Amorphous forms of complement-component c5a receptor

Abstract

There is a need to identify solid forms of Compound 1 that can improve important biological characteristics such as solubility, dissolution rate, and bioavailability without sacrificing stability and efficacy. The present disclosure addresses these needs and provides further related advantages.SOLUTION: Provided herein is an amorphous form of complement-component 5a receptor having the formula of Compound 1. Also provided herein are pharmaceutical compositions and methods of treatment using the amorphous form of Compound 1 described herein.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 932,644, filed November 8, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable.

[0003] Reference to a "Sequence Listing," a table, or an appendix listing a computer program submitted on a compact disc Not applicable. [Background technology]

[0004] Background of the Invention The complement system plays a central role in the clearance of immune complexes and in the immune response to infectious agents, foreign antigens, virus-infected cells, and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful and even potentially fatal outcomes due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested as a variety of disorders, including septic shock; ischemia / reperfusion injury of the myocardium and small intestine; transplant rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases.

[0005] The complement system is composed of a group of proteins normally present in serum in an inactive state. Complement activation involves three distinct pathways: the classical pathway, the alternative pathway, and the lectin pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RR Rich, Mosby Press; 1996, pp. 363-391): 1) The classical pathway is a calcium / magnesium-dependent cascade that is typically activated by the formation of an antigen-antibody complex. It can also be activated in an antibody-independent manner by the binding of C-reactive protein complexed with a ligand and by many pathogens, including gram-negative bacteria. 2) The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain susceptible surfaces (e.g., cell membrane polysaccharides of yeast and bacteria, and certain biopolymers). 3) The lectin pathway involves the initial binding of mannose-binding lectin and subsequent activation of C2 and C4, which is common to the classical pathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992); Suankratay, C. et al., J. Immunol. 160: 3006-3013 (1998)).

[0006] Activation of the complement pathway generates biologically active fragments of complement proteins, such as C3a, C4a, and C5a anaphylatoxins and the C5b-9 membrane attack complex (MAC), all of which affect leukocyte chemotaxis; activate macrophages, neutrophils, platelets, mast cells, and endothelial cells; and mediate inflammatory responses by enhancing vascular permeability, cell lysis, and tissue damage.

[0007] Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylatoxin C5a peptide is 100-fold more potent than C3a, on a molar basis, in inducing inflammatory responses.) C5a is the activated form of C5 (molecular weight 190 kD). C5a is present in human serum at approximately 80 μg / ml (Kohler, PF et al., J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, BF et al., Biochemistry 18: 1490-1497 (1979)). Biosynthesized as a single-chain promolecule, C5 is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulfide bond as well as non-covalent interactions (Ooi, YM et al., J. Immunol. 124: 2494-2498 (1980)).

[0008] Recent studies have identified (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, compound 1, as useful for the treatment of C5a-mediated diseases: [ka] Despite this determination, there remain challenges to the efficient delivery of biologically relevant amounts of Compound 1. For example, the low solubility of Compound 1 in aqueous environments makes the preparation of bioavailable formulations particularly challenging.

[0009] Thus, a need exists to identify solid forms of Compound 1 that can improve important biological characteristics such as solubility, dissolution rate, and bioavailability without sacrificing stability and efficacy. The present disclosure addresses these needs and further provides related advantages. Summary of the Invention

[0010] Brief Summary of the Invention Provided herein are amorphous forms of Compound 1, methods for making the same, and pharmaceutical compositions prepared using the amorphous forms of Compound 1.

[0011] In some embodiments, provided herein is an amorphous form of Compound 1, which is (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide: [ka]

[0012] Amorphous forms of Compound 1 can be characterized using a variety of techniques, including, but not limited to, X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and microscopy. Relevant characterizing properties from the listed techniques are further described herein.

[0013] In an additional aspect, provided herein is a method for producing an amorphous form of Compound 1. In some embodiments, the method for preparing an amorphous form of Compound 1 comprises: a) dissolving Compound 1 in a polar aprotic solvent to form a solution; and b) spray drying the solution to form an amorphous form of Compound 1.

[0014] In an additional aspect, provided herein is a method for preparing an amorphous form of Compound 1, the method comprising: a) dissolving Compound 1 in a polar aprotic solvent to form a solution, wherein the concentration of Compound 1 in the solution is 0.3 g / mL or less; b) optionally filtering the solution to form a filtrate; and c) removing the solvent from the solution or filtrate to form an amorphous form of Compound 1. [Brief explanation of the drawings]

[0015] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the powder X-ray diffraction (XRPD) pattern of the free base crystalline form described in Example 1. [Figure 2] FIG. 2 shows the powder X-ray diffraction (XRPD) pattern of the amorphous form of Compound 1 described in Example 2, Method 1. [Figure 3A] FIG. 3 shows the powder X-ray diffraction (XRPD) patterns of the crystalline starting material (A) and the amorphous product (B) described in Example 2, Method 2. [Figure 3B] FIG. 3 shows the powder X-ray diffraction (XRPD) patterns of the crystalline starting material (A) and the amorphous product (B) described in Example 2, Method 2. [Figure 4] FIG. 4 shows differential scanning calorimetry (DSC) thermograms of the amorphous form of Compound 1 as well as the crystalline form of Compound 1 (prepared in Example 1). [Figure 5] FIG. 5 shows the thermogravimetric analysis (TGA) thermogram of the amorphous form of Compound 1, as well as the DSC thermogram. [Figure 6] Figure 6 shows a dynamic vapor sorption (DVS) plot of the amorphous form of Compound 1. Adsorption data points are open circles; desorption data points are open triangles. [Figure 7] FIG. 7 shows the XRPD patterns of the amorphous form of Compound 1 before (top) and after (bottom) DVS. [Figure 8A] 8A-8D show scanning electron microscope (SEM) images of the amorphous form of Compound 1. Magnifications shown include 1,000× (A), 2,500× (B), 5,000× (C), and 10,000× (D). [Figure 8B] 8A-8D show scanning electron microscope (SEM) images of the amorphous form of Compound 1. Magnifications shown include 1,000× (A), 2,500× (B), 5,000× (C), and 10,000× (D). [Figure 8C]8A-8D show scanning electron microscope (SEM) images of the amorphous form of Compound 1. Magnifications shown include 1,000× (A), 2,500× (B), 5,000× (C), and 10,000× (D). [Figure 8D] 8A-8D show scanning electron microscope (SEM) images of the amorphous form of Compound 1. Magnifications shown include 1,000× (A), 2,500× (B), 5,000× (C), and 10,000× (D). [Figure 9A] 9A-9C show polarized light microscope (PLM) images of the amorphous form of Compound 1. The magnification shown is 40×. Panels A, B, and C are images from different sample preparations. [Figure 9B] 9A-9C show polarized light microscope (PLM) images of the amorphous form of Compound 1. The magnification shown is 40×. Panels A, B, and C are images from different sample preparations. [Figure 9C] 9A-9C show polarized light microscope (PLM) images of the amorphous form of Compound 1. The magnification shown is 40×. Panels A, B, and C are images from different sample preparations. [Figure 10] FIG. 10 shows the XRPD patterns of the amorphous form of Compound 1 as initially (time zero) prepared (bottom) and after 11 months of storage under ambient conditions (top). [Figure 11] FIG. 11 depicts the solubility plots of Compound 1 in IV formulations when prepared with the amorphous form of Compound 1 (filled circles) and the crystalline form of Compound 1 (filled squares). [Figure 12] 12 shows a plot of plasma concentration over time for rats administered a liquid suspension formulation containing the crystalline form of Compound 1 (bottom) and an equivalent amount of a liquid suspension formulation containing the amorphous form of Compound 1 (top). Further formulation details are provided in Example 10. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description of the Invention I. Overview The present disclosure provides an amorphous form of Compound 1. This form advantageously increases the aqueous solubility of the compound, providing an opportunity to prepare pharmaceutical compositions that can deliver biologically relevant amounts of Compound 1 without the need to administer excessive amounts of liquid, for example. Surprisingly, the amorphous form of Compound 1 disclosed herein exhibits low hygroscopicity and is physically stable under high humidity conditions. By comparison, most amorphous materials that lack a long-range ordered lattice are highly hygroscopic and unstable under high humidity conditions.

[0017] II. Definition The terms "about" and "approximately" used herein to modify a numerical value designate a close range around the stated value. When "X" is a value, "about X" or "approximately X" designates a value from 0.9X to 1.1X, more preferably from 0.95X to 1.05X. Reference to "about X" or "approximately X" specifically designates at least the values ​​X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, "about X" and "approximately X" are intended to teach and provide support for the recitation requirement in a claim, for example, "0.98X."

[0018] "Compound 1" is the compound having the IUPAC name (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, and the structure shown below: [ka]

[0019] "Amorphous form" refers to a solid form of a compound that does not have a definite crystalline structure, i.e., lacks an ordered, repeating pattern of constituent molecules.

[0020] "Substantially free" refers to an amount of 10% or less of another form, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5%, or less of another form.

[0021] The terms "treating" or "treatment" encompass both disease-modifying and symptomatic treatment, either of which may be prophylactic (i.e., prior to the onset of symptoms, so as to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, so as to reduce the severity and / or duration of symptoms).

[0022] As used herein, a condition is considered to be "responsive to C5a receptor modulation" if modulation of C5a receptor activity results in a decrease in the inappropriate activity of the C5a receptor.

[0023] The term "individual" refers to mammals, including primates (especially humans), domesticated companion animals (dogs, cats, horses, etc.), and livestock (cattle, pigs, sheep, etc.), with the doses described herein. In some embodiments, the term "individual" refers to a human.

[0024] III. Detailed Description of the Embodiments A. Amorphous Form of Compound 1 In some embodiments, provided herein is an amorphous form of Compound 1: [ka]

[0025] In some embodiments, the amorphous form of Compound 1 is characterized by an X-ray powder diffraction pattern without distinct peaks that is substantially free of other forms of Compound 1. In some embodiments, the amorphous form of Compound 1 is characterized by an X-ray powder diffraction pattern substantially according to Figure 2.

[0026] Differential scanning calorimetry (DSC) can also be used to characterize the amorphous forms of Compound 1 described herein. In some embodiments, the amorphous forms of Compound 1 are characterized by a glass transition temperature of about 108° C. as determined by differential scanning calorimetry. In some embodiments, the amorphous forms of Compound 1 are characterized by a differential scanning calorimetry (DSC) thermogram substantially according to FIG.

[0027] Thermogravimetric analysis (TGA) is another technique that can be used to characterize the amorphous form of Compound 1 described herein. In some embodiments, the amorphous form of Compound 1 is characterized by a weight loss of about 0.015% upon heating to approximately 235° C., as measured by thermogravimetric analysis (TGA). In some embodiments, the amorphous form of Compound 1 is characterized by a thermogravimetric analysis (TGA) thermogram substantially according to FIG.

[0028] Dynamic vapor sorption (DVS) is an additional method that can be used to characterize the amorphous form of Compound 1 described herein. In some embodiments, the amorphous form of Compound 1 is characterized by a weight gain of about 0.44% after undergoing dynamic vapor sorption (DVS) cycling from about 0% relative humidity (RH) to about 95% RH at 25° C. In some embodiments, the amorphous form of Compound 1 is characterized by a weight gain of about 0.31% after undergoing dynamic vapor sorption (DVS) cycling from about 0% relative humidity (RH) to about 65% RH at 25° C. In some embodiments, the amorphous form of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot that does not exhibit any hysteresis between sorption and desorption. In some embodiments, the amorphous form of Compound 1 is characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with FIG. 6.

[0029] Microscopy can also be used to characterize the amorphous forms of Compound 1 described herein. In some embodiments, scanning electron microscopy (SEM) is used. In some embodiments, the amorphous form of Compound 1 is characterized by a scanning electron microscopy (SEM) image having predominantly spherical particles. In some embodiments, the spherical particles, as determined by SEM, are about 2 μm to 50 μm. In some embodiments, the amorphous form of Compound 1 is characterized by a scanning electron microscopy (SEM) image substantially according to Figure 8A, Figure 8B, Figure 8C, or Figure 8D.

[0030] Polarized light microscopy (PLM) is another technique that can be used to characterize the amorphous form of Compound 1 described herein. In some embodiments, the amorphous form of Compound 1 is characterized by a polarized light microscopy (PLM) profile that lacks birefringence. In some embodiments, the amorphous form of Compound 1 is characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 9A, Figure 9B, or Figure 9C.

[0031] B. Methods for Making the Amorphous Form of Compound 1 In some embodiments, provided herein is a method for preparing an amorphous form of Compound 1, the method comprising: a) dissolving Compound 1 in a polar aprotic solvent to form a solution; and b) spray drying the solution to form an amorphous form of Compound 1.

[0032] In some embodiments, suitable polar aprotic solvents include, but are not limited to, dimethyl sulfoxide (DMSO), toluene, dimethylacetamide (DMAc), dioxane, isopropyl acetate (IPAc), tetrahydrofuran (THF), acetone, dichloromethane (DCM), acetonitrile (MeCN), and the like, and mixtures thereof. In some embodiments, the polar aprotic solvent is tetrahydrofuran (THF), acetone, dichloromethane (DCM), or a mixture thereof. In some embodiments, the polar aprotic solvent is tetrahydrofuran (THF). In some embodiments, the polar aprotic solvent is acetone. In some embodiments, the polar aprotic solvent is dichloromethane (DCM) or a mixture thereof.

[0033] In some embodiments, the solution is formed at room temperature. In some embodiments, forming the solution includes heating the solution. One of ordinary skill in the art will understand that the heating temperature will depend, in part, on one or more factors, including the particular solvent and amount of solvent. Such factors will also determine, in part, the length of time required to dissolve Compound 1. The solution can be heated, for example, to 40°C, 50°C, 60°C, 70°C, or higher.

[0034] Any suitable length of time for forming the solution can be used, ranging from a few minutes to several hours. For example, a mixture containing Compound 1 and one or more polar aprotic solvents can be mixed, with or without heating, for about 10 minutes, or about 20 minutes, or about 30 minutes, or about 40 minutes, or about 1 hour or more.

[0035] Those skilled in the art will readily recognize that there are numerous commercially available devices for spray drying samples, each of which is encompassed by the present application, including the Buchi B290 spray dryer.

[0036] In some embodiments, the spray dryer is heated to a temperature of about 50° C. to about 150° C. In some embodiments, the spray dryer is heated to a temperature of about 70° C. to about 90° C. In some embodiments, the spray dryer is heated to a temperature of about 80° C.

[0037] In some embodiments, the spray dryer uses pressurized gas to force the solution through a nozzle. Various pressures can be used to achieve the desired solid form. In some embodiments, the pressurized gas comprises molecular nitrogen.

[0038] In some embodiments, a specific amount of Compound 1 is dissolved in a polar aprotic solvent. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.05 g / mL to 2 g / mL. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.1 g / mL to 1.5 g / mL. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.2 g / mL to 1 g / mL. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.2 g / mL to 0.5 g / mL. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.3 g / mL to 0.5 g / mL. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is 0.5 g / mL or less. In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.25 mg / mL. Some Embodiments In some embodiments, the concentration of Compound 1 dissolved in the polar aprotic solvent is about 0.375 mg / mL.

[0039] In an additional embodiment, provided herein is a method for preparing an amorphous form of Compound 1, the method comprising: d) dissolving Compound 1 in a polar aprotic solvent to form a solution, wherein the concentration of Compound 1 in the solution is 0.3 g / mL or less; e) optionally filtering the solution to form a filtrate; and f) removing the solvent from the solution or filtrate to form an amorphous form of Compound 1.

[0040] Suitable polar aprotic solvents include those discussed in the previous method. In some embodiments, the polar aprotic solvent is tetrahydrofuran (THF), acetone, dichloromethane (DCM), or a mixture thereof. In some embodiments, the polar aprotic solvent is tetrahydrofuran (THF). In some embodiments, the polar aprotic solvent is acetone. In some embodiments, the polar aprotic solvent is dichloromethane (DCM) or a mixture thereof.

[0041] Generally, the amount of Compound 1 in the polar aprotic solvent does not exceed 0.3 g / mL. This concentration of Compound 1 avoids undesired nucleation and crushing of Compound 1 into non-amorphous forms. In some embodiments, the concentration of Compound 1 in the polar aprotic solvent does not exceed 0.28, 0.26, 0.24, 0.22, 0.2, 0.18, 0.16, 0.14, or 0.12 g / mL. In some embodiments, the concentration of Compound 1 in the polar aprotic solvent is about 0.11 g / mL.

[0042] The optional filtration step can be performed using a number of commercially available filters, including polyethylene filters. Filters of various sizes can also be used, including pore sizes of ∼2, 4, 6, 8, 10, 12, 14, 16, 18, 20 μm, or larger. In some embodiments, the filter pore size is 10 μm. This filtration can be performed using standard techniques, such as gravity, suction, and pressure.

[0043] The solvent can be removed from the solution or filtrate using a variety of techniques. For example, the solvent can be removed by reducing the pressure or increasing the temperature of the solution or filtrate. In some embodiments, a rotary evaporator is used to remove the solvent. In some embodiments, oven drying is also used. Suitable temperatures include about 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, or warmer.

[0044] C. Pharmaceutical Compositions As demonstrated herein, the amorphous form of Compound 1 advantageously provides increased aqueous solubility as well as increased pharmacokinetic exposure. Accordingly, provided herein are pharmaceutical compositions containing the amorphous form of Compound 1 or liquid pharmaceutical compositions prepared using the amorphous form of Compound 1. The pharmaceutical compositions may include one or more pharmaceutically acceptable excipients.

[0045] Pharmaceutical compositions containing the amorphous form of Compound 1 may be in a form suitable for oral use, such as tablets, troches, lozenges, liquid preparations, aqueous or oily suspensions, dispersible powders or granules, emulsions, and self-emulsifying formulations such as those described in U.S. Patent Application No. 2002-0012680, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the amorphous form of Compound 1 in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia gum; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, enterally or otherwise, thereby providing a sustained action over a longer period. Time-retardants, such as glyceryl monostearate or glyceryl distearate, may be used. They may also be coated by the techniques described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.

[0046] Formulations for oral use may also be presented as hard gelatin capsules in which the amorphous form of Compound 1 is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the amorphous form of Compound 1 is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Additionally, emulsions may be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono-, diglycerides, PEG esters, and the like.

[0047] Aqueous suspensions for oral use contain an amorphous form of Compound 1 mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents may be natural phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearates, or condensation products of ethylene oxide with long-chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate, and other poloxamers (e.g., poloxamer F-68). The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl benzoate, p-hydroxybenzoic acid esters, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0048] Accordingly, provided herein is an aqueous suspension containing an amorphous form of Compound 1 and at least one additive. In some embodiments, the at least one additive is at least one suspending agent and / or at least one wetting agent, as described above.

[0049] Oily suspensions for oral use can be prepared by suspending the amorphous form of Compound 1 in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents such as those listed above can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0050] The pharmaceutical compositions may be in the form of a sterile injectable or infusible aqueous or oily solution or suspension. Such solutions or suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as mentioned above. Sterile injectable preparations may also be prepared as sterile injectable solutions or suspensions in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, isotonic sodium chloride solution, isotonic aqueous buffer solution, and mixtures of saline, disintegrating agents such as PEG (e.g., PEG 200, PEG 400, PEG 800, etc.), and non-ionic surfactants such as Tween® 80. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are permitted for use in injectable and infusible preparations. Compositions for injectable or infusional administration optionally contain a local anesthetic, such as lignocaine, to alleviate pain at the injection site. The components may be supplied premixed or supplied separately, with mixing of the components occurring immediately prior to use. In some embodiments, mixing immediately prior to use is desirable to take advantage of the high initial solubility of the amorphous form of Compound 1 in certain liquid formulation mixtures.

[0051] Injectable or infusion compositions include, but are not limited to, intravenous administration, intramuscular administration, and subcutaneous or intrasternal injection. Thus, in some embodiments, provided herein is an injectable or infusion solution containing Compound 1 and at least one wetting agent or solvent, wherein the intravenous pharmaceutical composition is prepared using an amorphous form of Compound 1 described herein. In some embodiments, the injectable or infusion solution is prepared for intravenous administration. In some embodiments, the injectable or infusion solution is prepared for intramuscular administration. In some embodiments, the injectable or infusion solution is prepared for subcutaneous injection. In some embodiments, the injectable or infusion solution is prepared for intrasternal injection. In some embodiments, the at least one wetting agent or solvent in the injectable or infusion pharmaceutical composition comprises saline, a disintegrant, and a non-ionic surfactant.

[0052] Injectable or infusion compositions can be prepared at any time convenient for the medical practitioner or user; this includes immediately before use or sufficiently in advance of use. In some embodiments, the compositions are prepared immediately before use. Immediately before use includes 0-24 hours, 0-10 hours, 0-5 hours, or 0-1 hour before use. In some embodiments, the injectable or infusion composition is prepared 0-5 hours before use. Sufficient in advance typically refers to one or more days before use. Accordingly, methods for preparing an injectable or infusion solution are also provided herein. The methods include dissolving an amorphous form of Compound 1 with at least one wetting agent or solvent to prepare an injectable or infusion solution; and administering the injectable or infusion solution to a subject in need thereof.

[0053] Dispersible powders and granules suitable for preparation of an aqueous oral formulation or suspension by the addition of water provide the amorphous form of Compound 1 in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional additives, such as sweeteners, flavorings, and coloring agents, may also be present.

[0054] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums, such as gum acacia or gum tragacanth, natural phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0055] Syrups and elixirs may be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions may be prepared in combination with, for example, cyclodextrin, PEG, and surfactants.

[0056] The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the amorphous form of Compound 1 with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol. In addition, these compounds can be administered by intraocular delivery using solutions or ointments. Furthermore, transdermal delivery of the target compounds can be achieved using iontophoretic patches, etc. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds of the present invention are utilized. As used herein, topical application is also meant to include the use of mouthwashes and gargles.

[0057] The compounds of the present invention may also be combined with carriers that are polymers suitable as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be combined with carriers that represent a class of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles such as bubbles, stents, tubes, and prostheses. In one embodiment of the present invention, the compounds of the present invention are combined with polymers or semipermeable polymer matrices formed into stent or stent-graft devices.

[0058] D. Treatment method Also provided herein are methods of treating an individual suffering from a condition responsive to C5a receptor modulation.

[0059] In some aspects, provided herein are methods for treating an individual suffering from or susceptible to a disease or disorder involving pathological activation of the C5a receptor, comprising administering to the individual an effective amount of an amorphous form of Compound 1 described herein or a pharmaceutical formulation comprising Compound 1.

[0060] In some embodiments, the amorphous form of Compound 1 described herein is used to treat a patient suffering from a condition that responds to C5a receptor modulation.

[0061] Conditions that may be treated by C5a modulation: Autoimmune diseases--e.g., rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barré syndrome, pancreatitis, C3 glomerulopathy (C3G), hidradenitis suppurativa (HS), lupus nephritis, lupus glomerulonephritis, immunoglobulin A (IgA) nephropathy, psoriasis, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), immune-mediated vasculitis, tissue graft rejection, hyperacute rejection of transplanted organs; and the like.

[0062] Inflammatory disorders and related conditions--such as neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease (IBD), age-related macular degeneration (AMD, both wet and dry forms), inflammation associated with severe burns, lung injury, and ischemia-reperfusion injury, osteoarthritis, as well as acute (adult) respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), systemic inflammatory response syndrome (SIRS), atopic dermatitis, psoriasis, chronic urticaria, and multiple organ dysfunction syndrome (MODS). Also included are pathological sequelae associated with inflammation resulting from contact of blood with artificial surfaces that can cause complement activation, such as occurs during extracorporeal circulation of blood (e.g., during hemodialysis or via heart-lung machines in connection with vascular surgery, e.g., coronary artery bypass grafts or heart valve replacements) or in connection with contact with other artificial vascular or vessel surfaces (e.g., ventricular assist devices, artificial heart devices, transfusion tubing, blood storage bags, plasma exchange, platelet exchange, and the like). Also included are diseases associated with ischemia / reperfusion injury, such as those resulting from transplants, including solid organ transplants, and syndromes such as ischemic-reperfusion injury, ischemic colitis, and cardiac ischemia. The amorphous form of Compound 1 described herein may also be useful in the treatment of age-related macular degeneration (Hageman et al., PNAS 102: 7227-7232, 2005).

[0063] Cardiovascular and cerebrovascular disorders—e.g., myocardial infarction, coronary thrombosis, vascular occlusion, postoperative vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease. In one embodiment, an effective amount of the amorphous form of Compound 1 described herein may be administered to a patient at risk of myocardial infarction or thrombosis (i.e., a patient with one or more recognized risk factors for myocardial infarction or thrombosis, including, but not limited to, obesity, smoking, hypertension, hypercholesterolemia, a personal or genetic history of myocardial infarction or thrombosis) to reduce the risk of myocardial infarction or thrombosis.

[0064] Vasculitic Diseases—Vasculitic diseases are characterized by vascular inflammation. Leukocyte infiltration leads to destruction of the vascular wall, and the complement pathway is thought to play a major role in initiating leukocyte migration and the resulting damage manifested at the site of inflammation (Vasculitis, Second Edition, Edited by Ball and Bridges, Oxford University Press, pp 47-53, 2008). The amorphous form of Compound 1 described herein can be used to treat vasculitides, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (or ANCA-associated vasculitis, which includes microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and granulomatosis with polyangiitis, also known as Wegener's disease), Churg-Strauss syndrome, Henoch-Schönlein purpura, polyarteritis nodosa, rapidly progressive glomerulonephritis (RPGN), cryoglobulinemia, giant cell arteritis (GCA), Behcet's disease, and Takayasu's arteritis (TAK).

[0065] HIV infection and AIDS—The amorphous forms of Compound 1 described herein may be used to inhibit HIV infection, slow the progression of AIDS, or reduce the severity of the symptoms of HIV infection and AIDS.

[0066] Neurodegenerative Disorders and Related Diseases—In further embodiments, the amorphous forms of Compound 1 described herein may be used to treat Alzheimer's disease, multiple sclerosis, and cognitive decline associated with cardiopulmonary bypass surgery and related procedures.

[0067] Cancer—The amorphous forms of Compound 1 described herein are also useful for treating cancer and precancerous conditions in a subject. Specific cancers that can be treated include, but are not limited to, sarcomas, carcinomas, and mixed tumors. Examples of conditions that can be treated according to the present invention include fibrosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovial tumors, mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchial carcinoma, melanoma, renal cell carcinoma, hepatocellular carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, pleomorphic adenoma, hepatocellular papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma, and fibroma.

[0068] In some embodiments, the amorphous form of Compound 1 described herein can be used for the treatment of a disease selected from the group consisting of sepsis (and related disorders), COPD, rheumatoid arthritis, lupus nephritis, and multiple sclerosis.

[0069] In some embodiments, the amorphous form of Compound 1 described herein can be used for the treatment of a disease selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, C3 glomerulopathy, hidradenitis suppurativa, and lupus nephritis.

[0070] The therapeutic methods provided herein generally involve administering to a patient an effective amount of an amorphous form of Compound 1. Suitable patients include those suffering from or susceptible to (i.e., prophylactic treatment for) a disorder or disease identified herein. Typical patients for treatment as described herein include mammals, particularly primates, and particularly humans. Other suitable patients include domesticated companion animals, such as dogs, cats, and horses, or livestock animals, such as cattle, pigs, and sheep.

[0071] In general, the therapeutic methods provided herein comprise administering to a patient an effective amount of an amorphous form of Compound 1 described herein. The exact formulation, route of administration, and dosage for the pharmaceutical compositions of the present invention can be chosen by the individual physician in consideration of the patient's condition (see, e.g., Fingl et al. 1975, "The Pharmacological Basis of Therapeutics," incorporated herein by reference in its entirety, in particular Chapter 1, page 1). In some embodiments, an amorphous form of Compound 1 described herein is administered orally to a patient (e.g., a human). In some embodiments, an amorphous form of Compound 1 described herein is administered to a patient (e.g., a human) intravenously, intramuscularly, or via subcutaneous or intrasternal injection. The effective amount may be an amount sufficient to modulate C5a receptor activity and / or to reduce or alleviate symptoms presented by the patient. Preferably, the amount administered is sufficient to produce a plasma concentration of the compound (or, if the compound is a prodrug, an active metabolite thereof) high enough to detectably inhibit chemotaxis of white blood cells (e.g., neutrophils) in vitro.

[0072] For the treatment of most disorders by oral administration, one skilled in the art can determine the appropriate administration frequency. In some embodiments, an administration frequency of four times per day or less is preferred. In some embodiments, a twice-daily dosing regimen is used. In some embodiments, once-daily administration is used. The patient may be administered the amorphous form of Compound 1 in a fed or fasted state. In some embodiments, the patient ingests the amorphous form of Compound 1 with food. In some embodiments, the patient ingests the amorphous form of Compound 1 without food.

[0073] For treatment of most disorders via intravenous, intramuscular, or subcutaneous or intrasternal injection, one of skill in the art may determine the appropriate dosing frequency. In some embodiments, the dosing frequency is about once every two weeks. In some embodiments, the dosing frequency is about once every week. In some embodiments, the dosing frequency is about three times per week. In some embodiments, the dosing frequency is about two to five times per week. In some embodiments, the dosing frequency is about once every other day. In some embodiments, the dosing frequency is about once daily.

[0074] It will be understood, however, that the specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, concomitant medications (i.e., other drugs administered to the patient), and the severity of the particular disease being treated, as well as the judgment of the prescribing medical practitioner. In general, use of the minimum dosage sufficient to provide effective treatment is preferred. Patients are generally monitored for therapeutic effectiveness using medical or veterinary criteria appropriate to the condition being treated or prevented.

[0075] Dosage levels on the order of about 0.1 mg to about 140 mg / kg body weight / day are useful in the treatment or prevention of conditions involving pathogenic C5a activity (about 0.5 mg to about 7 g / human patient / day). The amount of amorphous form of Compound 1 that may be combined with a carrier material to provide a single dosage form will vary widely depending on the host being treated and the particular mode of administration. Unit dosage forms generally contain about 1 mg to about 500 mg of the amorphous form of Compound 1. When administered orally, transdermally, intravenously, or subcutaneously, it is preferred that a sufficient amount of the amorphous form of Compound 1 be administered to achieve a serum concentration of 5 ng (nanogram) / mL to 10 μg (microgram) / mL serum; more preferably, sufficient compound should be administered to achieve a serum concentration of 20 ng to 1 μg / mL serum; and most preferably, sufficient compound should be administered to achieve a serum concentration of 50 ng / mL to 200 ng / mL serum. For direct injection into the synovium (for the treatment of arthritis), a sufficient amount of the amorphous form of Compound 1 to achieve a local concentration of approximately 1 micromolar should be administered.

[0076] E. Combination Therapy The methods disclosed herein may include combination therapy with one or more additional therapeutic agents used in the treatment, prevention, inhibition, or amelioration of diseases or conditions involving pathological activation of the C5a receptor. Such one or more additional therapeutic agents may be administered simultaneously or sequentially with the amorphous form of Compound 1, by a route and in an amount typically used therefor. When the amorphous form of Compound 1 is used concurrently with additional therapeutic agents, pharmaceutical compositions containing such other agents in addition to the amorphous form of Compound 1 are preferred. Thus, pharmaceutical compositions of the present disclosure include those containing the amorphous form of Compound 1 as well as one or more other active ingredients or therapeutic agents.

[0077] Examples of the one or more additional therapeutic agents include corticosteroids, steroids, immunosuppressants, immunoglobulin G agonists, dipeptidyl peptidase IV inhibitors, lymphocyte function antigen-3Receptor antagonist, interleukin-2 ligand, interleukin-1β ligand inhibitor, IL-2 receptor α subunit inhibitor, HGF gene stimulator, IL-6 antagonist, IL-5 antagonist, α1 antitrypsin stimulator, cannabinoid receptor antagonist, histone deacetylase inhibitor, AKT protein kinase inhibitor, CD20 inhibitor, Abl tyrosine kinase inhibitor, JAK tyrosine kinase inhibitor, TNFα ligand inhibitor, hepatocellular carcinoma (CTC) inhibitor Molecular globin modulators, TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp70 family inhibitors, immunoglobulin agonists, CD30 antagonists, tubulin antagonists, sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotropic hormone ligands, Btk tyrosine kinase inhibitors, complement C1 small component inhibitors, erythropoietin receptor agonists, B lymphocyte stimulating factor ligand inhibitors inhibitors, cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, elongation factor 2 inhibitors, cell adhesion molecule inhibitors, factor XIII agonists, calcineurin inhibitors, immunoglobulin G1 agonists, inosine monophosphate dehydrogenase inhibitors, complement C1 small component inhibitors, thymidine kinase modulators, cytotoxic T-lymphocyte protein-4 modulators, angiotensin II receptor antagonists, angiotensin I I receptor modulators, TNF superfamily receptor 12A antagonists, CD52 antagonists, adenosine deaminase inhibitors, T cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, Syk tyrosine kinase inhibitors, type I interferon receptor antagonists, interferon α ligand inhibitors, macrophage migration inhibitory factor inhibitors, integrin α-V / β-6 antagonists, cysteine ​​protease stimulatory factors, p38MAP kinase inhibitor, TP53 gene inhibitor, Shiga-like toxin I inhibitor, fucosyltransferase 6 stimulator, interleukin-22 ligand, IRS1 gene inhibitor, protein kinase C stimulator, protein kinase C α inhibitor, CD74 antagonist, immunoglobulin gamma Fc receptor IIB antagonist, T cell antigen CD7 inhibitor, CD95 antagonist, N-acetylmannosamine kinase stimulator, cardiotrophin-1 ligand, leukocyte elastase inhibitor, CD40 ligand receptor antagonist, CD40 ligand modulator, IL-17 antagonist, TLR-2 antagonist, mannan-binding lectin serine protease-2 (MASP-2) inhibitors, factor B inhibitors, factor D inhibitors, C3aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists of chemokine receptors, particularly CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, and combinations thereof.

[0078] In some embodiments, the additional therapeutic agent used in the therapeutic methods herein is selected from the group consisting of obinutuzumab, rituximab, ocrelizumab, tositumomab, obinutuzumab, ibritumomab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17 valerate, halometasone, alclometasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-succinate, hydrocortisone Cortisone-17-butenoate (buteprate), ciclesonide and prednicarbate, GB-0998, Imugro, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimovab, beperminogen perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, Ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, Shinrize, conestat, methoxypolyethylene glycol-epoetin beta, belimumab, blissibimod, atacicept, seliciclib, neiflizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, cyclosporine, tacrolimus, voclosporin, canakinumab,Mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, Rosmapimod, QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprerestat, ASKP-1240, BMS- 986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, thymoglobulin, laquinimod, remestemcel-L, equine antithymocyte immunoglobulin, stempeucel, LIV-γ, octagam 10%, t2c-001, 99mTc-sestamibi, Claryg, Prosolva, pomalidomide, laquinimod, teplizumab, FCRx, Solnatide, foralarumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan + propagermanium, apocel, cannabidiol, RGI-2001, saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100, LT-1951, OMS721, ALN-CC5, ACH-4471, AMY-101, Acthar Gel, and CD4, + CD25 + Regulatory T cells, MEDI7814, P32, P59, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof. [Example]

[0079] IV. Working Examples The following examples are offered to help illustrate the described invention and are not intended to limit what the inventors regard as their invention.

[0080] Example 1: Preparation of the free base crystalline form of Compound 1 Crude compound 1 was prepared essentially as described in WO2016 / 053890.

[0081] The free base crystalline form of Compound 1 was prepared by dissolving 18 g of crude Compound 1 in 50 mL of acetone heated to 40°C (concentration approximately 0.36 g / mL). The warm solution was passed through a 10 μm polyethylene filter. The solution was then loaded onto a rotary evaporator with a bath temperature of 30°C and a rotation speed of 180 rpm. The collected solid was further dried in an oven at 45°C for 1 hour. XRPD data for this crystalline form is shown in Figure 1, and a table of measured peaks is listed below in Table 1. [Table 1]

[0082] Example 2: Preparation of an amorphous form of Compound 1 Method 1 Crude compound 1 was prepared essentially as described in WO2016 / 053890.

[0083] Crude Compound 1 (15 g) was dissolved in 40 mL of acetone at 40° C. The solution was spray-dried using a Buchi B290 spray dryer equipped with a peristaltic pump. The spray-drying process was completed using a target inlet temperature of 80° C., a target spray rate of 5 mL / min, and a process gas flow rate of 20.60 CFM. The spray-dried powder collected in the sample collection chamber was characterized by XRPD and was an amorphous form of Compound 1, as shown in FIG. 2. Method 2 The amorphous form of Compound 1 was prepared by dissolving 1 g of the free base crystalline form of Compound 1 in 9 mL of acetone without heating (concentration approximately 0.11 g / mL). The solution was passed through a 10 μm polyethylene filter by gravity. The solution was then loaded into a rotary evaporator with a bath temperature of 45°C and a rotation speed of 220 rpm. The collected solid was further dried in an oven at 45°C for 30 hours. XRPD data for the starting material (crystalline form) and the amorphous form produced from Method 2 are shown in Figures 3A and 3B. DSC data for the starting material (crystalline form) and the amorphous form produced from Method 2 are shown in Figure 4. Experimental details for DSC data collection are described in Example 3.

[0084] Example 3: Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) of the Amorphous Form of Compound 1 Differential scanning calorimetry data was collected to evaluate the physical characteristics of the amorphous form of Compound 1. A TA Instruments ~ Waters LLC differential scanning calorimeter model DSC25 was used. Samples were weighed into standard aluminum pans and sealed with standard aluminum lids with pinholes. Measurements were completed under nitrogen purging using a scan rate of 10 °C / min. DSC analysis determined that this amorphous form exhibited a glass transition temperature of approximately 108 °C. A plot of the DSC thermogram is shown in Figure 4.

[0085] The amorphous form of Compound 1 was also evaluated using thermogravimetric analysis (TGA). TGA data were collected on a TA Instrument Q500 TGA. Each sample was loaded into a pre-tared platinum crucible; the balance and furnace were purged with nitrogen and then analyzed with flow rates set at 40±5 and 60±5 mL / min, respectively. The heating step was programmed to begin at ambient temperature and ramp at 10°C / min. TGA analysis determined that the amorphous form of Compound 1 exhibited a weight loss of approximately 0.015% upon heating to approximately 139°C. A plot of the TGA thermogram is shown in Figure 5.

[0086] Example 4: Dynamic Vapor Sorption (DVS) of the Amorphous Form of Compound 1 To evaluate the hygroscopicity and physical stability of the amorphous form of Compound 1 under different humidity conditions, dynamic vapor sorption (DVS) data were collected at 25°C after pre-equilibrating the sample at 0% RH and removing unbound water. DVS was measured using a VTI SGA-100 water vapor sorption analyzer. Adsorption and desorption data were collected in 10% RH increments over a range of 5% to 95% RH under nitrogen purge. The equilibrium criteria used for the analysis were a weight change of less than 0.0100% in 5 minutes with a maximum equilibration time of 3 hours. The DVS test parameters are listed in Table 2. [Table 2]

[0087] The DVS of the amorphous form of Compound 1 showed a weight gain of 0.4% after undergoing dynamic water vapor sorption cycling from approximately 0% relative humidity (RH) to approximately 95% RH at 25 °C (Figure 6), indicating that the amorphous form of Compound 1 has low hygroscopicity. The DVS plot also showed no hysteresis between sorption and desorption. In addition, the XRPD results (Figure 7) showed no change before and after the DVS test.

[0088] Example 5: Scanning Electron Microscope (SEM) Images of the Amorphous Form of Compound 1 Scanning electron microscopy images were obtained using an FEI Quanta 200 scanning electron microscope equipped with an Everhart Thornley (ET) detector. These images were collected and analyzed using xTm software (v. 2.01) and XT Docu software (v. 3.2), respectively. Magnification was verified using National Institute of Standards and Technology (NIST)-traceable standards. Samples were prepared for analysis by placing a small amount on a carbon adhesive tab supported on an aluminum mount. The samples were then sputter-coated twice (at different orientations) with Au / Pd using a Cressington 108 automated sputter coater at approximately 20 mA and 0.13 mbar (Ar) for 75 seconds. Representative images of this amorphous morphology are shown in Figures 8A-8D. When viewed under magnification, these crystals were primarily spherical, ranging in size from 2 to 50 μm.

[0089] Example 6: Polarized Light Microscopy (PLM) Images of the Amorphous Form of Compound 1 Polarized light microscopy was performed using a Leica DM LP microscope equipped with a Spot Insight color camera. Different objectives were used with crossed polarized light and a first-order red correction to view the samples. The samples were placed on glass slides, a #1.5 cover slip was placed on top of the sample, and a drop of mineral oil was added. Images were acquired at ambient temperature using Spot Advanced software (v. 4.5.9). A micrometer bar is inset on the image as a size reference. Representative images of the amorphous form are shown in Figures 9A-9C. Notably, no birefringence was observed when viewing the amorphous form of Compound 1, supporting the conclusion that the solid form prepared herein is amorphous. When viewed under magnification, these crystals ranged in size from 6 to 20 μm.

[0090] Example 7: Stability of the amorphous form of Compound 1 A sample of the amorphous form of Compound 1 was examined by XRPD ( FIG. 10 ) when it was freshly prepared (top XRPD pattern, labeled “Time Zero (Initial)”). This sample was stored in a sealed glass container under normal ambient laboratory conditions. After 11 months, it was examined again by XRPD (bottom XRPD pattern, labeled “11 months under ambient conditions”).

[0091] A sample of the amorphous form of Compound 1 was tested by different analytical methods, and the data are reported in the "Time Zero" column (Table 3). These analytical methods include HPLC and Karl Fischer (KF). The sample was placed in two low-density polyethylene (LDPE) bags, sealed with cable ties, and then placed in a foil-lined high-density polyethylene (HDPE) bottle and heat-induction sealed, with 0.5 g of desiccant placed between the LDPE bags. The HDPE bottle was stored in an environmental chamber at 25°C and 60% relative humidity (RH). After 12 months in the environmental chamber, the sample was retested using the same analytical methods. The results are shown in Table 3. [Table 3]

[0092] Example 8: Amorphous forms of Compound 1 provide improved in vitro solubility The in vitro solubility of the crystalline form of Compound 1 and the amorphous form of Compound 1 was tested.

[0093] The amorphous form was prepared as described in Example 1, Method 1, and the crystalline form of Compound 1 was prepared as described in Example 2.

[0094] The crystalline and amorphous forms of Compound 1 were saturated in three different media: 0.1 N HCl solution, fasted-state simulated gastric fluid (FaSSGF), and fed-state simulated intestinal fluid (FeSSIF). The samples were shaken at 40 rpm in a 37°C water bath. The concentration of dissolved Compound 1 in the samples was measured by HPLC at four different time points (0.5, 1, 2, and 4 hours). [Table 4]

[0095] Example 9: IV formulations using amorphous forms of Compound 1 provide increased solubility Intravenous (IV) formulations of the crystalline form of Compound 1 and the amorphous form of Compound 1 were prepared by contacting the amorphous or crystalline form of Compound 1 with saline / PEG 400 / Tween® 80 (88:10:1). The crystalline form of Compound 1 was prepared as described in Example 8, and the amorphous form of the compound was prepared as described in Example 1: Preparation of the Free Base Crystalline Form of Compound 1.

[0096] Crude compound 1 was prepared essentially as described in WO2016 / 053890.

[0097] The free base crystalline form of Compound 1 was prepared by dissolving 18 g of crude Compound 1 in 50 mL of acetone heated to 40°C (concentration approximately 0.36 g / mL). The warm solution was passed through a 10 μm polyethylene filter. The solution was then loaded onto a rotary evaporator with a bath temperature of 30°C and a rotation speed of 180 rpm. The collected solid was further dried in an oven at 45°C for 1 hour. XRPD data for this crystalline form is shown in Figure 1, and a table of measured peaks is listed below in Table 1. [Table 5]

[0098] Example 2, Method 1 As demonstrated below in Table 5, the amorphous form of Compound 1 had improved aqueous solubility in the IV formulation compared to the crystalline form, particularly at early time points. A plot of solubility over time is shown in Figure 11. [Table 6]

[0099] Example 10: Aqueous suspension formulations using the amorphous form of Compound 1 provide increased bioavailability An in vivo rat PK study was conducted to compare the PK profile and bioavailability of the amorphous versus crystalline forms of Compound 1 in an aqueous suspension formulation containing 0.5% w / v hydroxypropylcellulose (Klucel GF grade) and 0.5% w / v poloxamer F-68 (BASF Kolliphor P188). Each animal was orally administered 10 mg / kg of Compound 1 in a dose volume of 5 mL / kg (dosing concentration 2 mg / mL). The suspension formulation containing the amorphous form of Compound 1 resulted in a significant increase in Cmax and AUC compared to the formulation containing the crystalline form of Compound 1 (Table 6). The PK profiles of these two formulations are shown in Figure 12. [Table 7]

[0100] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between this application and the references provided herein, the present application shall control.

Claims

1. Amorphous form of Compound 1 below 【Chemistry 1】 An amorphous form of Compound 1, characterized by a powder X-ray diffraction pattern having no distinct peaks, which is substantially free of other forms of Compound 1.

2. 2. The amorphous form of Compound 1 of claim 1, characterized by a powder X-ray diffraction pattern substantially in accordance with FIG.

3. 3. The amorphous form of Compound 1 of claim 1 or claim 2, further characterized by a glass transition temperature of about 108°C as determined by differential scanning calorimetry.

4. 3. The amorphous form of Compound 1 of claim 1 or claim 2, further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 4.

5. 5. The amorphous form of Compound 1 of any one of claims 1 to 4, further characterized by a weight loss of about 0.015% upon heating to approximately 235°C as measured by thermogravimetric analysis (TGA).

6. 5. The amorphous form of Compound 1 of any one of claims 1 to 4, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 5.

7. 7. The amorphous form of Compound 1 of any one of claims 1 to 6, further characterized by a weight gain of about 0.44% after being subjected to dynamic vapor sorption (DVS) cycling from about 0% relative humidity (RH) to about 95% RH at 25°C.

8. 7. The amorphous form of Compound 1 of any one of claims 1 to 6, further characterized by a weight gain of about 0.31% after undergoing dynamic vapor sorption (DVS) cycling from about 0% relative humidity (RH) to about 65% RH at 25°C.

9. 7. The amorphous form of Compound 1 of any one of claims 1 to 6, further characterized by a dynamic vapor sorption (DVS) plot that does not exhibit any hysteresis during adsorption and desorption.

10. 7. The amorphous form of Compound 1 of any one of claims 1 to 6, further characterized by a dynamic vapor sorption (DVS) plot substantially in accordance with Figure 6.

11. 11. The amorphous form of Compound 1 according to any one of claims 1 to 10, further characterized by a scanning electron microscope (SEM) image having predominantly spherical particles.

12. 12. The amorphous form of Compound 1 of claim 11, wherein the spherical particle size as determined by SEM is about 2 μm to 50 μm.

13. 11. The amorphous form of Compound 1 of any one of claims 1 to 10, further characterized by a scanning electron microscope (SEM) image substantially according to Figure 8A, Figure 8B, Figure 8C, or Figure 8D.

14. 14. The amorphous form of Compound 1 of any one of claims 1 to 13, further characterized by a polarized light microscope (PLM) profile lacking birefringence.

15. 14. The amorphous form of Compound 1 of any one of claims 1 to 13, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 9A, Figure 9B, or Figure 9C.

16. 1. A process for preparing an amorphous form of Compound 1, comprising: a) dissolving Compound 1 in a polar aprotic solvent to form a solution; b) spray drying the solution to form an amorphous form of Compound 1.

17. 17. The process of claim 16, wherein the polar aprotic solvent is selected from the group consisting of tetrahydrofuran (THF), acetone, dichloromethane (DCM), and mixtures thereof.

18. 17. The process of claim 16, wherein the polar aprotic solvent is THF.

19. 17. The process of claim 16, wherein the polar aprotic solvent is acetone.

20. 17. The process of claim 16, wherein the polar aprotic solvent is DCM.

21. 1. A process for preparing an amorphous form of Compound 1, comprising: a) dissolving Compound 1 in a polar aprotic solvent to form a solution, wherein the concentration of Compound 1 in the solution is 0.3 g / mL or less; b) optionally filtering the solution to form a filtrate; and c) removing the solvent from the solution or filtrate to form an amorphous form of Compound 1.

22. A pharmaceutical composition comprising an amorphous form of compound 1 according to any one of claims 1 to 15, and at least one pharmaceutically acceptable excipient.

23. 16. An aqueous suspension comprising an amorphous form of compound 1 according to any one of claims 1 to 15, and at least one additive.

24. 24. Aqueous suspension according to claim 23, wherein said at least one additive is at least one suspending agent and / or at least one wetting agent.

25. 25. An aqueous suspension according to claim 23 or claim 24, wherein the aqueous suspension further comprises a sweetening agent.

26. 16. An injectable or infusion solution comprising Compound 1 and at least one wetting agent or solvent, wherein said injectable or infusion solution is prepared using an amorphous form of Compound 1 according to any one of claims 1 to 15.

27. 27. The injectable or infusion solution of claim 26, prepared for intravenous administration.

28. 27. The injectable or infusion solution of claim 26, formulated for intramuscular administration.

29. 27. The injectable or infusion solution of claim 26, prepared for subcutaneous injection.

30. 30. The injectable or infusion solution of any one of claims 26 to 29, wherein the injectable or infusion solution is prepared immediately before use by dissolving an amorphous form of Compound 1 with at least one wetting agent or solvent.

31. 30. A method of using an injectable or infusion solution according to any one of claims 26 to 29, comprising: A method for preparing an injectable or infusion solution by dissolving an amorphous form of Compound 1 with at least one wetting agent or solvent; and A method for administering an injectable or infusion solution to a subject in need thereof, comprising:

32. 16. A method of treating an individual suffering from or susceptible to a disease or disorder involving pathological activation of the C5a receptor, comprising administering to the individual an effective amount of an amorphous form of compound 1 according to any one of claims 1 to 15.

33. 33. The method of claim 32, wherein the disease or disorder is an inflammatory disease or disorder.

34. 34. The method of claim 33, wherein the disease or disorder is selected from the group consisting of neutropenia, sepsis, septic shock, Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, age-related macular degeneration, chronic obstructive pulmonary disease, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, tissue graft rejection, cancer, and hyperacute rejection of a transplanted organ.

35. 33. The method of claim 32, wherein the disease or disorder is a cardiovascular or cerebrovascular disorder.

36. 36. The method of claim 35, wherein the disease or disorder is selected from the group consisting of myocardial infarction, coronary thrombosis, vascular occlusion, postoperative vascular reocclusion, atherosclerosis, traumatic central nervous system injury, and ischemic heart disease.

37. 33. The method of claim 32, wherein the disease or disorder is an autoimmune disease.

38. 38. The method of claim 37, wherein the disease or disorder is selected from the group consisting of rheumatoid arthritis, C3 glomerulopathy (C3G), hidradenitis suppurativa (HS), systemic lupus erythematosus, Guillain-Barré syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, immunoglobulin A (IgA) nephropathy, Crohn's disease, vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, immune-related vasculitis, tissue graft rejection, and hyperacute rejection of a transplanted organ.

39. 33. The method of claim 32, wherein the disease or disorder is a pathological sequela associated with the group consisting of insulin-dependent diabetes mellitus, diabetes mellitus, lupus nephropathy, Heymann nephritis, membranous nephritis, glomerulonephritis, contact hypersensitivity reactions, and inflammation resulting from contact of blood with artificial surfaces.

40. 33. The method of claim 32, wherein the disease or disorder is selected from the group consisting of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, C3 glomerulopathy, hidradenitis suppurativa, and lupus nephritis.

41. 33. The method of claim 32, wherein the disease or disorder is antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

42. 33. The method of claim 32, wherein the disease or disorder is granulomatosis with polyangiitis.

43. 33. The method of claim 32, wherein the disease or disorder is microscopic polyangiitis.

44. 33. The method of claim 32, wherein the disease or disorder is C3 glomerulopathy.

45. 33. The method of claim 32, wherein the disease or disorder is hidradenitis suppurativa.

46. 33. The method of claim 32, wherein the disease or disorder is lupus nephritis.

47. 47. The method of any one of claims 32 to 46, further comprising administering to the individual an effective amount of one or more additional therapeutic agents.

48. 48. The method of claim 47, wherein the one or more additional therapeutic agents is rituximab.

49. 48. The method of claim 47, wherein the one or more additional therapeutic agents is cyclophosphamide.

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