disclosed herein.

[0382] Systemic disorders that may involve the nervous system include a variety of diseases with presumed inflammatory and autoimmune pathomechanisms, including Behçet's disease, sarcoidosis, systemic lupus erythematosus, juvenile idiopathic arthritis, scleroderma, and Sjögren's syndrome. This group of diseases includes systemic inflammatory disorders with genetically defined dysregulation of the innate immune system and systemic autoimmune disorders characterized by alterations in adaptive immunity, such as autoantibodies and autoreactive T cells.

[0383] In some embodiments, the systemic inflammatory disorder is an autoimmune disorder.

[0384] In some embodiments, the systemic inflammatory disorder is selected from the group consisting of Behcet's disease, sarcoidosis, systemic lupus erythematosus, juvenile idiopathic arthritis, scleroderma, Sjogren's syndrome, myositis, e.g., dermatomyositis and polymyositis, vasculitis, giant cell arteritis, ankylosing spondylitis, polymyalgia rheumatica, and psoriatic arthritis. EXAMPLES

[0385] Example 1: Solubility of AP1189 salts method The solubility of AP1189 acetate, tosylate, fumarate and succinate salts was evaluated in 0.2 M buffers at pH 1.2, 4.5 and 6.8, or 0.5 M buffers at pH 1.2 and 4.5. The amounts of salts were suspended in the buffers and stirred at ambient temperature for 24 h, after which the supernatants were sampled and analyzed for AP1189 content by HPLC.

[0386] Exemplary Procedure for Formation of Acetate Salts 0.9 equivalents of acetic acid was added slowly with stirring to 3-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl]-propanal and aminoguanidine bicarbonate in ethanol. Heat at 50-55°C for 1 hour, add another 0.11 equivalents of acetic acid, and heat the mixture to reflux for at least 2 hours. Cool the suspension to 60°C and add tert-butyl methyl ether. Cool and hold at 2-5°C for 10-16 hours. Filter, wash with tert-butyl methyl ether, then recrystallize from ethanol.

[0387] This procedure produces a polymorph of AP1189 acetate corresponding to XRPD pattern 1 ("Form A" in Table 1b).

[0388] Exemplary Procedure for the Formation of Succinate Salt of AP1189 2-propanol:water 90:10 v / v was added to AP1189 acetate to prepare a slurry. 2-propanol:water 90:10 v / v was added to 1.1 equivalents of succinic acid. This counterion slurry was added to the acetate slurry. Temperature cycling was performed between ambient and 40°C for approximately 18 hours with a 4 hour hold period at ambient temperature and a 4 hour hold period at 40°C. The entire slurry was then isolated by Büschner filtration and washed with deionized water. The solid was dried under vacuum at ambient temperature.

[0389] This procedure produced a polymorph of AP1189 succinate salt corresponding to XRPD pattern 1 ("Form B" in Table 1b).

[0390] The tosylate salt of AP1189, having XRPD pattern 1, was prepared by crystallization from methanol.

[0391] The fumarate salt of AP1189 ("Form D" in Table 1b) having XRPD pattern 1 was prepared by crystallization from isopropyl alcohol:water 90:10 v / v.

[0392] result The results of the test are shown in Tables 1a and 1b. [Table 1]

[0393] In the pH 1.2 succinate experiment, there was insufficient material available at the time of the experiment to maintain a suspension.

[0394] [Table 2]

[0395] conclusion The test compounds showed significantly different solubilities, especially at low pH. Specifically, the acetate and succinate salts showed high solubility at pH 1.2, indicating the potential use of these compounds in applications where high solubility at low pH is desirable, such as in immediate release pharmaceutical formulations for gastric delivery.

[0396] Example 2: Further solubility studies of AP1189 salts Solubility of AP1189 acetate and AP1189 succinate Materials and Methods To separate vials containing 10.0 mL of buffer pH 1.2, 3.4 g of AP1189 succinate and 2.9 g of AP1189 acetate were added (one measurement per salt). The pH was measured to be 3.9 and 2.2 for the AP1189 acetate and AP1189 succinate solutions, respectively. As a result, the pH was adjusted to 1.2 in both solutions using concentrated hydrochloric acid. Both sample preparations were diluted 500 times with sample diluent (acetonitrile:water 1:1 v / v).

[0397] These diluted sample preparations were analyzed by HPLC within 5 hours after preparation, and the AP1189 content was determined from the area under the curve by comparison with standard solutions of AP1189 acetate and AP1189 succinate, respectively.

[0398] Equilibrium solubility was also evaluated at pH 4.5 and pH 6.8 according to the procedure described in WHO Technical Report Series 1019, 2019 annex 4: Protocol to conduct equilibrium solubility experiments for the purpose of Biopharmaceutics Classification System-based classification of active pharmaceutical ingredients for biowaiver.

[0399] result The sample material in both vials was allowed to completely dissolve before dilution. The solubility of the test compounds at pH 1.2 is shown in Table 2. The solubility of the test compounds at pH 4.5 and pH 6.8 is shown in Table 3 and all were found to be within 92%-95% purity.

[0400] Table 2. Measured concentrations of AP1189 acetate and AP1189 succinate in pH 1.2 samples. HPLC purity is also included in the table. The first purity result was obtained from the CoAs of the lot, the second purity result was determined in a solubility experiment.

[0401] [Table 3]

[0402] Table 3. Summary of equilibrium solubilities (including standard deviations) of AP1189 acetate and AP1189 succinate in pH 4.5 and 6.8 buffer solutions at 37° C. HPLC purity is also included in the table. The first purity result was obtained from the CoAs of the lot, and the second purity result was measured in the solubility experiment. [Table 4]

[0403] [Table 5] TIFF2024522817000011.tif40159

[0404] Example 3: Dissolution of AP1189 acetate and AP1189 succinate tablets In the dissolution experiment, the dissolution profile of a powder formulation based on AP1189 acetate is compared with that for 200 mg tablets made based on AP1189 acetate and AP1189 succinate.

[0405] Materials and Methods Tablets: RDT2101-6-T3-C1, AP1189 acetate (200 mg AP1189 acetate, 167 mg AP1189 equivalent) Tablets: RD2103-2-T1-C1, AP1189 succinate (200 mg AP1189 acetate equivalent, 167 mg AP1189) Powder: AP1189 Acetate (200 mg AP1189 Acetate) + Syrspend® SF Alka, suspended in 50 ml water.

[0406] Dissolution experiments were performed in a USP2 paddle apparatus at 37° C. The dissolution medium consisted of 500 ml of 0.1 N HCl + 50 ml of water, added to the chamber after addition of the tablet. Rotation speed: 50 rpm. Sampling time points: 5, 10, 15, 30, 45, and 60 min.

[0407] result The three products behaved nearly identically when exposed to acidic conditions simulating gastric conditions. All were immediate release products. At 5 min, 65-80% of the API was eluted. At 10 min, all three products had reached their maximum elution of approximately 80%. The less than 100% release was identified as being due to instability of the eluted samples prior to analysis in the HPLC sequence.

[0408] conclusion Two prototype tablets of AP1189 based on succinic acid or acetate, respectively, showed nearly identical dissolution profiles compared to the powder formulation.

[0409] Example 4: Decomposition of phenylpyrrole aminoguanidine compounds under acidic conditions Acidic conditions are likely to degrade the aminoguanidine derivatives disclosed in WO2007 / 141343, including by hydrolytic degradation of the imine moiety.

[0410] The stability of AP1189 in Ora-Sweet and Ora-Sweet SF was tested. Approximately 3.75 mg of AP1189 was suspended in 5 ml of Ora-Sweet or Ora-Sweet SF, and the suspension was analyzed by HPLC. No interference was observed from Ora-Sweet or Ora-Sweet SF to the PA1189 peak. However, at RRT 0.88, a sharp degradation peak was observed (more than 5.1% of the total area), indicating that AP1189 is unstable in Ora-sweet and Ora-Sweet SF.

[0411] To further characterize the stability of AP1189 in Ora-Sweet SF, a simple study was performed.

[0412] Suspensions were made at concentrations of 20 mg / ml and 3.5 mg / ml (400 mg and 15 mg formulations, respectively) and analyzed by HPLC at initial (T=0) and T=1 hour time intervals. The results show that AP1189 degrades in Ora-Sweet SF within 1 hour, which may correspond to its pH (pH 4.25): [Table 6]

[0413] Further, in addition to the finding that AP1189 is unstable in Ora Sweet SF, an alternative alkaline vehicle (pH>7.0), Syrspend SF Alka, was used to suspend AP1189. Experiments were conducted at the lowest (15 mg) and highest (400 mg) dosage strengths to evaluate the dispersion and physical stability of the suspension. The chemical stability of the suspension was evaluated by HPLC for 90 minutes at 30 minute intervals each. The results show that the API is stable in Syrspend SF Alka over 90 minutes (room temperature): [Table 7]

[0414] Forced degradation studies of AP1189 also demonstrated degradation at low pH, with at least 20% degradation occurring within 24 hours. Rapid pH-dependent degradation is also demonstrated in Examples 2 and 3 herein.

[0415] Therefore, protection of AP1189 from degradation has been attempted by suspending the AP1189 acetate in an alkaline medium (Syrspend® SF Alka suspension) and by protection from gastric acid by enteric-coated tablets (see examples below).

[0416] Example 5: Enteric-coated tablets reduce the absorption of AP1189 after a single dose Based on the discovery that AP1189 is degraded in acidic environment (see Example 4), an attempt was made to protect AP1189 from gastric acid by formulating enteric coated tablets. Enteric coating is a polymer barrier applied to oral pharmaceuticals to prevent its dissolution or disintegration in the gastric environment, thereby protecting the drug from the acidity of the stomach. The drug is released in the post-gastric (usually upper intestinal tract) region.

[0417] Materials and Methods AP1189 acetate powder for oral suspension was provided in individual vials, each containing 200 mg. AP1189 acetate powder was dispersed in a vehicle (Syrspend® SF Alka) and administered as an oral suspension. The alkaline excipient was selected to protect the API from acid degradation.

[0418] The 100 mg enteric coated AP1189 tablets prepared by wet granulation followed by compression and coating contained the ingredients listed in Table 4.

[0419] [Table 8]

[0420] Treatments were administered as oral suspensions in the fasted state and as enteric-coated tablets in the fed or fasted state according to the assigned treatment sequence. AP1189 tablets were given with 240 mL of still mineral water at room temperature. Subjects were dosed in an upright or semi-recumbent position and were not allowed to lie flat for 4 hours after dosing, except for study procedures or as clinically indicated.

[0421] This test is 21.6 to 28.7 kg / m 2 The study involved eight healthy male volunteers, aged 22-38 years, with a BMI of 0.01 to 0.05. Each subject received a single oral dose of 200 mg AP1189 on three occasions, separated by at least a 7-day washout. Each subject received each of the following treatments in a randomized order: Treatment A: AP1189 oral suspension (alkaline) equivalent to 200 mg on an empty stomach, Treatment B: Two enteric-coated tablets administered at 100 mg AP1189 per tablet, equivalent to 200 mg AP1189, by oral route under fasting conditions; Treatment C: Two enteric-coated tablets administered at 100 mg AP1189 per tablet, equivalent to 200 mg AP1189 by oral route in postprandial conditions (high-fat breakfast)

[0422] During each treatment period, blood samples were taken for measurement of AP1189 (and its identified metabolites, if present) at the following time points: pre-dose, then 0.25 hours, 0.50 hours, 0.75 hours, 1.00 hours, 1.50 hours, 2.00 hours, 3.00 hours, 4.00 hours, 6.00 hours, 8.00 hours, 12.00 hours, 16.00 hours, 24.00 hours, 36.00 hours, 48.00 hours, 72.00 hours, 96.00 hours and 120.00 hours after dosing (N=57).

[0423] result Figure 1 shows the mean AP1189 plasma concentrations versus time by treatment. Regarding PK results, 3 of 8 subjects had no measurable AP1189 concentrations after tablet dosing in the fasting state, whereas all subjects had measurable levels after suspension.

[0424] For enteric coated tablets, the average C max was reduced by 9.2 compared with the oral suspension (63.84 ng / mL vs. 589.40 ng / mL). 0-t The overall exposure, expressed as 0-t was approximately 8401 ng.h / mL for the suspension versus 1501 ng.h / mL for the tablet). 0-∞ was only measurable in two subjects using the tablet. AUC 0-t The median relative bioavailability was 10% with high interindividual variability (104%). max was delayed by the tablet (4 hours vs. 2 hours). The individual values ​​ranged from 1.5 to 3 hours after administration for the suspension and from 3 to 4 hours after administration for the tablet. 1 / 2 The mean values ​​for were approximately 19.8 hours for the suspension and 17.0 hours for the tablet (measured in only 4 of 8 subjects). Inter-individual variability was low for the two formulations, with CV% less than 21%. max and AUC 0-tFor the suspension, the interindividual variability, expressed as CV%, was low (approximately 19%) but very high (116-142%) for the tablet formulation. For the suspension, the mean Vd / F was approximately 667 L and the CL / F was approximately 23 L / h, with an interindividual variability of approximately 20%.

[0425] In the fasting state, C max was approximately one-third lower than in the postprandial state (63.84 ng / mL vs. 194.95 ng / mL). 0-t Overall exposure, expressed as AUC , was also low (1501.22 ng.h / mL in the fasting state vs. 3550.08 ng.h / mL in the postprandial state). 0~∞ was measurable in only two subjects in the fasting state. AUC 0-t The median relative bioavailability was 718% with high interindividual variability (90%).

[0426] Median t max is delayed in the postprandial state (12 vs. 4 hours). Individual values ​​ranged from 3 to 4 hours after dosing in the fasted state and from 4 to 24 hours after dosing in the postprandial state. 1 / 2 The mean value of was about 17.0 hours for the tablet in the fasting state (only 4 out of 8 subjects) and 19.6 hours for the tablet in the postprandial state. Regardless of the administration condition, the inter-individual variability was small, with the CV% being less than 22%. max and AUC 0-t For , the interindividual variability, expressed as CV%, was very high (116-142%) in the fasting state but moderate (43-45%) in the fed state. In the fed state, the mean Vd / F was approximately 1297 L and CL / F was approximately 50 L / h, with an interindividual variability of approximately 25%.

[0427] When the enteric-coated tablet was used after a meal, the average C max was reduced by one-third compared to oral suspension in the fasting state (194.95 ng / mL vs. 589.40 ng / mL). 0-t The overall exposure, as represented by the mean AUC0-t was approximately 8401 ng.h / mL for the suspension in the fasting state, versus 3550 ng.h / mL for the tablet in the fed state). 0-∞ was reduced by 1.9-fold (mean AUC 0-∞ was approximately 8812 ng.h / mL for the suspension in the fasting state, versus 4522 ng.h / mL for the tablet in the fed state). 0-t The median relative bioavailability was 40% with high interindividual variability (53%). max was delayed for the tablet in the fed state compared with the suspension in the fasted state (12 hours vs. 2 hours). Individual values ​​ranged from 1.5 to 3 hours after administration for the suspension and from 4 to 24 hours after administration for the tablet. 1 / 2 The mean values ​​for were approximately 19.8 hours for the suspension and 19.6 hours for the tablet. Inter-individual variability was low for the two formulations, with CV% less than 22%. max and AUC 0-t Regarding the effect of , inter-individual variability, expressed as CV%, was low for the suspension (approximately 19%), but was moderate for the tablets in the fed state (26-45%).

[0428] conclusion AP1189 Acetate Exposure (C max and AUC) were significantly decreased in the enteric-coated tablet formulation compared with the oral suspension under fasting conditions, and t max was delayed (4 hours vs. 2 hours). Based on AUC0-t, the relative bioavailability was 10% between the suspension and enteric-coated tablet in the fasted state. In the fasted state, formal statistics revealed that the bioavailability was statistically significantly lower for the tablet compared to the oral suspension. Food intake significantly increased AP1189 exposure after administration of the tablet formulation, with C max 2.4 times, AUC 0-t In addition, t max The onset of nausea and vomiting was delayed (12 hours vs. 4 hours). A single dose of 200 mg of AP1189 administered to healthy male subjects as a suspension, tablet in the fasting state, or tablet in the fed state was very well tolerated.

[0429] Data from administration of enteric-coated tablets demonstrated lower and more variable exposures and unpredictably higher bioavailability, both within and between subjects, compared with data from the suspension.

[0430] These findings demonstrate that formulating AP1189 into an enteric coated tablet formulation results in suboptimal absorption and therefore low bioavailability of the API.

[0431] Example 6: Enteric-coated tablets result in poor absorption of API with repeated dosing Materials and Methods 100 mg enteric coated AP1189 tablets were prepared as described in Example 5 and placebo tablets were manufactured in a similar manner containing the ingredients listed in Table 5: Table 5: Ingredients in 100 mg enteric coated AP1189 tablets versus placebo tablets. [Table 9]

[0432] This test is 19.6 to 27.4 kg / m 2 The study was conducted on 12 subjects aged 20-39 years with a BMI of 0.01 to 0.05. Each subject received a single 400 mg oral dose of moxifloxacin on day -8, followed by a 14-day repeat period of qdAP1189 acetate (200 mg, 2 tablets) or placebo as enteric-coated tablets. Blood samples were collected at the following time points: -Moxifloxacin was measured before administration on day 8, then 1.0, 2.0, 3.0, 4.0 and 5.0 hours after administration (N=6). --Day 1 (to fully mimic conditions on Day 14 before dosing), then 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 16.0 hours after dosing (N=14). -Measurement of AP1189 (and its identified metabolites, if present): Day 1: Pre-dose, then 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 16.0 hours after dosing; Days 2 to 6: Before administration Day 7: Pre-dose, then 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours after administration. Days 8 to 13: Before administration Day 14: Pre-dose, then 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 10.0, 12.0, and 16.0 hours after dosing. Day 15: 24.0 hours and 36.0 hours after administration on day 14, Day 16: 48.0 hours after administration on Day 14, Days 17, 18, and 19: 72.0, 96.0, and 120.0 hours after day 14 dosing (N=53).

[0433] result Mean AP1189 plasma concentrations are shown in Figure 2. For all subjects, on day 1, pre-dose samples contained no quantifiable AP1189. None of the pre-dose samples were lost. On day 1, three subjects had no measurable concentrations after dosing. For the other subjects, the first quantifiable concentration was observed 1-12 hours. For these subjects, concentrations were measurable up to 24 hours after dosing (time of next dose). On day 7, one subject had no measurable concentrations after dosing. For the other subjects, the first quantifiable concentration was observed 0-12 hours. Two subjects had measurable concentrations only pre-dose and 12 hours after dosing. For six subjects, concentrations were measurable up to 24 hours after dosing (time of next dose). On day 14, the first quantifiable concentration was observed 0-10 hours. Concentrations were measurable for 16 hours in one subject, 24 hours in three subjects, 36 hours in two subjects, 48 ​​hours in one subject, and up to 72 hours in the last subject.

[0434] conclusion Following administration of the 200 mg AP1189 acetate enteric coated tablet formulation, PK was highly unpredictable. The PK of moxifloxacin was consistent with that described in the literature. Multiple doses of AP1189 acetate 200 mg as tablets administered in the fed state were well tolerated in healthy male subjects.

[0435] Example 7: Immediate release tablets of A1189 acetate and AP1189 succinate Materials and Methods Immediate release tablets of AP1190 acetate and AP1189 succinate were prepared as exemplified for the 200 mg tablets. Tablets of other dosages can be prepared in a substantially similar manner by adjusting the amounts of granules and excipients in the compression step.

[0436] Granulation was similarly carried out in a 1 L high shear mixer and dried at 40° C. in a drying cabinet.

[0437] The AP1189 salt was mixed with the filler (microcrystalline cellulose), binder (maltodextrin), polysorbate 80, and sodium starch glycolate and wetted with purified water until a granulation was obtained.

[0438] [Table 10]

[0439] AP1189 Tablet Compression AP1189 granules were mixed with the fillers silicified microcrystalline cellulose and mannitol in a Turbula mixer. Magnesium stearate was added and mixing continued. All compressions were performed on a Diaf single punch press using 15.5x7.1 oval tooling.

[0440] [Table 11]

[0441] Film Coating The tablets were film coated with a white standard hypromellose film containing titanium dioxide (Table 8). The film was used to achieve approximately 4% weight gain and ensure uniform color.

[0442] [Table 12]

[0443] Table 9 shows the process parameters and actual weight gain measured during the film coating process. All tablets appeared nice and smooth with uniform color.

[0444] [Table 13]

[0445] Analysis results These batches were tested for assay, impurities, content uniformity, dissolution and disintegration and the results are shown in Table 10.

[0446] [Table 14]

[0447] The elution results tend to result in around 85% stabilization, which may be due to the instability of AP1189 in the acid environment during HPLC analysis.

[0448] Similarly, 50 mg AP1189 tablets were prepared (see Tables 11-12 below):

[0449] [Table 15] [Table 16]

[0450] Conclusion: The processes for manufacturing immediate release tablets containing AP1189 acetate and AP1189 succinate, respectively, were successfully demonstrated.

[0451] Example 8: Bioavailability of immediate release formulations of AP1189 acetate and succinate salts The pharmacokinetic profiles of immediate release formulations of AP1189 acetate and succinate salts were evaluated in detail below.

[0452] Materials and Methods Test items AP1189 acetate (200 mg) for suspension in SyrSpend SF Alka® in water AP1189 Acetate (AP1189 Tablets, 200 mg, batch RD2101-6-T3-C1) AP1189 succinate (SP1189 tablets, 200 mg, batch RD2103-2-T1-C1)

[0453] Preparation of Dose Formulations Syrspend SF ALKA formulation (suspension) was prepared for each dose by mixing 200 mg AP1189 acetate with 3.15 grams of Syrspend SF ALKA Unflavored (Fagron item number 33736-104). 50 mL of water was added at room temperature and the suspension was shaken vigorously by hand. The prepared formulation was administered within 90 minutes of preparation. All formulations were prepared in glass containers.

[0454] animal The study was carried out with 10 female Göttingen SPF minipigs (Ellegaard Göttingen Minipigs A / S, Denmark). Initially, 9 animals were assigned to the study. On day 9 of the study, one additional animal was assigned from the internal stock. The animals were 3-4 months old and weighed 7.5-9 kg on arrival. A 15-day pretreatment period (including a 5-day acclimatization period) was performed.

[0455] Housing, feeding The study was conducted in filtered air at a temperature of 21° C.±3° C. The room was illuminated to give a 12 hour light and 12 hour dark cycle.

[0456] SDS miniature pig diet (SMP(E)SQC) (Special Diets Services, Witham Essex, CM8 3AD, UK) was provided twice daily at approximately 125 g per animal per meal. The amount of food was adjusted slightly to allow the animals to grow rationally. The animals had free access to domestically produced high quality drinking water.

[0457] Randomization and allocation of animals On the day of arrival, animals were assigned a final number using a randomization scheme.

[0458] treatment The groups, dose levels and animal numbers are shown in Table 13 below.

[0459] [Table 17]

[0460] Treatment was for 5 days. The first treatment day was designated as day 1.

[0461] For animals in group 1, the daily dose was administered orally by oral gavage in a constant volume of 50 mL / animal for 5 days. After administration of the test formulation in suspension, approximately 10 mL of tap water was provided.

[0462] For animals in groups 2 and 3, the daily dose was administered orally in a tablet formulation. After administration of one tablet, 60 mL of tap water (10 mL in a syringe to ensure passage of the tablet, 50 mL by gavage) was administered. For 5 days, animals received 1 tablet / day.

[0463] result Figure 3 shows a comparison of the effect of the three different formulations on AUC. Figure 4 shows the effect of the three different formulations on AUC. max A comparison of the effects on

[0464] conclusion Exposure to AP1189 was confirmed for all treated animals, regardless of the formulation administered. max and AUC 0-24 ) appeared to be lower than both AP1189 (AP1189 acetate) and SP1189 (AP1189 succinate) tablets. For both formulations, T max was found either 1 or 2 hours after administration, with an estimated elimination half-life of approximately 4-5 hours. These findings demonstrate that immediate release solid oral formulations of AP1189 acetate or AP1189 succinate targeted to the gastric compartment promote high absorption of AP1189.

[0465] Example 9: Comparative bioavailability study in humans A single-center, open-label, three-part pharmacokinetic (PK) study was conducted. Twelve healthy, Caucasian, male subjects were randomly assigned to receive, on three separate occasions, the following single oral doses in randomized order: Treatment A: 100 mg of AP1189 powder for suspension equivalent to 83 mg of AP1189 in the fasting state; Treatment B: Two 50 mg AP1189 tablets (AP1189 acetate) equivalent to 100 mg AP1189 in the fasting state, Treatment C: Two 50 mg SP1189 tablets (AP1189 succinate) equivalent to 100 mg AP1189 in the fasting state.

[0466] During each study period, blood samples were collected from all subjects for PK purposes to measure AP1189 at the following time points: pre-dose, then 0.25 hours, 0.5 hours, 0.75 hours, 1.0 hours, 1.5 hours, 2.0 hours, 3.0 hours, 4.0 hours, 6.0 hours, 8.0 hours, 12.0 hours, 16.0 hours, 24.0 hours, 36.0 hours, 48.0 hours, 72.0 hours, 96.0 hours, and 120.0 hours after dosing.

[0467] Plasma samples were analyzed for AP1189 after two dosing rounds (n=8 for each dosage form). Derivation of PK parameters was performed using Phoenix WinNonlin® (Version Phoenix 8.1-Certara-Princeton-USA). A non-compartmental analysis (NCA) approach was chosen. The results are shown herein below in Tables 14 and 15 and presented in Figure 5.

[0468] Three subjects in Treatment Group A (receiving the suspension containing AP1189 acetate) experienced nausea and one subject vomited after dosing. These effects were not observed in Treatment Groups B and C.

[0469] The following AP1189 PK parameters were obtained for each subject who received AP1189 on Day 1 of each treatment period: t lagThe time before absorption began was also obtained directly from the concentration-time data, which was the time point immediately preceding the first quantifiable plasma concentration. C max The maximum observed concentrations measured in plasma were obtained directly from the concentration-time data. C max / DC max divided by the dose t max C max The time points at which this was evident were identified by inspection of plasma drug concentration versus time data using Phoenix® WinNonlin®. AUC 0-t The area under the concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration was calculated using the linear trapezoidal method (at least three concentrations above the LOQ were required). AUC 0-t / D AUC 0-t divided by the dose k e Terminal phase plasma elimination rate constants were estimated from log-linear regression analysis of the terminal phase of the plasma concentration-time profile. The number of points included in the terminal phase was determined by visual inspection of the semi-log plot of the plasma concentration-time profile. The regression included the last measured data point and was max A minimum of three data points, excluding r, must be available to be considered reliable. 2 The coefficient of determination for the goodness of fit of the regression line through the t 1 / 2 , AUC extrapolation, Vd / F or CL / F) were not determined (and therefore considered incalculable - NC). t 1 / 2 Apparent terminal elimination half-life is ln2 / k e (where k e is the elimination rate constant defined above). AUC 0-∞ The AUC from time 0 to infinity is AUC 0-∞ =AUC 0-t +AUCt-∞ where AUC 0-t is the area under the concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration calculated using the linear trapezoidal method, AUCt -∞ =Ct / k e where Ct was the measured concentration at the time of the last quantifiable concentration t. AUC was calculated only if there were at least three concentrations above the LOQ. AUC 0-∞ The extrapolated portion of had to be less than 20% to be considered a reliable value. AUC 0-∞ / D AUC 0-∞ divided by the dose CL / F The apparent volume of the central compartment from which drug was cleared per unit time was estimated using the following formula: CL / F = Dose / AUC 0-∞ Vd / F: Apparent volume of distribution based on terminal elimination. This estimate does not take into account bioavailability (F, fraction of 1) and is therefore nominally divided by this value when administering a drug via the extravascular route. Vd / F=CL / F / k e F rel The relative bioavailability of the tablet formulation compared to the solution was calculated using the individual dose-normalized AUC 0-∞ The ratio of values ​​was obtained (the solution is the reference formulation).

[0470] [Table 18]

[0471] [Table 19]

Claims

1. An immediate-release solid oral preparation containing a pharmaceutically acceptable salt of AP1189 of formula I ((E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine): 【Chemical 1】 wherein the pharmaceutically acceptable salt includes (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium acetate (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium succinate (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine DL-mandelate salt (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine hippurate salt (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine L-lactate salt (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium besylate (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidinium oxoglutarate (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine formate salt (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine DL-lactate salt (including its tautomeric forms and stereoisomeric forms); (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-arylideneamino]-guanidine glutamate salt (including its tautomeric forms and stereoisomeric forms); and ​ (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-arylideneamino]-guanidine adipate (including its tautomeric forms and stereoisomeric forms); selected from the group consisting of an immediate-release solid oral preparation further comprising at least one pharmaceutically acceptable excipient. [

2. ] The pharmaceutically acceptable salt of AP1189 is (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-arylideneamino]-guanidinium acetate (including its tautomeric forms and stereoisomeric forms) (AP1189 acetate); (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-arylideneamino]-guanidinium succinate (including its tautomeric forms and stereoisomeric forms) (AP1189 succinate); and further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of binders, disintegrants, and wetting agents, the immediate-release solid oral preparation according to claim 1. [

3. ] The immediate-release solid oral preparation according to any one of claims 1 to 2, wherein the oral preparation is an immediate-release tablet. [

4. ] The immediate-release solid oral preparation according to any one of claims 1 to 2, wherein 80% or more of the pharmaceutically acceptable salt of AP1189 is eluted into a solution within 15 minutes at the pH in gastric acid in the stomach. [

5. ] The immediate-release solid oral preparation according to any one of claims 1 to 2, wherein 80% or more of the salt is eluted into an aqueous solution within 15 minutes at pH 1 to 3 at a rotation speed of 50 rpm at 37 °C using a USP2 paddle apparatus. [

6. ] The immediate-release solid oral preparation according to any one of claims 1 to 2, wherein the solid oral preparation contains the pharmaceutically acceptable salt of AP1189 in an amount of 25 mg to 250 mg (calculated as the free base), and 80% or more of the salt is eluted into an aqueous solution within 15 minutes at pH 1 to 3 at a rotation speed of 50 rpm at 37 °C using a USP2 paddle apparatus. **Claim 7**: The immediate-release solid oral dosage form according to any one of claims 1 to 2, wherein the Cmax of the solid oral dosage form is 180 ng / mL or more, 200 ng / mL or more, 225 ng / mL or more, 250 ng / mL or more, 275 ng / mL or more, 300 ng / mL or more, 350 ng / mL or more, 400 ng / mL or more, 450 ng / mL or more, 500 ng / mL or more, 600 ng / mL or more, 700 ng / mL or more, 800 ng / mL or more, 900 ng / mL or more, 1000 ng / mL or more, 1200 ng / mL or more, 1400 ng / mL or more, 1600 ng / mL or more, 1800 ng / mL or more, 2000 ng / mL or more, 2200 ng / mL or more, 2400 ng / mL or more, 2600 ng / mL or more, 2800 ng / mL or more, 3000 ng / mL or more, 3200 ng / mL or more, 3400 ng / mL or more, 3600 ng / mL or more after administration of a single dose of a pharmaceutically acceptable salt of AP1189. **Claim 8**: The immediate-release solid oral dosage form according to claim 1, wherein the pharmaceutically acceptable salt of AP1189 is present in a dose of about 25 mg to about 650 mg per dosage form of the pharmaceutically acceptable salt of AP1189 (calculated as the free base). **Claim 9**: The pharmaceutically acceptable salt of AP1189 is a polymorphic form of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium acetate (including its tautomeric forms and stereoisomeric forms) (AP1189 acetate), or a polymorphic form of (E)-N-[1-(2-nitrophenyl)-1-H-pyrrol-2-yl-allylideneamino]-guanidinium succinate (including its tautomeric forms and stereoisomeric forms) (AP1189 succinate). The immediate-release solid oral dosage form according to any one of claims 1 to 2. **Claim 10**: A composition comprising the immediate-release solid oral dosage form according to any one of claims 1 to 2 for use in a method of treating or preventing a disease selected from kidney diseases, arthritis diseases, rheumatoid arthritis, inflammatory viral diseases or disorders, viral respiratory diseases or disorders, cardiovascular diseases, arteriosclerosis, systemic inflammatory diseases, or autoimmune diseases.

11. The pharmaceutically acceptable salt of AP1189 is administered in an amount of the pharmaceutically acceptable salt of AP1189 of 1 mg to 1000 mg, 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 per dose (calculated as the free base), the immediate-release solid oral preparation according to any one of Claims 1 to 2 or the composition for use according to Claim 10.

12. The pharmaceutically acceptable salt of AP1189 is administered once a day (QD), twice a day (BID) or three times a day (TID), the immediate-release solid oral preparation according to any one of Claims 1 to 2 or the composition for use according to Claim 10.

13. The pharmaceutically acceptable salt of AP1189 is administered once a day at a dose of m1 to 1000 mg per day, the immediate-release solid oral preparation according to any one of Claims 1 to 2 or the composition for use according to Claim 10.

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