(S)-1-((2apos; 2, 6-bis (difluoromethyl)-[2, 4apos; solid forms of-bipyridyl]-5-yl) oxy)-2, 4-dimethylpent-2-amine and salts thereof

Abstract

Disclosed herein are salts of the AAK1 inhibitor (S)-1-((2 ', 6-bis (difluoromethyl)-[2, 4'-bipyridyl]-5-yl) oxy)-2, 4-dimethylpent-2-amine and solid forms thereof, as well as pharmaceutical formulations comprising the same and methods of preparing the same.

Description

Technical Field

[0001] The present application relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine, solid forms of pharmaceutically acceptable salts thereof, compositions containing the same, and methods of use thereof. Background Art

[0002] Adaptor-associated kinase 1 (AAK1) is a member of the Ark1 / Prk1 family of serine / threonine kinases. AAK1 mRNA exists in two splice forms, referred to as the short splice form and the long splice form. The long form is predominant and is highly expressed in the brain and heart (Henderson and Conner, 2001). Mol. Biol. Cell. 2007, 18, 2698-2706). AAK1 is enriched in synaptosomal preparations and colocalizes with endocytic structures in cultured cells. AAK1 regulates clathrin-coated endocytosis, a process important in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 is associated with the AP2 complex, which links receptor cargo to the clathrin coat. Clathrin binding to AAK1 stimulates AAK1 kinase activity (Conner et al., Traffic 2003, 4, 885-890; Jackson et al., J. Cell. Biol. AAK1 phosphorylates the mu-2 subunit of AP-2, promoting the binding of mu-2 to the tyrosine-containing sorting motif on the cargo receptor (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Mu2 phosphorylation is not required for receptor uptake, but phosphorylation can enhance the efficiency of internalization (Motely et al., Mol. Biol. Cell. 2006, 17, 5298-5308).

[0003] AAK1 has been identified as an inhibitor of Neuregulin-1 / ErbB4 signaling in PC12 cells. Loss of AAK1 expression by RNA interference-mediated gene silencing or treatment with the kinase inhibitor K252a (which inhibits AAK1 kinase activity) results in enhanced Neuregulin-1-induced neurite outgrowth. These treatments result in increased ErbB4 expression and accumulation of ErbB4 in or near the plasma membrane (Kuai et al., Chemistry and Biology 2011, 18, 891-906). NRG1 and ErbB4 are putative schizophrenia susceptibility genes (Buonanno, Brain Res. Bull.2010, 83, 122-131). SNPs in these two genes are associated with multiple schizophrenia endophenotypes (Greenwood et al., Am. J. Psychiatry Neuregulin 1 and ErbB4 KO mouse models have shown schizophrenia-related morphological changes and behavioral phenotypes (Jaaro-Peled et al., Schizophrenia Bulletin 2010, 36,301-313; Wen et al., Proc. Natl. Acad. Sci. USA. 2010, 107, 1211-1216). In addition, single nucleotide polymorphisms in the introns of the AAK1 gene are associated with the age of onset of Parkinson's disease (Latourelle et al., BMC Med. Genet. 2009, 10, 98). These results suggest that inhibiting AAK1 activity may be useful in treating schizophrenia, cognitive deficits in schizophrenia, Parkinson's disease, neuropathic pain, bipolar disorder, and Alzheimer's disease.

[0004] Furthermore, studies using Huh-7.5 cells have demonstrated the potential use of AAK1 kinase inhibitors in the treatment of hepatitis C (HCV) infection. Reduction of AAK1 protein using RNA interference-mediated gene silencing, treatment with the kinase inhibitor sunitinib (a potent AAK1 inhibitor), and overexpression of a phosphorylation site mutant of Mu2 (an AAK1 substrate) all resulted in reduced HCV virion assembly. Furthermore, the same treatments were shown to inhibit HCV entry, suggesting that AAK1 inhibitors can disrupt two host-dependent stages of the viral life cycle (Neveu et al., 2011). PLoS Pathog. 2012, 8, 1-16; Neveu et al., J. Virol. Published online February 4, 2015). AAK1 inhibitors may also be useful against HIV and HBV (see, e.g., Boge et al., J. Biol. Chem. 1998, 273, 15773-15778).

[0005] Many AAK1 inhibitors have been disclosed in the literature. See, for example, Hartz, RA et al., J. Med. Chem., 2021 Aug 12;64(15):11090-11128. One example is the specific AAK1 inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine, which has been prepared on a small laboratory scale. See, e.g., U.S. Patent No. 9,902,722. Unfortunately, synthetic methods available in laboratory settings are rarely suitable for large-scale manufacture of pharmaceutically acceptable materials. For example, the production of potentially harmful reaction byproducts needs to be minimized, and the use of toxic solvents and reagents is preferably avoided. In addition, reaction conditions that are feasible on a gram scale are often inefficient or even dangerous when scaled up.

[0006] Similarly, solid forms (e.g., amorphous forms) of compounds sufficient for preclinical testing are not necessarily suitable for large-scale manufacturing and storage. Some forms may be more stable than others. For example, some forms may be more easily decomposed when exposed to heat or moisture; other forms may be converted into forms with pharmacological properties (e.g., bioavailability) different from the original form. Some may have solubility characteristics that lead to formulation difficulties; other forms may be more difficult to obtain without impurities that may affect their safety when administered to patients. Therefore, there is a need for a solid form of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine or a pharmaceutically acceptable salt thereof, which can be prepared in commercially useful quantities, is stable, and is easily formulated into a safe and effective dosage form. Summary of the invention

[0007] The present application relates to the solid form of the adaptor-associated kinase 1 (AAK1) inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J) and its salts.

[0008] One specific embodiment of the present invention encompasses a solid form of ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-ammonium dihydrogen phosphate (Compound K):

[0009] .

[0010] Other embodiments of the invention encompass methods of preparing Compound K and pharmaceutical compositions comprising the same. The invention also encompasses methods of using the same for treating or managing diseases and conditions, including pain (eg, neuropathic pain) and viral infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1A representative X-ray powder diffraction (XRPD) pattern of crystalline solid Form I of ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-ammonium dihydrogen phosphate (Compound K) is provided. The spectrum was obtained using a Bruker X-ray diffractometer with a LYNXEYE detector (copper Kα radiation).

[0012] Figure 2 A representative differential scanning calorimetry (DSC) thermogram of a crystalline solid form of Compound K is provided. The thermogram was obtained using a TA Instruments DSC Q2000 instrument and a sealed gold crucible filled under ambient conditions. Two scans were performed. After melting was complete in the first scan, the sample was rapidly cooled to -50°C at a rate of approximately -40 K / min, and then a second scan was recorded. In both scans, the heating rate was 10 K / min.

[0013] Figure 3 A flow chart of a process for preparing a tablet containing 50 mg of Compound K is provided. DETAILED DESCRIPTION

[0014] The present invention relates to (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J):

[0015]

[0016] and pharmaceutically acceptable salts thereof. Specific salts include hydrochlorides and phosphates.

[0017] 5.1 definition

[0018] Unless otherwise indicated, the phrases "compound of the invention," "compounds disclosed herein," and the like refer to compounds disclosed herein.

[0019] Unless otherwise indicated, the term "include" has the same meaning as "include, but are not limited to", and the term "includes" has the same meaning as "includes but is not limited to". Similarly, the term "for example" has the same meaning as the term "such as but not limited to".

[0020] Unless otherwise indicated, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or condition in a patient already suffering from the disease or condition, and / or prolonging the time a patient already suffering from the disease or condition is in remission. These terms encompass modulating the threshold, development, and / or duration of a disease or condition, or changing the way a patient responds to a disease or condition.

[0021] Unless otherwise indicated, a "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or sufficient to delay or minimize one or more symptoms associated with a disease or disorder. A "therapeutically effective amount" of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment or management of a disease or disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0022] Unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions taken in a patient suffering from a particular disease or condition that may lessen the severity of the disease or condition, or delay or slow the progression of the disease or condition.

[0023] Unless otherwise indicated, one or more adjectives immediately preceding a series of nouns should be interpreted as applicable to each noun. For example, the phrase "optionally substituted alkyl, aryl or heteroaryl" has the same meaning as "optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl".

[0024] 5.2 Salt and solid forms

[0025] The present invention is the result of extensive research and experimentation aimed at discovering a thermodynamically and chemically stable pharmaceutically acceptable salt of the AAK1 inhibitor (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J):

[0026]

[0027] Can it be manufactured on a large commercial scale with high purity. The study further aimed to find out whether any thermally stable crystalline solid form of these salts can be reproducibly prepared under such conditions and whether they have physical (e.g., flowability, solubility) properties suitable for use in the manufacture of pharmaceutical dosage forms.

[0028] First, a crystalline form of the free base of Compound J was prepared and studied. However, neither this nor any other solid form of the free base was found to exhibit sufficient stability and solubility properties for incorporation into a pharmaceutical dosage form.

[0029] Laboratory-scale reaction conditions were then developed to allow the formation and isolation of salts prepared by reacting the free base Compound J with 1.05–1.20 equivalents of various acids. While the specific conditions required to produce each salt (e.g., solvent, reaction temperature, cooling cycle, filtration) differed, 12 potentially useful crystalline salts were identified: hydrochloride, hydrobromide, methanesulfonate, citrate, fumarate, malate, phosphate, sulfate, L-tartrate, ethane-1,2-disulfonate, (+)-(1S)-camphorsulfonate, and R-(-)-mandelate. Any crystalline material obtained was characterized by XRPD, DSC, and TGA. The stoichiometric ratios were determined by HPCL. Of these, six possible leading candidates were identified:

[0030] Table 1

[0031]

[0032] Extensive further characterization coupled with the development of large-scale manufacturing, isolation and purification methods led to the discovery that of all the salts tested, ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridinyl]-5-yl)oxy)-2,4-dimethylpentan-2-ammonium dihydrogen phosphate (Compound K) was the most desirable:

[0033]

[0034] Further studies led to the selection of a specific crystalline form of this salt for large-scale manufacturing of dosage forms. This crystalline form is referred to herein as Form I and its XRPD spectrum is consistent with Figure 1 The spectra shown in are substantially the same, with diffraction peaks at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2θ. When used herein to refer to XPRD peaks, the term "about" means ± 0.2 degrees 2θ.

[0035] The melting point of the crystalline form I of compound K is about 184°C (see Figure 2 ), as determined by differential scanning calorimetry (DSC) (melting endotherm). When referring to temperature, the terms "substantially" and "about" mean ± 2°C.

[0036] Crystalline Form I of Compound K is the most stable form of this salt found: after storage for up to four weeks at 40°C and 75% relative humidity, the form itself, morphology and purity did not change. In addition, although the melting point of Form I is lower than that of the hydrochloride salt of Compound J (which is a form of it with a melting point of about 247°C), the phosphate salt does not show signs of concomitant degradation. Instead, Form I was observed to melt and recrystallize into another metastable form with a melting point of about 172.5°C. The aqueous solubility of Form I (26.8 mg / mL at 25°C) further facilitates its large-scale manufacturing and purification. In comparison, the aqueous solubility of the hydrochloride salt of Compound J was measured at 25°C at 2.9 mg / mL.

[0037] Despite its poor solubility, a crystalline form of the hydrochloride salt of Compound J was prepared. Its melting point (decomposition) was found to be about 247° C. The XRPD spectrum of the form exhibited peaks at about 9.2, 11.7, 13.9, 18.7, 22.2, 25.0 and 26.8 degrees 2θ.

[0038] Crystalline Form I of Compound K can be prepared from the free base (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J), which itself can be prepared by methods known in the art. See, for example, U.S. Pat. No. 9,902,722.

[0039] In broad terms, compound K can be prepared as follows:

[0040]

[0041] In this method, compound K is prepared by contacting compound J with phosphoric acid in a solvent under conditions sufficient to form compound K. Examples of solvents include water, methanol, ethanol, n-butanol, isobutanol, tert-butanol, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, THF and 2-methyl THF, and mixtures thereof. A specific solvent is isopropanol.

[0042] In some embodiments of the present invention, compound J is contacted with phosphoric acid at a temperature of about 0°C to about 100°C or about 50°C to about 60°C. (When referring to reaction conditions, the term "about" can be interpreted as ±10°C when used to refer to temperature, unless otherwise stated.) In some embodiments, compound J is contacted with phosphoric acid for about 0.5 hours to about 24 hours or about 2 hours to about 16 hours. (When referring to reaction conditions, the term "about" can be interpreted as ±5% when referring to time, unless otherwise stated. For example, "about 2 hours" is the same as 2 hours ±6 minutes.) In some embodiments, about 0.8 to about 1.2 molar equivalents (e.g., about 1 molar equivalent) of phosphoric acid is used relative to compound J. (Unless otherwise stated, when referring to molar equivalents or concentrations, the term "about" can be interpreted as ±5%.) In some embodiments, the concentration of compound J in the solvent is about 2% to about 25%.

[0043] In another method, compound K is prepared from compound S as follows:

[0044]

[0045] Here, compound S is neutralized with a base under conditions sufficient to form compound J, and compound J is contacted with phosphoric acid under conditions sufficient to form compound K. Suitable bases for neutralization include NaOH, KOH, Na2CO3, and K2CO3. The preferred base is sodium hydroxide.

[0046] The neutralization of compound S with a base can be carried out in a solvent such as water, water / MTBE, water / THF and water / 2-MeTHF (preferably the solvent is water / MTBE) at a temperature of about 0°C to about 60°C (e.g., about 20°C to about 40°C). In some embodiments of the present invention, neutralization is carried out for about 0.5 hours to about 24 hours (e.g., about 1 hour to about 2 hours). In some embodiments, about 0.8 to about 5 molar equivalents of base are used relative to compound S. In some embodiments, the concentration of compound S in the solvent is about 2% to about 25%.

[0047] The exposure of compound J to phosphoric acid in the second step shown above is usually carried out in a solvent such as water, methanol, ethanol, n-butanol, isopropanol, isobutanol, tert-butanol, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, THF and 2-methyl THF, or a mixture thereof. The preferred solvent is isopropanol.

[0048] In some embodiments, the exposure of Compound J to phosphoric acid is carried out at a temperature of about 0°C to about 100°C (e.g., about 50°C to about 60°C). In some embodiments, the exposure of Compound J to phosphoric acid is carried out for about 0.5 hours to about 24 hours (e.g., about 7 hours to about 14 hours). In some embodiments, in step 2, about 0.8 to about 1.2 molar equivalents of phosphoric acid are used relative to Compound J. In some embodiments, the concentration of Compound J in the solvent is about 2% to about 25%.

[0049] Compound S can be prepared as follows:

[0050]

[0051] In one embodiment, Compound S is prepared by exposing Compound J to hydrochloric acid in a solvent under conditions sufficient to form Compound S. In some embodiments, the solvent is water, IPA, a water / IPA mixture, MeOH, MeOH / water, EtOH, EtOH / water, n-BuOH, or n-BuOH / water. The preferred solvent is isopropanol.

[0052] Exposing Compound J to hydrochloric acid is carried out at a temperature of about 0°C to about 60°C (e.g., about 50°C to about 60°C) for about 0.5 hours to about 24 hours (e.g., about 4 hours to about 8 hours). Generally, about 0.8 to about 1.2 molar equivalents of hydrochloric acid are used relative to Compound J. In some embodiments, the concentration of Compound J in the solvent is about 2% to about 25%.

[0053] 5.3 How to use

[0054] One embodiment of the present invention encompasses methods of inhibiting adaptor associated kinase 1 (AAK1) in vitro and in vivo comprising contacting AAK1 with a compound of the present invention.

[0055] Another embodiment encompasses methods for treating and controlling diseases and conditions mediated by AAK1 activity. Diseases and conditions mediated by AAK1 activity are diseases and conditions having at least one symptom, severity or manifestation affected by AAK1 activity. Examples of such diseases and conditions are believed to include Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, schizophrenia (including cognitive deficits in schizophrenia) and viral infections. Specific methods include administering a therapeutically or prophylactically effective amount of an AAK1 inhibitor (e.g., a compound disclosed herein) to a patient (human or other mammal) in need thereof.

[0056] Another embodiment of the present invention encompasses a method of treating or controlling a disease or condition comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of an AAK1 inhibitor, wherein the disease or condition is Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, schizophrenia (including cognitive deficits in schizophrenia) or a viral infection. Specific types of pain include chronic pain, acute pain, and neuropathic pain. Specific types of neuropathic pain include fibromyalgia and peripheral neuropathy (e.g., diabetic neuropathy).

[0057] The present invention relates in part to methods of combating (e.g., treating) coronavirus infections. Coronaviruses are a group of related viruses that cause disease in mammals and birds. Coronaviruses can cause respiratory infections in humans ranging from mild to fatal. Mild illnesses include some cases of the common cold (with other possible causes, primarily rhinoviruses), while more deadly variants can cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19).

[0058] Specific embodiments of the present invention include treating patients infected with SARS-CoV2, HCoV NL63, MERS-CoV, CoV-229E, CoV-HKU1, or a virus with at least 95% sequence homology to SARS-CoV2, HCoV NL63, MERS-CoV, CoV-229E, or CoV-HKU1. See, for example, International Application No. PCT / US21 / 27946 filed on April 19, 2021.

[0059] When used to treat or manage a disease or condition, the compounds of the present invention are preferably administered as part of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, diluents or excipients.

[0060] Pharmaceutical compositions or preparations can exist in unit dosage forms containing a predetermined amount of active ingredient per unit dosage. The dosage levels of about 0.01 to about 250 mg / kg ("mg / kg") body weight / day, preferably about 0.05 to about 100 mg / kg body weight / day of the disclosed compound are typical in monotherapy, typical dosage levels for preventing and treating diseases. Typically, the disclosed pharmaceutical composition will be administered about 1 to about 5 times a day, or alternatively, administered as a continuous infusion. Such administration can be used as a chronic therapy or acute therapy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary according to the illness being treated, the severity of the illness, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and the age, sex, weight and condition of the patient. A preferred unit dosage formulation is a formulation containing a daily dose or subdose as described herein above, or an appropriate portion of the active ingredient thereof. Treatment can start with a small dose far below the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the best effect is achieved under the environment. In general, it is desirable to administer the compound at a concentration level that will generally provide effective results without causing any harmful or adverse side effects.

[0061] The compounds of the invention may be administered in combination with one or more additional therapeutic or prophylactic agents. For example, when used to treat pain, possible additional drugs include immunosuppressants and anti-inflammatory agents.

[0062] Immunosuppressants suitable for use in the methods and compositions of the present invention include those known in the art. Examples include aminopterin, azathioprine, cyclosporin A, D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate, minocycline, rapamycin, sulfasalazine, tacrolimus (FK506) and pharmaceutically acceptable salts thereof. A specific immunosuppressant is methotrexate.

[0063] Other examples include anti-TNF antibodies such as adalimumab, certolizumab pegol, etanercept, and infliximab. Others include interleukin-1 blockers such as anakinra. Others include anti-B cell (CD20) antibodies such as rituximab. Other drugs include T cell activation blockers such as abatacept.

[0064] Other examples include inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil (CellCept®) and mycophenolic acid (Myfortic®).

[0065] Anti-inflammatory drugs suitable for use in the methods and compositions of the invention include those known in the art. Examples include glucocorticoids and NSAIDs.

[0066] Examples of glucocorticoids include aldosterone, beclomethasone, betamethasone, cortisone, deoxycorticosterone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, and pharmaceutically acceptable salts thereof.

[0067] Examples of NSAIDs include salicylates (e.g., aspirin, amoxicillin, benolate, choline magnesium salicylate, diflunisal, faislamine, methyl salicylate, magnesium salicylate, salsalate, and pharmaceutically acceptable salts thereof), arylalkanoic acids (e.g., diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indomethacin, nabumetone, sulindac, tolmetin, and pharmaceutically acceptable salts thereof), arylpropionic acids (e.g., ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid, and pharmaceutically acceptable salts thereof), acid), suprofen and pharmaceutically acceptable salts thereof), aryl anthranilic acids (e.g., meclofenamic acid, mefenamic acid and pharmaceutically acceptable salts thereof), pyrazolidine derivatives (e.g., azapropazone, metamizole, oxyphenbutazone, phenylbutazone, sulfinpyrazone and pharmaceutically acceptable salts thereof), oxicams (e.g., lornoxicam, meloxicam, piroxicam, tenoxicam and pharmaceutically acceptable salts thereof), COX-2 inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib and pharmaceutically acceptable salts thereof) and sulfonanilides (e.g., nimesulide and pharmaceutically acceptable salts thereof).

[0068] Other agents used to treat pain, including but not limited to neuropathic pain and inflammatory pain, include agents such as pregabalin, lidocaine, duloxetine, gabapentin, carbamazepine, capsaicin and other serotonin / norepinephrine / dopamine reuptake inhibitors, and opioids such as oxycontin, morphine, and codeine.

[0069] In the treatment of pain caused by a known disease or condition, such as diabetes, infection (e.g., herpes zoster or HIV infection), or cancer, the compounds of the invention may be administered in combination with one or more additional therapeutic or preventive agents for the underlying disease or condition. For example, when used to treat diabetic neuropathy, the compounds of the invention may be administered in combination with one or more antidiabetic agents, antihyperglycemic agents, hypolipidemic / lipid-lowering agents, antiobesity agents, antihypertensive agents, and appetite suppressants. Examples of antidiabetic agents include biguanides (e.g., metformin, phenformin), glucosidase inhibitors (e.g., acarbose, miglitol), insulin (including insulin secretagogues and insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide, and glipizide), biguanide / glyburide combinations (e.g., Glucovance), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), PPAR-α agonists, PPAR-γ agonists, PPAR α / γ dual agonists, glycogen phosphorylase inhibitors, fatty acid binding protein (aP2) inhibitors, glucagon-like peptide-1 (GLP-1) or other GLP-1 receptor agonists, dipeptidyl peptidase IV (DPP4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, canagliflozin, and LX-4211).

[0070] 5.4 Pharmaceutical composition

[0071] The pharmaceutical preparation may be suitable for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or intradermal injection or infusion). Such preparations may be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier or excipient. Preferably, it is administered orally or by injection.

[0072] Pharmaceutical formulations suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.

[0073] For example, for oral administration in tablet or capsule form, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). Powders are prepared by pulverizing the compound to a suitable fineness and mixing with a similarly pulverized pharmaceutical carrier (such as an edible carbohydrate, such as starch or mannitol). Flavoring agents, preservatives, dispersants and coloring agents may also be present.

[0074] Capsules are made by preparing a powder mixture as described above and filling the formed gelatin sheath. Before the filling operation, glidants and lubricants (such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol) can be added to the powder mixture. Disintegrants or solubilizers such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the drug when the capsule is ingested.

[0075] In addition, when needed or necessary, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, etc. The lubricants used in these dosage forms include sodium oleate, sodium chloride, etc. Disintegrants include but are not limited to starch, methyl cellulose, agar, bentonite, xanthan gum, etc. Tablets are prepared, for example, by preparing a powder mixture, granulating or tableting, adding lubricants and disintegrants and pressing into tablets. By mixing the appropriate crushed compound with a diluent or alkali as described above, and optionally mixing with a binder (such as carboxymethyl cellulose, alginate, gelling agent or polyvinyl pyrrolidone), a solution retardant (such as paraffin), an absorption accelerator (such as a quaternary salt) and / or an absorbent (such as bentonite, kaolin or dicalcium phosphate) to prepare a powder mixture. The powder mixture can be granulated by wetting with a binder (such as syrup, starch paste, Acadia mucus or cellulose or polymer material solution) and extruding through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press, and the result is an imperfectly formed fragment of the granules. The granules can be lubricated by adding stearic acid, stearate, talcum or mineral oil to prevent adhesion to the tablet forming die. The lubricated mixture is then pressed into tablets. The compounds of the present disclosure can also be combined with a free-flowing inert carrier and directly pressed into tablets without granulation or tableting steps. A transparent or opaque protective coating can be provided, which is composed of a sealing coating of shellac, a coating of sugar or polymer material and a polishing coating of wax. Dyes can be added to these coatings to distinguish different unit doses.

[0076] Oral liquids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs are prepared by using a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.

[0077] If appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax, etc.

[0078] The compounds of formula (I) and pharmaceutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

[0079] Formula (I) compound and pharmaceutically acceptable salt thereof can also be delivered as a single carrier by using a monoclonal antibody coupled to the compound molecule. These compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl asparagine phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compound can be coupled with a class of biodegradable polymers that can be used to realize controlled release of drugs, such as crosslinking or amphiphilic block copolymers of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

[0080] Pharmaceutical formulations suitable for transdermal administration may be presented as discrete patches to maintain close contact with the epidermis of the recipient for a long period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986, 3(6), 318.

[0081] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0082] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

[0083] Pharmaceutical formulations suitable for nasal administration wherein the carrier is a solid include coarse powders having a particle size, for example, in the range of about 20 microns to about 500 microns, which are administered by snorting, i.e., by rapid inhalation through the nasal passages from a container of the powder held near the nose. Suitable formulations wherein the carrier is a liquid for administration as a nasal spray or nose drops include aqueous or oily solutions of the active ingredient.

[0084] Pharmaceutical formulations suitable for administration by inhalation include fine particle dusts or mists which can be generated by various types of metered, dosed pressurized aerosols, nebulizers or insufflators.

[0085] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0086] Pharmaceutical preparations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The preparations may be present in unit dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under freeze-dried (lyophilized) conditions, requiring only the immediate addition of a sterile liquid carrier, such as water for injection, before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0087] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0088] Preferred formulations contain high purity active pharmaceutical ingredients (API). To this end, potential impurities including those shown in Table 2 below were synthesized and 1 The products were characterized by H NMR and mass spectrometry.

[0089] Table 2

[0090]

[0091] The compounds in Table 2 were observed at various stages of bench-scale development work leading to the process of the present invention.

[0092] The present invention includes a method of testing the purity of Compound J or a pharmaceutically acceptable salt thereof by testing for the presence of one or more compounds listed in Table 1. Preferred methods include testing for the presence of one or more compounds using mass spectrometry and / or HPLC.

[0093] 5.5 Example

[0094] Various embodiments of the present invention may be understood by considering the examples provided below. In these examples, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight unless otherwise stated. Reagents may be purchased from commercial suppliers and used without further purification unless otherwise stated. (Reagents may also be prepared according to standard literature procedures known to those skilled in the art.)

[0095] Unless otherwise stated, reactions were performed at ambient temperature (or room temperature). Reactions were typically monitored by HPLC and terminated as judged by consumption of starting material.

[0096] The structure and purity of the compounds were confirmed by one or more of the following methods: proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, 13 C NMR spectroscopy, mass spectrometry, infrared spectroscopy, melting point, X-ray crystallography, LC-MS and / or HPLC. Chemical shifts are reported in parts per million (ppm, δ) downfield from a standard (e.g., an internal standard such as TMS). Alternatively, 1 H NMR chemical shifts are referenced to the signals of residual protons in deuterated solvents as known in the art. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, double of doublets; t, triplet; dt, double of triplets; q, quartet; br, broadened; and m, multiplet. Coupling constants are in Hertz (Hz). Mass spectrometry (MS) data were acquired using a mass spectrometer with APCI or ESI ionization.

[0097] 5.5.1 Synthesis of 6-bromo-2-(dimethoxymethyl)-3-fluoropyridine (Compound L1)

[0098]

[0099] HCl / MeOH solution (10 mL 3.9 M solution, 0.05 eq) was charged into a mixture of SM2 (158.5 g, 777 mmol, 1 eq), MeOH (1585 mL, 10V) and trimethoxymethane (166 g, 15.6 mol, 2.0 eq). The resulting mixture was aged at 60-65°C (reflux) until the reaction was complete (3-6 hours) and then cooled to 10-20°C. After being concentrated to 2-3V below 50°C and diluted with 2-Me-THF (10V), the reaction was quenched with 10% KCO (3V). The organic layer was separated and concentrated to 1-2V below 50°C. This was rinsed with 2-Me-THF (5V) and then diluted with more 2-Me-THF (5V) to give a solution of compound L1 in 2-Me-THF (845.2 g, 99% purity, 21.7% assay, 94.4% solution yield). LC-MS: m / z 250, 252, 220, 218 (M-OMe) 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.38 (dd, J = 3.5,8.6 Hz, 1H), 7.17-7.30 (m, 1H), 5.37-5.48 (m, 1H), 3.39 (s, 6H).

[0100] 5.5.2 Synthesis of 4-chloro-2-(dimethoxymethyl)pyridine (Compound L2)

[0101]

[0102] HCl / MeOH (42.3 mL 3.9 M solution, 0.20 eq) was charged into a mixture of SM3 (117.3 g, 819.5 mmol, 1 eq), MeOH (1160 mL, 10 V) and trimethoxymethane (174 g, 1.64 mol, 2.0 eq). The mixture was heated to 60-65 ° C (reflux) until the reaction was complete (6-10 hours) and then cooled to 10-20 ° C. After concentrating to 3-5 V and diluting with 2-Me-THF (10 V), the reaction was quenched with 10% K CO (3 V, pH 8-9). The organic layer was separated and concentrated to 1-2 V, rinsed with 2-Me-THF (5 V x 2), then diluted with 2-Me-THF (5 V) to give a solution of Compound L2 in 2-Me-THF (588.5 g, 99.18% HPLC purity, 22.3% assay, 85.3% solution yield). 1H NMR (400 MHz, chloroform-d) δ 8.42-8.57 (m, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 2.1, 5.3Hz, 1H), 5.28-5.39 (m, 1H), 3.38 (s, 6H). LC-MS m / z 187, 156 (M-OMe).

[0103] 5.5.3 Synthesis of 2',6-bis(dimethoxymethyl)-5-fluoro-2,4'-bipyridyl phosphate (Compound L4-phosphate)

[0104]

[0105] Preparation of L3: A mixture of compound L2 in 2-Me-THF (95.5 g, 1.00 eq., 5-6 V), 2-Me-THF (10 V), Pin2B2 (1.05 eq.), KOAc (3.0 eq.) and Xphos (0.02 eq.) was degassed by sparging with N2. Pd2(dba)3 (0.01 eq.) was added and the mixture was degassed again by sparging with N2. The reaction mixture was heated to 70-80 °C and stirred until the borylation of L2 was complete (16-24 hours) to produce L3, which was used directly in the next Suzuki coupling step.

[0106] Preparation of L4 via Suzuki coupling of L3 and L1: After cooling to 15-25°C, a solution of compound L1 in 2-Me-THF (0.96 eq., 5-6V), Na2CO3 (2.0 eq. solid) and H2O (5V) were added in sequence. After degassing by sparging with N2, the reaction mixture was aged at 70-80°C until the Suzuki coupling was complete (16-24 hours). After cooling to 15-25°C, the reaction mixture was filtered through a diatomaceous earth pad (0.5X) and the filter cake was rinsed with 2-Me-THF (1-2V). The organic layer in the filtrate was separated, concentrated to 1-2V, diluted with toluene (10V) and washed twice with L-cysteine / NaOH (pH>10) (5X, ratio of L-cysteine / NaOH / H2O: 1 / 0.5 / 9). The organic layer was then washed with H2O (5X) and concentrated to 5V to give a toluene solution of compound L4 free base in toluene. An analytical sample of L4 free base was obtained by crystallization in heptane / MTBE. 1HNMR (400 MHz, chloroform-d) δ 8.66-8.77 (m, 1H), 8.06 (d, J =1.22 Hz, 1H), 7.94(dd, J = 1.77, 5.20 Hz, 1H), 7.86 (dd, J = 3.55, 8.56 Hz, 1H), 7.51-7.60 (m,1H), 5.63 (s, 1H), 5.44-5.48 (m, 1H), 3.54-3.60 (m, 6H), 3.43-3.49 (m, 6H); mp 41.8℃ (DSC peak); XRPD 2θ: 6.70, 7.61, 9.67, 13.56, 13.77, 13.99, 15.36,19.36, 20.71, 21.81, 23.10, 26.96, 27.72, 28.02, 29.36, 31.88, 32.04, 39.09.

[0107] Preparation of L4 phosphate: A solution of 85% H3PO4 (based on 1.6 equivalents of compound L4 free base) in MeOH (1-2V) was added to the toluene solution of the above L4 within 2 hours to obtain a suspension. The suspension was concentrated to 3V below 45°C, and n-heptane (10V) was added within 2 hours. The mixture was concentrated to 10V below 45°C, and the batch temperature was adjusted to 15-25°C. After stirring for 6-8 hours, the mixture was filtered, and the filter cake was rinsed with n-heptane (1-2V). The wet cake was purged and dried with slight N2 at 40°C under reduced pressure to obtain 190.5 g L4-phosphate (93.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.63-8.72 (m, 1H), 8.24 (dd, J = 3.6, 8.7 Hz, 1H), 8.11 (d, J =1.1 Hz, 1H), 8.01 (dd, J = 1.8, 5.2 Hz, 1H), 7.92 (dd, J = 8.7, 9.9 Hz, 1H), 5.58 (s, 1H), 5.36 (s, 1H), 3.43 (s, 6H), 3.35 (s, 6H). LC-MS: [M+H] +17.73, 28.26, 29.55, 30.35, 31.10, 31.82, 34.13, 34.68, 36.04, 39.48.

[0108] 5.5.4 Synthesis of 5-fluoro-[2,4'-bipyridine]-2',6-dicarbaldehyde (Compound Q)

[0109]

[0110] The mixture of compound L4-phosphate (177 g, 111 g L4 free alkali = 1.0X), 1N HCl (1110 mL, 10V) and toluene (555 mL, 5V) was stirred at 15-25°C for 0.5-1.0 hour. Separate the organic phase and stir the water layer at 55-60°C for 2 hours. The mixture is slowly (3 hours) concentrated to remove the MeOH produced at 55-60°C under reduced pressure (-0.08 to -0.085 Mpa), and then cooled to 30-40°C. DCM (777V) is loaded and the pH of the mixture is adjusted to 5-7 with 15% NaCO (3.5-4.5X). Separate the layers and extract the water layer with DCM (2V). The organic layer combined is washed with H o (5V) and filtered through Na sO pad (1X). The filter pad was rinsed with DCM (2V) and the combined filtrate was concentrated to 8-10V. The reactor wall was sprayed with 2VDCM, and then n-heptane (8-10V) was loaded in 2.0-5.0 hours. The mixture was concentrated to 10-12V (DCM≤40% remaining in the supernatant) below 60°C under normal atmospheric pressure. The suspension was aged for 1.0-2.0 hours at 30-40°C, aged for 6-8 hours at 5-10°C, and filtered. The filter cake was washed with 1:4 DCM / n-heptane (1-2V) and dried under reduced pressure at 40-50°C to obtain 80.19 g of compound Q (98% yield). LC-MS: [M+H] + 231; [M+H+H2O] + 249; 1H NMR (400 MHz, CHLOROFORM-d) δ 10.27 (s, 1H), 10.18 (s, 1H), 8.91-9.00(m, 1H), 8.51-8.59 (m, 1H), 8.24-8.31 (m, 1H), 8.17(dd, J = 3.5, 8.7 Hz, 1H),7.77 (t, J = 9.0 Hz, 1H); mp. 150°C (DSC peak).

[0111] 5.5.5 Synthesis of 2',6-bis(difluoromethyl)-5-fluoro-2,4'-bipyridine (Compound H)

[0112]

[0113] Compound Q (30.0 g, 1.00X) and EtN (0.044X) in anhydrous DCM (KF≤0.02%, 20X) solution was cooled to 0-5°C. DAST (3.50X) was slowly added at 0-10°C, and the mixture was then aged at 20-25°C until the reaction was complete (approximately 24 hours). The reaction mixture was put into 15% KCO (28X) at 0-20°C for two hours, and aged for 0.5 hour at 20-25°C. The organic layer was separated, cooled to 10-20°C and treated with 1 M HCl (9.9-11.1X) at 10-25°C for 0.5-1 hour. After standing for 0.5 hour, the mixture was filtered through a diatomaceous earth pad (approximately 0.5X), followed by a small amount of flushing DCM (2.0-3.0X). The filtrate was allowed to stand, and the organic layer was separated, washed with H2O (10X), and filtered through a silica pad (about 1.5X). The silica pad was washed with DCM (5.0X – 6.0X, three times) until the purity of compound H in the filtrate fraction was reduced to <90%. The combined filtrate was concentrated to about 2-3V below 30°C and then co-distilled with isopropanol at 50°C until residual DCM < 5.0% (a total of 6-7X IPA used), with a final volume of 3-4V. The distillation residue was aged at 55-60°C for 0.5 hours, cooled to 35-40°C, and aged for 0.5 hours. Water (9.0-10.0X) was slowly added at 33-40°C (1-3 hours), and the mixture was stirred for 0.5 hours. After aging at 15-20°C, the suspension was filtered and the filter cake was washed with IPA / H2O (1:4, weight / weight, 1X), then H2O (2X). The wet cake was dried at 40-45°C under reduced pressure until KF <0.3% and residual IPA <0.1% (18-24 hours) to give 30.15 g of compound H (82% yield). Melting point (mp) 75°C (DSC peak). LC-MS: [M+H] + 275.2; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.71-8.89 (m, 1H),8.22 (s, 1H), 7.91-8.12 (m, 2H), 7.71 (t, J = 8.9 Hz, 1H), 7.00 (s, 1H), 6.87(s, 1H), 6.82-7.05 (m, 1H), 6.59 (s, 1H), 6.73 (s, 1H).

[0114] 5.5.6 Synthesis of (S)-2-amino-2,4-dimethylpentan-1-ol benzoate (Compound D-benzoate)

[0115]

[0116] BF3.Et2O (200 g, 2.0 equivalents) was slowly added to a mixture of NaBH4 (53 g, 2.0 equivalents) in THF (1.0 L) at 0-10 ° C. The reaction mixture was heated to 15 ° C, and then (S)-(α)-methylleucine (100 g, 1.0 equivalents) was added at < 25 ° C within 1 hour. The mixture was aged for 5-8 hours at 20-25 ° C, and then slowly quenched in a 10% NaOH aqueous solution (750 mL) at 25-30 ° C. The organic layer was separated, washed with a 15% NaCl aqueous solution (200 mL), and then diluted with n-heptane (300 mL). 2N HCl (about 300 mL) was added to the mixture until the pH reached 1-2. The organic layer was separated and extracted with 1 N HCl (300 mL). The combined aqueous layer was basified with 30% NaOH (about 500 mL) until pH>13, then extracted with MTBE (500 mL x 3). The combined organic extracts were dried over anhydrous Na2SO4 (100-200 g), filtered, concentrated to about 200 mL, and then rinsed with MTBE (200-500 mL) until the moisture content in the concentrate was <0.5%. The solution of amino alcohol D was then slowly (5 hours) added to a solution of benzoic acid (93 g, 1.1 equivalents) in MTBE (500 mL) at 45-50°C. After stirring for 1 hour, the mixture was slowly (5-8 hours) cooled to 20-25°C and aged for 5-8 hours to obtain a suspension. The suspension was filtered, the filter cake was washed with 1 / 1 MTBE / n-heptane (150 mL), and dried under reduced pressure at 40-50°C to obtain compound D-benzoate with a yield of 92%. mp. 125.4℃(DSC peak); 1H NMR (400 MHz, methanol-d4) δ 7.88-7.99 (m, 2H), 7.27-7.46 (m, 3H),3.45-3.62 (m, 2H), 1.69-1.87 (m, 1H), 1.56-1.66 (m, 1H), 1.44-1.54 (m, 1H),1.29 (s, 3H), 1.00 (d, J = 6.60 Hz, 6H); XRPD 2θ: 6.67, 6.83, 12.84, 13.37,15.16, 16.95, 17.83, 19.90, 20.32, 21.23, 22.28, 23.70, 24.09, 24.42, 26.24,26.91, 27.49, 30.60, 32.64, 33.98, 34.98, 35.13.

[0117] 5.5.7 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine hydrochloride (Compound S)

[0118]

[0119] Solid t-BuOK (2.5-3.0 equivalents based on compound H) was charged in batches to a mixture of compound D-benzoate (1.2 equivalents based on compound H) and THF (10.5-11.6X) at 15-20°C. The mixture was warmed to 20-25°C, stirred for 3-5 hours, and then cooled to 0-5°C. A solution of compound H (1.00X) in THF (3.6-4.5X) was added slowly (approximately 1 hour) while keeping the batch temperature below 20°C. The reaction mixture was aged at 20-25°C until the reaction was complete (1-3 hours). MTBE (6X) was added, and the mixture was cooled to 10-15°C. H2O (9.0-11.0X) was added slowly (1-3 hours) while keeping the batch temperature below 25°C. The layers were separated and the aqueous layer was extracted with MTBE (2.2X). The combined organic layers were concentrated to 2-3 V under reduced pressure at below 30 °C. Free base Compound J: 1H NMR (400 MHz, DMSO-d6) δ8.70-8.84 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.33 (s, 1H), 8.22 (br d, J =5.0 Hz, 1H), 7.81 (d, J =8.8 Hz, 1H), 7.17-7.41 (m, 1H), 6.89-7.13 (m, 1H),3.82-3.95 (m, 2H), 1.74-1.88 (m, 1H), 1.55 (br s, 2H), 1.33-1.46 (m, 2H),1.12 (s, 3H), 0.93 (t, J = 7.1 Hz, 6H). After the solvent was exchanged to IPA to 2-3V by co-distillation (6.0-6.5X), more IPA (3.8-4.2X) was added and the mixture was heated to 50-60°C. A solution of 35% HCl (0.44-0.47X) in IPA (1.3-1.5X) was added slowly (about 1 hour) while keeping the batch at 50-60°C. The resulting suspension was aged at 50-60°C for 1.0-2.0 hours, cooled to 20-30°C over 2.0-4.0 hours, stirred at 20-30°C for 1.0-2.0 hours, and then filtered. The filter cake was washed with MTBE (3.5-4.0X) and dried at 40-50°C under reduced pressure for 16-24 hours to give Compound S. LC-MS m / z 386.1; mp. 246.4°C (DSC peak), 1 H NMR (400 MHz, DMSO-d6) δ8.81 (d, J = 5.3 Hz, 1H), 8.51 (br s, 2H), 8.45 (d, J = 8.9 Hz, 1H), 8.34 (s,1H), 8.24 (d, J = 5.1 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.56-7.87 (m, 1H), 6.90-7.23 (m, 1H), 4.29 (s, 2H), 1.72-1.91 (m, 2H), 1.54-1.72 (m, 1H), 1.42(s, 3H), 0.86-1.00 (m, 6H).

[0120] 5.5.8 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K)

[0121]

[0122] A mixture of compound S (9.5 kg, 1.0X), MTBE (76.0 kg, 8.0X), water (50.0 kg, 5.3X) was treated with 20% NaOH aqueous solution (0.95 kg NaOH solid in 4.0 kg water) at 35-40°C until all solids dissolved (2.0-5.0 hours). The reaction mixture was cooled to 20-25°C and stirred for 1.0-2.0 hours. The organic layer was separated, washed with water (46.5 kg, 4.9X), and concentrated to about 25 L (2-3X) under reduced pressure at ≤30°C. Solvent was exchanged to IPA (79.0 kg IPA, 8.3X) by co-distillation at ≤50°C under reduced pressure, and the final volume was 29-38 L (3-4X), and the distillation residue was then diluted with IPA (60 kg) and heated to 50-60°C. A solution of H3PO4 (2.8 kg, 0.29X) in IPA (5.0 kg, 0.53X) was added over 2.0-4.0 hours. More IPA (22.0 kg, 2.3X) was added and the batch was stirred at 50-60°C for 2.0-4.0 hours. The batch was cooled to 15-20°C over 2.0-4.0 hours and then stirred at 15-20°C for 1.0-2.0 hours. The resulting suspension was filtered and the filter cake was washed with IPA (27.0 kg, 2.84X) and MTBE (31 kg, 3.3X) successively. The wet cake was dried under reduced pressure at 45-55°C for 17-24 hours to obtain compound K. The salt ratio between compound J and phosphoric acid in compound K was determined to be 1:1 (two separate HPLC methods using UV and IC detectors, respectively). The purity of compound K was 98.7-99.9 area % by HPLC. The crystallinity of Compound K was confirmed by XRPD and further supported by DSC. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.1 Hz, 1H), 8.41(d, J = 8.8 Hz, 1H), 8.31 (s, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.88 (brd, H),7.47 (t, J H-C-F = 54 Hz, 1H), 7.04 (t, J H-C-F= 54 Hz, 1H), 4.03-4.29 (m, 2H), 1.72-1.87 (m, 1H), 1.60-1.69 (m, 1H), 1.49-1.59 (m, 1H), 1.33 (s, 3H), 0.92(d, J = 6.6, 3H), 0.87 (d, J = 6.6, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 21.62,22.74, 24.61, 24.82, 44.69 54.57, 72.80, 110.53 (t, J C-F = 237 Hz), 113.84 (t,J C-F = 238 Hz), 116.68, 122.19, 125.03, 140.07 (t, J C-F = 22 Hz), 144.13,145.98, 150.52, 152.80 (t, J C-F = 25 Hz), 153.51. 20.84,21.67, 23.23, 23.95, 24.41, 24.72, 25.27, 26.37, 30.14.

[0123] 5.5.9 Synthesis of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine phosphate (Compound K)

[0124]

[0125] Compound K seeds (0.18 g) were added to a solution of compound J (9.14 g) in IPA (100 mL) at 50-60 ° C. A solution of 85% phosphoric acid (2.87 g, 1.05 equivalents) in IPA (7 mL) was added within 2-4 hours. The suspension was aged for 2-4 hours, cooled to 15-20 ° C and aged for 1-2 hours within 2-4 hours. The suspension was filtered, and the filter cake was washed with IPA (20 mL), followed by washing with MTBE (44 mL). The wet cake was dried under reduced pressure at 45-55 ° C for 17-24 hours to obtain 11.3 g of compound K, 98% yield.

[0126] Compound K seed formation: IPA (1.0 mL) was added to compound J (50.08 mg, 0134 mmol, 1.0 eq) to form a clear solution at ambient temperature, and then phosphoric acid (0.156 mL, 1M in IPA, 0.156 mmol, 1.20 eq) was added. The mixture was stirred for 6 hours to obtain a suspension, and then aged at 60 ° C for 30 min. After cooling to room temperature, heptane (0.5 mL) was added, and the resulting mixture was stirred for 1 hour. The resulting suspension was filtered, and the filter cake was washed with MTBE (0.5 mL) and dried under reduced pressure at 45-48 ° C overnight to obtain compound K seeds (59.28 mg, 94.4% yield).

[0127] The salt ratio, purity, XRPD, DSC and TGA data were essentially the same as those obtained for Compound K in Example 2.

[0128] 5.5.10 Tablet Dosage Form

[0129] A batch of 20,000 tablets containing 10, 20 or 50 mcg of Compound K was prepared using the ingredients shown below:

[0130] Table 3

[0131]

[0132] 1 One mg of compound K is equivalent to 0.7973 mg of free base (compound J).

[0133] 2 The amount of Compound K was adjusted to achieve potency according to the supplier's certificate of analysis, assay (wt%, HPLC). The ratio of silicified microcrystalline cellulose and anhydrous calcium hydrogen phosphate was adjusted accordingly.

[0134] 3 Opadry II White was dispersed in purified water at 15% solids to coat the cores. A 50% reserve coating was prepared to compensate for losses during film coating and to ensure adequate use per tablet. Purified water was removed during production.

[0135] Figure 3 A flow chart representing tablet manufacturing is shown. The same process is used for all three strengths; however, the compression / coating flow chart depicts the process for the 50 mg strength only. As depicted in the flow chart, the excipient grade, screen size, and blending time can be adjusted based on process requirements and batch size. Reference Figure 3 , a solid oral dosage form of compound K is prepared according to the following steps:

[0136] 1. Adjust the amount of Compound K to achieve potency according to the supplier's Certificate of Analysis, Assay (wt%, HPLC).

[0137] 2. Sift Compound K, silicified microcrystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium into a bin blender and blend. Note: Adjust the proportional amounts of silicified microcrystalline cellulose and anhydrous calcium hydrogen phosphate according to the potency of Compound K determined in step 1.

[0138] 3. Sift talc and colloidal silicon dioxide into the blend from step 2 and blend.

[0139] 4. Sift the hydrogenated vegetable oil into the blend from step 3 and blend.

[0140] 5. Compress the blend from step 4.

[0141] 6. The tablet cores from step 5 were then coated with Opadry II White aqueous dispersion to a weight gain of approximately 4%.

[0142] 7. Package the coated tablets from step 6 into HDPE bottles induction sealed with child resistant caps.

[0143] Each reference (eg, patents, patent applications, and publications) cited herein is hereby incorporated by reference in its entirety.

Claims

1. A crystalline compound, the compound being ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-ammonium dihydrogen phosphate (Compound K): 。 2. The crystalline compound of claim 1, whose XPRD pattern comprises a peak at one or more of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.86, 21.65, 23.96, 24.48 or 24.73 degrees 2θ.

3. The crystalline compound of claim 1 having a melting point of about 184°C.

4. A composition comprising an active pharmaceutical ingredient (API), an excipient and a lubricant, wherein the API is a crystalline compound, and the compound is a pharmaceutically acceptable salt of (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridyl]-5-yl)oxy)-2,4-dimethylpentan-2-amine (Compound J): 。 5. The composition of claim 4, comprising less than 0.05 (e.g., less than 0.01, 0.005, or 0.001) weight percent of at least one compound listed in Table 2.

6. A tablet comprising the composition according to claim 4.

7. The tablet according to claim 6, which is coated.

8. The tablet of claim 6, comprising 10, 20 or 50 mg of a pharmaceutically acceptable salt of Compound J.

9. The composition of claim 4 or the tablet of claim 6, wherein the pharmaceutically acceptable salt of Compound J is Compound K.

10. A method for treating or controlling pain in a patient, comprising administering a therapeutically effective amount of the compound of claim 1 to a patient in need thereof.

11. A method for treating or controlling pain in a patient, comprising administering a therapeutically effective amount of the formulation of claim 4 to a patient in need thereof.

12. The method of claim 10 or 11, wherein the pain is neuropathic pain.

Images