Acid addition salts, compositions, and methods of treatment therewith

Abstract

Acid addition salts of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine and crystalline forms thereof are provided. Also provided are pharmaceutical compositions comprising the acid addition salts and crystalline forms thereof disclosed herein and a pharma- ceutically acceptable excipient, as well as methods of treating diseases or disorders, such as diseases or disorders associated with neuroinflammation, comprising administering to a subject in need thereof a therapeutically effective amount of the acid addition salts or pharmaceutical compositions of the acid addition salts disclosed herein.

Description

[Technical field]

[0001] This application claims priority to U.S. Non-provisional Patent Application No. 17 / 588,847, filed January 31, 2022, and No. 17 / 931,688, filed September 13, 2022, the disclosures of which are incorporated by reference herein as if set forth in their entireties. [Background technology]

[0002] Compound 1 (3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine) is an orally bioavailable, brain-penetrant mixed lineage kinase (MLK) inhibitor with IC 1000-fold increase in MLK1, MLK2, MLK3, and mitogen-activated protein kinase 12 (DLK). 50 are 19 nM, 42 nM, 14 nM, and 150 nM, respectively. Compound 1 also inhibited the activity (IC 50 11 nM) and tyrosine protein kinase ABL1 (IC 50 Compound 1 also inhibits autophagy in in vitro and in vivo models. Compound 1 inhibits lipopolysaccharide-induced tumor necrosis factor alpha (TNFα) release in microglial cells and HIV-1 Tat-induced cytokine release in human monocytes. [ka]

[0003] In vitro, Compound 1 further prevents the destruction and phagocytosis of cultured neuronal axons by microglial cells. Compound 1 reduces N-formylmethionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis of wild-type neutrophils in vitro. In mice, Compound 1 exhibits excellent pharmacokinetic properties and central nervous system (CNS) penetration suitable for BID or qD administration. Compound 1 (10 mg / kg i.p.) reduced inflammatory cytokine production, protected neuronal structures, and altered the morphological and ultrastructural response of microglia to HIV-1 Tat exposure in an in vivo mouse model of HIV-1-associated neurocognitive impairment. Compound 1 significantly reduces fMLP-induced neutrophil recruitment to the peritoneum in wild-type mice. Compound 1 has demonstrated neuroprotective properties in models of HIV-1-associated neurocognitive disorder (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), perioperative neurocognitive disorder (PND), delirium with dementia (DSD), neurotoxic effects of SARS-CoV-2 spike protein, and blood-brain barrier (BBB) ​​repair. Compound 1 has anti-inflammatory and anti-fibrotic properties and demonstrated protection against lipotoxic hepatocyte apoptosis in a mouse model of nonalcoholic steatohepatitis (NASH). Summary of the Invention [Problem to be solved by the invention]

[0004] However, Compound 1 is water insoluble and, when administered without excipients such as dimethylsulfoxide (DMSO), which are contraindicated in human formulations, only low plasma serum concentrations of Compound 1 are obtained. There is a significant unmet need for a means to administer Compound 1 to treat diseases or disorders, such as diseases or disorders associated with neuroinflammation. The present disclosure meets these and other needs, as will be apparent from reference to the disclosures below. [Means for solving the problem]

[0005] Acid addition salts of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine are provided. In some embodiments, the salts are selected from tartrates, phosphates, and fumarate salts. Also provided is a substantially crystalline tartrate salt of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine.

[0006] Also provided is a pharmaceutical composition comprising an acid addition salt disclosed herein and a pharma- ceutically acceptable excipient.

[0007] Also provided is a method of treating a disease or disorder, such as a disease or disorder associated with neuroinflammation, comprising administering to a subject in need thereof a therapeutically effective amount of an acid addition salt disclosed herein, or a pharmaceutical composition of an acid addition salt disclosed herein.

[0008] Also provided is a process for preparing the acid addition salts disclosed herein, comprising contacting 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine with an acid, such as an acid selected from tartaric acid, fumaric acid, and phosphoric acid, in a polar protic solvent to form the acid addition salt, and isolating the acid addition salt.

[0009] These and other aspects of the invention disclosed herein will be explained further as the patent disclosure proceeds. [Brief description of the drawings]

[0010] drawing [Figure 1] 1 shows the mean plasma concentrations (ng / mL) of Compound 1 free base, tartrate, and phosphate salts over time in mice. [Diagram 2] 1 shows an X-ray diffractogram obtained from an XRPD analysis of the tartrate salt of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0012] The articles "a," "an," "the," and "said" when introducing elements of the disclosure or in an embodiment are intended to mean that there are one or more elements. The terms "comprising," "including," and "having" are inclusive and mean that there may be additional elements other than the listed elements.

[0013] The term "and / or" when in the context of a list of two or more items means that any listed item can be used alone or in combination with one or more of the listed items. For example, the phrase "A and / or B" means either or both of A and B, i.e., A only, B only, or a combination of A and B. Similarly, the phrase "A, B, and / or C" means A only, B only, C only, A and B in combination, A and C in combination, B and C in combination, or A, B and C in combination.

[0014] The range of values ​​is disclosed and "n 1 From 2 "Up to" or "n 1 From 2 When the expression "between" is used (n 1 and 2is a numerical value), and unless otherwise specified, this notation is intended to include the numerical value itself and the range therebetween. The range may be an integer or may be continuous between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, comparing the range "1 to 3 μM (micromolar)", this is intended to include everything between 1 μM, 3 μM, and any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0015] The term "about" qualifies the numerical value that it modifies and expresses such value as a variable within a margin of error. When no margin of error is given, such as the standard deviation for the average value given in a chart or table of data, the term "about" means a range that includes the stated value and a range that is included by rounding up or down to that numerical value taking into account significant digits.

[0016] The term "acid addition salt" refers to a salt of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine with an inorganic or organic acid capable of forming a salt by an acid-base reaction, selected from tartrate and phosphate. Examples of inorganic acids used to form acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, hydroiodic acid, etc. Examples of organic acids include acetic acid, adipic acid, alginic acid, L-ascorbic acid, butyric acid, camphoric acid, formic acid, glutaric acid, glutamic acid, lactic acid, aspartic acid, malic acid, pamoic acid, hippuric acid, xinafoic acid, gluconic acid, benzoic acid, maleic acid, fumaric acid, citric acid, succinic acid, oxalic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-diaminetetraacetic ... Examples of suitable acids include sulfonic acid, (+)-camphor-10-sulfonic acid, digluconic acid, gentisic acid, glycerophosphoric acid, glycolic acid, heptanoic acid, hexanoic acid, 2-hydroxyethanesulfonic acid, malonic acid, DL-mandelic acid, mesitylenesulfonic acid, nicotinic acid, oxalic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyroglutamic acid, trichloroacetic acid, trifluoroacetic acid, and undecanoic acid.

[0017] The term "amorphous" refers to any solid material that (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, or order over only short distances (e.g., less than 10A), or both. Amorphous materials thus include partially crystalline materials and crystalline mesophases, for example with one or two dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals). Amorphous solids can be characterized by known techniques, such as X-ray powder diffraction (XRPD) crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, differential scanning calorimetry (DSC), or some combination of these techniques. As shown below, amorphous solids give diffuse XRPD patterns, typically consisting of one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or more).

[0018] The term "polymorphs" refers to different crystalline forms of the same compound, including, but not limited to, hydrates (e.g., water bound in the crystalline structure) and solvates (e.g., solvents bound other than water) of the same compound in the solid state molecular crystalline form.

[0019] The term "crystalline" refers to any solid material that exhibits three-dimensional order, giving a characteristic XRPD pattern with sharply defined peaks, in contrast to amorphous solid materials.

[0020] The term "substantially crystalline" refers to a compound and / or salt that is crystalline to at least a particular weight percentage. Particular weight percentages include 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, and 99.9%. In some embodiments, substantially crystalline refers to a tartrate salt that is at least 70% crystalline. In some embodiments, substantially crystalline refers to a tartrate salt that is at least 80% crystalline. In some embodiments, substantially crystalline refers to a tartrate salt that is at least 85% crystalline. In some embodiments, substantially crystalline refers to a tartrate salt that is at least 90% crystalline. In some embodiments, substantially crystalline refers to a tartrate salt that is at least 95% crystalline.

[0021] For example, the term "substantially as shown" when referring to an XRPD pattern includes a pattern that may not necessarily be identical to that shown herein, but is within the limits of experimental error or variation as considered by one of ordinary skill in the art. For example, one of ordinary skill in the art will understand that peak positions (2θ) will typically vary by as much as 0.1 to 0.2 degrees depending on the solvent used and the instrument used to measure the diffraction. Furthermore, one of ordinary skill in the art will understand that relative peak intensities will exhibit instrument-to-instrument variability as well as variability due to crystallinity, preferred orientation, sample surface preparation, and other factors known to those of ordinary skill in the art, and should be taken only as a qualitative measure.

[0022] Similarly, as used herein, "substantially as shown" when referring to, for example, solid state NMR and Raman spectra is intended to encompass the variations associated with these analytical techniques known to those of skill in the art. 13 The chemical shifts of C typically vary by up to 0.2 ppm for well-defined peaks and even more for broad lines, while the Raman shifts typically have variations of about 2 cm 1 (Raman spectra are typically measured in cm -1 ) is used.

[0023] The term "solvate" refers to a molecular complex containing a drug substance and one or more solvent molecules (e.g., ethanol) in a stoichiometric or non-stoichiometric ratio. If the solvent is tightly bound to the drug, the resulting complex has a well-defined stoichiometry that is independent of humidity. However, if the solvent is weakly bound, such as in channel solvates or hygroscopic compounds, the solvent content depends on humidity and drying conditions. In such cases, the complex is often non-stoichiometric.

[0024] The term "hydrate" refers to a solvate that contains a drug substance and a stoichiometric or non-stoichiometric amount of water.

[0025] The term "channel hydrate" refers to a hydrate structure that has open structural voids through which water molecules can fully or partially escape without significant change in the crystal structure.

[0026] The term "2 theta value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment, which is the common abscissa unit of a diffraction pattern. In the experimental setup, if the reflection is diffracted when the incident beam forms an angle theta (θ) with a particular lattice plane, the reflected beam should be recorded at an angle 2 theta (2θ). When a specific 2θ value for a particular polymorphic form is mentioned herein, it is intended to mean the 2θ value (in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, CuKa (wavelength 1.54056 A) was used as the radiation source.

[0027] The term "disease" as used herein is generally intended to be synonymous and is used interchangeably with the terms "disorder," "syndrome," and "condition" (in medical conditions), all of which reflect an abnormal condition of the human or animal body or one of its parts that impairs normal functioning, typically manifests itself as characteristic signs and symptoms, and reduces the lifespan or quality of life of the human or animal.

[0028] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule containing a fixed ratio of therapeutic agents, or in multiple separate capsules for each therapeutic agent. Additionally, such administration also includes administration of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0029] As used herein, "dose" refers to the amount of a compound administered to an individual at a particular time to treat or prevent a disease or disorder.

[0030] As used herein, "in need of treatment" and "in need of" when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., a doctor, nurse, clinical nurse, etc.) that an individual needs or will benefit from treatment. This judgment is made based on a variety of factors within the expertise of the caregiver, including knowledge that the individual is ill or will become ill as a result of a disease, condition, or disorder treatable by the salts described herein. Thus, the salts described herein can be used protectively or prophylactically, or the salts described herein can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0031] "Patient" is generally synonymous with "subject" and includes all mammals, including humans. Examples of patients include humans, as well as farm animals such as cows, goats, sheep, pigs, and rabbits, and pet animals such as dogs, cats, rabbits, and horses. In certain embodiments, the patient is a human.

[0032] The terms "prevent", "preventing", or "prevention" as used herein refer to the prevention of a particular disorder, or the prevention of the onset or development of one or more symptoms associated with a particular disorder, and do not necessarily refer to complete prevention of the disorder. For example, the terms "prevent", "preventing", and "prevention" refer to the administration of protective or prophylactic treatment to individuals who may eventually develop at least one symptom of a disease or condition, but have not yet done so. Such individuals may be identified based on risk factors known to correlate with subsequent disease development. Alternatively, prophylactic therapy may be administered as a protective measure without prior identification of risk factors. Delaying the onset of at least one symptom may also be considered a prevention or prophylactic method.

[0033] As used herein, a "therapeutically effective amount" of a therapeutic agent, composition, or combination is an amount that is non-toxic and effective to produce some desired therapeutic effect when administered to a subject or patient (e.g., a human subject or patient). The exact therapeutically effective amount for a subject may depend, for example, on the subject's size and health, the nature and extent of symptoms, the therapy or combination of therapies selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician. In some embodiments, the therapeutically effective amount is a standard dose.

[0034] The terms "treat", "treating" or "treatment" as used herein refer to administering therapy to an individual who is already experiencing at least one symptom of a disease or condition or who has previously experienced at least one symptom of a disease or condition. For example, "treatment" can include alleviating, reducing or ameliorating the symptoms of a disease or condition, preventing further symptoms, improving the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g., arresting the progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, reducing the condition caused by the disease or condition, or halting the symptoms of the disease or condition. For example, the term "treat" in reference to a disorder refers to reducing the severity of one or more symptoms associated with that particular disorder. Thus, treating a disorder does not necessarily mean reducing the severity of all symptoms associated with the disorder, nor does it necessarily mean completely reducing the severity of one or more symptoms associated with the disorder.

[0035] When an integer is used in the methods disclosed herein, the word "about" can be inserted before the integer.

[0036] Throughout this specification, unless the context requires otherwise, "comprise" or variations such as "comprises" or "comprising" are understood to imply the inclusion of a stated step or element or integer, or group of steps or elements or integers, but not to the exclusion of other steps or elements or integers, or group of elements or integers.

[0037] Throughout this specification, unless otherwise stated or the context specifically requires otherwise, references to a single step, composition of matter, group of steps, or group of compositions of matter shall be interpreted as encompassing one and more (i.e., one or more) of that step, composition of matter, group of steps, or group of compositions of matter.

[0038] Each embodiment described herein applies mutatis mutandis to every other embodiment unless stated otherwise.

[0039] Those skilled in the art will understand that the invention described herein may undergo variations and modifications other than those specifically described. It should be understood that the present invention includes all such variations and modifications. The present invention includes all steps, features, compositions, and compounds referred to or shown herein, individually or collectively, and any combination or any two or more of said steps or features, unless otherwise specified.

[0040] The present invention is not to be limited in scope by the specific embodiments described herein, which are for the purpose of illustration only, and functionally equivalent products, compositions, and methods are clearly within the scope of the invention described herein.

[0041] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0042] Acid addition salts Acid addition salts of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine are provided which are selected from tartrate, phosphate, and fumarate salts.

[0043] In certain embodiments, the acid addition salt is a tartrate salt. In certain embodiments, the tartrate salt is a (D)-(-) tartrate salt. In certain embodiments, the tartrate salt is a (L)-(+) tartrate salt. In certain embodiments, the tartrate salt is a mixture of (L)-(+) tartrate salt and (D)-(-) tartrate salt.

[0044] In certain embodiments, the acid addition salt is a phosphate salt.

[0045] In certain embodiments, the acid addition salt is a fumarate salt.

[0046] Also provided is a substantially crystalline tartrate salt of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine.

[0047] In certain embodiments, the tartrate salt is substantially in Form 1.

[0048] In certain embodiments, the tartrate salt is a mixture of (L)-(+) and (D)-(-) tartrate salts.

[0049] In certain embodiments, the tartrate salt is the (L)-(+) tartrate salt.

[0050] In certain embodiments, the tartrate salt is a (D)-(-) tartrate salt.

[0051] In certain embodiments, the tartrate salt has a molar ratio of tartaric acid to Compound 1 of about 1:1.

[0052] In certain embodiments, the tartrate salt is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 16.1±0.2, 17.6±0.2, 21.3±0.2, and 22.8±0.2 2θ units.

[0053] In certain embodiments, the tartrate salt is characterized by an XRPD pattern comprising three or more peaks selected from 4.7±0.2, 6.8±0.2, 8.5±0.2, 9.5±0.2, 11.3±0.2, 13.1±0.2, 18.9±0.2, 26.6±0.2, 28.3±0.2, 31.6±0.2, 35.2±0.2, 40.9±0.2, 45.0±0.2, and 48.8±0.2 units 2θ.

[0054] In certain embodiments, the Tartrate Salt is characterized by an XRPD pattern substantially as shown in FIG.

[0055] Also provided is a process for preparing the acid addition salt of claim 1, comprising contacting 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine with an acid selected from tartaric acid, fumaric acid, and phosphoric acid in a polar protic solvent to form the acid addition salt, and isolating the acid addition salt.

[0056] In certain embodiments, 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine and an acid are mixed in a ratio of 1:2 to 2:1 and then dissolved in a polar protic solvent. In certain embodiments, the ratio is 1:1.

[0057] Suitable polar protic solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. In certain embodiments, the polar protic solvent is methanol. In certain embodiments, the polar protic solvent is ethanol.

[0058] In certain embodiments, the polar protic solvent is heated, hi certain embodiments, methanol is heated.

[0059] In certain embodiments, the isolating step comprises adding ether until the solution of the contacting step becomes cloudy.

[0060] In certain embodiments, the isolating step comprises allowing the solution of the contacting step to stand until a solid precipitates out. In certain embodiments, the solid is filtered and washed with ether. In certain embodiments, the isolated addition salt is dissolved in hot ethanol, cooled, and precipitates out as a powder.

[0061] Pharmaceutical Compositions The salts of the present disclosure can be administered as raw chemicals, but can also be provided as pharmaceutical formulations. Accordingly, pharmaceutical compositions comprising an acid addition salt as described herein and a pharma- ceutical acceptable excipient are also provided.

[0062] In certain embodiments, the unit dosage formulation contains an effective dose, or an appropriate fraction thereof, of a therapeutic agent.

[0063] The salts described herein can be administered orally or by injection at a dose of 300 μg / kg to 25 mg / kg (free base equivalent) per day. The dosage range for adults is typically 0.02 g / day to 2 g / day (free base equivalent).

[0064] Appropriate formulations depend on the route of administration selected. Any well-known techniques, carriers, or excipients can be suitable and are understood in the art. The pharmaceutical compositions disclosed herein can be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, or compressing processes.

[0065] The salts described herein can be administered in various forms. The most suitable route of administration can depend, for example, on the condition and disorder of the recipient. The formulations can be conveniently provided in unit dosage form and can be prepared by any method well known in the art of pharmacy. In certain embodiments, the salts disclosed herein are administered orally.

[0066] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin ("gelcaps"), and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol ("softgels").

[0067] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can be optionally coated or scored and formulated to provide a slow or controlled release of the active ingredient therein.

[0068] The push-fit capsules can contain active ingredients mixed with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0069] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Additionally, stabilizers may be added.

[0070] In certain embodiments, the salt disclosed herein is orally administered as a suspension. When present, the suspension comprises undissolved particles of the salt disclosed herein mixed with a liquid vehicle such as water. In certain embodiments, the suspension comprises an equimolar amount of the tartrate salt of compound 1 compared to the free base of compound 1. In certain embodiments, the suspension comprises an equimolar amount of the phosphate salt of compound 1 compared to the free base of compound 1. In certain embodiments, the suspension may further comprise a complexing agent to stabilize the suspension during storage.

[0071] The exact amount administered to a patient is the responsibility of the attending physician. The specific dosage level for a patient depends on a variety of factors, such as the activity of the specific salt used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combination, the exact disorder being treated, and the severity of the indication or condition being treated. The route of administration may also vary depending on the condition and its severity.

[0072] In certain cases, it may be appropriate to administer at least one salt as described herein in combination with another therapeutic agent. The multiple therapeutic agents (at least one of which is a salt as disclosed herein) may be administered in any order, and may even be administered simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, integrated form, or in multiple forms (by way of example only, either as a single tablet or as two separate tablets). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. If not simultaneously, the timing of the multiple administrations may be any time period ranging from a few minutes to 4 weeks.

[0073] Treatment method Also provided is a method of treating a disease or disorder comprising administering to a subject in need of treatment a therapeutically effective amount of an acid addition salt disclosed herein, or a pharmaceutical composition of an acid addition salt disclosed herein.

[0074] In certain embodiments, the disease or disorder is a disease or disorder associated with neuroinflammation.

[0075] In certain embodiments, the disease or disorder associated with neuroinflammation is a neurodegenerative disorder, which is selected from Alzheimer's dementia, HIV-1 associated dementia, spongiform encephalopathy, Creutzfeldt-Jakob disease, stroke, trauma, multiple sclerosis, Parkinson's disease, including post-infectious parkinsonism, tauopathies, including progressive supranuclear palsy and frontotemporal dementia, HIV infection of the central nervous system, HIV-associated neurocognitive disorder (HAND), hereditary hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, and Down's syndrome.

[0076] The treatment method can also reduce or alleviate the symptoms of neurodegenerative disorders. These symptoms include, but are not limited to, memory loss, forgetfulness, lethargy, anxiety, agitation, loss of inhibitions, cognitive decline, deficits in cortical sensory modalities, reading and writing difficulties, and mood changes. Other symptoms of neurodegenerative disorders that affect bodily functions include, but are not limited to, partial or complete paralysis, muscle weakness, partial or complete loss of sensation, seizures, pain of unknown origin, and decreased attention.

[0077] In certain embodiments, the disease or disorder is drug-induced peripheral neuropathy, diabetic neuropathy, HIV-associated neuropathy, ototoxicity and hearing loss, and acute injuries to the inner ear including acoustic trauma, blast noise (e.g., as experienced by military personnel), exposure to ototoxic chemotherapeutic agents for the treatment of cancer (such as cisplatin), and treatment with aminoglycoside antibiotics.

[0078] In certain embodiments, the disease or disorder is a psychological disorder, including depression or major depressive disorder (MDD), bipolar disorder, and post-traumatic stress disorder.

[0079] In certain embodiments, the disease or disorder is selected from metabolic diseases such as type 1 and type 2 diabetes, hyperglycemia, diabetic complications (such as retinopathy, nephropathy, neuropathy, ulcers, microangiopathy, macroangiopathy, gout, and diabetic foot disease), insulin resistance, metabolic syndrome (syndrome X), hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, fatty liver, non-alcoholic steatohepatitis (NASH), chronic heart failure, atherosclerosis, peripheral inflammation and hepatitis (such as viral hepatitis), non-alcoholic fatty liver disease (NAFLD), and metabolically associated fatty liver disease (MAFLD).

[0080] In certain embodiments, the disease or disorder is selected from metabolic diseases such as type 1 and type 2 diabetes, hyperglycemia, diabetic complications (such as retinopathy, nephropathy, neuropathy, ulcers, microangiopathy, macroangiopathy, gout, and diabetic foot disease), insulin resistance, metabolic syndrome (syndrome X), hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, fatty liver, non-alcoholic steatohepatitis (NASH), chronic heart failure, atherosclerosis, peripheral inflammation and hepatitis (such as viral hepatitis), and metabolically associated fatty liver disease (MAFLD).

[0081] In certain embodiments, the disease or disorder is a proliferative disorder, such as liver cancer, pancreatic ductal adenocarcinoma, glioblastoma, or metastatic breast cancer.

[0082] In certain embodiments, the disease or disorder is an inflammatory disease such as bacterial sepsis, otitis media, endotoxemia, mucosal hyperplasia, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, and ulcerative colitis, and a respiratory disease or condition such as asthma, chronic obstructive pulmonary disease (COPD), and acute inhalation-induced pulmonary injury.

[0083] In certain embodiments, the disease or disorder is an autoimmune disease, such as multiple sclerosis, rheumatoid arthritis, lupus, and Crohn's disease.

[0084] In certain embodiments, the disease or disorder is ischemic injury, including traumatic brain injury such as cerebrovascular disease, stroke, subarachnoid hemorrhage, cerebral ischemia / reperfusion, myocardial infarction, and ischemic heart disease.

[0085] In certain embodiments, the disease or disorder is an ischemic injury, including traumatic brain injury such as stroke, subarachnoid hemorrhage, cerebral ischemia / reperfusion, myocardial infarction, and ischemic heart disease.

[0086] In certain embodiments, the disease or disorder is pain, including inflammatory pain, neuropathic pain, back pain (such as discogenic pain), arthritis and autoimmune disease (such as rheumatoid arthritis), and cancer pain, including pain due to bone metastases.

[0087] In certain embodiments, the method is for the treatment and / or prevention of cytokine storm, delirium, or delirium in dementia in patients infected with SARS-CoV-2, patients with COVID-19, patients with COVID-19 infection of the central nervous system, patients with long-term COVID with neurological sequelae, or patients with MAFLD with end-organ damage.

[0088] In certain embodiments, the method is for the treatment and / or prevention of cytokine storm, delirium, or delirium in dementia in patients infected with SARS-CoV-2, patients suffering from COVID-19, or patients with MAFLD with end-organ damage.

[0089] In some embodiments, the method is for the treatment and / or prevention of a peripheral disease or adverse event associated with another indication, such as NAFLD associated with AIDS chemotherapy, chimeric antigen receptor T cell (CAR-T cell)-associated encephalopathy syndrome (CRES), and cognitive impairment ("brain fog") associated with cancer or immunosuppressive chemotherapy. EXAMPLES

[0090] Working Example Example 1 - Screening and preparation of salts Compound 1 has limited solubility in typical aqueous and organic carriers. In order to improve solubility, attempts were made to prepare acid addition salts from suitable acidic carboxylic acids (e.g., fumaric, maleic, citric, tartaric), standard mineral acids (e.g., hydrobromic, sulfuric, phosphoric), and sulfonic acids (e.g., toluenesulfonic, methanesulfonic, ethanesulfonic, benzenesulfonic).

[0091] A dual solvent system containing methanol and ether was used by dissolving the salt in a small amount of methanol and then adjusting the solubility by adding ether until slightly turbid. The samples were then left in the reaction vessel as necessary until precipitation occurred. Ethanol and 95% ethanol were also explored for some salts, but the salts were generally insoluble in these latter solvents, even when sufficiently diluted.

[0092] phosphoric acid A solution of 1 molar equivalent of 48% aqueous phosphoric acid in methanol was added to the solution of compound 1 in methanol to obtain a homogeneous solution. The solvent was removed under reduced pressure and pumped dry to remove traces of water from the aqueous phosphoric acid solution. The residue was dissolved in a small amount of methanol (heated and cooled to room temperature) and ether was added. A solid precipitate formed almost immediately. The white powder salt had low solubility in methanol, less than other acid salts disclosed herein.

[0093] It dissolved when heated, but precipitated when the concentrated solution was cooled. The white powder was collected, washed with ether, and dried. 27 H 30 N 5 O 4 P. MW=520 g / mol. Calculated for mono salt: C, 62.42; H, 5.82; N, 13.48; O, 12.32; P, 5.96. Found: C, 61.95; H, 5.99; N, 13.22.

[0094] Fumaric acid Compound 1 and fumaric acid were mixed in a 1:1 molar ratio and dissolved in a small amount of methanol by heating. The mixture was cooled and ether was added until it became cloudy. The solution was allowed to stand to give a white powder, which was filtered and washed with ether. The solid can also be dissolved in hot ethanol and then cooled to precipitate a white powder. 31 H 33 N 5 O 6 - MW=572 g / mol. Calculated for mono salt: C, 65.14; H, 5.82; N, 12.25; O, 16.79. Found: C, 65.89, H 6.13, N 13.05.

[0095] tartaric acid Compound 1 and tartaric acid were mixed in a 1:1 molar ratio and dissolved in a small amount of methanol by heating. After cooling, ether was added until the mixture became cloudy. On standing, a solid precipitated. The precipitate was filtered and washed with ether. The filtered powder was poorly soluble in methanol, but was somewhat soluble on heating. The resulting crystalline material was analyzed using XRPD, yielding the spectrum shown in Figure 2.

[0096] The tartrate salt exhibited unusual behavior in water. When increasing amounts of water were added to the dry powder and heated, the sample went from a slurry to a homogeneous gel to a flowing solution. When cooled and examined during this process, the material progressed from a slurry to a clear viscous gel. Further addition of water followed by continued heating dissolved the gel and gave a flowing solution. When the sample was cooled, the solution remained homogeneous. If the gel was inverted, it would flow after one minute. The gel-like solution could also be transferred using a pipette. The sample was allowed to stand for 2-3 days with no change in appearance or behavior. The gel-like appearance could be diluted with water to give a homogeneous solution with flow, or the gel form could be heated to give a typical solution (although it would gel again on cooling). Optically pure D- and L-tartaric acids were used. Calculated values ​​for the mono salt: C, 67.47; H, 6.19; N, 12.29. Actual values: C, 65.89; H, 6.13; N, 13.05.

[0097] Maleic Acid The same procedure was used for maleic acid as for its isomer, fumaric acid. After storing in the refrigerator overnight, the solution precipitated, but the precipitate was somewhat viscous and did not filter well.

[0098] Citric acid Compound 1 and citric acid were mixed in a 1:1 molar ratio and treated with methanol / ether to obtain a viscous material without any solid precipitate.

[0099] sulfuric acid When a methanolic solution containing one equivalent of sulfuric acid was added to a methanolic solution of compound 1, a taffy-like paste-like material was immediately precipitated, even when repeated under much more dilute conditions. Attempts to dissolve this material, even with extensive dilution with methanol or heating, were unsuccessful.

[0100] Hydrobromic Acid To a solution of compound 1 in methanol was added one molar equivalent of hydrobromic acid (a solution of 33% hydrogen bromide in acetic acid was used). The homogeneous solution was repeatedly dried under reduced pressure and redissolved in methanol under continuous vacuum to remove residual acetic acid. The residue was then dissolved in methanol. Ether was added until it first became cloudy and then allowed to stand. A viscous solid was obtained. Repeating the process diluted the solution. Ethanol and 95% ethanol were also tried. The viscous solid was poorly soluble in methanol.

[0101] Organic sulfonic acid (TolSO 3 H, PhSO 3 H, MeSO 3 H, EtSO 3 H) Compound 1 and an organic sulfonic acid were weighed out in a 1:1 molar ratio and mixed. Each showed good solubility in methanol. However, in each case, when ether was added at the onset of turbidity, the salt precipitated as a thin film of viscous liquid on the walls and bottom of the vial. Refrigeration, scratching, and increasing dilution were unsuccessful in preparing the acid addition salt. The thin viscous liquid did not solidify or crystallize.

[0102] solubility The water and salt were mixed and heated with repeated vortexing and sonication to ensure that the salt solids remained saturated. The samples were left for 1 hour and then filtered through a syringe filter. Aliquots were removed by pipette and diluted 4-fold with methanol to prevent subsequent precipitation. The solutions remained homogenous. Each was injected using an autosampler that had been previously validated to give repeatable injection volumes, as determined by comparing the "total area" integrals at two UV wavelengths using an Agilent HPLC-MS.

[0103] When an excess of the free base was mixed with water without heating, the free base solid floated on the water. In contrast, the three acid addition salts sank to the bottom and were easily distinguishable from the free base powder.

[0104] The free base was poorly soluble in methanol, ethanol, or 95% ethanol at room temperature, but became soluble when heated or heavily diluted. Salts prepared from fumaric, tartaric, and phosphoric acids gave powdered solids that dissolved in methanol, ethanol, or 95% ethanol. The phosphate salt was the least soluble in methanol of the three salts tested. The fumarate and tartrate salts dissolved readily in hot methanol.

[0105] The following salts may be prepared using methods generally described above and are expected to have similar activity, when prepared, to those prepared in the Examples disclosed herein.

[0106] To a solution of compound 1 in methanol, add 1 molar equivalent of hydrochloric acid. The homogeneous solution is dried under reduced pressure. The residue is dissolved in a small amount of methanol (heated and then cooled to room temperature) and ether is added. A solid precipitates out of solution.

[0107] summary Pharmaceutically acceptable salts were prepared using tartaric, fumaric, and phosphoric acids. The tartrate salt dissolved kinetically the fastest. When heated with a small amount of water, the tartrate salt gave a homogeneous gelatinous material that became a mobile solution upon addition of more water.

[0108] The melting points and relative water solubility of the acid addition salts are given below.

[0109] [Table 1]

[0110] Example 2 - X-ray Powder Diffraction (XRPD) A sample of the tartrate salt prepared above was packed into a borosilicate capillary tube (1.0 mm outer diameter, 0.01 mm wall thickness) and then flame sealed. A second empty capillary tube was prepared in the same way to collect background. X-ray data were collected at room temperature (292.3 K) on a Rigaku XtaLAB Synergy-S diffraction system equipped with a HyPix-6000HE HPC detector and controlled by CrysalisPro, v42.59a. Cu Kα radiation (λ = 1.54184 Å, slits fully open, 9.0 mR) was generated by a PhotonJet-S microfocus source operated at 50 kV and 1 mA.

[0111] With a sample-to-detector distance of 34 mm, φ was rotated 720° in 300 s (2.4° / s), with ω = −52.16, θ = 0.00, and κ = 134.00°.

[0112] The background image was then subtracted from the sample image to obtain the data presented herein.

[0113] Example 3 - Studies in mice The pharmacokinetic behavior of the salts in vivo was measured when administered under conditions that mimicked the administration of Compound 1 as a typical solid tablet or pill. Aqueous suspensions of the free base, phosphate, and tartrate salts were administered to mice in equimolar amounts at mass ratios of 1.00, 1.36, and 1.23, taking into account the contribution of the acid component to the formulation weight. The free base and its phosphate and tartrate salts were administered at equivalent active drug concentrations. However, due to the additional contribution of phosphoric acid and tartaric acid to the formulation weight, these two salt forms were administered at slightly higher total weight concentrations so that the dose contained the same 10 mg / kg of free base drug.

[0114] To generate pharmacokinetic curves (AUC), blood was drawn at frequent intervals using microbleeds. Both salts showed a larger AUC, shorter T max , and a larger C max As shown by the above, the exposure was better.

[0115] The dose suspensions were analyzed prior to dosing in animals to ensure that the actual concentrations were known. The three samples were dosed at the same drug concentration as the free base, so the AUC values ​​were directly comparable. AUC last represents the AUC (area under the curve) or total amount of drug in circulating plasma over the 6 hour study time course and is a relevant parameter for calculating the oral bioavailability of an administered drug.

[0116] The mean plasma concentrations over the first 4 hours are shown in Table 3 and in the figure. The superior solubility and faster dissolution rate of the phosphate and tartrate salts compared to the free base, as seen by the Cmax, result in more rapid and complete absorption over the first 4 hours after dosing (Table 2). Examination of the Tmax indicates that the tartrate salt is absorbed most rapidly, followed by the phosphate and the free base. The Tmax for the free base and phosphate salts are max The T values ​​indicate that they take longer to reach peak concentrations in plasma than tartrate. maxwas reached most quickly, suggesting that although the phosphate was superior to the free base in key pharmacokinetic measures, the tartrate salt also dissolves faster than both the phosphate and the free base.

[0117] [Table 2]

[0118] Comparing standard deviations for similar ng / ml plasma concentrations, the free base is more variable than phosphate, but tartrate is not.

[0119] [Table 3]

[0120] All U.S. or foreign references, patents, or applications cited in this application are hereby incorporated by reference as if set forth herein in their entirety. In the event of a conflict, the present disclosure will control.

[0121] From the above description, those skilled in the art can easily ascertain the essential features of the present invention. Thereafter, various changes and modifications can be made to the present invention to adapt it to various applications and conditions without departing from the spirit and scope of the present invention.

Claims

1. Tartrate salt of 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine.

2. 2. The tartrate salt of claim 1, substantially in Form 1.

3. 2. The tartrate salt of claim 1, wherein the molar ratio of tartaric acid to 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine is about 1:

1.

4. 3. The tartrate salt of claim 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 16.1±0.2, 17.6±0.2, 21.3±0.2, and 22.8±0.2 2θ units.

5. 3. The tartrate salt of claim 2, characterized by an XRPD pattern comprising three or more peaks selected from 4.7±0.2, 6.8±0.2, 8.5±0.2, 9.5±0.2, 11.3±0.2, 13.1±0.2, 18.9±0.2, 26.6±0.2, 28.3±0.2, 31.6±0.2, 35.2±0.2, 40.9±0.2, 45.0±0.2, and 48.8±0.2 in units 2θ.

6. 6. The tartrate salt of claim 5, characterized by an XRPD pattern substantially as shown in Figure 2.

7. 10. A pharmaceutical composition comprising the tartrate salt of claim 1 and a pharmaceutically acceptable excipient.

8. A pharmaceutical composition for treating a neurodegenerative disease, comprising a therapeutically effective amount of the tartrate salt of claim 1.

9. 9. The pharmaceutical composition of claim 8, wherein the neurodegenerative disorder is selected from Alzheimer's disease, perioperative neurocognitive disorder (PND), delirium complicated with dementia (DSD), HIV-1 associated cognitive disorder, spongiform encephalopathy, Creutzfeldt-Jakob disease, stroke, trauma, multiple sclerosis, Parkinson's disease, tauopathies including progressive supranuclear palsy and frontotemporal dementia, HIV infection of the central nervous system, hereditary hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, and Down's syndrome.

10. contacting 3-(1H-indol-5-yl)-5-[4-[(4-methyl-1-piperazinyl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine with an acid in a polar protic solvent to form a tartrate salt; and isolating the tartrate salt.

2. A method for preparing the tartrate salt of claim 1, comprising:

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