Crystalline ABDNAZ compositions and methods of making and using same

Abstract

The present invention relates to compositions comprising solid crystalline non-shock sensitive or non-explosion sensitive particles comprising 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ), methods for preparing said crystalline forms, and uses thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 208,631, filed June 9, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to compositions comprising solid crystalline non-shock sensitive or non-explosion sensitive particles comprising 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ), methods for preparing said crystalline forms, and uses thereof. [Background technology]

[0003] The present invention relates to a novel desensitized ABDNAZ composition for use in the prevention or treatment of diseases or conditions associated with oxidative stress, inflammation, and hypoxia.As an energetic compound that derives its high energy value endogenously from both oxidative action and ring strain, ABDNAZ has highly unfavorable properties of shock sensitivity and susceptibility to explosion, which may lead to inadvertent injury or death or damage to equipment or facilities during manufacture, transportation, formulation, and storage.

[0004] It is therefore an object of the present invention to provide a stable desensitized ABDNAZ composition that is inactivated against mechanical shock and explosion and is therefore safer to prepare, handle, formulate and transport. Another object of the present invention is to provide a desensitized ABDNAZ composition that has improved therapeutic activity over prior art compositions. A further object of the present invention is to provide a desensitized ABDNAZ composition that has improved solubility over prior art compositions. Moreover, it is a further object of the present invention to overcome many of the handling and transport problems previously associated with shock-sensitive and explosion-sensitive materials.

[0005] Methods for the synthesis of ABDNAZ are described in U.S. Patent No. 7,507,842 and U.S. Patent No. 8,471,041, etc. However, the shock and explosion sensitivity of the ABDNAZ thus synthesized is highly variable and cannot be predicted or controlled. Therefore, the present invention provides an improved class of "desensitized" ABDNAZ, which includes inertness to shock, impact, or explosion, improved solubility in water and DMSO, and improved anti-cancer activity.

[0006] Cancer remains a major health problem, despite many advances made in the detection and treatment of the disease. Current strategies for cancer management rely on early diagnosis and aggressive treatment. Treatment options often include surgery, radiation therapy, chemotherapy, hormonal therapy, or a combination thereof. Although many patients benefit from such therapies, there remains a need for better therapeutic agents to treat various types of cancer.

[0007] Prostate, breast, and lung cancers are the leading causes of cancer-related deaths. Prostate cancer is the most common form of cancer in men, with an estimated incidence of 30% in men over 50 years of age. Furthermore, clinical findings indicate that human prostate cancer has a tendency to metastasize to bone, and the disease appears to inevitably progress from an androgen-dependent to an androgen-resistant state, increasing the mortality rate of patients. Breast cancer remains the leading cause of death in women. Its cumulative risk is relatively high, with one report indicating that approximately one in eight women in the United States is expected to develop some type of breast cancer by the age of 85. Similarly, lung cancer is the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of these cases.

[0008] Furthermore, inflammation, oxidative and nitrative stress, and hypoxia are characteristics of a diverse range of diseases, including cancer, ischemia-reperfusion injury, autoimmunity, and trauma, and effective therapies remain an unmet clinical need. ABDNAZ is currently being clinically evaluated as an anti-inflammatory and antioxidant agent that is cytotoxic to tumors but not to non-malignant tissues, for the prevention and / or treatment of several conditions and diseases. These conditions / diseases include various cancers, ischemia-reperfusion injury (IRI), and autoimmune, degenerative, and inflammatory diseases. In addition, ABDNAZ is also being investigated as an anti-radiation or radioprotectant to be used against nuclear radiation that may occur during military conflict or nuclear meltdown, as well as a radioprotectant and chemoprotectant intended to reduce the undesirable side effects of chemotherapy and radiotherapy in the treatment of cancer.

[0009] However, to summarize the above, despite its many advantageous properties, ABDNAZ drug substance is prone to explosion upon shock or impact, thereby creating potential safety issues during production, transportation, storage, and formulation of the drug substance for therapeutic use. Thus, there remains a need to create a routinely non-explosive form of ABDNAZ for use in therapeutic applications, allowing for safe storage, transportation, and general handling of ABDNAZ. Summary of the Invention

[0010] The present invention is based, in part, on the discovery, preparation and use of novel ABDNAZ forms that are insensitive to impacts and shocks, as well as explosions.

[0011] In one embodiment, the compound of formula I: [ka] A composition is provided comprising solid crystalline non-shock sensitive or non-explosion sensitive particles comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises a solvated form of the compound. In some embodiments, the composition comprises tetrahydrofuran (THF). In some embodiments, the concentration of THF in the composition is at least about 330 ppm. In some embodiments, the particles are in clathrate form. In some embodiments, the particles comprise THF. In some embodiments, the concentration of THF in the particles is at least about 330 ppm. In some embodiments, the composition further comprises n-heptane. In some embodiments, the concentration of n-heptane in the composition is at least about 800 ppm. In some embodiments, the particles comprise n-heptane. In some embodiments, the concentration of n-heptane in the particles is at least about 800 ppm.

[0012] In some embodiments, the composition has a bulk density of 0.1 g / cm 3 ~0.6g / cm 3 In some embodiments, the bulk density is in the range of 0.15 g / cm 3 ~0.5g / cm 3 , 0.15g / cm 3 ~0.4g / cm 3 , or 0.16 g / cm 3 ~0.3g / cm 3 In some embodiments, the bulk density of the particles is about 0.45 g / cm 3 In some embodiments, the Dv(10) of the particles is less than about 40 μm. In some embodiments, the Dv(50) of the particles is less than about 200 μm. In some embodiments, the Dv(90) of the particles is less than about 400 μm. In some embodiments, the particles are substantially acicular in shape. In some embodiments, the solubility of the composition is greater than about 20 mg / mL in DMSO at 25° C. In some embodiments, the angle of repose of the particles is less than about 45 degrees.

[0013] In some embodiments, the viability of cancer cells treated with the composition is lower than the viability of cancer cells treated with a shock-sensitive or blast-sensitive composition containing an equivalent amount of ABDNAZ. In some embodiments, the viability of HCT 116 cells treated with about 8 μM of ABDNAZ of the composition is at least about 50% lower than the viability of HCT 116 cells treated with about 8 μM of ABDNAZ of the shock-sensitive or blast-sensitive composition. In some embodiments, the viability of SCC VII cells treated with about 4 μM of ABDNAZ of the composition is at least about 25% lower than the viability of SCC VII cells treated with about 4 μM of ABDNAZ of the shock-sensitive or blast-sensitive composition. In some embodiments, the viability of A549 cells treated with about 20 μM of ABDNAZ of the composition is at least about 25% lower than the viability of A549 cells treated with about 20 μM of ABDNAZ of the shock-sensitive or blast-sensitive composition. In some embodiments, the measurement is performed about 24 hours after each treatment.

[0014] In some embodiments, the viability of HCT116 cells treated with about 10 μM of ABDNAZ of the composition is less than about 25% of the viability of untreated HCT116 cells. In some embodiments, the viability of SCC VII cells treated with about 4 μM of ABDNAZ of the composition is less than about 50% of the viability of untreated SCC VII cells. In some embodiments, the viability of A549 cells treated with about 20 μM of ABDNAZ of the composition is less than about 50% of the viability of untreated A549 cells. In some embodiments, the measurement is performed about 24 hours after each treatment.

[0015] In some embodiments, the particles are dispersed in a dedusting agent, hi some embodiments, the dedusting agent is polyethylene glycol.

[0016] In some aspects, a pharmaceutical composition is provided comprising the composition described herein and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition further comprises N,N-dimethylacetamide. In some embodiments, the pharmaceutical composition further comprises an anticoagulant.

[0017] In some embodiments, a mixture is provided that comprises the composition described herein or the pharmaceutical composition described herein and a blood sample.In some embodiments, the blood sample is an autologous blood sample or is collected from the subject to be treated with the compound.In some embodiments, the concentration of the compound of formula I is 0.1mg / mL blood to 10mg / mL blood.

[0018] In another aspect, the present invention provides a method for producing a crystalline form of a compound of formula I, the method comprising the steps of: (a) dissolving a compound of formula I in tetrahydrofuran; (b) adding the solution of step (a) to n-heptane with stirring; and (c) cooling the solution produced by step (b) to produce a crystalline form of formula I. In some embodiments, the THF solution produced in step (a) is combined with n-heptane in step (b) in a ratio of about 1:3 (v / v) to about 1:10 (v / v). In some embodiments, during step (b), the addition occurs over a period of about 10 minutes to about 6 hours.

[0019] In one embodiment, there is provided a crystalline form of a compound of formula I having the characteristics described herein.

[0020] In some embodiments, the compositions described herein are characterized in that they are resistant to oxidative stress using the Series 3 Type(a)(ii) Test set forth in the United Nations Manual of Tests and Criteria, seventh edition, 2019, with a 40 mm sample of the composition. 3In some embodiments, the crystalline forms described herein are non-shock sensitive as determined by exposing a 40 mm sample of the crystalline form to an energy of 40 J using the Series 3 Type(a)(ii) Test as set forth in the United Nations Manual of Tests and Criteria, seventh edition, 2019. 3 is non-shock sensitive as determined by exposing it to an energy of 40 J.

[0021] In one aspect, the present invention provides a method in a subject in need of cancer treatment, the method comprising administering to the subject an effective amount of a composition, pharmaceutical composition, or mixture described herein, thereby treating the cancer in the subject. In another aspect, the present invention provides a method in a subject in need of cancer treatment or protection of non-malignant tissue from damage associated with radiation and / or chemotherapy treatment of cancer, the method comprising administering to the subject an effective amount of a composition described herein, a pharmaceutical composition described herein, or a mixture described herein, thereby treating the cancer in the subject. In some embodiments, a composition or pharmaceutical composition described herein is combined with blood collected from the subject to create a mixture. The mixture is then administered to the subject.

[0022] In one aspect, the present invention provides a method for treating or preventing ischemic or hypoxic conditions in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of the composition described herein, the pharmaceutical composition described herein, or the mixture described herein.In some embodiments, the ischemic condition is an acute ischemic condition or a chronic ischemic condition.In some embodiments, the acute ischemic condition is myocardial infarction, ischemic stroke, pulmonary embolism, perinatal hypoxia, circulatory shock, altitude sickness, or acute respiratory failure.In some embodiments, the chronic ischemic condition is atherosclerosis, chronic venous insufficiency, chronic heart failure, cardiac cirrhosis, diabetes, macular degeneration, sleep apnea, Raynaud's disease, systemic sclerosis, nonbacterial thrombotic endocarditis, occlusive arterial disease, angina pectoris, transient ischemic attack, or chronic alcoholic liver disease. In some embodiments, the hypoxic condition is cancer, gastric or duodenal ulcer, liver or kidney disease, thrombocytopenia, blood clotting disorder, chronic disease, therapeutic intervention resulting in anemia (such as cancer chemotherapy), or altitude sickness. In some embodiments, the cancer is bladder cancer, breast cancer, clear cell renal cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, colorectal cancer, head and neck cancer, cervical cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large intestinal cancer, ... large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia cell-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0023] In some embodiments, the pharmaceutical composition of the methods described herein comprises at least 0.5 mg of a compound of formula I and is administered intravenously, intranasally, intraauricularly, intraperitoneally, subcutaneously, or orally.

[0024] In one aspect, provided herein is a method of protecting normal tissue from toxicity caused by chemotherapy and / or radiation therapy, the method comprising subcutaneously administering to a subject in need thereof an effective amount of a composition, pharmaceutical composition, or mixture described herein before the subject is exposed to chemotherapy and / or radiation therapy. In some embodiments, the subject has cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, at least about 0.5 mg of a compound of formula I is administered to the subject. In some embodiments, about 0.5 mg to 4 mg of a compound of formula I is administered to the subject. In some embodiments, the amount of the compound of formula I is administered in one or more divided injections. In some embodiments, the toxicity to normal tissue is acute mucositis or dysphagia. In some embodiments, the mucositis is delayed mucositis.

[0025] In one aspect, provided herein is a method in a subject in need of treatment for a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disease, a neurodegenerative disease, and a neuromuscular disorder, the method comprising administering to the subject a loading dose of a composition, pharmaceutical composition, or mixture described herein in an amount effective to ameliorate a symptom of the disorder, followed by administering a maintenance dose of a composition, pharmaceutical composition, or mixture described herein to maintain the improvement in the symptom over time.

[0026] In one aspect, provided herein is a method for increasing compliance and tolerability in a subject in need of treatment for an autoimmune disorder, an inflammatory disease, a neurodegenerative disease, or a neuromuscular disorder, the method comprising administering a therapeutically effective amount of a composition, pharmaceutical composition, or mixture described herein, wherein administration of the therapeutically effective amount is free of hematological, neurological, pulmonary, metabolic, cardiovascular, dermatological, nephrological, gastrointestinal, genitourinary, inflammatory, autoimmune, thyroid, and immunodeficiency related side effects, and wherein treatment with RRx-001 or an analog thereof is at least 1 mg / m 2 The cumulative dose is completed.

[0027] In one aspect, provided herein is a method in a subject in need of preventing the initiation, development or worsening of a symptom of a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disease, a neurodegenerative disease, and a neuromuscular disorder, the method comprising administering to the subject an effective amount of a composition, pharmaceutical composition, or mixture described herein to prevent the initiation, development, or worsening of the symptom of the disorder.

[0028] In one aspect, provided herein is a method in a subject in need of preventing the initiation, development or worsening of a symptom of a disorder selected from the group consisting of an autoimmune disorder, an inflammatory disease, a neurodegenerative disease, and a neuromuscular disorder, the method comprising administering to the subject an effective amount of a composition, pharmaceutical composition, or mixture described herein to prevent the initiation, development, or worsening of the symptom of the disorder.

[0029] In one aspect, provided herein is a method of improving physical movement in a mammal, the method comprising administering to said mammal an effective amount of a composition, pharmaceutical composition, or mixture described herein prior to said physical movement.

[0030] In one aspect, provided herein is a method for preventing or treating pulmonary hypertension (PH) in a patient, the method comprising administering a therapeutically effective amount of a composition, pharmaceutical composition, or mixture described herein.

[0031] In another aspect, the present invention provides a crystalline form of the compound of formula I produced by the method described herein. In some embodiments, the composition may include a solvated form of the compound, and the solvent may be, for example, tetrahydrofuran (THF). Alternatively, or in addition, the composition may include particles in a clathrate form, and the particles may include, for example, THF. In another aspect, the present invention provides a pharmaceutical composition comprising the composition described herein.

[0032] The present application can be understood by reference to the following description taken in conjunction with the accompanying drawings. [Brief description of the drawings]

[0033] [Figure 1A] 1 shows a graph plotting relative cell viability as a function of sample dose. [Figure 1B] 1 shows a graph plotting relative cell viability as a function of sample dose. [Figure 1C] 1 shows a graph plotting relative cell viability as a function of sample dose. [Diagram 2] 1 shows a graph plotting turbidity as a function of sample concentration. [Diagram 3] A and B show exemplary SEM images of ABDNAZ particles having a substantially acicular shape. [Figure 4] 1 shows exemplary SEM images of ABDNAZ particles having a substantially bulky or round shape. [Figure 5A] 1 shows the bulk density of THF-free crystallized RRx-001 particles. [Figure 5B] 1 shows the bulk density of THF-containing crystallized RRx-001 particles. [Figure 5C] 1 shows the bulk density of non-impact sensitive RRx-001 particles. [Figure 5D] 1 shows the bulk density of impact sensitive RRx-001 particles. [Figure 5E] 1 shows an empirical probability function for bulk density. [Figure 5F] 1 shows an empirical probability function for bulk density. [Figure 5G] 1 shows box plots based on statistical analysis of bulk density. [Figure 5H] 1 shows box plots based on statistical analysis of bulk density. [Figure 6A] 1 shows the D10 of THF-free crystallized RRx-001 particles. [Figure 6B]This shows the D10 of THF-containing crystallized RRx-001 particles. [Figure 6C] 1 shows the D10 of non-impact sensitive RRx-001 particles. [Figure 6D] 1 shows the D10 of impact sensitive RRx-001 particles. [Figure 6E] 4 shows the empirical probability function for D10. [Figure 6F] 4 shows the empirical probability function for D10. [Figure 6G] Box plots based on the statistical analysis of D10 are shown. [Figure 6H] Box plots based on the statistical analysis of D10 are shown. [Figure 7A] 1 shows the D50 of THF-free crystallized RRx-001 particles. [Figure 7B] 1 shows the D50 of THF-containing crystallized RRx-001 particles. [Figure 7C] 1 shows the D50 for non-impact sensitive RRx-001 particles. [Figure 7D] 1 shows the D50 of impact sensitive RRx-001 particles. [Figure 7E] The empirical probability function of D50 is shown. [Figure 7F] The empirical probability function of D50 is shown. [Figure 7G] Box plots based on the statistical analysis of D50 are shown. [Figure 7H] Box plots based on statistical analysis of D50 are shown. [Figure 8A] 1 shows the D90 of THF-free crystallized RRx-001 particles. [Figure 8B] 1 shows the D90 of THF-containing crystallized RRx-001 particles. [Figure 8C] 1 shows the D90 for non-impact sensitive RRx-001 particles. [Figure 8D] 1 shows the D90 of impact sensitive RRx-001 particles. [Figure 8E] The empirical probability function of D90 is shown. [Figure 8F] The empirical probability function of D90 is shown. [Figure 8G] Box plots based on statistical analysis of D90 are shown. [Figure 8H] Box plots based on statistical analysis of D90 are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present invention provides, in part, non-shock-sensitive or non-explosion-sensitive crystalline forms of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ), methods for producing the crystalline forms, and methods for treating various medical conditions using such compositions.

[0035] Dinitroazetidine, ABDNAZ, of formula C5H6BrN3O5, has the following chemical structure: [ka] has.

[0036] This compound is being clinically evaluated for the treatment of cancer and other ischemic / hypoxic diseases and disorders, as well as for protecting non-malignant tissues from chemotherapy and / or radiation toxicity.Previous synthesis of this compound (Straessler et al. ORG. PROCESS RES. DEV. (2012) 16, 512-517) has led to crystalline forms of this compound.However, these crystalline forms can be explosive, and show high variability in terms of impact or explosion sensitivity, for example, under conventional impact or explosion sensitivity tests.

[0037] As a result, the characteristics of the crystalline form of the compound may affect the transportation, storage, and use of the compound.

[0038] The present invention is based in part on the discovery that the transport, storage and use of a compound can be made safer by eliminating the impact or explosion sensitivity of the crystalline form of the compound. This is achieved by changing or "tuning" the physiochemical properties of the crystal, such as its impact or explosion sensitivity and flowability, without changing the essential chemical properties of the composition. Tuning the crystalline form of the compound is achieved by carrying out a specific recrystallization step at the end of the synthesis using certain crystallization conditions, which ensures the production of a material with normal sensitivity.

[0039] Various aspects of the invention are presented in the following sections, however, an aspect of the invention described in a particular section is not limited to any particular section. Further, if a variable is not provided with a definition, the preceding definition of that variable takes precedence.

[0040] definition To facilitate the understanding of this invention, several terms and phrases are defined below.

[0041] As used herein, the terms "a," "an," and "the" mean "one or more" and include the plural unless the context is inappropriate.

[0042] As used herein, the term "subject" refers to an organism that is to be treated by the method of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, and the like), and most preferably, humans. In the context of the present invention, the term "subject" generally refers to an individual that is to receive or has received treatment (e.g., administration of a compound of the present invention and optionally one or more other agents) for a condition characterized by dysregulation of the apoptotic process.

[0043] As used herein, the term "effective amount" refers to an amount of a compound (e.g., a compound of the present invention) sufficient to produce a beneficial or desired result. An effective amount may be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treat" includes any effect (e.g., alleviation, reduction, regulation, mitigation, or elimination) that results in the improvement of, or the alleviation of symptoms of, a condition, disease, disorder, and the like.

[0044] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active excipient or carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0045] As used herein, the term "pharmaceutical acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water emulsions or water / oil emulsions, etc.), and various types of wetting agents. The composition may also include stabilizers and preservatives. Examples of carriers are stabilizers and adjuvants (see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ).

[0046] As used herein, the term "pharmaceutical acceptable salt" refers to any circulating salt (e.g., acid or base) of the compound of the present invention that is suitable for pharmaceutical administration and can provide the compound of the present invention or its active metabolite or residue upon administration to a subject. As known to those skilled in the art, the "salt" of the compound of the present invention can be derived from inorganic or organic acids and bases.

[0047] Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharma- ceutical acceptable, may be utilized in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharma- ceutical acceptable acid addition salts.

[0048] Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of the formula NW4 + (Wherein, W is C 1~4 alkyl), and the like.

[0049] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include Na + , NH4 + , and NW4 + (Wherein, W is C 1~4 Examples of suitable cations include the anions of the compounds of the present invention combined with appropriate cations, such as alkyl groups, alkyl groups, and the like.

[0050] For therapeutic use, the salts of the compounds of the invention are contemplated as pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0051] Throughout this specification, when compositions and kits are described as having, including, or comprising certain components, or when processes and methods are described as having, including, or comprising certain steps, this additionally contemplates the existence of compositions and kits of the invention that consist essentially of or consist of the recited components, and processes and methods according to the invention that consist essentially of or consist of the recited process steps.

[0052] As a general matter, unless expressly stated otherwise, designations of percentages of compositions are by weight. Further, unless a definition is provided for a variable, the preceding definition of that variable controls.

[0053] I. Crystalline form of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) The present invention relates, in part, to a compound of formula I: [ka] The present invention provides a non-shock sensitive crystalline form of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ).

[0054] In one embodiment, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein the solid crystalline non-shock sensitive or non-explosion sensitive particles have an angle of repose of less than about 45 degrees.

[0055] The composition may include a compound in a solvated form, and the solvent may be, for example, tetrahydrofuran (THF). In some embodiments, the solvent is any solvent or any combination of solvents described herein.

[0056] Alternatively, or in addition, the composition can include particles in a clathrate form, which can include, for example, THF. In some embodiments, the solvent is any solvent or any combination of solvents described herein.

[0057] The particles may have a combination of the characteristics described herein. For example, the median particle size of the particles may be in the range of 50 μm to 300 μm, 50 μm to 200 μm, or 50 μm to 100 μm. The particles may have a Dv(10), D10, or x 10 The particles may have a particle size distribution in which Dv(50), D50, or x is less than 50 μm, less than 40 μm, less than 30 μm, or less than 20 μm. 50 and / or the particles may have a particle size distribution in which the value of Dv(90), D90, or x is less than 100 μm, less than 90 μm, less than 80 μm, less than 70 μm, or less than 60 μm. 90 and / or the particles may have a particle size distribution in which the value of D10 or x is less than 300 μm, less than 250 μm, less than 200 μm, less than 150 μm, or less than 100 μm. 10 The particle size distribution may have a value of greater than 20 μm, greater than 30 μm, greater than 40 μm, or greater than 50 μm.

[0058] In some embodiments, the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein have a Dv(10), D10, or x 10 is less than about 40 μm, and Dv(50), D50, or x50 is less than about 200 μm, and / or Dv(90), D90, or x 90 In some embodiments, the non-impact sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein have a particle size distribution in which Dv(10), D10, or x is less than about 400 μm. 10 is less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 μm, and Dv(50), D50, or x 50 is less than about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, or 300 μm; and / or Dv(90), D90, or x 90 is less than about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, or 800 μm.

[0059] Depending on the recrystallization conditions, the resulting crystals may contain, for example, less than 800, 700, 600, 500, 400, 300, 200, or 100 ppm of residual or trace tetrahydrofuran, as determined, for example, by gas chromatography. Alternatively, or in addition, the resulting crystals may contain, for example, less than 900, 800, 700, 600, 500, 400, 300, 200, or 100 ppm of residual or trace n-heptane, as determined, for example, by gas chromatography.

[0060] In some embodiments, the concentration of tetrahydrofuran in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 330 ppm. In some embodiments, the concentration of tetrahydrofuran in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm. In some embodiments, the concentration of tetrahydrofuran in a non-impact sensitive or non-explosion sensitive ABDNAZ particle or composition described herein is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, less than 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm.In some embodiments, the concentration of tetrahydrofuran in a non-shock sensitive or non-explosion sensitive ABDNAZ particle or composition described herein is in the range of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970 0, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3 000, 3500, or 4000 ppm, with independently selected lower limits of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm, where the upper limit is greater than the lower limit.

[0061] In some embodiments, the non-shock sensitive or non-explosion sensitive ABDNAZ particles described herein are substantially needle-like in shape. Figures 3A and 3B show examples of substantially needle-like shapes. In some embodiments, the non-shock sensitive or non-explosion sensitive ABDNAZ particles described herein are not substantially bulky or round in shape. Figure 4 shows examples of substantially bulky or round shapes. In some embodiments, the shape is determined based on SEM images.

[0062] In certain embodiments, the composition has a bulk density of 0.1 g / cm 3 ~0.6g / cm3 For example, the bulk density is in the range of 0.15 g / cm 3 ~0.5g / cm 3 , 0.15g / cm 3 ~0.4g / cm 3 , or 0.16 g / cm 3 ~0.3g / cm 3 It is.

[0063] In some embodiments, the bulk density of the non-impact sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is about 0.45 g / cm 3 In some embodiments, the bulk density of the composition is less than about 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 g / cm 3 In some embodiments, the bulk density of the non-impact sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is less than about 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 g / cm 3 In some embodiments, the bulk density of the non-impact sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is greater than about 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 g / cm 3 and an independently selected lower limit of about 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 g / cm 3 where the upper bound is greater than the lower bound.

[0064] In some embodiments, the solubility or equilibrium solubility of the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is greater than about 20 mg / mL in DMSO. In some embodiments, the solubility or equilibrium solubility of the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is greater than about 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 mg / mL. In some embodiments, the solubility or equilibrium solubility is measured at 25° C. In some embodiments, the solubility or equilibrium solubility is measured at 37° C. In some embodiments, the solubility or equilibrium solubility is measured in DMSO. In some embodiments, the solubility or equilibrium solubility is measured according to the method described in N. Colclough et al., "High throughput solubility determination with application to selection of compounds for fragment screening" Bioorganic & Medicinal Chemistry Vol. 16, Issue 13 (2008): 6611-6616.

[0065] In some embodiments, the viability of cancer cells treated with non-shock-sensitive or non-blast-sensitive ABDNAZ crystals or ABDNAZ compositions described herein is lower than the viability of cancer cells treated with shock-sensitive or blast-sensitive ABDNAZ crystals or ABDNAZ compositions. In some embodiments, the cancer cells are HCT-116, SCC VII, or A549. In some embodiments, the cell viability is measured 24 hours after treatment. In some embodiments, the cell viability is measured using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric assay. In some embodiments, the cell viability is measured as optical density (OD) at 570 nm. In some embodiments, the cell viability is measured relative to a control that does not receive any treatment. In some embodiments, the cell viability is measured and / or compared with HCT116 at a dose of about 10 μM. In some embodiments, the cell viability is measured and / or compared with SCC VII at a dose of about 4 μM. In some embodiments, cell viability is measured and / or compared with A549 at a dose of about 20 μM, hi some embodiments, cell viability is measured and / or compared with A549 at a dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 30 μM.

[0066] In some embodiments, the viability of cancer cells treated with non-shock-sensitive or non-blast-sensitive ABDNAZ particles or ABDNAZ compositions described herein is lower than the viability of cancer cells treated with shock-sensitive or blast-sensitive particles or compositions containing the same amount of ABDNAZ. In some embodiments, the viability of cancer cells treated with non-shock-sensitive or non-blast-sensitive ABDNAZ particles or ABDNAZ compositions described herein is at least about 25% lower than the viability of cancer cells treated with shock-sensitive or blast-sensitive particles or compositions containing the same amount of ABDNAZ. In some embodiments, the viability of cancer cells treated with non-shock-sensitive or non-blast-sensitive ABDNAZ particles or ABDNAZ compositions described herein is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% lower than the viability of cancer cells treated with shock-sensitive or blast-sensitive particles or compositions containing the same amount of ABDNAZ.

[0067] In some embodiments, the viability of cancer cells treated with about 8 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 50% lower than the viability of cancer cells treated with about 8 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in HCT 116 cell line 24 hours after treatment. In some embodiments, the viability of cancer cells treated with about 8 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% lower than the viability of cancer cells treated with about 8 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in HCT 116 cell line 24 hours after treatment.

[0068] In some embodiments, the "(theoretically)" in front of the ABDNAZ concentration indicates that the concentration may be based on the total amount of ABDNAZ added in a given volume, and therefore may not necessarily correspond to the concentration of ABDNAZ actually dissolved in or available to the cells.

[0069] In some embodiments, the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 25% lower than the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in SCC VII cell line 24 hours after treatment. In some embodiments, the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% lower than the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in SCC VII cell line 24 hours after treatment.

[0070] In some embodiments, the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 25% lower than the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in A549 cell line 24 hours after treatment. In some embodiments, the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% lower than the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the shock-sensitive or blast-sensitive crystals or compositions described herein when measured in A549 cell line 24 hours after treatment.

[0071] In some embodiments, the viability of cancer cells treated with about 10 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is less than about 25% of the viability of the control when measured in HCT 116 cell line 24 hours after treatment. In some embodiments, the viability of cancer cells treated with about 10 μM of ABDNAZ (theoretical) of the non-shock-sensitive or non-blast-sensitive crystals or compositions described herein is less than about 20, 25, 30, 35, 40, or 45% of the viability of the control when measured in HCT 116 cell line 24 hours after treatment.

[0072] In some embodiments, when measured in SCC VII cell line after 24 hours of treatment, the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of non-shock sensitive or non-blast sensitive crystal or composition described herein is less than about 50% of the viability of the control.In some embodiments, when measured in SCC VII cell line after 24 hours of treatment, the viability of cancer cells treated with about 4 μM of ABDNAZ (theoretical) of non-shock sensitive or non-blast sensitive crystal or composition described herein is less than about 30, 35, 40, 45, 50, 55, 60, 65, or 70% of the viability of the control.

[0073] In some embodiments, when measured in A549 cell line after 24 hours of treatment, the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the non-shock sensitive or non-blast sensitive crystals or compositions described herein is less than about 50% of the viability of the control. In some embodiments, when measured in A549 cell line after 24 hours of treatment, the viability of cancer cells treated with about 20 μM of ABDNAZ (theoretical) of the non-shock sensitive or non-blast sensitive crystals or compositions described herein is less than about 30, 35, 40, 45, 50, 55, 60, 65, or 70% of the viability of the control.

[0074] II. Methods for Preparing Crystalline Forms of ABDNAZ Methods for preparing ABDNAZ are disclosed in U.S. Patent No. 7,507,842 ("the '842 patent") and U.S. Patent No. 8,471,041 ("the '041 patent"). The method disclosed in the '842 patent involves reacting 1-tert-butyl 3,3-dinitroazetidine (DNAZ) with bromoacetyl bromide and boron trifluoride etherate, from which ABDNAZ is isolated by cooling the reaction mixture, adding dichloromethane, filtering the formed DNAZ HBr, washing the dichloromethane filtrate with water, drying it, and then evaporating the dichloromethane. The process disclosed in the '041 patent involves reacting 3,3-dinitroazetidine (DNAZ) with bromoacetyl bromide and boron trifluoride etherate in dichloromethane to produce a reaction mixture containing ABDNAZ and the hydrobromide salt of DNAZ, separating the DNAZ therefrom, adding ethanol to the dichloromethane and ABDNAZ, evaporating the dichloromethane under reduced pressure to form an ABDNAZ / ethanol suspension, and then filtering the ethanol from the ABDNAZ / ethanol suspension.

[0075] However, these patents do not address the unpredictable and therefore dangerous impact or explosion sensitivity of the resulting ABDNAZ and its susceptibility to detonation of an explosive ("explosion sensitivity").

[0076] Crystalline forms of ABDNAZ that are non-shock sensitive or non-explosion sensitive can be produced, for example, as described herein, for example, as shown in the following synthetic scheme. [ka]

[0077] In some embodiments, HAZ is 1-tert-butylazetidin-3-ol. In some embodiments, HMNAZ is 1-tert-butyl-3-hydroxymethyl-3-nitroazetidine. In some embodiments, TBDNAZ is 1-tert-butyl-3,3-dinitroazetidine. In some embodiments, ADNAZ is 1-acetyl-3,3-dinitroazetidine. In some embodiments, DNAZ is 3,3-dinitroazetidine.

[0078] In some embodiments, RRx-001 is synthesized according to the above synthesis scheme. In some embodiments, HAZ is methanesulfonylated to activate the alcohol for nucleophilic substitution with sodium nitrite. In some embodiments, the resulting intermediate (denoted as "RRx-001 stage 1" in the scheme) is trapped with formaldehyde to produce HMNAZ. In some embodiments, TBDNAZ is produced from HMNAZ by introducing a second nitro group using potassium ferricyanide (III) as a catalyst. In some embodiments, the tert-butyl group of TBDNAZ is replaced with an acetyl group via Lewis acid catalyzed dealkylation acetylation, thus obtaining ADNAZ. In some embodiments, the acetyl group of ADNAZ is removed under acidic conditions and then replaced with a bromoacetyl group using Schotten-Baumann conditions, thus producing a high density form of ABDNAZ. In some embodiments, the high density form of ABDNAZ is recrystallized to obtain a non-shock sensitive low density form of ABDNAZ.

[0079] Formation of RRx-001 stage 1 and stage 2 (HMNAZ) from HAZ In some embodiments, the HAZ is methanesulfonylated. In some embodiments, methanesulfonylation of the HAZ is to activate an alcohol for nucleophilic substitution by sodium nitrite. In some embodiments, methanesulfonyl chloride is added to the HAZ for methanesulfonylation of the HAZ. In some embodiments, water is removed before methanesulfonyl chloride is added to the HAZ. In some embodiments, water is removed by azeotropic distillation of the starting material solution in toluene. In some embodiments, the amount of triethylamine is increased slightly during the next step to ensure that a basic pH is maintained, thus reducing the amount of NOx released. In some embodiments, the product solution is carried directly into the next step. In some embodiments, the amount of reagents (sodium nitrite and formaldehyde) in the second step is doubled to provide a higher yield. In some embodiments, addition and stirring times of about 4 hours each are used. In some embodiments, addition times of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 hours are used. In some embodiments, stirring times of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 hours are used. In some embodiments, the aqueous workup is carried out at an elevated temperature (e.g., about 35° C.) to keep the product in solution. In some embodiments, the elevated temperature is about 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, or 50° C. In some embodiments, water is added to facilitate azeotropic removal of residual formaldehyde prior to concentrating the organic phase via distillation. In some embodiments, isolation from toluene / n-heptane (about 1:1) gives a pale yellow product of sufficient purity (99.8%-a / a, 99%-w / w). In some embodiments, isolation from pure toluene gives a white to off-white and analytically pure product at the expense of about 4% of the theoretical yield.

[0080] Generation of RRx-001 stage 3 (TBDNAZ) from HMNAZ In some embodiments, the terminal oxidant for oxidative nitration (sodium persulfate) was added in portions to facilitate dissolution in the reaction mixture. In some embodiments, the reaction temperature is increased to 22-32°C to prevent crystallization of RRx-001 stage 3 (TBDNAZ). In some embodiments, a quench with sodium sulfite is introduced after conversion is complete to replace dichloromethane with toluene to allow dilution and extraction of the product. In some embodiments, an additional aqueous wash is introduced to remove residual salts from the organic phase. In some embodiments, only azeotropic drying (instead of solvent exchange) is used when the process solvent for the next step is also toluene. In some embodiments, the RRx-001 stage 3 solution in toluene (approximately 32%-w / w) is stored under refrigerated conditions.

[0081] Generation of RRx-001 stage 4 (ADNAZ) from TBDNAZ In some embodiments, TBDNAZ and acetic anhydride are converted to ADNAZ under reflux with BF3 catalysis. In some embodiments, after an in-process safety control at 50° C. to ensure the reaction has started, TBDNAZ and acetic anhydride are converted to ADNAZ under reflux with BF3 catalysis. In some embodiments, an upper time limit is introduced to prevent decomposition of ADNAZ. In some embodiments, the product is kept in solution by dilution with THF during the quench with aqueous potassium carbonate. In some embodiments, the addition of ethanol improves phase separation. In some embodiments, the product is crystallized from n-propanol / n-heptane after solvent exchange. In some embodiments, safety precautions are taken to prevent handling of shock- or explosion-sensitive materials. For example, (i) in some embodiments, the filter cake is washed with water since the dry ADNAZ is shock- or explosion-sensitive, and (ii) THF is used to separate the water-wet filter cake from the filter.

[0082] Generation of RRx-001 stage 5 (DNAZ) and stage 6 (ABDNAZ "high density") In some embodiments, the acetyl group is removed under acidic conditions. In some embodiments, methanesulfonic acid is used. In some embodiments, 5 eq of acid and 15 eq of water are used. In some embodiments, the reaction is carried out at about 40° C. In some embodiments, the reaction is carried out at 20° C. or higher, 25° C. or higher, 30° C. or higher, 35° C. or higher, 40° C. or higher, 45° C. or higher, or 50° C. In some embodiments, the reaction mixture is quenched into aqueous potassium phosphate to avoid viscosity changes and salting out precipitation problems.

[0083] In some embodiments, potassium phosphate is used as the base for the subsequent acylation. In some embodiments, Schotten-Baumann conditions are used to keep most of the nucleophile in the aqueous phase, where it cannot form impurities due to displacement of the unstable α-bromide. The only impurity produced under these conditions is from the reaction of the secondary amine RRx-001 stage 5 with the product. In some embodiments, the amount of this impurity is limited by adjusting the toluene / THF ratio (so the solvent system is polar) and / or limiting the addition time (both lower and upper limits). In some embodiments, a mild acid workup is required to ensure the stability of RRx-001 stage 6 in solution. In some embodiments, crystallization from toluene / MiBK (MiBK=4-methyl-2-pentanone) gives API-quality product. In some embodiments, THF is used to separate the product from the filter due to the impact or explosion sensitivity of RRx-001 stage 6. In some embodiments, the solution of RRx-001 stage 6 in THF needs to be stored at low temperature.

[0084] RRx-001 Stage 7 In some embodiments, high density ABDNAZ (dry) is dissolved in ethyl acetate. In some embodiments, the resulting solution is added to rapidly stirred n-heptane. In some embodiments, the solvent is then changed to THF. In some embodiments, the RRx-001 Stage 6 solution in THF is slowly added to rapidly stirred n-heptane at elevated temperature (e.g., 30-35° C.) with a slow cooling rate to facilitate controlled crystallization.

[0085] The final step of the synthesis, recrystallization of ABDNAZ from stage 6 material to stage 7 material, has been found to be important in creating the non-shock sensitive or non-explosion sensitive material described herein. In this step, the protocol includes the following steps: (a) dissolving the compound of formula I or the shock sensitive or explosion sensitive ABDNAZ (such as ABDNAZ of stage 6 material) in tetrahydrofuran, (b) adding the solution of step (a) to n-heptane, for example at room temperature, and (c) cooling the solution of step (b) to, for example, 15°C, 10°C, or 5°C, thereby providing a non-shock sensitive crystalline form of the compound of formula I. During step (b), the tetrahydrofuran solution is added to heptane in a ratio of about 1:5 (v / v, i.e., volume of THF solution:volume of heptane=1:5) over a period of at least 30 minutes while the heptane is stirred for at least 1 hour. During step (c), the mixture is stirred for at least 30 minutes, 45 minutes, or at least 1 hour. The resulting material may be recovered by filtration and drying. In some embodiments, if another solvent, such as acetone or dichloromethane, is added to the heptane during step (b), the resulting material becomes shock-sensitive or explosion-sensitive.

[0086] In some embodiments, the protocol includes step (a) of dissolving the compound of formula I or shock-sensitive or explosion-sensitive ABDNAZ (such as ABDNAZ of stage 6 material) in solvent 1. In some embodiments, the protocol includes step (b) of adding the solution of step (a) to solvent 2 at temperature T1. In some embodiments, the protocol includes step (c) of cooling the solution of step (b) from temperature T1 to T2, thereby providing a non-shock-sensitive crystalline form of the compound of formula I. In some embodiments of step (b), the solution of step (a) is added to solvent 2 in a ratio of about 1:R1 (v / v, volume of THF solution: volume of heptane = 1:R1). In some embodiments of step (b), the solution of step (a) is added to solvent 2 over a period of t1 while solvent 2 is stirred. In some embodiments of step (c), the mixture is stirred for a period of t2. In some embodiments, the resulting material can be recovered by filtration and drying.

[0087] In some embodiments, solvent 1 is an aprotic polar solvent. In some embodiments, solvent 1 is a borderline aprotic polar solvent. In some embodiments, the dielectric constant of the solvent is less than about 10. In some embodiments, the dielectric constant of the solvent is less than about 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 20, 30, 40, or 50. In some embodiments, the dipole moment of the solvent is less than about 2. In some embodiments, the dipole moment of the solvent is less than about 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, or 5.5. In some embodiments, the solvent is tetrahydrofuran, dichloromethane, ethyl acetate, or any combination thereof. In some embodiments, the solvent is tetrahydrofuran. In some embodiments, solvent 1 is an oxygen-containing solvent. In some embodiments, solvent 1 is an alcohol, an ester, or a ketone. In some embodiments, solvent 1 is ethyl acetate (EtOAc), methyl isobutyl ketone (MiBK), tetrahydrofuran (THF), dichloromethane, or any combination thereof. In some embodiments, solvent 1 is acetic acid, ethyl acetate, diethyl ether, methylene chloride, n-butyl acetate, chlorobenzene, o-dichlorobenzene, or any combination thereof.

[0088] In some embodiments, solvent 2 is a non-polar solvent. In some embodiments, solvent 2 is a polar solvent. In some embodiments, solvent 2 is n-heptane, methyl isobutyl ketone (MiBK), dichloromethane, or any combination thereof.

[0089] In some embodiments, solvent 1 is EtOAc and solvent 2 is n-heptane. In some embodiments, solvent 1 is ethanol and solvent 2 is dichloromethane. In some embodiments, solvent 1 is MiBK and solvent 2 is n-heptane. In some embodiments, solvent 1 is THF and solvent 2 is n-heptane.

[0090] In some embodiments, the concentration of solvent 1 in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 330 ppm. In some embodiments, the concentration of solvent 1 in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, , 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm. In some embodiments, the concentration of Solvent 1 in a non-shock sensitive or non-explosion sensitive ABDNAZ particle or composition described herein is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970 , 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm.In some embodiments, the concentration of Solvent 1 in a non-shock sensitive or non-explosion sensitive ABDNAZ particle or composition described herein is in the range of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 0, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000 , 3500, or 4000 ppm, with an independently selected lower limit of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, or 4000 ppm. 40, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, or 4000 ppm, where the upper limit is greater than the lower limit.

[0091] In some embodiments, the concentration of solvent 2 in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 800 ppm. In some embodiments, the concentration of solvent 2 in the non-shock sensitive or non-explosion sensitive ABDNAZ particles or compositions described herein is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 ppm. In some embodiments, the concentration of Solvent 2 in a non-shock sensitive or non-explosion sensitive ABDNAZ particle or composition described herein is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, less than 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 ppm.In some embodiments, the concentration of Solvent 2 in a non-shock sensitive or non-explosion sensitive ABDNAZ particle or composition described herein has an upper limit of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, , 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000 , 4500, or 5000 ppm, with an independently selected lower limit of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 40 0, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 ppm, where the upper limit is greater than the lower limit.

[0092] In some embodiments, T1 is about 30° C. to about 35° C. In some embodiments, T1 is at least 20° C. In some embodiments, T1 is about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95° C. In some embodiments, T1 is at least about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95° C. In some embodiments, T1 is less than about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95° C. In some embodiments, T1 has an upper limit of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95° C. and an independently selected lower limit of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95° C., where the upper limit is greater than the lower limit.

[0093] In some embodiments, T2 is about 0° C. to about 10° C. In some embodiments, T2 is less than about 20° C. In some embodiments, T2 is about −20, −17.5, −15, −12.5, −10, −7.5, −5, −2.5, 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, or 90° C. In some embodiments, T2 is at least about -20, -17.5, -15, -12.5, -10, -7.5, -5, -2.5, 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C. In some embodiments, T2 is less than about -20, -17.5, -15, -12.5, -10, -7.5, -5, -2.5, 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C. In some embodiments, T2 has an upper limit of about -20, -17.5, -15, -12.5, -10, -7.5, -5, -2.5, 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C, independently. and the lower limit selected is about -20, -17.5, -15, -12.5, -10, -7.5, -5, -2.5, 0, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 55, 60, 65, 70, 75, 80, 85, or 90°C, where the upper limit is greater than the lower limit.

[0094] In some embodiments, R1 is about 5. In some embodiments, R1 is about 3 to about 10. In some embodiments, R1 is about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50. In some embodiments, R1 is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50. In some embodiments, R1 is less than about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50. In some embodiments, R1 has an upper limit of about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50, and is independently In some embodiments, the lower limit selected is about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50, where the upper limit is greater than the lower limit.

[0095] In some embodiments, t1 is about 0.5 hours. In some embodiments, t1 is about 10 minutes to about 6 hours. In some embodiments, t1 is at least about 10 minutes. In some embodiments, t1 is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, t1 is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 210, or 240 minutes. In some embodiments, t1 is less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, t1 has an upper limit of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours and an independently selected lower limit of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 210, or 240 minutes, where the upper limit is longer than the lower limit.

[0096] In some embodiments, t2 is at least about 2 hours. In some embodiments, t2 is at least about 0.5 hours. In some embodiments, t2 is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, t2 is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, t2 is less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours. In some embodiments, t2 has an upper limit of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours and an independently selected lower limit of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or 10 hours, where the upper limit is longer than the lower limit.

[0097] The resulting compounds may be tested for impact or explosive susceptibility using one or more standard protocols as described, for example, in the United Nations Manual of Tests and Criteria, seventh edition, 2019 (Orange Book). For example, the explosiveness of a compound (e.g., crystalline ABDNAZ) may be determined by the Series 3 Type(a)(ii) Test procedure using a BAM Fallhammer, as described in the Orange Book. The test is performed using a 40 mm impactor placed in an impact device. 3The test is performed by subjecting each sample to an energy of 40 J (e.g., using a 10 kg drop from a height of 40 cm). The test is performed on six separate samples under the same experimental conditions, and the operator determines whether an explosion occurs. If no explosion occurs in all six samples, the material is characterized as not impact or explosion sensitive, or non-impact or non-explosion sensitive. However, if one of the samples fails the test and causes an explosion, the material is characterized as impact or explosion sensitive.

[0098] The conventional RRx-001 composition showed positive results in the BAM Fallhammer test at 40 joules (10 kg mass at 0.4 m height), comparable to the explosives TNT, HMX, and RDX. Based on this, RRx-001 is classified as a Class 1 explosive. Therefore, a facility, preferably far from densely populated centers, with special equipment and permits, and meeting the latest explosives safety and environmental regulations, is required, as well as personnel properly trained and certified to synthesize and store such compounds. There are only a handful of facilities worldwide with the appropriate CMC / cGMP expertise and equipment for clinical use. Therefore, large-scale manufacturing of the advanced RRx-001 composition is limited to niche contract manufacturing organizations (CMOs) that have the capacity and experience to provide late-stage clinical testing material and be a realistic option for commercialization. However, with the compositions disclosed in this invention, the results of the BAM Fallhammer test (10 kg mass, 0.40 m height, 40 J) were found to be non-reactive and consistently and repeatedly negative.

[0099] Another standard test evaluates whether a material can be detonated with a No. 8 detonator. A "No. 8 test detonator" refers to a metal capsule containing a primary explosive charge used to detonate a test material, in this case ABDNAZ. The aforementioned ABDNAZ compositions had variable detonation susceptibility, i.e., sometimes the ABDNAZ was detonatable and sometimes the ABDNAZ was non-detonable.

[0100] III. Pharmaceutical Compositions The present invention provides pharmaceutical compositions comprising an active therapeutic agent and one or more pharma- ceutically acceptable carriers (additives) and / or diluents. In certain embodiments, the active therapeutic agent is ABDNAZ, such that the present invention provides pharmaceutical compositions comprising ABDNAZ formulated with one or more pharma- ceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may comprise ABDNAZ in a therapeutically effective amount. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in liquid form, including those adapted for: (1) oral administration, e.g., drenching (aqueous or non-aqueous solution or suspension), and (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection (e.g., as a sterile solution or suspension, or sustained release formulation).

[0101] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, agent, or composition containing a compound of the invention that is effective to produce some desired therapeutic effect in at least a subpopulation of cells of an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0102] The phrase "pharmacologically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment.

[0103] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect, which in some embodiments will range from about 0.1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent, out of 100 percent.

[0104] In some embodiments, when the pharmaceutical composition of the present invention is administered intravenously, water is an excipient. In some embodiments, saline and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injections. In some embodiments, suitable pharmaceutical excipients also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like.

[0105] In some embodiments, the pharmaceutical compositions of the present invention, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Additionally, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.

[0106] In some embodiments, any of the pharmaceutical compositions described herein may be manufactured by conventional mixing, dissolving, granulating, dragee-making, granulating, emulsifying, encapsulating, encapsulating or lyophilizing processes. In some embodiments, the pharmaceutical composition may be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate the processing of the compound into a medicament-usable preparation. Depending on the selected route of administration, the formulation is appropriately made.

[0107] In some embodiments, the pharmaceutical compositions of the invention are formulated according to routine procedures as pharmaceutical compositions adapted for intravenous administration to humans. In some embodiments, the pharmaceutical compositions of the invention are solutions in sterile isotonic aqueous buffer for intravenous administration. In some embodiments, any of the compositions described herein may be formulated for injection in aqueous solutions, e.g., in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. In some embodiments, the solutions may contain formulating agents such as suspending, stabilizing and / or dispersing agents. In some embodiments, the pharmaceutical compositions may also include solubilizing agents as required. In some embodiments, pharmaceutical compositions for intravenous administration may optionally include a local anesthetic, such as lignocaine, to ease pain at the site of the injection. In some embodiments, the ingredients are supplied separately or mixed together in unit dosage form, e.g., as a lyophilized powder or water-free concentrate in a hermetically sealed container, e.g., an ampoule or sachet indicating the quantity of active agent. In some embodiments, when the pharmaceutical compositions of the invention are administered by infusion, they may be dispensed, e.g., in an infusion bottle containing sterile pharmaceutical grade water or sterile saline. In other embodiments, where a pharmaceutical composition of the invention is administered by injection, an ampoule of sterile water for injection or sterile saline can be provided so that the ingredients may be mixed prior to administration.

[0108] In some embodiments, the liquid dosage form for oral administration of the compound of the present invention includes pharma- ceutically acceptable emulsions, microemulsions, solutions, aqueous or oily suspensions, syrups and elixirs.In some embodiments, in addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.

[0109] Besides inert diluents, the oral compositions in some embodiments can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives.

[0110] In some embodiments, in addition to the active compound, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0111] In some embodiments, pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0112] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. In some embodiments, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0113] In some embodiments, these compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. In some embodiments, the prevention of microbial action on the subject compound may be ensured, for example, by including various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol sorbic acid, and the like). It may also be desirable to include isotonicity agents in the composition, such as sugars, sodium chloride, and the like. In other embodiments, the absorption of injectable pharmaceutical forms may be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin. In some embodiments, liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices, as well as EHD aerosol devices, typically include compositions with pharma- ceutical acceptable excipients. In some embodiments, the pharma-ceutical acceptable excipients are liquids, such as alcohol, water, polyethylene glycol, or perfluorocarbons. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of the compound. In some embodiments, the material is a liquid, such as an alcohol, glycol, polyglycol, or fatty acid. Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those of skill in the art (see, for example, Biesalski, US Pat. No. 5,112,598; Biesalski, US Pat. No. 5,556,611).

[0114] In some embodiments, the preparations of the invention can be administered, for example, orally or parenterally. As used herein, the phrases "parenteral administration" and "administered parenterally" refer to a mode of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0115] In some embodiments, systemic formulations include those designed for administration by injection (e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral or pulmonary administration.Systemic formulations can be made in combination with additional active agents that improve the mucociliary clearance of airway mucosa or reduce mucus viscosity.Such active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetylcysteine, homocysteine ​​and phospholipids.

[0116] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" refer to administration other than directly to the central nervous system (e.g., subcutaneous administration) such that a compound, drug, or other substance enters the patient's body and is therefore subject to metabolic and other similar processes.

[0117] In some embodiments, the compositions described herein may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g., as by spray), rectal, intravaginal, parenteral, intracisternal, and topical.

[0118] In some embodiments, the compositions described in this application may be formulated for topical administration as powders, ointments or drops (including buccal and sublingual), solutions, gels, ointments, creams, suspensions, etc., as are well known in the art.

[0119] In some embodiments, the pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner for buccal administration.

[0120] In some embodiments, for transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0121] In some embodiments, the pharmaceutical composition may take the form of a solution, suspension, emulsion, tablet, pill, granule, capsule, liquid-containing capsule, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use.In one embodiment, the pharmaceutically acceptable excipient is a capsule (e.g., Grosswald et al., U.S. Pat. No. 5,698,155).A general discussion of the preparation of pharmaceutical compositions can be found in Remington, "The Science and Practice of Pharmacy," 19th Edition.

[0122] In other embodiments, the pharmaceutical composition, when in capsule, tablet or pill form, may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. In some embodiments, a selectively permeable membrane surrounding an osmotically active driving compound is also suitable for orally administered compounds. In some embodiments, in these latter platforms, fluid in the capsule environment is absorbed by the driving compound, which swells and exudes the drug or drug composition through an opening. In some embodiments, these delivery platforms may provide an essentially zero-level delivery profile, as opposed to the spiked profiles of immediate release formulations. In some embodiments, a time-delay material such as glycerol monostearate or glycerol stearate may also be used. In some embodiments, oral compositions may include standard excipients, such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. In some embodiments, such excipients are of pharmaceutical grade.

[0123] In some embodiments, the crystalline forms of ABDNAZ described herein and / or pharmaceutical compositions thereof may also be formulated in rectal or vaginal pharmaceutical compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0124] In some embodiments, the actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied to provide an amount of the active ingredient compound 1 that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and which is not toxic to the patient.

[0125] In some embodiments, the selected dosage will depend on a variety of factors, including the activity of the particular compound of the invention, or esters, salts, or amides thereof, being employed, the route of administration, the time of administration, the rate of excretion or rate of metabolism of the particular compound being employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or substances used in combination with the particular compound being employed, the age, sex, weight, medical condition, health status and medical history of the patient being treated, and similar factors well known in the medical arts.

[0126] A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of pharmaceutical composition required.For example, a physician or veterinarian can start the dosage of the composition of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0127] In some embodiments, a suitable daily dose of the composition of the present invention will be the lowest dose of the compound that is effective to produce a therapeutic effect. Such an effective amount will generally depend on the factors described above. In some embodiments, the compound is administered at about 0.01 mg / kg to about 200 mg / kg, more preferably about 0.1 mg / kg to about 100 mg / kg, and even more preferably about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are administered in combination with another agent (e.g., as a sensitizer), the effective amount may be less than when the agent is used alone.

[0128] In some embodiments, the effective daily amount of the active compound may be administered as two, three, four, five, six or more separate doses administered at appropriate intervals throughout the day, optionally in unit dosage form. In some embodiments, dosing is administered once per day.

[0129] The above description describes multiple aspects and embodiments of the present invention. This patent application specifically contemplates all combinations and permutations of the aspects and embodiments.

[0130] IV. Therapeutic Administration When used to treat or prevent the above diseases or disorders, the compositions disclosed herein may be administered or applied alone or in combination with other agents. Also, ABDNAZ and / or its pharmaceutical compositions may be administered or applied alone or in combination with other pharmacologic active agents (e.g., other anti-cancer agents, other arthritis agents, etc.).

[0131] The compositions disclosed herein and another therapeutic agent may act additively or synergistically. In one embodiment, the crystalline forms of ABDNAZ disclosed herein and / or pharmaceutical compositions thereof are administered simultaneously with the administration of another therapeutic agent. In another embodiment, the crystalline forms of ABDNAZ formulations and / or pharmaceutical compositions thereof are administered before or after the administration of another therapeutic agent.

[0132] Sequential or simultaneous administration of each therapeutic agent may be by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue.

[0133] It is understood that the therapeutic agents may be administered by the same route or by different routes. In some embodiments, a first therapeutic agent of a selected combination may be administered by intravenous administration, while the other therapeutic agent(s) of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection.

[0134] In particular, in one embodiment, the crystalline forms of ABDNAZ disclosed herein and / or pharmaceutical compositions thereof may be administered in combination with other chemotherapeutic agents (e.g., alkylating agents (e.g., nitrogen mustards (e.g., cyclophosphamide, ifosfamide, mechlorethamine, melphalen, chlorambucil, hexamethylmelamine, thiotepa), alkylsulfonates (e.g., busulfan), nitrosoureas, triazines), antimetabolites (e.g., folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, cytosine arabinoside, etc.), purine analogs (e.g., mercaptopurine, thiogunaine, pentostatin, etc.), natural products (e.g., For example, vinblastine, vincristine, etoposide, teniposide, dactinomycin, daunorubicin, doxurubicin, bleomycin, mithramycin, mitomycin C, L-asparaginase, interferon alpha), platinum coordination complexes (e.g., cisplatinum, carboplatin, etc.), apoptosis inducers, glutathione depleting agents, or other agents capable of altering the redox state of cells).Those skilled in the art will also recognize that the compositions disclosed herein may also be used in simultaneous combination therapy with both the chemotherapeutic agents and radiation therapy listed above.

[0135] In some embodiments, the compositions disclosed herein may be administered orally. The compositions disclosed herein may also be administered by any other convenient route, such as by injection or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal mucosa, intestinal mucosa, etc.). Administration may be systemic or local. A variety of delivery systems are known, such as embedding in liposomes, microparticles, microcapsules, capsules, etc., which may be used to administer the compositions disclosed herein. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topically (especially to the ear, nose, eye, or skin). The mode of administration will be at the discretion of the physician and will depend in part on the site of the condition. In most cases, administration will result in release of ABDNAZ and / or its pharmaceutical composition into the bloodstream.

[0136] In some embodiments, the compositions disclosed herein may be administered via a medical device, for example, using drug infusion devices, systems, and methods such as those described in International Publication No. WO 2019 / 241276, the disclosure of which is incorporated herein in its entirety.

[0137] In certain embodiments, it may be desirable to administer the compositions disclosed herein locally to the area that needs treatment.This can be achieved, for example, but not limited to, by local infusion during surgery, local application (e.g., in combination with wound dressing after surgery), by injection, by catheter, by suppository, or by implant, said implant being a porous, non-porous, or gel-like material, including membranes such as sialastic or fibrous membranes.In one embodiment, administration can be performed by direct injection at the site (or former site) of disease or injury.

[0138] In certain embodiments, it may be desirable to introduce the compositions disclosed herein into the central nervous system by any suitable route, including intraventricular, intrathecal, and epidural injection. Intraventricular injection may be facilitated, for example, by an intraventricular catheter attached to a reservoir, such as an Ommaya reservoir.

[0139] In other embodiments, the compositions disclosed herein can also be administered directly to the lungs by inhalation.For administration by inhalation, ABDNAZ and / or its pharmaceutical composition can be conveniently delivered to the lungs by several different devices.For example, ABDNAZ and / or its pharmaceutical composition can be delivered directly to the lungs using a metered dose inhaler ("MDI") that utilizes a canister containing a suitable low boiling point propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas).

[0140] In another embodiment, a dry powder inhaler ("DPI") device can be used to administer the compositions disclosed herein to the lungs. DPI devices typically use mechanisms such as a gas burst that can create a dry powder cloud inside a container, which can then be inhaled by the patient, and are well known in the art. In certain embodiments, a popular variation is the multiple dose DPI ("MDDPI") system, which allows for the delivery of more than one therapeutic dose. MDDPI devices are commercially available from several pharmaceutical companies (e.g., Schering Plough, Madison, NJ). For example, gelatin capsules and cartridges for use in inhalers or insufflators can be formulated to contain a powder mix of the compositions disclosed herein and a suitable powder base, such as lactose or starch, for these systems.

[0141] In some embodiments, another type of device that can be used to deliver the compositions disclosed herein to the lungs is a liquid spray device, such as that supplied by Aradigm Corporation, Hayward, Calif. Liquid spray systems use extremely small nozzle holes that aerosolize liquid drug formulations, which can then be inhaled directly into the lungs.

[0142] In some embodiments, a nebulizer is used to deliver the compositions disclosed herein to the lungs. A nebulizer creates aerosols from liquid drug formulations, for example by using ultrasonic energy to form fine particles that can be easily inhaled (see, for example, Verschoyle et al., British J.Cancer, 1999,80,Suppl.2,96). Examples of nebulizers include the devices provided by Sheffield Pharmaceuticals, St. Louis, MO (Armer et al., U.S. Pat. No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No. 5,970,974) and Batelle Pulmonary Therapeutics, Columbus, OH.

[0143] In other embodiments, electrohydrodynamic ("EHD") aerosol devices are used to deliver the compositions disclosed herein to the lungs of a patient. EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see, e.g., Noakes et al., U.S. Pat. No. 4,765,539). When delivering ABDNAZ and / or its pharmaceutical compositions to the lungs with an EHD aerosol device, the electrochemical properties of the formulation may be an important parameter to be optimized. EHD aerosol devices may deliver drugs to the lungs more efficiently than existing pulmonary delivery technologies.

[0144] In some embodiments, the compositions disclosed herein may be delivered in vesicles, in particular liposomes (e.g., Langer, 1990, Science, 249:1527-1533; Treat et al., in "Liposomes in the Therapy of Infectious Disease and Cancer," Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989)).

[0145] In some embodiments, the compositions disclosed herein can be delivered via sustained release systems, such as oral sustained release systems. In other embodiments, pumps can be used (e.g., Langer, supra, Sefton, 1987, CRC Crit. Ref Biomed. Eng. 14:201; Saudek et al., 1989, N. Engl. J Med. 321:574).

[0146] In some embodiments, polymeric materials may be used (e.g., "Medical Applications of Controlled Release," Langer and Wise (eds.), CRC Press, Boca Raton, Florida (1974); "Controlled Drug Bioavailability," Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).

[0147] In other embodiments, polymeric materials are used for oral sustained release delivery. Polymers include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose (most preferably, hydroxypropylmethylcellulose). Other cellulose ethers have also been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3)1-9). Factors that affect drug release are well known to those skilled in the art and have been described in the art (Bamba et al., Int. J. Pharm. 1979, 2, 307).

[0148] In other embodiments, enteric coating formulations can be used for oral sustained release administration. Coating materials include polymers whose solubility is pH-dependent (i.e., pH-controlled release), polymers whose swelling, dissolution or erosion rate is slow or pH-dependent (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release), and polymers that form a firm layer that is broken down by increasing pressure (i.e., pressure-controlled release).

[0149] In other embodiments, osmotic delivery systems are used for oral sustained release administration (Verma et al., Drug Dev. Ind. Pharm., 2000, 26:695-708). In some embodiments, OROS™ osmotic devices are used for oral sustained release delivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

[0150] In yet another embodiment, a controlled release system may be placed in proximity to the target of the ABDNAZ and / or pharmaceutical composition, thus requiring only a fraction of the systemic dose (e.g., Goodson, in "Medical Applications of Controlled Release," supra, vol. 2, pp. 115-138 (1984)). Other conventional controlled release systems may also be used (Langer, 1990, Science 249:1527-1533).

[0151] In other embodiments, the particles are dispersed in a dedusting additive, for example, the dedusting agent is polyethylene glycol (e.g., PEG-400).

[0152] In another aspect, the present invention provides a mixture comprising a composition or pharmaceutical composition disclosed herein and a blood sample.

[0153] In some embodiments, the concentration of the compound of formula I is 0.1 mg / mL to 10 mg / mL of blood, or 0.2 mg / mL to 5 mg / mL of blood, or 0.4 mg / mL to 2.5 mg / mL of blood. In some circumstances, it may be useful to administer the compound of formula I at a concentration of 1 mg of compound per 2.5 mL of blood.

[0154] Dose of ABDNAZ administered An exemplary ABDNAZ dosage is 2 In one particular embodiment, the dose of ABDNAZ administered to a patient is about 1 mg / m 2 ~about 2mg / m 2 , about 2mg / m 2 ~about 4mg / m 2 , about 4mg / m 2 ~about 6mg / m 2 , about 6mg / m 2 ~about 8mg / m 2 , about 8mg / m 2 ~about 10mg / m 2, about 10mg / m 2 ~about 12mg / m 2 , about 12mg / m 2 ~about 14mg / m 2 , about 14mg / m 2 ~about 16mg / m 2 , about 16mg / m 2 ~about 18mg / m 2 , about 18mg / m 2 ~about 20mg / m 2 , about 20mg / m 2 ~about 25mg / m 2 , about 25mg / m 2 ~about 30mg / m 2 , about 30mg / m 2 ~about 35mg / m 2 , about 35mg / m 2 ~about 40mg / m 2 , about 40mg / m 2 ~about 45mg / m 2 , about 45mg / m 2 ~about 50mg / m 2 , about 50mg / m 2 ~about 60mg / m 2 , or about 60 mg / m 2 ~about 75mg / m 2 It is.

[0155] The dose of ABDNAZ administered to a patient may be further characterized according to both the amount of ABDNAZ and the mode of delivery, such as intravenous infusion. Thus, in certain embodiments, each dose of a formulation containing ABDNAZ is about 1 mg / m 2 ~about 90mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 1 mg / m 2 ~about 10mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 1 mg / m 2 ~about 2.5mg / m 2In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 2.5 mg / m 2 ~about 5mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 5 mg / m 2 ~about 10mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 5 mg / m 2 ~about 7mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 8 mg / m 2 ~about 9mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 10 mg / m 2 ~about 20mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 1 mg / m 2 ~about 1.5mg / m 2 , about 1.5mg / m 2 ~about 2mg / m 2 , about 2mg / m 2 ~about 2.5mg / m 2 , about 2.5mg / m 2 ~about 3mg / m 2 , about 3mg / m 2 ~about 3.5mg / m 2 , about 3.5mg / m 2 ~about 4mg / m 2 , about 4mg / m 2 ~about 4.5mg / m 2 , about 4.5mg / m 2 ~about 5mg / m 2 , about 5mg / m 2 ~about 5.5mg / m 2 , about 5.5mg / m 2~about 6mg / m 2 , about 6mg / m 2 ~about 6.5mg / m 2 , about 6.5mg / m 2 ~about 7mg / m 2 , about 7mg / m 2 ~about 7.5mg / m 2 , about 7.5mg / m 2 ~about 8mg / m 2 , about 8mg / m 2 ~about 8.5mg / m 2 , about 8.5mg / m 2 ~about 9mg / m 2 , about 9mg / m 2 ~about 9.5mg / m 2 , about 9.5mg / m 2 ~about 10mg / m 2 , about 10mg / m 2 ~about 12mg / m 2 , about 12mg / m 2 ~about 14mg / m 2 , about 14mg / m 2 ~about 16mg / m 2 , about 16mg / m 2 ~about 18mg / m 2 , about 18mg / m 2 ~about 20mg / m 2 , about 20mg / m 2 ~about 25mg / m 2 , about 25mg / m 2 ~about 30mg / m 2 , about 30mg / m 2 ~about 35mg / m 2 , about 35mg / m 2 ~about 40mg / m 2 , about 40mg / m 2 ~about 45mg / m 2 , or about 45 mg / m 2 ~about 50mg / m 2 In certain embodiments, each dose of the formulation containing ABDNAZ is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 3 mg / m 2 ~about 8mg / m 2 The patient is administered ABDNAZ by intravenous infusion providing ABDNAZ in amounts ranging from 0.1 to 10 mg / kg.

[0156] In a more specific embodiment, each dose of the compositions disclosed herein is about 1.25 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 2.5 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 5 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 8.4 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 1 mg / m 2 , about 1.5mg / m 2 , about 2mg / m 2 , about 2.5mg / m 2 , about 3mg / m 2 , about 3.5mg / m 2 , about 4mg / m 2 , about 4.5mg / m 2 , about 5mg / m 2 , about 5.5mg / m 2 , about 6mg / m 2 , about 6.5mg / m 2 , about 7mg / m 2 , about 7.5mg / m 2 , about 8mg / m 2 , about 8.5mg / m 2 , about 9mg / m 2 , about 9.5mg / m 2 , about 10mg / m 2 , about 12mg / m 2 , about 14mg / m 2 , about 16mg / m 2 , about 18mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , or about 50 mg / m2 The patient is administered ABDNAZ by intravenous infusion providing the patient with ABDNAZ in an amount of

[0157] The methods described herein may be further characterized according to the dose of ABDNAZ administered to the patient. The doses of ABDNAZ described herein for use in combination with temozolomide and radiation therapy are selected in view of the administration schedule and the amount of temozolomide and radiation therapy. The dose of ABDNAZ is m 2 The number of milligrams of ABDNAZ that will be administered to a patient based on the patient's surface area measured in .

[0158] In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion. In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion. 2 ~about 20mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 2.5 mg / m 2 ~about 5mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 5 mg / m 2 ~about 10mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 10 mg / m 2 ~about 16.5mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount ranging from about 2.5 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 5 mg / m 2In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 10 mg / m 2 In certain embodiments, each dose of the compositions disclosed herein is administered to the patient by intravenous infusion providing ABDNAZ in an amount of about 16.5 mg / m 2 The patient is administered ABDNAZ by intravenous infusion providing the patient with ABDNAZ in an amount of

[0159] In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion providing ABDNAZ in an amount of about 0.1 mg to about 20 mg. In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion providing ABDNAZ in an amount of about 0.1 mg to about 10 mg. In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion providing ABDNAZ in an amount of about 0.5 mg to about 4.0 mg. In certain embodiments, each dose of the compositions disclosed herein is administered to a patient by intravenous infusion to provide ABDNAZ in an amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg. Doses of 0.5 mg to 66 mg of ABDNAZ may be administered to a subject, although the actual dose will be determined based on a variety of factors disclosed herein.

[0160] As described in the following section, in one method for administering ABDNAZ to a subject, the compound is provided in a liquid formulation containing PEG (e.g., PEG-400) at a concentration of 2mg / mL.In one method, for every 1mg of compound in the liquid formulation to be administered, the compound is combined with 2.5mL of the subject's blood to form a mixture, and then the mixture is administered to the subject.For example, a dose of 0.5mg (in 0.25mL of liquid formulation) is combined with 1.25mL of blood, or a dose of 66mg of ABDNAZ (in 33mL of liquid formulation) is combined with 165mL of blood before administration to the subject.

[0161] In some embodiments, the amount of ABDNAZ crystal form and / or pharmaceutical composition thereof administered will, of course, depend on factors such as the subject being treated, the subject's weight, the severity of the affliction, the mode of administration, and the judgment of the prescribing physician, among others. For example, the dosage of ABDNAZ as a crystal and / or pharmaceutical formulation may be delivered in a single dose, multiple applications, or by controlled release. In some embodiments, administration may be repeated intermittently, provided alone or in combination with other drugs, and may continue as long as necessary to effectively treat the disease state or disorder.

[0162] The appropriate dosage range for oral administration depends on the effectiveness of the radiation sensitizing effect, but is generally about 0.001 mg to about 100 mg of ABDNAZ crystalline form per kg of body weight. The dosage range can be easily determined by methods known to those skilled in the art.

[0163] A suitable dosage range for intravenous (iv) administration is about 0.01 mg to about 100 mg per kg / body weight. A suitable dosage range for intranasal administration is generally about 0.01 mg / kg body weight to about 1 mg / kg body weight. Suppositories generally contain about 0.01 milligrams to about 50 milligrams of ABDNAZ per kg / body weight, or about 0.5% to about 10% by weight of ABDNAZ. Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 mg per kg / body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

[0164] Exemplary ABDNAZ Formulations The present invention provides formulations comprising crystalline forms of ABDNAZ, such as formulations containing whole blood (e.g., autologous blood from a patient to be treated), ABDNAZ (e.g., crystalline forms of ABDNAZ), an anticoagulant, and optionally one or more of water, polyethylene glycol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulation consists essentially of whole blood, ABDNAZ (e.g., crystalline forms of ABDNAZ), and an anticoagulant. In certain embodiments, the ABDNAZ formulation consists of whole blood, ABDNAZ (e.g., crystalline forms of ABDNAZ), an anticoagulant, and optionally one or more of water, polyethylene glycol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulation consists of whole blood, ABDNAZ (e.g., crystalline forms of ABDNAZ), an anticoagulant, and optionally one or more of water, polyethylene glycol having a number average molecular weight in the range of about 200 g / mol to about 600 g / mol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulation comprises whole blood, ABDNAZ (e.g., a crystalline form of ABDNAZ), an anticoagulant, water, a polyethylene glycol having a number average molecular weight ranging from about 200 g / mol to about 600 g / mol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulation comprises whole blood, ABDNAZ (e.g., a crystalline form of ABDNAZ), an anticoagulant, and optionally one or more of water, a polyethylene glycol having a number average molecular weight of about 400 g / mol, and N,N-dimethylacetamide. In certain embodiments, the ABDNAZ formulation comprises whole blood, ABDNAZ (e.g., a crystalline form of ABDNAZ), an anticoagulant, water, a polyethylene glycol having a number average molecular weight of about 400 g / mol, and N,N-dimethylacetamide.

[0165] Anticoagulants The ABDNAZ crystalline form formulations may be further characterized according to the identity and / or amount of the anticoagulant. Thus, in certain embodiments, the anticoagulant comprises one or more of heparin and citrate. In certain embodiments, the anticoagulant is a solution comprising an alkali metal citrate, dextrose, and water. In certain embodiments, the anticoagulant is present in the ABDNAZ formulation in an amount ranging from about 0.1% wt / wt to about 15% w / w. In certain embodiments, the anticoagulant is present in the ABDNAZ formulation in an amount ranging from about 1% wt / wt to about 10% w / w. In certain embodiments, the anticoagulant is present in the ABDNAZ formulation in an amount ranging from about 2% wt / wt to about 8% w / w.

[0166] The formulations may be further characterized according to the identity of the anticoagulant in the ABDNAZ formulations described herein. Thus, in certain embodiments, the anticoagulant comprises one or more of heparin and citrate. In certain embodiments, the anticoagulant is a solution comprising an alkali metal citrate, dextrose, and water.

[0167] Whole blood volume in ABDNAZ formulation The ABDNAZ crystalline form formulation may be further characterized according to the amount of whole blood in the ABDNAZ formulation. Thus, in certain embodiments, whole blood constitutes at least 30% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes at least 40% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes at least 50% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes at least 60% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes at least 75% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes at least 90% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes about 60% wt / wt to about 99% wt / wt of the ABDNAZ formulation. In certain embodiments, whole blood constitutes about 70% wt / wt to about 95% wt / wt of the ABDNAZ formulation. In certain embodiments, the whole blood comprises about 75% wt / wt to about 90% wt / wt of the ABDNAZ formulation. In certain embodiments, the whole blood is present in the ABDNAZ formulation at about 5 mL to about 10 mL, the whole blood is present in the ABDNAZ formulation at about 10 mL to about 15 mL, the whole blood is present in the ABDNAZ formulation at about 9 mL to about 11 mL, the whole blood is present in the ABDNAZ formulation at about 10 mL to about 20 mL, the whole blood is present in the ABDNAZ formulation at about 20 mL to about 30 mL, the whole blood is present in the ABDNAZ formulation at about 30 mL to about 50 mL, the whole blood is present in the ABDNAZ formulation at about 50 mL to about 70 mL, or the whole blood is present in the ABDNAZ formulation at about 70 mL to about 90 mL. In certain embodiments, the whole blood is present in the ABDNAZ formulation at about 90 mL to about 110 mL. In certain embodiments, the whole blood is present in the ABDNAZ formulation at about 95 mL to about 105 mL. In certain embodiments, the whole blood is present in the ABDNAZ formulation at about 100 mL.

[0168] Volume of ABDNAZ formulation administered to subject The method may be further characterized according to the volume of the composition described herein (e.g., ABDNAZ formulation) administered to the patient. Thus, in certain embodiments, the volume of the composition described herein (e.g., ABDNAZ formulation) is in the range of about 10 mL to about 200 mL. In certain embodiments, the volume of the composition described herein (e.g., ABDNAZ formulation) is in the range of about 10 mL to about 15 mL, about 15 mL to about 20 mL, about 20 mL to about 30 mL, or about 30 mL to about 50 mL. In certain embodiments, the volume of the composition described herein (e.g., ABDNAZ formulation) is in the range of about 50 mL to about 200 mL. In certain embodiments, the volume of the composition described herein (e.g., ABDNAZ formulation) is in the range of about 75 mL to about 150 mL. In certain embodiments, the volume of the composition described herein (e.g., ABDNAZ formulation) is in the range of about 90 mL to about 140 mL. In certain embodiments, the volume of a composition described herein (e.g., an ABDNAZ formulation) ranges from about 100 mL to about 140 mL. In certain embodiments, the volume of a composition described herein (e.g., an ABDNAZ formulation) ranges from about 100 mL to about 120 mL.

[0169] One of the more specific exemplary formulations is an intravenous formulation containing ABDNAZ (e.g., a crystalline form of ABDNAZ disclosed herein) for intravenous administration to a patient, comprising the following: a. Whole blood, which is at least 60% v / v volume of the product; b. polyethylene glycol, having a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation; c. N,N-dimethylacetamide, at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. Water, and f. anticoagulants, The intravenous formulation comprises:

[0170] Another more specific exemplary formulation is the following: a. Whole blood, which is at least 60% v / v volume of the product; b. polyethylene glycol, having a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation; c. N,N-dimethylacetamide, at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. Water, and f. anticoagulants, The formulation consists essentially of:

[0171] Another more specific exemplary formulation is the following: a. Whole blood, which is at least 60% v / v volume of the product; b. polyethylene glycol, having a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation; c. N,N-dimethylacetamide, at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. Water, and f. anticoagulants, It is a formulation consisting of:

[0172] Another more specific exemplary formulation is an intravenous formulation containing ABDNAZ (e.g., a crystalline form of ABDNAZ disclosed herein) for intravenous administration to a patient, comprising: a. A blood product (e.g., red blood cells, plasma, or whole blood) that is at least 30% v / v volume of the product; b. optionally, polyethylene glycol at a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation; c. optionally, N,N-dimethylacetamide, at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation; d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. optionally, water, and f. optionally, an anticoagulant; The intravenous formulation comprises:

[0173] Another more specific exemplary formulation is an intravenous formulation containing ABDNAZ (e.g., a crystalline form of ABDNAZ disclosed herein) for intravenous administration to a patient, comprising: a. Whole blood, at least 30% v / v volume of the product; b. polyethylene glycol (e.g., at a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation); cN,N-dimethylacetamide (e.g., at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation), d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. Water, and f. anticoagulants, The intravenous formulation comprises:

[0174] Another more specific exemplary formulation is the following: a. Whole blood, at least 30% v / v volume of the product; b. polyethylene glycol (e.g., at a concentration of about 0.4 μL / mL to about 30 μL / mL in the formulation); cN,N-dimethylacetamide (e.g., at a concentration of about 0.2 μL / mL to about 15 μL / mL in the formulation), d. ABDNAZ at a concentration of at least 10 μg / mL in the formulation; e. Water, and f. anticoagulants, The formulation consists essentially of:

[0175] Exemplary Features of Intravenous Formulations Intravenous formulations can be characterized, for example, according to the identity of the polyethylene glycol described herein below, the anticoagulant, the concentration of ABDNAZ (e.g., the crystalline forms of ABDNAZ disclosed herein), the amount of whole blood, and other characteristics.

[0176] Polyethylene glycol The formulations may be further characterized according to the identity of the polyethylene glycol in the ABDNAZ formulations described herein. Thus, in certain embodiments, the polyethylene glycol is a polyethylene glycol having a number average molecular weight ranging from about 200 g / mol to about 600 g / mol. In certain embodiments, the polyethylene glycol is a polyethylene glycol having a number average molecular weight of about 400 g / mol.

[0177] In certain embodiments, the polyethylene glycol is present in the formulation at a concentration of about 0.4 μL / mL to about 4 μL / mL. In certain embodiments, the N,N-dimethylacetamide is present in the formulation at a concentration of about 0.2 μL / mL to about 2 μL / mL.

[0178] Concentration of ABDNAZ The formulations may be further characterized according to the concentration of ABDNAZ in the ABDNAZ formulations described herein. Thus, in certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration of at least 20 μg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration of at least 50 μg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration of at least 100 μg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration of at least 150 μg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration ranging from about 10 μg / mL to about 1 mg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration ranging from about 10 μg / mL to about 0.5 mg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration ranging from about 10 μg / mL to about 250 μg / mL. In certain embodiments, the ABDNAZ formulation contains ABDNAZ at a concentration ranging from about 20 μg / mL to about 200 μg / mL.

[0179] Volume of whole blood The formulations may be further characterized according to the amount of whole blood in the ABDNAZ formulations described herein. Thus, in certain embodiments, whole blood comprises at least 30% wt / wt of the formulation. In certain embodiments, whole blood comprises at least 40% wt / wt of the formulation. In certain embodiments, whole blood comprises at least 50% wt / wt of the formulation. In certain embodiments, whole blood comprises at least 75% wt / wt of the formulation. In certain embodiments, whole blood comprises at least 90% wt / wt of the formulation. In certain embodiments, whole blood comprises about 60% wt / wt to about 99% wt / wt of the formulation. In certain embodiments, whole blood comprises about 70% wt / wt to about 95% wt / wt of the formulation. In certain embodiments, whole blood comprises about 75% wt / wt to about 90% wt / wt of the formulation. In certain embodiments, whole blood is present in about 90 mL to about 110 mL of the formulation. In certain embodiments, the whole blood is present in the formulation at about 95 mL to about 105 mL. In certain embodiments, the whole blood is present in the formulation at about 100 mL.

[0180] Unit Dose Forms for Intravenous Preparations The formulations may be further characterized according to the volume of a unit dose of the ABDNAZ formulations described herein. Thus, in certain embodiments, the formulation is a unit dose form having a volume ranging from about 10 mL to about 200 mL. In certain embodiments, the formulation is a unit dose form having a volume ranging from about 10 mL to about 15 mL, about 15 mL to about 20 mL, about 20 mL to about 30 mL, about 30 mL to about 40 mL, or about 40 mL to about 50 mL. In certain embodiments, the formulation is a unit dose form having a volume ranging from about 50 mL to about 200 mL. In certain embodiments, the formulation is a unit dose form having a volume ranging from about 75 mL to about 150 mL. In certain embodiments, the formulation is a unit dose form having a volume ranging from about 90 mL to about 140 mL. In certain embodiments, the formulation is a unit dose form having a volume ranging from about 100 mL to about 140 mL. In certain embodiments, the formulation is in a unit dose form having a volume ranging from about 100 mL to about 120 mL.

[0181] Characterization of pain effects upon intravenous administration to subjects The formulations described herein may be further characterized according to the degree of pain experienced by a patient upon intravenous administration of the ABDNAZ formulation to the patient. Thus, in certain embodiments, the formulations are characterized by the characteristic that any pain experienced by the patient at the site of intravenous administration resulting from intravenous administration of the formulation to the patient at a rate ranging from 10 mL / hour to 50 mL / hour is Grade 2 or less. In certain embodiments, the formulations are characterized by the characteristic that any pain experienced by the patient at the site of intravenous administration resulting from intravenous administration of the formulation to the patient at a rate ranging from 10 mL / hour to 50 mL / hour is Grade 1 or less.

[0182] The above description describes multiple aspects and embodiments of the present invention. This patent application specifically contemplates all combinations and permutations of the aspects and embodiments.

[0183] V. Treatment application The present invention provides, in part, methods of treating or preventing diseases associated with abnormalities in cell proliferation using a crystalline form of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) or a pharmaceutical composition thereof.

[0184] In one embodiment, a method is provided for treating, preventing, or alleviating any of the diseases or conditions described herein using the crystalline forms of ABDNAZ described herein. In some embodiments, a use of any of the crystalline forms or compositions of ABDNAZ described herein in the manufacture of a medicament for treating, preventing, or alleviating any of the diseases or conditions described herein is provided. In some embodiments, a crystalline form and a composition of ABDNAZ described herein are provided for use in treating, preventing, or alleviating any of the diseases or conditions described herein. In some embodiments, the disease is associated with abnormal cell proliferation.

[0185] In one embodiment, a method for treating or preventing cancer is provided.In some embodiments, the method comprises administering to a subject in need thereof an effective amount of any of the crystals or compositions described herein.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.In some embodiments, the administration is intravenous or oral.

[0186] In another aspect, a method for treating or preventing an ischemic or hypoxic condition is provided.In some embodiments, the method comprises administering an effective amount of any of the crystals or compositions described herein to a subject in need thereof.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.In some embodiments, the administration is intravenous or oral.

[0187] In another aspect, a method for treating or preventing a neurodegenerative disease, an allergic disease, an autoimmune disease, a fibrotic disease, an inflammatory disease, an infectious disease, a pulmonary disease, a cardiac disease, a vascular disease, or a metabolic disease is provided.In some embodiments, the method comprises subcutaneous administration of an effective amount of any of the crystals or compositions described herein to a subject in need thereof.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.

[0188] In another aspect, a method for protecting against toxicity to normal tissue caused by chemotherapy and / or radiation therapy is provided.In some embodiments, the method comprises subcutaneous administration of an effective amount of any of the crystals or compositions described herein to a subject in need thereof, said subcutaneous administration being performed before said subject is exposed to chemotherapy and / or radiation therapy.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.

[0189] In another aspect, a method for treating a patient suffering from hypovolemia or hypoperfusion is provided.In some embodiments, the method comprises administering to a patient in need thereof a blood product comprising any of the crystals or compositions described herein.In some embodiments, the subject is a mammal.In some embodiments, the subject is a human.

[0190] In some embodiments, the method generally involves administering a therapeutically effective amount of a composition disclosed herein to a patient in need of such treatment or prevention. In certain circumstances, 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) is activated intracellularly by the reducing environment of tumor cells. In other circumstances, the subject is irradiated to activate ABDNAZ. Without being bound by theory, 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) may form free radicals upon irradiation or reduction, which may then disrupt cell replication and kill the cell, possibly by interfering with DNA replication and / or reacting with cell membranes. However, other mechanisms currently unknown may be shown to be responsible for the effectiveness of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) in treating or preventing abnormal cell proliferation. In other situations, 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone (ABDNAZ) can be activated by both intracellular reduction and external irradiation. In these embodiments, synergistic or additive effects can be observed.

[0191] In another aspect, the invention provides a method of treating a disease or disorder characterized by an abnormality in cell proliferation in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition described herein, a pharmaceutical composition described herein, or a mixture described herein, thereby treating the abnormality in cell proliferation in the subject.

[0192] In some embodiments, the disease or disorder characterized by abnormal cell proliferation is inflammation, cardiovascular disease, and autoimmune disease. In some embodiments, the inflammatory disease is arthritis, diabetic retinopathy, diabetes, rheumatoid arthritis, neovascular glaucoma, and psoriasis. In some embodiments, the cardiovascular disease is arteriosclerosis, pulmonary hypertension, systemic hypertension, angina pectoris, cardiac syndrome X, myocardial infarction, peripheral arterial disease, or Raynaud's disease.

[0193] In another aspect, the present invention provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition described herein, a pharmaceutical composition described herein, or a mixture described herein, thereby treating cancer in the subject.

[0194] In some embodiments, the cancer is an angiogenic solid cancer, including, but not limited to, lung cancer, breast cancer, ovarian cancer, gastric cancer, pancreatic cancer, laryngeal cancer, esophageal cancer, testicular cancer, liver cancer, parotid cancer, biliary tract cancer, colon cancer, rectal cancer, cervical cancer, uterine cancer, endometrial cancer, kidney cancer, bladder cancer, prostrate, thyroid cancer, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma (including, but not limited to, astrocytoma, glioblastoma), neuroblastoma, sarcoma (including, but not limited to, angiosarcoma, chondrosarcoma).

[0195] In another aspect, the present invention provides a method of treating a hemolytic condition in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition described herein, a pharmaceutical composition described herein, or a mixture described herein, thereby treating the hemolytic condition in the subject.

[0196] In some embodiments, the hemolytic condition is sickle cell disease. In other embodiments, the hemolytic condition is any of the following: sickle cell crisis, thalassemia, hemoglobin C disease, hemoglobin SC disease, sickle cell thalassemia, hereditary spherocytosis, hereditary elliptocytosis, hereditary ovalocytosis, glucose-6-phosphate deficiency and other red blood cell enzyme deficiencies, paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria (PCH), thrombotic thrombocytopenic purpura / hemolytic uremic syndrome (TTP / TTP), and / or other hemolytic conditions. The hemolytic condition is selected from one of exemplary hemolytic conditions including: HUS, idiopathic autoimmune hemolytic anemia, drug-induced immune hemolytic anemia, secondary immune hemolytic anemia, non-immune hemolytic anemia caused by chemical or physical agents, malaria, falciparum malaria, bartonellosis, babesiosis, clostridium infection, severe Haemophilus influenzae type b infection, extensive burns, transfusion reactions, rhabdomyolysis (myoglobinemia), transfusion of aged blood, cardiopulmomonary bypass, and hemodialysis.

[0197] In some embodiments, the compositions described herein or the pharmaceutical compositions described herein are combined with blood collected from a subject to create a mixture. The mixture is then administered to the subject. In some embodiments, the blood is whole blood (e.g., autologous whole blood or allogeneic whole blood). In other embodiments, the blood is a blood product, including, but not limited to, one or more of plasma, red blood cells. In another embodiment, the compositions described herein or the pharmaceutical compositions described herein are combined with blood products for transfusion to a patient suffering from hemorrhagic shock and suffering from reduced blood volume or hypoperfusion. In another embodiment, the compositions described herein or the pharmaceutical compositions described herein are administered to a patient separately from the blood product.

[0198] In another aspect, the present invention provides an in vitro method for sterilization. Biological solutions can be treated with the present invention, which is toxic to pathogenic bacteria, viruses and cells. The process can also be catalyzed by the application of external energy, such as light and heat.

[0199] In another aspect, the present invention provides a method of treatment for a patient suffering from a bacterial infection. In some embodiments, the bacterial infection can be a gram-positive bacterial infection or a gram-negative bacterial infection. In certain embodiments, the bacterial infection is a gram-positive coccal infection or a gram-positive bacillus infection. In certain other embodiments, the bacterial infection is a gram-negative bacterial infection. In certain other embodiments, the bacterial infection is a gram-negative coccal infection or a gram-negative bacillus infection.

[0200] The type of bacterial infection may also be characterized according to whether anaerobic or aerobic bacteria cause the bacterial infection. In certain embodiments, the bacterial infection is an anaerobic bacterial infection. In certain other embodiments, the bacterial infection is an aerobic bacterial infection.

[0201] In certain embodiments, the bacterial infection is a mycobacterial infection. In further particular embodiments, the bacterial infection is an infection with a bacteria selected from the group including Mycobacterium tuberculosis, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes, Mycobacterium smegmatis, Bacillus anthracis, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa, Acinetobacter baumannii, Yersinia enterocolytica, Francisella tularensis, Eubacterium lentum, Bacteroides fragilis, Fusobacterium nucleatum, Porphyromonas asaccharolyticus, Clostridium perfringens, and Clostridium difficile. In yet other embodiments, the bacterial infection is a Mycobacterium tuberculosis (abbreviated as "MTB" or "TB") infection.

[0202] In certain other embodiments, the bacterial infection is selected from the group consisting of members of the genus Peptostreptococci (Peptostreptococci asaccharolyticus, Peptostreptococci magnus, Peptostreptococci micros, Peptostreptococci prevotii), members of the genus Porphyromonas (Porphyromonas asaccharolytica, Porphyromonas canoris, Porphyromonas gingivalis, Porphyromonas macaccae), members of the genus Actinomyces (Actinomyces israelii, Actinomyces odontolyticus), members of the genus Clostridium (Clostridium innocuum, Clostridium clostridioforme, Clostridium difficile), members of the genus Anaerobiospirillum, members of the genus Bacteroides (Bacteroides tectum, Bacteroides ureolyticus, Bacteroides gracilis (Campylobacter gracilis)), members of the Prevotella genus (Prevotella intermedia, Prevotella heparinolytica, Prevotella orisbuccae, Prevotella bivia, Prevotella melaninogenica), members of the Fusobacterium genus (Fusobacterium naviforme, Fusobacterium necrophorum, Fusobacterium varium, Fusobacterium ulcerans, Fusobacterium russii), or members of the Bilophila genus (Bilophila wadsworthia).

[0203] In certain other embodiments, the bacterial infection is caused by antibiotic-resistant bacteria, both aerobic and anaerobic, gram-positive and gram-negative.

[0204] In another aspect, the invention provides a method of treating or preventing an ischemic or hypoxic condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition described herein, a pharmaceutical composition described herein, or a mixture described herein. In some embodiments, the subject is a mammal.

[0205] In some embodiments, the ischemic condition is an acute ischemic condition or a chronic ischemic condition.In other embodiments, the acute ischemic condition is myocardial infarction, ischemic stroke, pulmonary embolism, perinatal hypoxia, circulatory shock, altitude sickness or acute respiratory failure.In certain embodiments, the chronic ischemic condition is atherosclerosis, chronic venous insufficiency, chronic heart failure, cardiac cirrhosis, diabetes, macular degeneration, sleep apnea, Raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, occlusive arterial disease, angina pectoris, transient ischemic attack or chronic alcoholic liver disease.In some embodiments, the hypoxic condition is cancer, gastric or duodenal ulcer, liver or kidney disease, thrombocytopenia, blood coagulation disorder, chronic disease, therapeutic intervention that causes anemia (such as cancer chemotherapy) or altitude sickness. In other embodiments, the cancer is bladder cancer, breast cancer, clear cell renal cancer, squamous cell carcinoma of the head and neck, squamous cell carcinoma of the lung, malignant melanoma, colorectal cancer, head and neck cancer, cervical cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large intestinal cancer (DLC), diffuse large intestinal cancer (LV) or diffuse large intestinal cancer (LV). The following are the most common types of lymphoma: large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia cell-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0206] Additional conditions contemplated for treatment or prevention using the compositions described herein include nitric oxide-related rheumatoid arthritis, diabetes (including neuropathy and vascular disease), and systemic lupus erythematosus.

[0207] Contemplated pharmaceutical compositions may contain at least 0.5 mg of a compound of formula I and are administered intravenously, intranasally, intraauricularly, intraperitoneally, subcutaneously, or orally.

[0208] Cancer Type When the compositions disclosed herein are administered to a subject suffering from cancer for the treatment of cancer, the method can be further characterized according to the type of cancer to be treated.For example, in certain embodiments, cancer is solid tumor.For example, cancer can be brain cancer, bladder cancer, breast cancer, cervical cancer, bile duct cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer or uterine cancer.

[0209] In certain embodiments, the cancer is brain cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is cholangiocarcinoma or lung cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is small cell lung cancer. In certain other embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is leukemia or lymphoma. In certain embodiments, the cancer is B-cell lymphoma or non-Hodgkin's lymphoma.

[0210] Further examples of cancers to be treated include, for example, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer, and uterine cancer.

[0211] Cancers include angiogenic tumors, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid gland cancer, biliary tract cancer, thyroid cancer, acral lentigo melanoma, actinic keratosis, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous cell carcinoma, anal canal cancer, anal cancer, anorectal cancer, astrocytic tumor, Bartholin's gland carcinoma, basal cell carcinoma, biliary tract cancer, bone malignancies, bone marrow cancer, bronchial carcinoma, bronchial adenocarcinoma, carcinoid, cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma / choroid plexus carcinoma. papilloma / carcinoma), chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue carcinoma, cystadenoma, digestive system cancer, duodenal cancer, endocrine system cancer, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, endothelial cell carcinoma, ependymoma, epithelial cell carcinoma, Ewing's sarcoma, eye and orbit cancer, female genital tract cancer, focal nodular hyperplasia, gallbladder cancer, antrum cancer, gastric fundus cancer, gastrinoma, glioblastoma , glucagonoma, cardiac cancer, hemangiblastomas, hemangioendotheliomas, hemangiomas, hepatic adenomas, hepatic adenomatosis, hepatobiliary cancer, hepatocellular carcinoma, Hodgkin's disease, ileal cancer, insulinoma, intraepithelial neoplasia, intraepithelial squamous cell neoplasia, intrahepatic cholangiocarcinoma, invasive squamous cell carcinoma, jejunal cancer, joint cancer, Kaposi's sarcoma, pelvic cancer, large cell carcinoma, colon cancer, leiomyosarcoma, lentigo maligna melanoma, lymphoma, male reproductive tract cancer, malignant melanoma, malignant mesothelioma, medulloblastoma, medulloepithelioma, meningeal cancer, mesothelial carcinoma, metastatic cancer, oral cancer, mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal cancer, nervous system cancer, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin's lymphoma, oat cell carcinoma, oligodendroglial carcinoma, oral cancer, osteosarcoma, papillary serous adenocarcinoma, penile cancer, pharyngeal cancer, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, retinoblastoma, rhabdomyoblastoma It is contemplated that the cancer may be a myosoma, a sarcoma, a serous carcinoma, a paranasal sinus cancer, a skin cancer, a small cell carcinoma, a small intestine cancer, a smooth muscle carcinoma, a soft tissue cancer, a somatostatin-secreting tumor, a spinal cancer, a squamous cell carcinoma, a striated muscle carcinoma, a submesothelial carcinoma, a superficial spreading melanoma, a T-cell leukemia, a tongue cancer, an undifferentiated carcinoma, a ureteral cancer, a urethral cancer, a bladder cancer, a urinary system cancer, a cervical cancer, a uterine cancer, an uveal melanoma, a vaginal cancer, a wart carcinoma, a VIPoma, a vulvar cancer, a differentiated carcinoma, or a Wilms' tumor.

[0212] The present invention also provides a method for treating brain metastasis. For example, the method may use a specific administration regimen of ABDNAZ, radiation therapy, and optionally additional anticancer drugs. The method may further be characterized according to the type of brain metastasis to be treated. For example, brain metastasis may be characterized according to the type of primary tumor from which brain metastasis originates. In certain embodiments, brain metastasis is brain metastasis originating from melanoma, lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, gastric cancer, testicular cancer, uterine cancer, endometrial cancer, or esophageal cancer. In certain other embodiments, brain metastasis is brain metastasis originating from melanoma, lung cancer, breast cancer, colon cancer, or kidney cancer. In yet other embodiments, brain metastasis is originating from melanoma.

[0213] Exemplary cancers from which brain metastases may originate include, but are not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, kidney cancer, stomach cancer, testicular cancer, and uterine cancer.In yet other embodiments, the cancer is selected from the group consisting of angiosarcoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid gland cancer, biliary tract cancer, thyroid cancer, acral lentigo melanoma, actinic keratosis, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous cell carcinoma, anal canal cancer, anal cancer, anorectal cancer, astrocytic tumor, Bartholin's gland carcinoma, basal cell carcinoma, biliary tract cancer, bone malignancies, bone marrow cancer, bronchial carcinoma, bronchial adenocarcinoma, carcinoid, cholangiocarcinoma, chondrosarcoma, choroid plexus papilloma / choroid plexus carcinoma. papilloma / carcinoma), chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue carcinoma, cystadenoma, digestive system cancer, duodenal cancer, endocrine system cancer, endodermal sinus tumor, endometrial hyperplasia, Endometrial stromal sarcoma, endometrioid adenocarcinoma, endothelial cell carcinoma, ependymoma, epithelial cell carcinoma, Ewing's sarcoma, eye and orbital cancer, female genital cancer, focal nodular hyperplasia, gallbladder cancer, antrum cancer, gastric fundus cancer, gastrinoma, glial bud Cell tumor, glucagonoma, cardiac cancer, hemangiblastomas, hemangioendotheliomas, hemangiomas, hepatic adenomas, hepatic adenomatosis, hepatobiliary cancer, hepatocellular carcinoma, Hodgkin's disease, ileal cancer, insulinoma, intraepithelial neoplasia, interepithelial squamous cell neoplasia, intrahepatic cholangiocarcinoma, invasive squamous cell carcinoma, jejunal cancer, joint cancer, Kaposi's sarcoma, pelvic cancer, large cell carcinoma, colon cancer, leiomyosarcoma, lentigo maligna melanoma, lymphoma, male liver Genital cancer, malignant melanoma, malignant mesothelioma, medulloblastoma, medulloepithelioma, meningeal cancer, mesothelial carcinoma, metastatic cancer, oral cancer, mucoepidermoid carcinoma, multiple myeloma, muscle cancer, nasal cancer, nervous system cancer, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin's lymphoma, oat cell carcinoma, oligodendroglial carcinoma, oral cancer, osteosarcoma, papillary serous adenocarcinoma, penile cancer, pharyngeal cancer, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, omentum melanoma, rhabdomyosarcoma, sarcoma, serous carcinoma, cancer of the paranasal sinuses, skin cancer, small cell carcinoma, small intestine cancer, smooth muscle carcinoma, soft tissue carcinoma, somatostatin-secreting tumor, spinal cancer, squamous cell carcinoma, rhabdomyocarcinoma, submesothelial carcinoma, superficial spreading melanoma, T-cell leukemia, tongue cancer, undifferentiated carcinoma, ureteral cancer, urethral cancer, bladder cancer, urinary system cancer, cervical cancer, uterine cancer, uveal melanoma, vaginal cancer, warty carcinoma, VIPoma, vulvar cancer, differentiated carcinoma, or Wilms' tumor.

[0214] Combination with other additional anticancer drugs In certain embodiments, the methods described herein further comprise administering to the subject an additional anti-cancer agent. In certain embodiments, the additional anti-cancer agent is temozolomide, cisplatin, carboplatin, trastuzumab, or sunitinib. In yet other embodiments, the additional anti-cancer agent is temozolomide. In certain embodiments, for any given day that temozolomide is administered to the patient, temozolomide is administered at a dose of about 75 mg / m 2 ~about 150mg / m 2 is administered orally at a dosage of

[0215] Further exemplary additional anti-cancer agents include, for example, azacitidine, azathioprine, bleomycin, capecitabine, carmustine, chlorambucil, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, fulvestrant, gemcitabine, hydroxyurea, idarubicin, imatinib, lomustine, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, procarbazine, raloxifene, teniposide, thiotepa, thioguanine, tamoxifen, toremifene, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, and pharmaceutically acceptable salts thereof.

[0216] In yet other embodiments, the additional anticancer agent is abraxane, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, amethanthrone acetate, amrubicin, amsacrine, anastrozole, anthramycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan , cactinomycin, carusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, celecoxib, chlorambucil, cilormycin, cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, dexorumaplatin, desaguanine, desaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropizine, epirubicin hydrochloride, elbrozole, esorubicin hydrochloride, estramustine, estramustine sodium phosphate, etanidazole, etoposide, etoposide phosphate, etopurine, fadrozole hydrochloride, fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurosita Vin, foskidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, herceptin, hydroxyurea, idarubicin hydrochloride, ifosfamide, irmofosine, iproplatin, irinotecan, irinotecan hydrochloride, lanreotide acetate, lapatinib, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine, methotrexate,Methotrexate sodium, metoprine, meturedepa, mitindomide, mitocalcin, mitochromine, mitogillin, mitomarcine, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, periomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, promestane, porfimer sodium, porfiromycin (portiromycin), prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, ribopurin, romidepsin, safingol, safingol hydrochloride, semustine, simtrazene, sparphosate sodium, sparsomycin, spirogermanium hydrochloride , spiromustine, spiroplatin, stem cell therapy drug, streptonigrin, streptozocin, sulofenur, tallysomycin, tecogalan sodium, taxotere, tegafur, teroxantrone hydrochloride, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestrone acetate, triciribine phosphate, trimetrexa vintrexate, trimetrexate glucuronate, triptorelin, tuburozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglisinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrocidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, or zorubicin hydrochloride.

[0217] Characterization of anticancer effects When the compositions described herein are administered to a cancer patient to treat cancer, the therapy may be further characterized according to the anti-cancer effects of the treatment, such as (i) a reduction in the size of at least one tumor in the patient, and / or (ii) a reduction in the number of tumors in the patient.

[0218] Thus, in certain embodiments, the therapeutic methods described herein are characterized by a reduction in the size of at least one tumor in the patient by at least 20%. In certain other embodiments, the size of at least one tumor in the patient is reduced by at least 35%. In certain other embodiments, the size of at least one tumor in the patient is reduced by at least 50%. In certain other embodiments, the size of at least one tumor in the patient is reduced by at least 60%, 70%, 80% or 90%. In certain other embodiments, the size of at least one tumor in the patient is reduced by about 5%-50%, 10%-50%, 20%-50%, 5%-75%, 10%-75%, 20%-75%, or 50%-90%.

[0219] Where the cancer to be treated is brain metastasis, the method may be further characterized according to the reduction in the number and / or size of brain metastases. In certain embodiments, the number of brain metastases in the patient is reduced by at least 20%. In certain other embodiments, the number of brain metastases in the patient is reduced by at least 35%. In still other embodiments, the number of brain metastases in the patient is reduced by at least 50%. In certain other embodiments, the number of brain metastases in the patient is reduced by at least 60%, 70%, 80% or 90%. In certain other embodiments, the number of brain metastases in the patient is reduced by about 5%-50%, 10%-50%, 20%-50%, 5%-75%, 10%-75%, 20%-75%, or 50%-90%.

[0220] Patients to be treated Therapeutic methods can be further characterized according to the patient to be treated. In certain embodiments, the patient is an adult. In certain other embodiments, the patient is a child.

[0221] In certain embodiments, the patient does not suffer from anemia or is not hypovolemic, hi certain embodiments, the patient has at least 95% of their average daily blood volume.

[0222] Protect your organization It is contemplated that in certain circumstances, the compounds described herein can be used to protect normal tissues from toxicity that may occur when a subject is undergoing chemotherapy and / or radiation.The method includes subcutaneous administration of an effective amount of a non-shock-sensitive or non-blast-sensitive composition, pharmaceutical composition, or mixture containing a compound of formula I described herein to a subject in need thereof, said subcutaneous administration being performed before said subject is exposed to chemotherapy and / or radiation therapy.

[0223] In certain circumstances, the subject has cancer (e.g., head and neck cancer). It is also contemplated that at least about 0.5 mg (e.g., 0.5 mg to 4 mg) of a compound of formula I is administered to the subject, which administration (e.g., by injection) can be in a single dose or multiple divided dose injections.

[0224] Under certain circumstances, the toxicity to normal tissues to be prevented may be acute mucositis (eg, delayed mucositis) or dysphagia.

[0225] VI. Kits for use in medical applications The present invention also provides therapeutic kits comprising ABDNAZ (e.g., the crystalline forms of ABDNAZ disclosed herein) and / or pharmaceutical compositions thereof. The therapeutic kits may also contain other compounds (e.g., chemotherapeutic agents, natural products, apoptosis inducers, etc.) or pharmaceutical compositions thereof.

[0226] Therapeutic kits may have a single container containing ABDNAZ (e.g., crystalline forms of ABDNAZ disclosed herein) and / or pharmaceutical compositions thereof with or without other components (e.g., other compounds or pharmaceutical compositions of such other compounds), or may have separate containers for each component. In some embodiments, the therapeutic kits include ABDNAZ (e.g., crystalline forms of ABDNAZ disclosed herein) and / or pharmaceutical compositions thereof packaged for co-administration with a second compound (preferably a chemotherapeutic drug, natural product, apoptosis inducer, etc.) or pharmaceutical composition thereof. The components of the kit may be precomplexed, or each component may be in a separate, distinct container prior to administration to a patient.

[0227] The components of the kit may be provided in one or more liquid solutions, preferably aqueous solutions, more preferably sterile aqueous solutions. The components of the kit may also be provided as solids, which may be converted to a liquid by addition of a suitable solvent, which is preferably provided in a separate container.

[0228] The container of the therapeutic kit can be a vial, test tube, flask, bottle, syringe, or any other means of containing a solid or liquid.If there is more than one component, the kit usually contains a second vial or other container, which allows for separate administration.The kit can also contain another container for pharma-ceutically acceptable liquid.

[0229] Preferably, the therapeutic kit will contain a device that allows for administration of the components of the kit (eg, one or more needles, syringes, eyedroppers, pipettes, etc.).

[0230] Enumeration of embodiments The embodiments listed below are representative of some aspects of the present invention. 1. Compound of Formula I: [ka] or a pharma-ceutically acceptable salt thereof, wherein the solid crystalline, non-shock sensitive particles have an angle of repose of less than about 45 degrees.

[0231] 2. The composition of embodiment 1, wherein the composition comprises the compound in a solvated form.

[0232] 3. The composition of embodiment 2, wherein the composition comprises tetrahydrofuran (THF).

[0233] 4. The composition of any one of the preceding embodiments, wherein the composition comprises the particles in clathrate form.

[0234] 5. The composition of embodiment 4, wherein the particles comprise THF.

[0235] 6. The composition of any one of the preceding embodiments, wherein the composition further comprises n-heptane.

[0236] 7. The bulk density of the composition is 0.1 g / cm 3 ~0.6g / cm 3 The composition according to any one of embodiments 1 to 6, wherein the range is

[0237] 8. The bulk density is 0.15 g / cm 3 ~0.5g / cm 3 , 0.15g / cm 3 ~0.4g / cm 3 , or 0.16 g / cm 3 ~0.3mg / cm 3 The composition of any one of embodiments 1 to 7, wherein

[0238] 9. The composition of any one of the preceding embodiments, wherein the particles are dispersed in a dedusting agent.

[0239] 10. The composition of embodiment 9, wherein the dedusting agent is polyethylene glycol.

[0240] 11. A pharmaceutical composition comprising the composition according to any one of embodiments 1 to 10 and a pharma- ceutically acceptable carrier.

[0241] 12. The pharmaceutical composition according to embodiment 11, further comprising N,N-dimethylacetamide.

[0242] 13. The pharmaceutical composition according to embodiment 11 or 12, further comprising an anticoagulant.

[0243] 14. A mixture comprising a composition according to any one of embodiments 1 to 10 or a pharmaceutical composition according to any one of embodiments 11 to 13, and a blood sample.

[0244] 15. The mixture of embodiment 14, wherein the blood sample is collected from a subject who will be treated with the compound.

[0245] 16. The mixture of embodiment 15, wherein the concentration of the compound of formula I is from 0.1 mg / mL of blood to 10 mg / mL of blood.

[0246] 17. A method for producing a crystalline form of a compound of formula I, comprising the steps of: (a) dissolving a compound of formula I in tetrahydrofuran; (b) adding the solution of step (a) to n-heptane with stirring; and (c) cooling the solution produced by step (b), thereby producing a crystalline form of the composition of any one of embodiments 1-8; The method comprising:

[0247] 18. The method of embodiment 17, wherein the solution produced by step (a) is combined with the heptane in step (b) in a ratio of 1:5 (v / v).

[0248] 19. The method of embodiment 17 or 18, wherein during step (b), the addition is carried out for at least 30 minutes, 45 minutes, or 1 hour.

[0249] 20. A crystalline form of the compound of formula I produced by the method of any one of embodiments 17-19.

[0250] 21. The composition is subjected to a Series 3 Type (a) (ii) Test as set forth in the United Nations Manual of Tests and Criteria, seventh edition, 2019, with a 40 mm sample of the composition. 3 11. The composition of any one of the preceding embodiments, which is non-shock sensitive as determined by exposing the composition to an energy of 40 J.

[0251] 22. The non-shock sensitivity of the compound is measured by subjecting a 40 mm sample of the compound to a Series 3 Type(a)(ii) Test as set forth in the United Nations Manual of Tests and Criteria, seventh edition, 2019. 3 to 40 J of energy.

[0252] 23. A method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition according to any one of embodiments 1-10, a pharmaceutical composition according to any one of embodiments 11-13, or a mixture according to any one of embodiments 14-16, thereby treating said cancer in said subject.

[0253] 24. The method according to embodiment 23, wherein the composition according to any one of embodiments 1-10 or 21 or the pharmaceutical composition according to any one of embodiments 11-13 is combined with blood withdrawn from the subject to create a mixture, and then the mixture is administered to the subject.

[0254] 25. A method for the treatment or prevention of an ischemic or hypoxic condition in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition according to any one of embodiments 1-10 or 21, a pharmaceutical composition according to any one of embodiments 11-13, or a mixture according to any one of embodiments 14-16.

[0255] 26. The method of embodiment 25, wherein the ischemic condition is an acute ischemic condition or a chronic ischemic condition.

[0256] 27. The method of embodiment 26, wherein said acute ischemic condition is myocardial infarction, ischemic stroke, pulmonary embolism, perinatal hypoxia, circulatory shock, altitude sickness or acute respiratory failure.

[0257] 28. The method of embodiment 26, wherein the chronic ischemic condition is atherosclerosis, chronic venous insufficiency, chronic heart failure, cardiac cirrhosis, diabetes, macular degeneration, sleep apnea, Raynaud's disease, systemic sclerosis, nonbacterial thrombotic endocarditis, occlusive arterial disease, angina pectoris, transient ischemic attack, or chronic alcoholic liver disease.

[0258] 29. The method of embodiment 25, wherein the hypoxic condition is cancer, gastric or duodenal ulcer, liver or kidney disease, thrombocytopenia, blood clotting disorders, chronic disease, therapeutic interventions that result in anemia, such as cancer chemotherapy, or altitude sickness.

[0259] 30. The cancer is bladder cancer, breast cancer, clear cell renal cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, colorectal cancer, head and neck cancer, cervical cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma 30. The method of embodiment 29, wherein the primary lymphoma is selected from the group consisting of DLBCL, EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia cell-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL).

[0260] 31. The method according to any one of embodiments 23-30, wherein the pharmaceutical composition comprises at least 0.5 mg of a compound of formula I and is administered intravenously, intranasally, intraauricularly, intraperitoneally, subcutaneously, or orally.

[0261] 32. A method for protecting normal tissues from toxicity caused by chemotherapy and / or radiation therapy, comprising subcutaneously administering to a subject in need thereof an effective amount of a composition according to any one of embodiments 1-10 or 21, a pharmaceutical composition according to any one of embodiments 11-13, or a mixture according to any one of embodiments 14-16, before said subject is exposed to said chemotherapy and / or radiation therapy.

[0262] 33. The method of embodiment 32, wherein the subject has cancer.

[0263] 34. The method of embodiment 33, wherein the cancer is head and neck cancer.

[0264] 35. The method of any one of embodiments 32-34, wherein at least about 0.5 mg of the compound of formula I is administered to the subject.

[0265] 36. The method of embodiment 35, wherein about 0.5 mg to 4 mg of the compound of formula I is administered to the subject.

[0266] 37. The method according to embodiment 35 or 36, wherein said amount of the compound of formula I is administered in one or more divided injections.

[0267] 38. The method of any one of embodiments 32-37, wherein the toxicity to normal tissue is acute mucositis or dysphagia.

[0268] 39. The method of embodiment 38, wherein the mucositis is delayed mucositis. EXAMPLES

[0269] Having now broadly described the invention, the same will be more readily understood by reference to the following examples, which are provided merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0270] Example 1. Synthesis of a non-shock sensitive ABDNAZ crystalline form The crystalline form of ABDNAZ was prepared according to the following synthesis scheme. [ka]

[0271] In the final recrystallization step (converting stage 6 material to stage 7 material), ABDNAZ was dissolved in THF and the solution of ABDNAZ (relative volume 5) was added to rapidly stirred n-heptane (relative volume 25) over 1 h at room temperature. The resulting suspension was cooled to 5° C. and stirred for 1 h before being isolated by filtration.

[0272] The crystalline material, which was dried and then characterized, was analytically pure by LC-purity and assay.

[0273] Samples of the crystalline material were subjected to standard drop tests according to the Series 3 Type(a)(ii) Test procedure using a BAM Fallhammer as described in the United Nations Manual of Tests and Criteria, seventh edition, 2019. The tests were performed on 40 mm samples of the crystalline material produced by the aforementioned method. 3 The test was performed by placing the crystalline material in an impact device and subjecting it to an energy of 40 J. Tests were performed on six separate samples of the crystalline material under identical experimental conditions, with the operator determining whether an explosion occurred. No explosion occurred in any of the samples, and as a result, the crystalline material produced in this example was characterized as not explosive or impact sensitive. In other words, the material was non-impact sensitive.

[0274] Example 2. Biological activity of non-shock sensitive ABDNAZ crystal forms Samples 1 and 3 were prepared as shock sensitive ABDNAZ crystal forms. Samples 2 and 4 were prepared according to the synthesis scheme shown above in Example 1. Samples 2 and 4 were found to be non-shock sensitive.

[0275] Cancer cell lines HCT-116, SCC VII, and A549 were obtained from the American Type Culture Collection (ATCC, Rockville, MD, USA) and maintained according to the ATCC instructions. All culture reagents were obtained from Invitrogen (Carlsbad, CA, USA).

[0276] These cancer cell lines were split into 96-well dishes at 2,000 cells per well and treated with varying concentrations of sample 1, 2, 3, or 4. Cell proliferation was assessed 24 hours after treatment with sample 1, 2, 3, or 4 using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric assay. The absorbance of the formazan solution was measured spectrophotometrically at a wavelength of 570 nm. The measured optical density (OD) value was directly proportional to the number of viable cells. The experiment was repeated twice for each combination of cell line, sample, and sample concentration. The percentage of cell viability compared to the control is plotted in Figure 1A-C.

[0277] The results showed that the non-shock sensitive crystalline forms of ABDNAZ (samples 2 and 4) were more effective in suppressing the viability of cancer cell lines compared to the shock sensitive forms of ABDNAZ (samples 1 and 3).

[0278] Example 3. Solubility of non-shock sensitive ABDNAZ crystal forms Samples 5 and 6 were prepared according to the synthetic scheme shown above in Example 1. Samples 5 and 6 were found to be non-shock sensitive. Samples 7 and 8 were prepared as shock sensitive ABDNAZ crystal forms.

[0279] The solubility of these samples was measured by serially diluting each sample with DMSO. The assay was performed in a 96-well microplate. To each well, 100 μL of DMSO and a set amount of each sample were added. The initial amount of each sample was sufficient to saturate the DMSO, characterized by the precipitation of undissolved particles in each well. The samples were kept at 25°C during the test using an incubator shaker and agitated at 50 rpm for 4 hours.

[0280] Additional DMSO was added to each well to serially dilute the samples. After each DMSO addition, the samples were stirred at 50 rpm for 4 hours while the temperature was maintained at 25° C. The undissolved amount of each sample was then quantified based on absorbance at 250 nm compared to buffer using a UV-Vis spectrophotometer.

[0281] The resulting turbidity is plotted in Figure 2. Based on this plot, the solubility of each sample is determined, as summarized in Table 1 below. [Table 1]

[0282] Example 4. Statistical analysis of bulk density and particle size distribution of RRx-001 particles The differences between the THF-containing and non-THF-containing samples based on bulk density, D10, D50, and D90 measurements were statistically significant (non-parametric test (Wilcoxon) and Kolmogorov-Smirnov test).

[0283] Comparison of bulk density measurements and distributions Graphical depictions of the bulk density of the crystals reveal a clear separation between THF-containing and non-THF-containing samples, as well as between shock-sensitive and non-shock-sensitive samples: Figure 5A shows the bulk density of THF-free crystallized RRx-001 particles, Figure 5B shows the bulk density of THF-containing crystallized RRx-001 particles, Figure 5C shows the bulk density of non-shock-sensitive RRx-001 particles, and Figure 5D shows the bulk density of shock-sensitive RRx-001 particles.

[0284] Empirical probability functions for bulk density are shown in Figures 5E and 5F, and box plots are shown in Figures 5G and 5H. The visual separation is accompanied by a statistically significant finding based on a nonparametric Wilcoxon rank sum test with continuity correction to test the null hypothesis that the true bulk density position shift is zero (i.e., median equality) against the alternative that the true position shift is not zero. The Wilcoxon test confirmed a statistically significant difference between impact-sensitive and non-impact-sensitive particles (statistic W = 1.5, paired two-sided p-value = 0.0001) and between THF-containing and non-THF-containing particles (statistic W = 153, p-value = 0.0022). Kolmogorov-Smirnov (KS) tests comparing the distributions of bulk density also confirmed statistically significant differences between impact-sensitive and non-impact-sensitive particles (KS statistic W = 0.95, p = 0.0001) and between THF-containing and non-THF-containing particles (KS statistic W = 0.6166 and p = 0.0125).

[0285] Comparison of D10 measurement distributions Graphical depictions of the D10 measurements reveal a clear separation between THF-containing and non-THF-containing samples, as well as between shock-sensitive and non-shock-sensitive samples: Figure 6A shows the D10 of THF-free crystallized RRx-001 particles, Figure 6B shows the D10 of THF-containing crystallized RRx-001 particles, Figure 6C shows the D10 of non-shock-sensitive RRx-001 particles, and Figure 6D shows the D10 of shock-sensitive RRx-001 particles.

[0286] Empirical probability functions for D10 are shown in Figures 6E and 6F, and box plots are shown in Figures 6G and 6H. The visual separation is accompanied by a statistically significant finding based on a nonparametric Wilcoxon rank sum test with continuity correction to test the null hypothesis that the true D10 position shift is zero (i.e., median equality) against the alternative that the true position shift is not zero. The Wilcoxon test identified a statistically significant difference between impact-sensitive and non-impact-sensitive particles (statistic W = 21.5, paired two-sided p-value = 0.0200) and between THF-containing and non-THF-containing particles (statistic W = 153.5 and p-value = 0.0002). Kolmogorov-Smirnov (KS) tests comparing the distributions of D10 also confirmed statistically significant differences between impact-sensitive and non-impact-sensitive particles (KS statistic W = 0.5666, p = 0.1032) and between THF-containing and non-THF-containing particles (KS statistic W = 0.8666 and p = 0.0001).

[0287] Comparison of D50 measurement distributions Graphical depictions of the D50 measurements reveal a clear separation between THF-containing and non-THF-containing samples, as well as between shock-sensitive and non-shock-sensitive samples: Figure 7A shows the D50 of THF-free crystallized RRx-001 particles, Figure 7B shows the D50 of THF-containing crystallized RRx-001 particles, Figure 6C shows the D50 of non-shock-sensitive RRx-001 particles, and Figure 7D shows the D50 of shock-sensitive RRx-001 particles.

[0288] Empirical probability functions for D50 are shown in Figures 7E and 7F, and box plots are shown in Figures 7G and 7H. The visual separation was accompanied by a statistically significant finding based on a nonparametric Wilcoxon rank sum test with continuity correction to test the null hypothesis that the true D50 position shift is zero (i.e., median equality) against the alternative that the true position shift is not zero. The Wilcoxon test confirmed a statistically significant difference between impact-sensitive and non-impact-sensitive particles (statistic W=20.5, paired two-sided p-value=0.0173) and between THF-containing and non-THF-containing particles (statistic W=160 and p-value<0.0001). Kolmogorov-Smirnov (KS) tests comparing the distributions of D50 also confirmed statistically significant differences between impact-sensitive and non-impact-sensitive particles (KS statistic W = 0.6, p = 0.0720) and between THF-containing and non-THF-containing particles (KS statistic W = 0.8666 and p = 0.0001).

[0289] Comparison of D90 measurement distributions Graphical depictions of the D90 measurements reveal a clear separation between THF-containing and non-THF-containing samples, as well as between shock-sensitive and non-shock-sensitive samples: Figure 8A shows the D90 of THF-free crystallized RRx-001 particles, Figure 8B shows the D90 of THF-containing crystallized RRx-001 particles, Figure 8C shows the D90 of non-shock-sensitive RRx-001 particles, and Figure 8D shows the D90 of shock-sensitive RRx-001 particles.

[0290] Empirical probability functions for D90 are shown in Figures 8E and 8F, and box plots are shown in Figures 8G and 8H. The visual separation is accompanied by a statistically significant finding based on a nonparametric Wilcoxon rank sum test with continuity correction to test the null hypothesis that the true D90 position shift is zero (i.e., median equality) against the alternative that the true position shift is not zero. The Wilcoxon test confirmed a statistically significant difference between impact-sensitive and non-impact-sensitive particles (statistic W=25, paired two-sided p-value=0.0354) and between THF-containing and non-THF-containing particles (statistic W=153 and p-value=0.0002). Kolmogorov-Smirnov (KS) tests comparing the distributions of D90 also confirmed statistically significant differences between impact-sensitive and non-impact-sensitive particles (KS statistic W = 0.55, p = 0.1225) and between THF-containing and non-THF-containing particles (KS statistic W = 0.8666 and p = 0.0001).

[0291] Incorporation by Reference The entire disclosure of each patent document and each scientific article mentioned herein is incorporated by reference for all purposes.

[0292] Equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the foregoing embodiments should be considered in all respects as illustrative rather than limiting the invention described herein. Thus, the scope of the present invention is indicated not by the foregoing description but rather by the appended claims, and all changes that come within the meaning and range of equivalence of the claims are intended to be embraced within the scope of the present invention.

Claims

1. A composition comprising a solid crystalline non-shock-sensitive or non-explosive-sensitive particle comprising a compound of formula I: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof.

2. The composition according to claim 1, wherein the composition comprises the compound in a solvated form.

3. The composition according to claim 1, wherein the composition comprises tetrahydrofuran (THF).

4. The composition according to claim 3, wherein the concentration of THF in the composition is at least about 330 ppm.

5. The composition according to claim 1, wherein the particles are in a clathrate form.

6. The composition according to claim 1, wherein the particles comprise THF.

7. The composition according to claim 6, wherein the concentration of THF in the particles is at least about 330 ppm.

8. The composition according to claim 1, wherein the composition further comprises n-heptane.

9. The composition according to claim 8, wherein the concentration of n-heptane in the composition is at least about 800 ppm.

10. The composition according to claim 1, wherein the particles comprise n-heptane.

11. The composition according to claim 10, wherein the concentration of n-heptane in the particles is at least about 800 ppm.

12. The bulk density of the composition is in the range of 0.1 g / cm ３ to 0.6 g / cm ３ and the composition according to any one of claims 1 to 9.

13. The bulk density is in the range of 0.15 g / cm ３ to 0.5 g / cm ３ , 0.15 g / cm ３ ~0.4 g / cm ３ , or 0.16 g / cm ３ ~0.3 g / cm ３ , which is the composition according to claim 1.

14. The bulk density of the particles is less than about 0.45 g / cm ３ , which is the composition according to claim 1.

15. The Dv(10) of the particles is less than about 40 μm, which is the composition according to any one of claims 1 to 9.

16. The Dv(50) of the particles is less than about 200 μm, which is the composition according to any one of claims 1 to 9.

17. The Dv(90) of the particles is less than about 400 μm, which is the composition according to any one of claims 1 to 9.

18. The particles are substantially needle-shaped, which is the composition according to any one of claims 1 to 9.

19. The solubility of the composition is greater than about 20 mg / mL in DMSO at 25°C, which is the composition according to any one of claims 1 to 9.

20. The angle of repose of the particles is less than about 45 degrees, which is the composition according to any one of claims 1 to 9.

21. The survival rate of cancer cells treated with the composition is lower than the survival rate of cancer cells treated with a shock-sensitive or explosion-sensitive composition containing an equal amount of ABDNAZ, which is the composition according to any one of claims 1 to 9.

22. When measured 24 hours after each treatment, (i) the survival rate of HCT 116 cells treated with about 8 μM of ABDNAZ in the composition is at least about 50% lower than the survival rate of HCT 116 cells treated with about 8 μM of ABDNAZ in a shock-sensitive or explosion-sensitive composition, (ii) the survival rate of SCC VII cells treated with about 4 μM of ABDNAZ in the composition is at least about 25% lower than the survival rate of SCC VII cells treated with about 4 μM of ABDNAZ in a shock-sensitive or explosion-sensitive composition, or (iii) the survival rate of A549 cells treated with about 20 μM of ABDNAZ in the composition is at least about 25% lower than the survival rate of A549 cells treated with about 20 μM of ABDNAZ in a shock-sensitive or explosion-sensitive composition, the composition according to any one of claims 1 to 9.

23. When measured 24 hours after each treatment, (i) the survival rate of HCT 116 cells treated with about 10 μM of ABDNAZ in the composition is less than about 25% of the survival rate of untreated HCT 116 cells, (ii) the survival rate of SCC VII cells treated with about 4 μM of ABDNAZ in the composition is less than about 50% of the survival rate of untreated SCC VII cells, or (iii) the survival rate of A549 cells treated with about 20 μM of ABDNAZ in the composition is less than about 50% of the survival rate of untreated A549 cells, the composition according to any one of claims 1 to 9.

24. The particles are dispersed in a dust remover, the composition according to any one of claims 1 to 9.

25. The dust remover is polyethylene glycol, the composition according to claim 24.

26. A pharmaceutical composition comprising the composition according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier.

27. Further comprising N,N-dimethylacetamide, the pharmaceutical composition according to claim 26.

28. Further comprising an anticoagulant, the pharmaceutical composition according to claim 26.

29. A mixture comprising the composition according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 26 and a blood sample.

30. The mixture according to claim 29, wherein the blood sample is collected from a subject to be treated with the compound.

31. The mixture according to claim 30, wherein the concentration of the compound of formula I is 0.1 mg / blood mL to 10 mg / blood mL.

32. A method for producing a crystalline form of the compound of formula I, comprising the following steps: (a) dissolving the compound of formula I in tetrahydrofuran; (b) adding the solution of step (a) to n-heptane with stirring; and (c) cooling the solution produced by step (b) to thereby produce a crystalline form of the compound of formula I. A method comprising the above steps.

33. The method according to claim 32, wherein the THF solution produced in step (a) is combined with the n-heptane in a ratio of about 1:3 (v / v) to about 1:10 (v / v) in step (b).

34. The method according to claim 32 or 33, wherein the addition is carried out over a period of about 10 minutes to about 6 hours during step (b).

35. A crystalline form of the compound of formula I produced by the method according to claim 32 or 33.

36. The composition is tested using the Series 3 Type (a)(ii) Test as shown in the United Nations Manual of Tests and Criteria, seventh edition, 2019, for a 40 mm sample of the composition. ３The composition according to any one of claims 1 to 9, which is non-impact sensitive as determined by exposing it to 40 J of energy.

37. The crystalline form of the compound is non-impact sensitive as determined by exposing a 40 mm sample of the crystalline form of the compound to 40 J of energy using the Series 3 Type (a)(ii) Test as shown in the United Nations Manual of Tests and Criteria, seventh edition, 2019. ３ The crystalline form of the compound according to claim 35, which is non-impact sensitive as determined by exposing it to 40 J of energy.

38. A composition, pharmaceutical composition, or mixture for use in the method of treatment in a subject in need of treatment for cancer, wherein the method comprises treating the cancer in the subject by administering to the subject an effective amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

39. The composition, pharmaceutical composition, or mixture according to claim 38, wherein the composition according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 26 is combined with blood collected from the subject to create a mixture, and then the mixture is administered to the subject.

40. The composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 for use in the treatment or prevention of ischemia or hypoxia in a subject in need thereof.

41. The composition, pharmaceutical composition, or mixture according to claim 40, wherein the ischemic state is an acute ischemic state or a chronic ischemic state.

42. The acute ischemic state is myocardial infarction, ischemic stroke, pulmonary embolism, perinatal hypoxia, circulatory shock, altitude sickness, or acute respiratory failure, the composition, pharmaceutical composition, or mixture according to claim 41.

43. The chronic ischemic state is atherosclerosis, chronic venous insufficiency, chronic heart failure, cardiac cirrhosis, diabetes, macular degeneration, sleep apnea, Raynaud's disease, systemic sclerosis, non-bacterial thrombotic endocarditis, obstructive arterial disease, angina pectoris, transient cerebral ischemic attack, or chronic alcoholic liver disease, the composition, pharmaceutical composition, or mixture according to claim 41.

44. The hypoxic state is cancer, gastric ulcer or duodenal ulcer, liver disease or kidney disease, thrombocytopenia, blood coagulation disorder, chronic disease, a therapeutic intervention that causes anemia such as cancer chemotherapy, or altitude sickness, the composition, pharmaceutical composition, or mixture according to claim 40.

45. The cancer is bladder cancer, breast cancer, clear cell renal carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, colorectal cancer, head and neck cancer, cervical cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small cell lung cancer (SCLC), triple negative breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T cell / histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid leukemia cell-1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin lymphoma (NHL), or small lymphocyte lymphoma (SLL), the composition, pharmaceutical composition, or mixture according to claim 44.

46. The pharmaceutical composition contains at least 0.5 mg of the compound of formula I and is administered intravenously, intranasally, intratympanically, intraperitoneally, subcutaneously, or orally, the composition, pharmaceutical composition, or mixture according to claim 38.

47. A composition, pharmaceutical composition, or mixture for use in a method of protecting normal tissues from toxicity caused by chemotherapy and / or radiotherapy, the method comprising administering to a subject in need of such protection an effective amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 subcutaneously before the subject is exposed to the chemotherapy and / or radiotherapy, the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

48. The subject has cancer, the composition, pharmaceutical composition, or mixture according to claim 47.

49. The cancer is a head and neck cancer, the composition, pharmaceutical composition, or mixture according to claim 48.

50. At least about 0.5 mg of the compound of formula I is administered to the subject, the composition, pharmaceutical composition, or mixture according to claim 47.

51. About 0.5 mg to 4 mg of the compound of formula I is administered to the subject, the composition, pharmaceutical composition, or mixture according to claim 50.

52. The amount of the compound of formula I is administered in one or more divided injections, the composition, pharmaceutical composition, or mixture according to claim 50.

53. The toxicity to the normal tissue is acute mucositis or dysphagia, the composition, pharmaceutical composition, or mixture according to claim 47.

54. The mucositis is late-onset mucositis, the composition, pharmaceutical composition, or mixture according to claim 53.

55. A composition, pharmaceutical composition, or mixture for use in a method of treating a disorder selected from the group consisting of autoimmune deficiency, inflammatory disease, neurodegenerative disease, and neuromuscular disorder in a subject in need thereof, wherein the method comprises administering to the subject an amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 effective to improve the symptoms of the disorder, and then administering a maintenance dose of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 to maintain the improvement of the symptoms over a long period of time, the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

56. A composition, pharmaceutical composition, or mixture for use in a method of enhancing adaptability and tolerance in a subject in need of treatment for autoimmune deficiency, inflammatory disease, neurodegenerative disease, or neuromuscular disorder, wherein the method comprises administering a therapeutically effective amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29, and administration of the therapeutically effective amount does not cause hematological, neurological, pulmonary, metabolic, cardiovascular, dermatological, nephrological, gastrointestinal, urogenital, inflammatory, autoimmune, thyroid, and immunodeficiency-related side effects, and in the subject, treatment with RRx-001 or an analog thereof is completed at a cumulative dose of at least 1 mg or 1 mg / m ２ of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

57. A composition, pharmaceutical composition, or mixture for use in a method of preventing the induction, onset, or exacerbation of symptoms of a disorder selected from the group consisting of autoimmune deficiency, inflammatory diseases, neurodegenerative diseases, and neuromuscular disorders, in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 to prevent the induction, onset, or exacerbation of the symptoms of the disorder, the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

58. A composition, pharmaceutical composition, or mixture for use in a method of preventing the induction, onset, or exacerbation of symptoms of a disorder selected from the group consisting of autoimmune deficiency, inflammatory diseases, neurodegenerative diseases, and neuromuscular disorders, in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the composition according to claim 10 or 11, the pharmaceutical composition according to claim 27, or the mixture according to claim 30 to prevent the induction, onset, or exacerbation of the symptoms of the disorder, the composition according to claim 10 or 11, the pharmaceutical composition according to claim 27, or the mixture according to claim 30.

59. A composition, pharmaceutical composition, or mixture for use in a method of improving body movement in a mammal, wherein the method comprises administering to the mammal, prior to the body movement, an effective amount of the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29, the composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29.

60. The composition according to any one of claims 1 to 9, the pharmaceutical composition according to claim 26, or the mixture according to claim 29 for preventing or treating pulmonary hypertension (PH) in a patient.

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