Dihydroorotate dehydrogenase (DHOD) inhibitor salts

Abstract

The present disclosure provides a salt of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid. The present disclosure also provides a pharmaceutical composition comprising the salt of the invention, and a method of treating, preventing or ameliorating a disease or condition comprising administering the salt of the invention.

Description

[Technical field]

[0001] The present disclosure provides a salt of 3-(2,3,5,6-tetrafluoro-3'-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid (PP-001). The present disclosure also provides pharmaceutical compositions comprising the salt of PP-001, and methods of treating, preventing, or ameliorating a disease or condition comprising administering a salt of PP-001. [Background technology]

[0002] The small molecule compound 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid, shown below (referred to herein as PP-001), is a potent dihydroorotate dehydrogenase (DHODH) inhibitor. [ka]

[0003] See, for example, US 7,365,094, US 8,354,433 and US 9,795,590, which are incorporated herein by reference. PP-001 has application in the treatment of diseases and conditions associated with DHOD activity. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] US7,365,094 [Patent Document 2] US8,354,433 [Patent Document 3] US9,795,590 Summary of the Invention

[0005] In some embodiments, the disclosure provides a compound of formula I; [ka] During the ceremony, Y * teeth, i) A single atomic cation with a +1 charge; ii) A single atomic cation with a +2 charge; iii) a carboxyalkylammonium cation optionally substituted with one or more hydroxyl or amino groups; iv) a dialkylammonium cation optionally substituted with one or more hydroxyl groups; or v) an alkylammonium cation optionally substituted with one or more hydroxyl groups; It is.

[0006] In some embodiments, the Y * is a single atomic cation having a +1 charge. In some embodiments, the single atomic cation having a +1 charge is a sodium cation or a potassium cation.

[0007] In some embodiments, Y * is a single atomic cation having a +2 charge. In some embodiments, the single atomic cation having a +2 charge is a calcium cation, a magnesium cation, or a zinc cation.

[0008] In some embodiments, the Y * is a carboxyalkylammonium cation. In some embodiments, the carboxyalkylammonium cation is a carboxy(C3-C6)alkylammonium cation. In some embodiments, the carboxy(C3-C6)alkylammonium cation is a carboxypentylammonium cation. In some embodiments, the carboxypentylammonium cation is substituted with one amino group. In some embodiments, the carboxypentylammonium cation is lysine.

[0009] In some embodiments, the Y *is a dialkylammonium cation. In some embodiments, the dialkylammonium cation is a (C3-C6) dialkylammonium cation. In some embodiments, the (C3-C6) dialkylammonium cation is a hexylammonium alkyl cation. In some embodiments, the hexylammonium alkyl cation is a hexylammonium methyl cation. In some embodiments, the hexylammonium methyl cation is substituted with 4-5 hydroxyl groups. In some embodiments, the hexylammonium methyl cation is meglumine.

[0010] In some embodiments, the Y * is an alkylammonium cation. In some embodiments, the alkylammonium cation is a (C3-C6) alkylammonium cation. In some embodiments, the (C3-C6) alkylammonium cation is a butylammonium cation. In some embodiments, the butylammonium cation is a tert-butylammonium cation. In some embodiments, the tert-butylammonium cation is substituted with 2-3 hydroxyl groups. In some embodiments, the tert-butylammonium cation is tromethamine.

[0011] In some embodiments, the solubility of the compound of formula I is greater than 1 mg / mL at 37° C., pH 6.4-6.5 and 1 atmosphere.

[0012] In some embodiments, the bioavailability of the compound of formula I in dogs is greater than 20%. In some embodiments, the bioavailability of the compound of formula I in dogs is 20%-99%. In some embodiments, the bioavailability of the compound of formula I in dogs is 40%-95%.

[0013] In some embodiments, the bioavailability of the compound of formula I in dogs is at least twice as high as the free acid form of the compound.

[0014] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula I as described herein and a pharma- ceutically acceptable excipient, carrier, diluent, or combination thereof.

[0015] In some embodiments, the disclosure provides a method of treating an inflammatory or autoimmune disease comprising administering to a subject in need of treatment an effective amount of a pharma- ceutically acceptable composition comprising a compound of Formula I as described herein and a pharma- ceutically acceptable excipient, carrier, diluent, or combination thereof, hi some embodiments, said administration is by oral administration.

[0016] In some embodiments, the present disclosure provides * wherein is a potassium cation.

[0017] In some embodiments, the disclosure provides compounds of formula I as described herein, wherein the bioavailability of the compound of formula I in dogs is greater than 20%.

[0018] In some embodiments, the disclosure provides compounds of formula I described herein, wherein the solubility of the compound of formula I is greater than 1 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37°C. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows the solubility over time of various PP-001 salts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The present disclosure relates to salts of 3-(2,3,5,6-tetrafluoro-3′-trifluoromethoxybiphenyl-4-ylcarbamoyl)-thiophene-2-carboxylic acid.

[0021] Different salt forms of a given compound may have different properties such as solubility, dissolution rate, suspension stability, grinding stability, vapor pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration performance, drying, density, melting point, degradation stability, stability against phase change to other forms, color, and even chemical reactivity. More importantly, different salt forms of a small molecule compound may alter its dissolution, dissolution performance, pharmacokinetics, and bioavailability, which affects the efficacy and safety performance of the drug.

[0022] In particular, in some embodiments, the salt form of a drug may affect its dissolution, in vivo absorption, which may affect its clinical therapeutic efficacy and safety to some extent. In some embodiments, for slightly soluble solid or semi-solid oral formulations, the impact of the salt form may be very important. The present disclosure has identified various salts of PP-001 that have beneficial properties for different applications and indications.

[0023] Unless otherwise defined herein, scientific and technical terms used in this disclosure shall have the meaning commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular. As used herein, "a" or "an" may mean one or more. As used herein, when used in conjunction with the word "comprising," the words "a" or "an" may mean one or more. As used herein, "another" or "further" may mean at least a second or more.

[0024] Throughout this application, the term "about" is used to indicate that a value includes the inherent error variation of the method / device being used to determine the value or the variation that exists between test subjects. Typically, the term "about" is meant to encompass a variation of less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%, depending on the context.

[0025] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or where the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers only to alternatives and "and / or."

[0026] As used herein, the terms "comprising" (and any variation or form of "comprising", such as "comprise" and "comprises"), "having" (and any variation or form of "having", such as "have" and "has"), "including" (and any variation or form of "including", such as "includes" and "include") or "containing" (and any variation or form of "containing", such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0027] Use of the term "for example" and its corresponding abbreviation "eg" (whether italicized or not) means that the specific terms described are representative examples and embodiments of the present disclosure that are not intended to be limited to the specific examples referenced or cited, unless expressly stated otherwise.

[0028] As used herein, "between" refers to a range that includes both ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any number that falls within the range between x and y.

[0029] As used herein, the term "room temperature" generally refers to about 15° C. to about 32° C. In some embodiments, the term refers to about 18° C. to about 22° C. In some embodiments, the term refers to 20±5° C.

[0030] As used herein, the term "pharmacologically acceptable" excipient, carrier, diluent, or ingredient refers to a substance suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergies), i.e., with a reasonable benefit / risk ratio.

[0031] As used herein, the term "pharmaceutical acceptable ingredient" refers to a substance suitable for use in humans and / or animals without undue side effects (toxicity, irritation, allergies, etc.), i.e., with a reasonable benefit / risk ratio.

[0032] As used herein, the term "effective amount" refers to the amount of a therapeutic agent for treating, alleviating or preventing a target disease or condition, or an amount that shows a detectable therapeutic or preventive effect. The exact effective amount for a subject depends on the size and health of the subject, the nature and extent of the condition, and the therapeutic agent and / or combination of therapeutic agents selected. Therefore, it is not useful to specify the exact effective amount in advance. However, for a particular condition, the effective amount can be determined using routine experimentation, and can be determined by the clinician.

[0033] As used herein, the term "administration" or "administering" refers to a route of introducing a compound or composition provided herein into an individual to perform its intended function. Examples of administration routes that can be used include, but are not limited to, parenteral administration, such as subcutaneous, intravenous or intramuscular injection or infusion, or oral administration.

[0034] In some embodiments, the present disclosure provides a compound of formula I: [ka] During the ceremony, Y * teeth i) A single atomic cation with a +1 charge; ii) A single atomic cation with a +2 charge; iii) a carboxyalkylammonium cation optionally substituted with one or more hydroxyl or amino groups; iv) a dialkylammonium cation optionally substituted with one or more hydroxyl groups; or v) an alkylammonium cation optionally substituted with one or more hydroxyl groups; It is.

[0035] As used herein, the term compound refers to a compound having the indicated cation (Y * For example, in some embodiments, the compound is a compound of formula I.

[0036] Various cations of PP-001, namely Y * can be used. The disclosure herein provides beneficial properties of various cations. The terms "salt" and "cation" as described herein are interchangeable. Thus, the phrase "salt of PP-001" is intended to include PP-001 and a cation as described herein. In some embodiments, the Y * is a single charged atom. For example, in some embodiments, the Y * is a positively charged cation. In some embodiments, the single atomic cation has a +1 charge. One of ordinary skill in the art will appreciate that the "charge" of an atom or compound can depend on many factors, such as pH and temperature. One of ordinary skill in the art will appreciate that charge is affected by pH, depending on the pKa value of the atom or compound. As used herein, unless otherwise indicated, Y * When referring to the charge of the molecule, the pH is about 6 to 8. In some embodiments, the pH is about 6.4 to 7.5. In some embodiments, the pH is about 6.4 to 6.5. In some embodiments, the temperature is 37°C.

[0037] In some embodiments, the single atomic cation having a +1 charge is a lithium cation, a sodium cation, a potassium cation, and a rubidium cation. In some embodiments, the single atomic cation having a +1 charge is a sodium cation and a potassium cation. In some embodiments, the single atomic cation having a +1 charge is a sodium cation. In some embodiments, the single atomic cation having a +1 charge is a potassium cation.

[0038] In some embodiments, the present disclosure provides * wherein is a potassium ion.

[0039] In some embodiments, Y * is a single atomic cation having a +2 charge. In some embodiments, the single atomic cation having a +2 charge is a copper cation, an iron cation, a calcium cation, a magnesium cation, or a zinc cation. In some embodiments, the single atomic cation having a +2 charge is a calcium cation, a magnesium cation, or a zinc cation.

[0040] In some embodiments, the Y * is a carboxyalkylammonium cation optionally substituted with one or more hydroxyl or amino groups. The term carboxyalkylammonium has the general formula: [ka] In some embodiments, x is 1 to 15. In some embodiments, x is 1 to 8. In some embodiments, x is 1 to 6. In some embodiments, x is 1, 2, 3, 4, 5, or 6.

[0041] Unless otherwise indicated, the term alkyl as used herein, when used alone or in combination with other groups or atoms, refers to a saturated straight or branched chain of 1 to 15 hydrogen-substituted carbon atoms. Those of skill in the art reading this disclosure as a whole will recognize that "x" can refer to both straight and branched carbons, although the general formulas refer only to straight carbons throughout. In some embodiments, the term alkyl includes 1 to 8 carbons. In some embodiments, the term alkyl includes 3 to 6 carbons. In some embodiments, the term alkyl includes 1, 2, 3, 4, 5, or 6 carbons. In some embodiments, an alkyl may be straight-chained. In some embodiments, an alkyl may be branched. In some embodiments, the term refers to methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl. In some embodiments, the alkyl group may be substituted with methyl, ethyl, hydroxyl, amino, or halogen, such as chloro or fluoro.

[0042] In some embodiments, the carboxyalkylammonium cation is a carboxy(C3-C5)alkylammonium cation. In some embodiments, the carboxyalkylammonium cation is a carboxypentylammonium cation, a carboxybutylammonium cation, or a carboxypropylammonium cation, which may be substituted with methyl, ethyl, a hydroxyl group, an amino group, or a halogen, such as chloro or fluoro. In some embodiments, the carboxyalkylammonium cation is a carboxypentylammonium cation, a carboxybutylammonium cation, or a carboxypropylammonium cation, which may be substituted with an ammonium group. In some embodiments, the carboxy(C3-C6)alkylammonium cation is a carboxypentylammonium cation. In some embodiments, the carboxypentylammonium cation is substituted with one or more hydroxyl groups. In some embodiments, the carboxypentylammonium cation is substituted with one or more ammonium groups. In some embodiments, the carboxypentylammonium cation is substituted with one ammonium group. In some embodiments, the carboxypentylammonium cation is lysine.

[0043] In some embodiments, Y * is a dialkylammonium cation, optionally substituted with one or more hydroxyl groups. The term dialkylammonium refers to compounds having the general formula: [ka]

[0044] In some embodiments, x is 1 to 15. In some embodiments, x is 1 to 8. In some embodiments, x is 1 to 6. In some embodiments, x is 1, 2, 3, 4, 5 or 6. In some embodiments, x is 3 to 6. In some embodiments, y is 1 to 15. In some embodiments, y is 1 to 8. In some embodiments, y is 3 to 6. In some embodiments, y is 1 to 6. In some embodiments, y is 1, 2, 3, 4, 5 or 6. In some embodiments, x is 1 to 6 and y is 1. In some embodiments, x is 5 or 6 and y is 1. In some embodiments, R1 is a hydrogen atom or a hydroxyl group. In some embodiments, R2 is a hydrogen atom or a hydroxyl group.

[0045] In some embodiments, the dialkylammonium cation is a (C1-C6) dialkylammonium cation. In some embodiments, the alkyl chains of the dialkylammonium cation may be the same or different, for example, a propylammonium methyl cation or a butylammonium ethyl cation. In some embodiments, the (C1-C6) dialkylammonium cation is a hexylammonium alkyl cation. In some embodiments, the hexylammonium alkyl cation is a hexylammonium methyl cation. In some embodiments, the hexylammonium methyl cation is substituted with a methyl, ethyl, hydroxyl group, amino group, or halogen, for example, chloro or fluoro. In some embodiments, the hexylammonium methyl cation is substituted with a hydroxyl group. In some embodiments, the hexylammonium methyl cation is substituted with 4-5 hydroxyl groups. In some embodiments, the hexylammonium methyl cation is substituted with 5 hydroxyl groups. In some embodiments, the hexylammonium methyl cation is meglumine.

[0046] In some embodiments, Y *is an alkyl ammonium cation, optionally substituted with one or more hydroxyl groups. The term alkyl ammonium cation refers to compounds having the general formula: [ka]

[0047] In some embodiments, x is 1 to 15. In some embodiments, x is 1 to 8. In some embodiments, x is 3 to 6. In some embodiments, R3 is a hydrogen atom or a hydroxyl group. In some embodiments, the term alkylammonium refers to a branched alkylammonium compound.

[0048] In some embodiments, the alkylammonium cation is a (C3-C6) alkylammonium cation. For example, in some embodiments, the alkylammonium cation is a propylammonium, isopropylammonium, butylammonium, 2'-butylammonium, tert-butylammonium, pentylammonium, 2'-pentylammonium, isopentylammonium cation, etc. In some embodiments, the alkylammonium cation is substituted with methyl, ethyl, a hydroxyl group, an ammonium group, or a halogen, such as chloro or fluoro. In some embodiments, the alkylammonium cation is substituted with a hydroxyl group. In some embodiments, the (C3-C6) alkylammonium cation is a butylammonium cation. In some embodiments, the butylammonium cation is a tert-butylammonium cation. In some embodiments, the tert-butylammonium cation is substituted with methyl, ethyl, a hydroxyl group, an amino group, or a halogen, such as chloro or fluoro. In some embodiments, the tert-butylammonium cation is substituted with 2 to 3 hydroxyl groups. In some embodiments, the tert-butylammonium cation is substituted with 3 hydroxyl groups. In some embodiments, the tert-butylammonium cation is tromethamine.

[0049] In some embodiments, the present disclosure provides * is a single atom cation having a +1 charge. * is a potassium cation.

[0050] In some embodiments, the compound of formula I has increased solubility compared to the non-salt form of PP-001. As used herein, the terms "non-salt form of PP-001" and "free acid form" are interchangeable and refer to the PP-001 compound without any associated salt and can include both PP-001 or the deprotonated charged form of PP-001 in the absence of a countercation. One of skill in the art will appreciate that whether PP-001 is protonated or deprotonated depends on many factors, such as the pH and temperature of its environment.

[0051] In some embodiments, the increased solubility of the salt forms described herein may facilitate dissolution of the PP-001 compound. One of skill in the art will appreciate that solubility in a given solvent depends on many factors, including but not limited to the type of solvent, temperature, pH, and pressure. Solubility, as defined herein, is the ability of a solvent to dissolve a solute, i.e., PP-001. Solubility can be described in units of concentration, such as molality, molarity, mole fraction, mole ratio, weight / volume, or weight / weight. As used herein, solubility is expressed as a weight / volume concentration, unless otherwise specified.

[0052] In some embodiments, solubility can be expressed as an absolute value or a relative value. As used herein, in relative terms, the solubility of a given PP-001 salt can be compared to the solubility of PP-001 in its non-salt form. As a purely illustrative example of how to calculate "increased solubility," if the solubility of a given PP-001 salt is "1.2 mg / mL" and the solubility of PP-001 in its non-salt form is "1.0 mg / mL," the increase in solubility would be 20%, i.e., (1.2 mg / mL-1.0 mg / mL) / 1.0 mg / mL. In some embodiments, the solubility of the compounds described herein is 5% more, 10% more, 20% more, 30% more, 40% more, or 50% more than the non-salt form.

[0053] Equilibrium solubility is the concentration limit at which a solute can be homogeneously dissolved in a solvent in the presence of excess solid at thermodynamic equilibrium. Apparent solubility may be higher or lower than equilibrium solubility due to incomplete dissolution caused by temporary supersaturation or insufficient time to reach equilibrium. Equilibrium can be defined as fully converged when there is no longer any significant change over a certain time frame. In some embodiments, the compound of formula I has an increased equilibrium solubility compared to the equilibrium solubility of non-salt form PP-001.

[0054] In some embodiments, the dissolution rate is how quickly the solubility limit is reached. In some embodiments, the compounds described herein have an increased dissolution rate in a given solvent compared to the dissolution rate of PP-001 in its non-salt form.

[0055] In some embodiments, PP-001 may be more advantageous when the compound has low solubility. For example, in some embodiments, when sustained release of PP-001 is desired, reduced solubility may be desirable. In such situations, a particular salt of PP-001 may be selected to reduce solubility in a particular environment.

[0056] In some embodiments, the compound of formula I exhibits increased solubility when placed in various solvents, such as water, buffers (e.g., phosphate buffer), media (e.g., fasted simulated intestinal fluid (FaSSIF) media or simulated gastric fluid (SGF) media), organic solvents, etc. In some embodiments, the solvent further comprises a co-solvent. In some embodiments, the co-solvent is water. Similarly, in some embodiments, when determining solubility, the solvent can include other salts or counterions that can further alter the solubility of the compound of formula I.

[0057] The solubility of ionic acids and bases is pH dependent. In some embodiments, this pH dependence is due to the fact that charged species have a higher affinity for aqueous environments than neutral forms. In some embodiments, the Henderson-Hasselbach equation can be used to determine the increase in solubility of a solute with respect to the change in pH of the solution relative to the pKa (acidic) or pKa (basic) of the ionic solute (acid or base). In some embodiments, when determining solubility, the pH of the solvent and / or solution containing the solvent and solute (e.g., a compound described herein) is about 5.0 to about 8.0, about 5.5 to about 7.5, about 6.0 to about 7.0, or about 6.4 to 6.5.

[0058] In some embodiments, the temperature at which the solubility is measured may affect the calculation of the solubility. In some embodiments, the solubility is measured at about 18°C ​​to about 45°C, or about 20°C to about 28°C. In some embodiments, the solubility is measured at about 24°C to about 26°C, or about 25°C. In some embodiments, the solubility is measured at about 30°C to about 40°C, or about 37°C. In some embodiments, the solubility is measured under negative pressure, 1 atmosphere, or positive pressure. In some embodiments, the solubility is measured under about 1 atmosphere.

[0059] In some embodiments, solubility can be determined using one of two approaches: thermodynamic solubility or kinetic solubility. Thermodynamic solubility refers to the traditional method of weighing a compound in a particular solvent (buffer) and measuring the dissolved analyte after equilibrium is reached. Kinetic solubility is determined by preparing a concentrated stock solution containing the solute in an organic solvent (e.g., DMSO) and then diluting the stock solution to the desired concentration in an aqueous buffer (e.g., PBS). In some embodiments, solubility can be determined by HPLC-UV or LC-MS / MS after filtering or spinning down to remove insoluble material.

[0060] In some embodiments, the thermodynamic solubility is determined using fasting simulated intestinal fluid (FaSSIF) medium or simulated gastric fluid (SGF) medium. In some embodiments, the thermodynamic solubility is determined using FaSSIF medium. In some embodiments, the thermodynamic solubility of the compound is greater than 0.8 mg / mL, greater than 0.9 mg / mL, greater than 1 mg / mL, greater than 1.1 mg / mL, greater than 1.5 mg / mL, or greater than 2.0 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37° C. In some embodiments, the thermodynamic solubility of the compound is greater than 0.8 mg / mL, greater than 0.9 mg / mL, greater than 1 mg / mL, greater than 1.1 mg / mL, greater than 1.5 mg / mL, or greater than 2.0 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37° C. In some embodiments, the thermodynamic solubility of the compound is greater than 1.5 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37° C. In some embodiments, the thermodynamic solubility of the compound is greater than 2 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37° C. In some embodiments, the thermodynamic solubility is measured after 12 hours, 18 hours, or 24 hours. In some embodiments, the thermodynamic solubility of the compound is greater than 1 mg / mL after 24 hours in FaSSIF medium at pH 6.4-6.5 and 37° C.

[0061] In some embodiments, the present disclosure provides * is a pharma- ceutically acceptable cation, and the solubility of the compound of formula I is greater than 1 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37° C. In some embodiments, the present disclosure provides: In some embodiments, the present disclosure provides: * is a single atomic cation having a +1 charge, and the solubility of the compound of formula I is greater than 1 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37°C.

[0062] In some embodiments, the compounds of formula I described herein have improved bioavailability. As used herein, the term "bioavailability" generally refers to the percentage (weight / weight) of an administered dose of a compound that reaches the systemic circulation. In some embodiments, bioavailability is determined for parenteral or oral administration. In some embodiments, bioavailability is determined for oral administration. In some embodiments, bioavailability is determined for oral administration in animals. In some embodiments, the animals are dogs, rats, and mice.

[0063] Methods for determining the percent of a compound in the systemic circulation, e.g., the percent in blood, are known to those of skill in the art, and include, for example, HPLC and LC / -MS to determine the area under the curve (AUC). Methods for determining bioavailability are further outlined in Example 2 herein. In some embodiments, bioavailability can be determined in dogs. Those skilled in the art will appreciate that dogs are a useful model that, in some cases, corresponds to bioavailability in humans. In some embodiments, the bioavailability of the compound in dogs is greater than 20% (w / w). In some embodiments, the bioavailability of the compound in dogs is 20%-99% (w / w). In some embodiments, the bioavailability of the compound in dogs is 40%-95% (w / w). In some embodiments, the bioavailability of the compound in dogs is 60%-95% (w / w). In some embodiments, the bioavailability of the compound in dogs is 80%-95% (w / w). In some embodiments, the present disclosure provides a method for determining the bioavailability of a compound in dogs, comprising administering to a subject a compound having a medicament for use in a method for treating a subject having a medicament ... * is a pharma- ceutically acceptable cation, and the bioavailability of the compound of formula I in dogs is greater than 20%. * is a single atom cation carrying a +1 charge, and the bioavailability of the compound of formula I in dogs is greater than 20%.

[0064] In some embodiments, the bioavailability of the compound in humans is greater than 20% (w / w). In some embodiments, the bioavailability of the compound in humans is 20%-99% (w / w). In some embodiments, the bioavailability of the compound in humans is 40%-95% (w / w). In some embodiments, the bioavailability of the compound in humans is 60%-95% (w / w). In some embodiments, the bioavailability of the compound in humans is 80%-95% (w / w). In some embodiments, the present disclosure provides a method for the preparation of a compound comprising administering to a subject ... * is a pharma- ceutically acceptable cation, and the bioavailability of the compound of formula I in humans is greater than 20%. * is a single atom cation having a +1 charge, providing a compound of formula I with a bioavailability in humans of greater than 20%.

[0065] In some embodiments, the bioavailability of the compound of formula 1 in dogs is at least 1.5-fold, 2-fold, 2.5-fold, or 3.0-fold higher than the free acid form of the compound. In some embodiments, the bioavailability of the compound in dogs is at least 2-fold higher than the free acid form of the compound.

[0066] In some embodiments, the bioavailability of the compound of formula 1 in humans is at least 1.5-fold, 2-fold, 2.5-fold, or 3.0-fold greater than the free acid form of the compound. In some embodiments, the bioavailability of the compound in humans is at least 2-fold greater than the free acid form of the compound.

[0067] In some embodiments, the compounds of formula I described herein have improved crystalline stability, i.e., remain in crystalline form for a longer period of time than the non-salt form of PP-001.In some embodiments, the compounds of formula I described herein have improved chemical stability, i.e., remain in their chemical form without being degraded, e.g., oxidized, for a longer period of time than the non-salt form of PP-001.

[0068] In some embodiments, the compound of formula I can be used in pharmaceutical compositions.In some embodiments, the present disclosure provides pharmaceutical compositions comprising the compound of formula I described herein and a pharma- ceutically acceptable excipient, carrier, diluent, or combinations thereof.In some embodiments, the pharmaceutical compositions comprising the compound of formula I are suitable for oral administration or parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

[0069] In some embodiments, the compounds of formula I described herein are prepared and then combined with one or more pharma- ceutically acceptable excipients immediately prior to administration to a subject, e.g., less than two weeks, less than one week, less than three days, or less than one day prior to administration to a subject.

[0070] In some embodiments, the compounds of formula I described herein are combined with one or more pharma- ceutically acceptable excipients and are then stable for an extended period of time before being administered to a subject, for example, more than one day, more than one week, more than two weeks, more than three weeks, or more than one month before being administered to a subject. In some embodiments, the compounds of formula I described herein are combined with one or more pharma- ceutically acceptable excipients for storage and then dissolved in a delivery solvent for parenteral administration.

[0071] In some embodiments, the disclosure provides a method of treating an inflammatory or autoimmune disease, comprising administering to a subject in need thereof an effective amount of a pharma- ceutically acceptable composition comprising a compound of formula I as described herein and a pharma- ceutically acceptable excipient, carrier, diluent, or combination thereof.

[0072] In some embodiments, administration is by oral administration. In some embodiments, administration is by parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion. In some embodiments, administration is by infusion.

[0073] All references cited herein, including patents, patent applications, articles, textbooks, and the like, and the references cited therein, are hereby incorporated by reference in their entirety, unless already cited otherwise. EXAMPLES

[0074] Example 1A - Dynamic Solubility All references cited herein, including patents, patent applications, articles, textbooks, and the like, and the references cited therein, are hereby incorporated by reference in their entirety, unless already cited otherwise.

[0075] Approximately 8 mg of each salt (calculated as free base) was weighed into each glass vial, then 4 mL of FaSSIF was added (target concentration 2 mg / mL). Samples were kept stirring with a magnetic stir bar at a speed of 100 RPM at 25°C. Then, at the initial, 0.5 hour, 1 hour, 2 hours, and 24 hour time points, 0.5 mL of sample solution was transferred to a 1.5 mL centrifuge tube and centrifuged at 12,000 RPM for 10 minutes. The supernatant was diluted with the appropriate 50% ACN and analyzed by HPLC.

[0076] The HPLC method for testing the solubility was performed as shown in Table A.

[0077] Table A: HPLC conditions for PP-001 salt solubility test [Table 1]

[0078] The results of the salt solubility tests are shown in Table B.

[0079] Table B: Solubility results of PP-001 in 4 mL of FaSSTF medium [Table 2]

[0080] The solubility curves of the tested PP-001 salts are summarized in FIG.

[0081] Example 1B - Thermodynamic Solubility Equilibrium solubility test procedure: Approximately 30 mg of each salt was weighed into each glass vial and then 3 mL of FaSSIF was added (target concentration 10 mg / mL). Once the solids were completely dissolved, more sample was added to maintain saturation. The samples were kept stirring with a magnetic stir bar at 400 rpm at 37°C. Then, at the 2 hour time point, 0.5 mL of the sample solution was transferred to a 1.5 mL centrifuge tube and centrifuged at 12,000 RPM for 10 minutes. The supernatant was diluted with appropriate 50% ACN and analyzed by HPLC. The pH was tested after 24 hours. The results are shown in Table 1.

[0082] Table 1. Thermodynamic solubility of PP-001 salts in 3 mL of FaSSIF [Table 3]

[0083] Example 2 - Bioavailability of salts of PP-001 in rats Experimental Method PP-001 salts (benzathine, sodium, magnesium, calcium, potassium, zinc, lysine, meglumine, tromethamine) were formulated as 2 mg / mL suspensions for single oral (PO) administration doses in 50 mM pH 6.8 phosphate buffer in a volume of 2 mL / kg. The suspensions were stirred continuously prior to administration.

[0084] A total of 27 male SD rats were used (n=3). The 27 male SD rats assigned to the study were divided into 9 groups, and rats in each group were orally administered one formulation of PP-001 salt at a dose level of 4 mg / kg (dosing volume 2 mL / kg). Food was available ad libitum throughout the survival period of the study, except for the period from fasting before dosing to 4 hours after dosing. Drinking water was available ad libitum to all animals daily.

[0085] Plasma samples were collected into EDTA-K3 tubes via the jugular vein cannula at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. For analytical batches of single oral doses, plasma concentrations of PP-001 salts were measured using LC-MS / MS with a lower limit of quantification of 1 ng / mL.

[0086] Pharmacokinetic analysis Pharmacokinetic parameters of PP-001 salts were determined by noncompartmental analysis using WinNonlin version 8.0 (Pharsight, Mountain View, CA). Area under the curve from time of administration to the last measurable concentration, AUC 0-t was calculated by the linear trapezoidal rule. Area under the concentration-time curve extrapolated to infinity AUC inf was calculated using the regression of the natural logarithm of the concentration value versus the sampling time of the terminal slope (λZ, k). This value corresponds to the half-life (T 1 / 2 ) is also used to calculate

[0087] T1 / 2 =0.693 / k The bioavailability was calculated as follows:

[0088] F-AUC _PO / AUC _IV ×Dose _IV / Dose _PO ×100% In the formula, PO is oral administration and IV is intravenous injection. The results are shown in Tables 2, 3 and 4.

[0089] Table 2. Mean pharmacokinetic parameters of salts of PP-001 after oral administration to rats (n=3). [Table 4]

[0090] Table 3. Mean pharmacokinetic parameters of salts of PP-001 after oral administration to rats (n=3). [Table 5]

[0091] Table 4. Mean pharmacokinetic parameters of salts of PP-001 after oral administration to rats (n=3). [Table 6]

[0092] Example 3 - Bioavailability of Salts of PP-001 in Dogs Experimental Method Based on the solubility results and the bioavailability results in rats, certain salts of PP-001 were selected for bioavailability determination in dogs.

[0093] PP-001 salts (sodium, potassium, calcium, tromethamine) were prepared as 2 mg / mL suspensions in 50 mM pH 6.8 phosphate buffer with a single oral (PO) dose volume of 2 mL / kg. The suspensions were stirred continuously prior to administration.

[0094] A total of six male beagle dogs were used (n=3). Six male dogs were assigned to the study, divided into two periods with six dogs per period, and two dosing cycles separated by a seven-day washout period. Food was available ad libitum for the duration of the study except for the pre-dose fasting period and 4 hours post-dose. Drinking water was available ad libitum to all animals daily. Formulated PP-001 salt was orally administered to male beagle dogs at 4 mg / kg in a dosing volume of 2 mL / kg.

[0095] Plasma samples were collected into EDTA-K3 tubes via the jugular vein cannula at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. For analytical batches of single oral doses, plasma concentrations of PP-001 salts were measured using LC-MS / MS with a lower limit of quantification of 10 ng / mL.

[0096] Pharmacokinetic analysis Pharmacokinetic parameters of PP-001 salts were determined by noncompartmental analysis using WinNonlin version 8.0 (Pharsight, Mountain View, CA). Area under the curve from time of administration to the last measurable concentration, AUC 0-t was calculated by the linear trapezoidal rule. Area under the concentration-time curve extrapolated to infinity AUC inf was calculated using the regression of the natural logarithm of the concentration value versus the sampling time of the terminal slope (λZ, k). This value corresponds to the half-life (T 1 / 2 ) is also used to calculate

[0097] (T 1 / 2 )=0.693 / k The bioavailability was calculated as follows:

[0098] F-AUC _PO / AUC _IV ×Dose _IV / Dose _PO ×100% where PO is oral administration and IV is intravenous injection. The results are shown in Table 5.

[0099] Table 5. Mean pharmacokinetic parameters of salts of PP-001 after oral administration to dogs (n=3). [Table 7]

[0100] Example 4. Summary The results of Examples 1, 2 and 3 are summarized in Table 6 below.

[0101] Table 6 [Table 8]

[0102] As Table 6 shows, the solubility of the various salt forms of PP-001 varies widely and does not necessarily correlate with increased bioavailability. For example, the PP-001Ca cation has a lower solubility compared to the PP-001 free acid, but has a greater than three-fold increase in bioavailability in dogs. In another example, the PP-001K cation shows both increased solubility (>100% increase) and increased bioavailability in dogs (>400% increase).

Claims

1. A compound of formula I: 【Chemistry 1】 [In the formula, Y ＊ teeth, vi) a single atomic cation having a +1 charge; vii) a single atom cation having a +2 charge; viii) a carboxyalkylammonium cation optionally substituted with one or more hydroxyl or amino groups; ix) a dialkylammonium cation optionally substituted with one or more hydroxyl groups; or x) an alkylammonium cation optionally substituted with one or more hydroxyl groups; It is.]

2. Y ＊ The compound of claim 1 , wherein is a single-atom cation having a +1 charge.

3. 3. The compound of claim 2, wherein the single atomic cation having a +1 charge is a sodium cation or a potassium cation.

4. Y ＊ The compound of claim 1 , wherein is a single-atom cation having a +2 charge.

5. 5. The compound of claim 4, wherein the single atomic cation having a +2 charge is a calcium cation, a magnesium cation, or a zinc cation.

6. Y ＊ The compound of claim 1 , wherein is a carboxyalkylammonium cation.

7. The carboxyalkylammonium cation is carboxy(C ３ -C ６ ) an alkyl ammonium cation.

8. The carboxy (C ３ -C ６ 8. The compound according to claim 7, wherein the alkyl ammonium cation is a carboxypentyl ammonium cation.

9. The compound of claim 8, wherein the carboxypentylammonium cation is substituted with one amino group.

10. 10. The compound of claim 9, wherein the carboxypentylammonium cation is lysine.

11. Y ＊ The compound of claim 1 , wherein is a dialkylammonium cation.

12. The dialkylammonium cation is ３ -C ６ 12. The compound of claim 11, wherein said cation is a dialkylammonium cation.

13. Said (C ３ -C ６ 13. The compound according to claim 12, wherein the dialkyl ammonium cation is a hexyl ammonium alkyl cation.

14. 14. The compound of claim 13, wherein the hexylammonium alkyl cation is a hexylammonium methyl cation.

15. 15. The compound of claim 14, wherein the hexylammonium methyl cation is substituted with 4 to 5 hydroxyl groups.

16. 16. The compound of claim 15, wherein the hexylammonium methyl cation is meglumine.

17. Y ＊ The compound of claim 1 , wherein is an alkylammonium cation.

18. The alkyl ammonium cation (C ３ -C ６ 20. The compound of claim 17, wherein said cation is an alkyl ammonium cation.

19. Said (C ３ -C ６ 20. The compound of claim 18, wherein the alkyl ammonium cation is a butyl ammonium cation.

20. 20. The compound of claim 19, wherein the butylammonium cation is a tert-butylammonium cation.

21. 21. The compound of claim 20, wherein the tert-butylammonium cation is substituted with 2 to 3 hydroxyl groups.

22. 22. The compound of claim 21, wherein the tert-butylammonium cation is tromethamine.

23. 2. The compound of claim 1, wherein the compound of formula I has a solubility of greater than 1 mg / mL at 37° C., pH 6.4-6.5 and 1 atmosphere.

24. 2. The compound of claim 1, wherein the bioavailability of the compound of formula I in dogs is greater than 20%.

25. 25. The compound of claim 24, wherein the bioavailability of the compound of formula I in dogs is between 20% and 99%.

26. 26. The compound of claim 25, wherein the bioavailability of the compound of formula I in dogs is between 40% and 95%.

27. 10. The compound of claim 1, wherein the bioavailability of the compound of formula I in dogs is at least twice that of the free acid form of the compound.

28. a. a compound according to claim 1; and b. A pharma- ceutically acceptable excipient, carrier, diluent, or combination thereof.

23. A pharmaceutical composition comprising:

29. A method for treating an inflammatory or autoimmune disease, comprising administering to a subject in need of treatment an effective amount of a) a compound of formula I: 【Chemistry 2】 [In the formula, Y ＊ teeth, i) a single atomic cation carrying a +1 charge; ii) a single atomic cation having a +2 charge; iii) a carboxyalkylammonium cation optionally substituted with one or more hydroxyl or amino groups; iv) a dialkylammonium cation optionally substituted with one or more hydroxyl groups; or v) an alkylammonium cation optionally substituted with one or more hydroxyl groups; is.]; and b) a pharma- ceutically acceptable excipient, carrier, diluent, or combination thereof; Administering a pharma- ceutically acceptable composition comprising:

30. 30. The method of claim 29, wherein the administration is by oral administration.

31. A compound of formula I: 【Chemistry 3】 [In the formula, Y ＊ is the potassium ion.

32. A compound of formula I: 【Chemistry 4】 [In the formula, Y ＊ is a pharma- ceutically acceptable cation, wherein the bioavailability of the compound of formula I in dogs is greater than 20%.

33. A compound of formula I: 【Chemistry 5】 [In the formula, Y ＊ is a pharma- ceutically acceptable cation.], wherein the solubility of the compound of formula I is greater than 1 mg / mL in FaSSIF medium at pH 6.4-6.5 and 37°C.

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