Methods and compositions for treating HSD-1 mediated disorders

Abstract

Methods for preparing triazole derivatives and compositions useful as HSD-1 inhibitors are provided.

Description

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 478,792, filed on January 6, 2023, the contents of which are incorporated herein by reference as if written in their entirety.

[0002] Glucocorticoids (GCs) are corticosteroids that bind to glucocorticoid receptors (GRs), which are present on many cell types in the human body. GCs are involved in cardiovascular, metabolic, immune, skeletal, muscle, skin, ocular, psychiatric, cognitive, circadian, and homeostatic functions. GCs can also bind to mineralocorticoid receptors (MRs) and nongenomic receptors.

[0003] Important natural GCs include cortisol (medically known as hydrocortisone) and corticosterone. Synthetic GCs include prednisolone, methylprednisolone, dexamethasone and many other GCs and derivatives of these substances. In addition, inactive congeners that do not activate GR (such as cortisone, prednisone) are commonly referred to as GCs. Cortisol and synthetic GCs are both used as medicines for treating autoimmune diseases and other illnesses. However, excessive natural or synthetic GCs in the human body can lead to a variety of symptoms and diseases, including hyperglycemia, insulin resistance, obesity, hyperlipidemia, hypertension and Cushing's syndrome. The most common causes of this type of excess are tumors that secrete cortisol or hormones that increase cortisol secretion (such as ACTH or CRH), or by excessive administration of hydrocortisone or synthetic GCs during medical treatment.

[0004] 11β-Hydroxysteroid dehydrogenase (HSD) is an enzyme that regulates intracellular levels of glucocorticoids. The HSD enzyme consists of two isoforms: nicotinamide adenine dinucleotide phosphate-dependent type 1 (HSD-1), which converts inactive cortisone to active cortisol; and nicotinamide adenine dinucleotide oxidative type 2 (HSD-2), which converts cortisol to cortisone. HSD-1 is the main source of intracellular cortisol and is considered to be the main source of intracellular GC synthesis in many cell types. Excessive intracellular GC activates GR and MR, which, together with non-genomic receptors, leads to tissue-specific morbidity observed in subjects with GC excess. Therefore, inhibiting HSD-1 can improve those symptoms.

[0005] Novel and effective HSD-1 inhibitors, including 4-(5-(2-(4-chloro-2,6-difluorophenoxy)propan-2-yl)-4-methyl-4h-1,2,4-triazol-3-yl)-3-fluorobenzamide and related compounds, have been described in US Pat. No. 8,377,923, the contents of which are incorporated herein by reference in their entirety, as HSD-1 inhibitors with promising potential.

[0006] There is a need for new and improved methods for producing 4-(5-(2-(4-chloro-2,6-difluorophenoxy)propan-2-yl)-4-methyl-4h-1,2,4-triazol-3-yl)-3-fluorobenzamide and related compounds that are amenable to large-scale, high-purity synthesis for use as HSD-1 inhibitors for the treatment of HSD-1-mediated diseases.

[0007] Citation of any reference in this application shall not be construed as an admission that such reference is prior art to the present application. Summary of the Invention

[0008] Provided is a compound having structural formula II

[0009]

[0010] Also provided is a compound having structural formula XIII:

[0011]

[0012] Also provided is a compound having structural formula XIV:

[0013]

[0014] Also provided is a composition comprising a compound having structural formula I:

[0015]

[0016] or a salt thereof, wherein the composition contains an undetectable amount of a compound having structural formula II:

[0017]

[0018] Also provided is a composition comprising a compound having structural formula I:

[0019]

[0020] or a salt thereof, wherein the composition contains a detectable amount of about 0.20% or less of a compound having structural formula XIII:

[0021]

[0022] Also provided is a composition comprising a compound having structural formula I:

[0023]

[0024] or a salt thereof, wherein the composition contains a detectable amount of about 0.20% or less of a compound having structural formula XIV:

[0025]

[0026] Also provided is a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable carrier.

[0027] Also provided is a method for treating an HSD-1 mediated disorder in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a composition or pharmaceutical composition described herein.

[0028] Also provided is a method for treating GC excess or a condition thereof in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition or pharmaceutical composition described herein. Conditions of GC excess include Cushing's syndrome and autonomous cortisol secretion. GC excess may also result from the use of one or more GC medications.

[0029] These and other aspects of the disclosure disclosed herein will be set forth in greater detail as the patent publication proceeds. DETAILED DESCRIPTION

[0030] Abbreviations and definitions

[0031] To facilitate understanding of the present disclosure, a number of terms and abbreviations as used herein are defined below:

[0032] When introducing elements of the present disclosure or the preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0033] When a range of values ​​is disclosed and the notation "from n1 to n2" or "between n1 and n2" is used (where n1 and n2 are numbers), then unless otherwise indicated, this notation is intended to include the numbers themselves as well as the ranges between them. Such ranges can be integers or continuous between and including the endpoints. For example, the range "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbon appears in integer units. In contrast, for example, the range "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and each value with any number of significant figures in between (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0034] As used herein, the term "about" when referring to a measurable value (such as an amount of a compound, dosage, time, temperature, etc.) is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5% or even 0.1% from the specified amount.

[0035] The term "detectable" refers to a measurable amount measured using an HPLC method with a detection limit of 0.05 area %.

[0036] As used herein, the term "chlorinating agent" refers to a compound or salt that adds one or more chlorine atoms to an organic compound in a chemical reaction.

[0037] As used herein, the term "hydrating agent" refers to a compound, salt, catalyst, or combination thereof that effects the net addition of one or more water molecules to an organic compound in a chemical reaction.

[0038] As used herein, the term "intermediate" refers to the main organic product of a chemical reaction or a salt thereof that has not been isolated or purified (ie, a "crude product") before proceeding to the next step in the process.

[0039] As used herein, the term "non-nucleophilic base" refers to a sterically hindered organic base that is a poor nucleophile. Examples of non-nucleophilic bases include N,N-diisopropylethylamine (DIPEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-dimethylpyridine (2,6-lutidine), 2,6-di-tert-butylpyridine, tert-butyl-lithium, tert-butyl-phosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidinium (LiTMP), sodium hydride, potassium hydride, sodium tert-butoxide, and potassium tert-butoxide.

[0040] As used herein, the term "nucleophilic catalyst" refers to a Lewis base that catalyzes a reaction of a compound by donating an electron pair.

[0041] As used herein, the term "polar solvent" refers to a solvent having a large dipole moment.

[0042] As used herein, the term "polar aprotic solvent" refers to a polar solvent that lacks an acidic hydrogen. Therefore, they are not hydrogen bond donors. Examples of polar aprotic solvents include acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, hexamethylphosphoric triamide (HMPT), pyridine, and tetrahydrofuran (THF).

[0043] As used herein, the term "disease" is intended to be generally synonymous with the terms "disorder," "syndrome," and "condition" (as in medical conditions), and are used interchangeably, as all reflect an abnormal condition of the human or animal body or a part thereof that impairs normal function, is generally manifested by obvious signs and symptoms, and reduces the life span or quality of life of the human or animal.

[0044] The term "combination therapy" means the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described herein. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single dosage unit having a fixed ratio of active ingredients or in multiple separate dosage units of each active ingredient. In some embodiments, the dosage unit is a tablet. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0045] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or condition or to affect a clinical endpoint.

[0046] The term "therapeutically acceptable" refers to those compounds (or salts) that are suitable for use in contact with the tissues of patients without undue toxicity, irritation or allergic response, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0047] As used herein, "treating" or "treatment" and the like means administering therapy to an individual who has exhibited at least one symptom of a disease or disorder or has previously exhibited at least one symptom of a disease or disorder. For example, "treating" can include alleviating, alleviating, or ameliorating symptoms of a disease or disorder, preventing other symptoms, ameliorating potential metabolic causes of symptoms, inhibiting a disease or disorder, such as preventing the development of a disease or disorder, relieving a disease or disorder, causing the disease or disorder to subside, alleviating a disorder caused by a disease or disorder, or stopping the symptoms of a disease or disorder. For example, the term "treating" with respect to a disorder refers to a reduction in the severity of one or more symptoms associated with the particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, nor does it necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0048] The term "patient" is generally synonymous with the term "subject" and includes all animals, including humans. Examples of patients include humans and primates, such as cynomolgus monkeys. Preferably, the patient is a human.

[0049] The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes the compounds listed above in salt form, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts that are not pharmaceutically acceptable salts may be used in the preparation and purification of the compounds in question. Base addition salts may also be formed and are pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, reference is made to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0050] As used herein, the term "treatment acceptable salt" refers to a salt or zwitterionic form of a compound disclosed herein that is water-soluble or oil-soluble or dispersible and as defined herein as treatment acceptable. Salts can be prepared during the final separation and purification of the compound, or separately by reacting the appropriate compound in free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (benzenesulfonate / besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (hydroxyethylsulfonate), lactate, maleate, The compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, n-propyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordination of the compound with an alkali metal or alkaline earth metal ion. Thus, the present invention encompasses sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0051] Base addition salts can be prepared during the final separation and purification of the compound by reacting the carboxyl group with a suitable base (such as hydroxide, carbonate or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary or tertiary amine. The cation for the treatment of an acceptable salt includes lithium, sodium, potassium, calcium, magnesium and aluminum, and nontoxic quaternary ammonium cations, such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, benzhydrylamine, N,N-dibenzylphenethylamine, 1-ephe namine and N,N'-dibenzylethylenediamine. Other representative organic amines that can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidines and piperazine.

[0052] In the following examples and throughout this disclosure, the following abbreviations may be used: Boc = tert-butoxycarbonyl; DMSO = dimethyl sulfoxide; DCM = dichloromethane; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EtOAc = ethyl acetate; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOH = ethanol; TsOH = p-toluenesulfonic acid; 1 H-NMR=proton nuclear magnetic resonance; HPLC=high performance liquid chromatography; UPLC=ultra performance liquid chromatography; TLC=thin layer chromatography. Other abbreviations may be used and will be familiar to those skilled in the art in this context.

[0053] Compounds and compositions

[0054] Provided is a compound having structural formula II

[0055]

[0056] Also provided is a composition comprising a compound having structural formula I:

[0057]

[0058] or a salt thereof, wherein the composition contains an undetectable amount of a compound having structural formula II:

[0059]

[0060] Also provided is a compound having structural formula XIII:

[0061]

[0062] Also provided is a composition comprising a compound having structural formula I:

[0063]

[0064] or a salt thereof, wherein the composition contains a detectable amount of about 0.2% or less of a compound having structural formula XIII:

[0065]

[0066] Also provided is a compound having structural formula XIV:

[0067]

[0068] Also provided is a composition comprising a compound having structural formula I:

[0069]

[0070] or a salt thereof, wherein the composition contains about 0.2% or less of a detectable amount of a compound having structural formula XIV:

[0071]

[0072] Prior art methods

[0073] US Patent No. 8,377,923 ('923) reports the preparation of a compound of Formula I (referred to as Example 186 in '923) using the method of Example 15 of '923 with appropriate starting materials as shown in the following scheme.

[0074]

[0075] The coupling step was performed at 70-100°C using imidoyl chloride 102 and propionyl hydrazide 103 in a 1:1 ratio using DMF as solvent without any other base. The coupled product was subsequently cyclized to the triazole with HCl in ethyl acetate and then hydrated with sodium hydroxide and hydrogen peroxide. '923 does not indicate the purity or yield of Example 15 or Example 186.

[0076] Amplification method

[0077] Subsequently, a method was developed for the large-scale synthesis of the compound of formula I. The coupling step was performed using 1.2 equivalents of imidoyl chloride in DMAc / H2O with 1.5 equivalents of lutidine as the base at a temperature of 0-10°C. Although increasing the amount of imidoyl chloride improved the yield, it was found that the method produced detectable amounts of the compound of formula II

[0078]

[0079] The compound persists during subsequent processing and purification steps and is thus retained in the final product.

[0080] Improved amplification method

[0081] A large-scale synthetic method for preparing a composition of formula I having an undetectable amount of a compound of formula II has been discovered. The novel method is based on the discovery that the formation of a compound of formula II can be reduced, if not completely suppressed, by using dichloromethane as a solvent for the coupling step. The solvent exchange allows for greater reactivity between the starting materials, reduces reaction time, and allows the use of limited amounts of imidoyl chloride while maintaining yield. In addition, the favorable partition coefficient of dichloromethane allows other impurities (including DMF-related impurities formed during the imidoyl chloride synthesis) to enter the aqueous layer that is discarded during the treatment process. The method comprises making a compound of formula IV:

[0082]

[0083] or a salt thereof, reacted with a chlorinating agent and a catalyst to form an intermediate having structural formula V:

[0084]

[0085] The intermediate and the compound of formula III

[0086]

[0087] and a non-nucleophilic base in dichloromethane to form a second intermediate having structural formula VI:

[0088]

[0089] The second intermediate reacts with a strong acid to form a triazole intermediate having structure XII:

[0090]

[0091] The triazole intermediate is subjected to hydration conditions to provide the compound of formula I.

[0092] In some embodiments, the chlorinating agent is independently selected from thionyl chloride, oxalyl chloride, and phosphorus oxychloride.

[0093] In some embodiments, the chlorinating agent is thionyl chloride.

[0094] In some embodiments, the catalyst is dimethylformamide.

[0095] In some embodiments, the chlorinating reagent is used in a molar excess of about 1.5:1 to 4:1 relative to the compound of Formula IV or V or the intermediate.

[0096] In some embodiments, the non-nucleophilic base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), pyridine, 2,6-lutidine (2,6-lutidine), and 2,6-di-tert-butylpyridine.

[0097] In some embodiments, the non-nucleophilic base is 2,6-lutidine.

[0098] In some embodiments, the non-nucleophilic base is used in a molar excess of about 1.1:1 to 3:1 relative to the intermediate of Formula III.

[0099] In some embodiments, the strong acid is selected from hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, perchloric acid, chloric acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid.

[0100] In some embodiments, the strong acid is p-toluenesulfonic acid.

[0101] In some embodiments, the hydrating conditions are potassium carbonate and hydrogen peroxide.

[0102] In some embodiments, the compound of formula III is prepared as follows to give a compound having structural formula VIII:

[0103]

[0104] or a salt thereof, reacted with ethyl 2-bromo-2-methylpropionate and a base to form an intermediate having structural formula IX:

[0105]

[0106] The intermediate is hydrolyzed to form an intermediate of structural formula X:

[0107]

[0108] The intermediate reacts with tert-butyl carbazate, carbodiimide and a nucleophilic catalyst to form a second intermediate of structural formula XI:

[0109]

[0110] The second intermediate is then reacted with a strong acid to form compound III.

[0111] In some embodiments, the carbodiimide is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0112] In some embodiments, the carbodiimide is EDC.

[0113] In some embodiments, the nucleophilic catalyst is selected from 4-dimethylaminopyridine (DMAP) and hydroxybenzotriazole (HOBt).

[0114] In some embodiments, the nucleophilic catalyst is 4-dimethylaminopyridine (DMAP).

[0115] In some embodiments, the strong acid is selected from hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonic acid.

[0116] In some embodiments, the strong acid is hydrochloric acid.

[0117] In some embodiments, ethyl 2-bromo-2-methylpropanoate is used in a molar excess of about 1.5:1 to 3:1 relative to the compound of Formula VIII.

[0118] In some embodiments, the base is selected from sodium carbonate and potassium carbonate.

[0119] In some embodiments, the base is potassium carbonate.

[0120] In some embodiments, the base is used in a molar excess of about 1.5:1 to 3:1 relative to the compound of Formula VIII.

[0121] Pharmaceutical composition

[0122] Although the compounds and salts described herein can be applied as raw chemicals, they can also be provided as pharmaceutical preparations. Therefore, pharmaceutical preparations are provided herein, comprising one or more of certain compounds disclosed herein or one or more pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The one or more carriers must be "acceptable" in the sense that they are compatible with the other ingredients of the preparation and harmless to the recipient. Appropriate formulations depend on the selected route of administration. Any well-known technology, carrier, and excipient can be used when appropriate and as understood in the art. Pharmaceutical compositions disclosed herein can be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, grinding, emulsifying, encapsulating, embedding, or compression processes.

[0123] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, intranasal, pulmonary (including inhalation and aerosolization), transdermal, rectal and topical (including transdermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend on, for example, the recipient's disease and condition. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Typically, these methods include the step of associating a compound described herein or a pharmaceutically acceptable salt thereof ("active ingredient") with a carrier that constitutes one or more auxiliary ingredients. Typically, the formulations are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

[0124] It should be understood that in addition to the ingredients particularly mentioned above the formulations described above 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.

[0125] The compounds and salts described herein can be administered orally or by injection at a dose of 0.001 to 500 mg / kg per day. The dosage range for adults is typically 0.1 mg to 2 g per day. Tablets or other presentations provided as discrete units can conveniently contain an amount of one or more compounds that is effective at such a dose or as a multiple of the dose, for example, units containing 0.05 mg to 500 mg, typically about 0.2 mg to 200 mg.

[0126] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.

[0127] The compounds and salts described herein can be administered in various modes, such as orally, topically or by injection. The exact amount of compound administered to the patient will be the responsibility of the attending physician. The specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the exact condition being treated, and the severity of the indication or disorder being treated. In addition, the route of administration may vary depending on the disorder and its severity.

[0128] Indications and treatments

[0129] Also provided are methods for treating an HSD-1 mediated disorder in a human or animal subject in need of such treatment, the methods comprising administering to the subject an amount of a compound disclosed herein, or a salt thereof, or a composition thereof.

[0130] Also provided is a method for treating glucocorticoid excess or a disorder thereof in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound disclosed herein, or a salt thereof, or a composition thereof.

[0131] In some embodiments, the glucocorticoid excess disorder is Cushing's syndrome.

[0132] In some embodiments, Cushing's syndrome may be caused by any of Cushing's disease, adrenal Cushing's syndrome, ectopic ACTH secretion, ectopic CRH secretion, or rare conditions such as Carney complex.

[0133] In some embodiments, the glucocorticoid excess disorder is autonomous cortisol secretion (also known as mild autonomous cortisol secretion, mild [autonomous] cortisol excess, subclinical Cushing's syndrome, or latent hypercortisolism).

[0134] In some embodiments, the glucocorticoid excess disorder results from the use of one or more glucocorticoid medications.

[0135] Also provided is a method of reducing the severity of one or more side effects of treatment with one or more glucocorticoid drugs in a subject.

[0136] In some embodiments, the side effect is selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes, dyslipidemia, weight gain, Cushingoid features, growth inhibition, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, dermatoporosis, skin atrophy, eczema, purpura, erosion, striae, delayed wound healing, easy bruising, acne, hirsutism, alopecia, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataracts, glaucoma, ptosis, mydriasis, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, susceptibility to infection, and reactivation of latent infection.

[0137] In some embodiments, the HSD-1 mediated disorder is selected from diabetes, nonalcoholic fatty liver disease, idiopathic intracranial hypertension, diabetic wound healing, hyperglycemia, insulin resistance, obesity, hyperlipidemia, and hypertension.

[0138] In some embodiments, the HSD-1 mediated disorder is selected from diabetes, hyperlipidemia, non-alcoholic fatty liver disease, obesity, idiopathic intracranial hypertension, and diabetic wound healing.

[0139] In addition to their use in the treatment of humans, certain compounds, salts, and formulations disclosed herein are also useful in the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, reptiles, and the like.

[0140] Example

[0141] Synthesis method

[0142] The following invention is further illustrated by the following examples.All IUPAC names were generated using ChemDraw 21.0 from CambridgeSoft.

[0143] In the following examples and throughout this disclosure, the following abbreviations may be used: Boc = tert-butoxycarbonyl; DMSO = dimethyl sulfoxide; DCM = dichloromethane; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EtOAc = ethyl acetate; EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOH = ethanol; TsOH = p-toluenesulfonic acid; 1 H-NMR=proton nuclear magnetic resonance; HPLC=high performance liquid chromatography; UPLC=ultra performance liquid chromatography; TLC=thin layer chromatography. Other abbreviations may be used and will be familiar to those skilled in the art in this context.

[0144] Example 1

[0145]

[0146] Step 1

[0147]

[0148] The mixture of 4-chloro-2,6-difluorophenol (Formula VIII, 1.0 equivalents) and ethyl α-bromoisobutyrate (2.0 equivalents) in DMF (5 volumes) is cooled to 0-10 ° C. Add DMF (5 volumes) containing K2CO3 (1.5 equivalents), and the mixture is raised to 50 ± 5 ° C and stirred for 20 hours. The reaction mixture is loaded into a separate container containing water (10 volumes) and ethyl acetate (20 volumes). The organic layer is separated, neutralized with 1M HCl (10 volumes) and washed with 30% brine (10 volumes). The organic layer is then concentrated to about 2 volumes, and ethanol is used to replace the solvent and is concentrated to about 2 volumes. The crude ethanol solution containing the compound of Formula IX is used for the next step without further purification.

[0149] Step 2

[0150]

[0151] To the crude ethanol solution of step 1 (2 volumes) was charged an additional 10 volumes of EtOH and cooled to 0-10° C. Water (7 volumes) containing NaOH (2.0 equivalents) was added and the mixture was stirred at 25±5° C. for 1 hour. The reaction mixture was neutralized with 6M HCl (2 volumes) and then concentrated to approximately 7 volumes. Ethyl acetate (17 volumes) was added and stirred for 30 minutes, then the organic layer was separated, washed with 30% brine (10 volumes), concentrated, and the solvent was exchanged with ethyl acetate and acetonitrile, then concentrated again to approximately 3.5 volumes. The crude solution containing the compound of formula X was used in the next step without further purification.

[0152] Step 3

[0153]

[0154] Into the crude acetonitrile solution (3.5 volumes) of step 2, t-butyl carbazate (1.05 equivalents), DMAP (0.05 equivalents) and another 7 volumes of acetonitrile were loaded. The mixture was cooled to 0-10° C. and EDC (1.2 equivalents) was loaded, and the reaction mixture was then concentrated to approximately 3 volumes at 25 ± 5° C. with stirring for 1 hour. Ethyl acetate (23 volumes) and 0.5M HCl (7.5 volumes) were added and stirred for 15 minutes. The organic layer was separated, washed with 30% brine (10 volumes), concentrated, and solvent exchanged using ethyl acetate, and then concentrated again to approximately 3 volumes. The crude solution containing the compound of formula XI was used in the next step without further purification.

[0155] Step 4

[0156]

[0157] The crude ethyl acetate solution (3 volumes) from step 3 was dissolved in another 2 volumes of ethyl acetate and then charged with 4N HCl in ethyl acetate (4.5 equivalents) at 0-10°C and stirred at 25±5°C for 20 hours. The reaction mixture was then concentrated to approximately 2 volumes. Ethyl acetate (2 volumes) was added and the reaction mixture was stirred for 30 minutes. The resulting crystals were filtered, washed with ethyl acetate (4 volumes), and dried in a vacuum oven at 40°C to provide the compound of formula III (90.9% overall yield for steps 1-4).

[0158] Step 5

[0159]

[0160] The compound of 4-cyano-2-fluoro-N-methylbenzamide (Formula IV, 1.0 equivalent) and SOCl (2.0 equivalents), DMF (0.1 equivalent) and toluene (6 volumes) are loaded into a reaction vessel. The mixture is heated to 75 ± 5 ℃ and stirred for 2 hours, then heated to 100 ± 5 ℃ and stirred for 16 hours. The reaction mixture is concentrated to approximately 2.5 volumes. The mixture is redissolved in the toluene of 6 volumes, concentrated to approximately 1.5 volumes, then dissolved in DCM (3.5 volumes). The thick solution containing the compound of Formula V is not further purified and is used for the next step.

[0161] Step 6

[0162]

[0163] A reaction vessel was charged with the compound of Formula III (step 4, 1.0 equiv), 2,6-lutidine (1.5 equiv) and acetonitrile (5 vol). The mixture was cooled to -10 ± 5°C and the crude DCM solution from step 6 (1.05 equiv) was added dropwise. A 5% aqueous NaHCO solution (6 vol) was added dropwise for 4 hours and then stirred at -5 ± 5°C for 1 hour. The organic layer was separated and the aqueous layer was washed with DCM (3.5 vol). The combined organic layers were washed with 20% brine (6 vol) and separated again. The crude solution containing the compound of Formula VI was used in the next step without further purification.

[0164] Step 7

[0165]

[0166] The TsOH aqueous solution (0.05 equivalent) is loaded into the crude DCM solution of step 7, concentrated to about 1.5 volumes at 20 ± 5 ° C under vacuum, and then toluene (7 volumes) is loaded. The reaction mixture is heated to 90 ± 10 ° C and stirred for 1.5 hours, then cooled to 50 ± 10 ° C. 5% NaHCO aqueous solution (6 volumes) is added dropwise for 6 hours, then stirred for 40 minutes. Water (6 volumes) is added dropwise for 4 hours, then stirred for another 40 minutes. The organic phase is separated, concentrated, and recrystallized from ethanol and water. The obtained crystals are filtered, washed with a mixture of ethanol and water, and dried in a vacuum oven at 50 ° C to provide a brown solid compound of formula XII (for steps 7-8, 46.3% overall yield, 95.96% purity).

[0167] Step 8

[0168]

[0169] The mixture of formula XII (step 8) in DMSO (8 volumes) is heated to 50 ± 5 ° C and stirred for 1 hour. The mixture is cooled to 25 ± 5 ° C and K2CO3 (0.5 equivalent) is loaded. 30% H2O2 aqueous solution (1.5 equivalents) is added dropwise for 2 hours, and then stirred for 30 minutes. 15.7% Na2SO3 aqueous solution (1.2 volumes) is loaded into the reaction mixture, stirred for 1 hour, then demineralized water (6.5 volumes) is loaded and stirred for 2-3 hours. The solid is filtered, washed with water, dried at 45 ± 5 ° C in a vacuum oven, and recrystallized from a mixture of ethanol and water, providing a compound of formula I (87.8% yield, 99.73% purity) as an off-white solid.

[0170] Example 2

[0171]

[0172] Step 1

[0173]

[0174] A mixture of compound 201 (1.0 eq), tert-butyl carbazate (1.2 eq), HOBt (1.2 eq), EDC (1.2 eq) and triethylamine (1.5 eq) in DCM (5 vol) was stirred at 25 ± 5 °C until completion. Water (8 vol) was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated, washed with 35% citric acid until the pH of the solution was between 6 and 7, washed with 25% NaHCO 3 until the pH of the solution was between 7 and 8, washed with water, and concentrated. The crude solid containing compound 202 was used in the next step without further purification.

[0175] Step 2

[0176]

[0177] A mixture of crude compound 202 (Example 2, Step 1, 1.0 eq), ethyl acetate (18 vol) and 4M HCl in ethyl acetate (34 eq) was stirred at 25±5° C. until completion. The reaction mixture was concentrated and the crude solid containing salt 203 was used in the next step without further purification.

[0178] Step 3

[0179]

[0180] A mixture of crude salt 203 (Example 2, Step 2, 1.0 equiv), 2,6-lutidine (2.5 equiv) and dichloromethane (5 vol) was charged into a flask and cooled to -10 ± 5 ° C. A solution of Formula V in dichloromethane (1.1 equiv, 2.3 vol) was added to the reaction mixture. The mixture was stirred at -10 ± 5 ° C for 16 hours. 3% NaHCO3 aqueous solution (40 vol) was added to the reaction and then stirred at 10 ± 5 ° C for 1 hour. The mixture was filtered, the filter cake was washed with water, and toluene (5 vol) was charged into the filter cake. The resulting solution of compound 204 was used in the next step without further purification.

[0181] Step 4

[0182]

[0183] To a solution of compound 204 (Example 2, Step 3, 1.0 equiv) was charged with p-toluenesulfonic acid monohydrate (0.05 equiv), warmed to 95±5° C., and stirred for 60 h. The reaction mixture was filtered, the filter cake was washed with toluene, and the resulting crude solid 205 was used in the next step without further purification.

[0184] Step 5

[0185]

[0186] A mixture of crude compound 205 (Example 2, Step 4, 1.0 equiv), DMSO (10 vols), and KCO (0.5 equiv) was placed in a round-bottom flask. 30% aqueous H2O2 (3 equiv) was added dropwise, followed by stirring at 15±5°C for 16 h. 15.7% aqueous Na2SO3 (20 vols) was added dropwise to the reaction mixture. The solid was filtered, washed with acetonitrile, dried in a vacuum oven at 45±5°C, reprecipitated from a mixture of DMF and water, filtered, and dried again to provide the compound of Formula II (91.51% purity) as an off-white solid.

[0187] Example 3

[0188]

[0189] Step 1

[0190]

[0191] A solution of the compound of formula VI (Example 1, step 6, 1.0 equivalent) in dimethylacetamide was heated to 90±10° C. and stirred for 3 h. The mixture was purified using column chromatography to give compound 301 in 10.04% yield and compound XII in 55.7% yield.

[0192] Step 2

[0193]

[0194] A mixture of compound 301, DMSO (20 volumes) and KCO (0.5 equivalents) was placed in a round-bottom flask. 30% H2O2 aqueous solution (3 equivalents) was added dropwise and then stirred at 25 ± 5 ° C for 20 h. Water was added to the reaction mixture and stirred. The solid was filtered, washed with water, and dried in a vacuum oven at 45 ± 5 ° C to provide the compound of formula XIII (94.9% purity) as an off-white solid.

[0195] Example 4

[0196]

[0197] Step 1

[0198]

[0199] A mixture of the compound of formula IV (1.0 equivalent) in water (3 volumes) was placed in a round-bottom flask. Sulfuric acid (3 volumes) was added dropwise, and the mixture was heated to 90 ± 10°C and stirred for 64 hours. Water (5 volumes) was added, and the solid was filtered and washed with water until the filtrate pH was between 5 and 7. The solid was dried at 50°C for 24 hours.

[0200] The solid intermediate was charged into a reactor containing toluene (10.5 volumes) and thionyl chloride (3 equivalents). The mixture was heated to 75 ± 5 ° C, stirred until clear, and then stirred at 100 ° C for another 16 h. The mixture was concentrated and charged into acetonitrile (10 volumes), then added to a mixture of acetonitrile (7 volumes) and 40% aqueous methylamine solution (9 volumes) and stirred at 25 ° C for 3 h. The mixture was adjusted to pH 6 to 7 with 6M HCl, washed with ethyl acetate, concentrated, and recrystallized from ethanol to provide compound 402, which was used in the next step without further purification.

[0201] Step 2

[0202]

[0203] A solution containing compound 402 (1.0 eq), DMF (0.1 eq), thionyl chloride (3 eq) and toluene (6 vol) was heated to 75±5° C. and stirred for 3 h, then heated to 100±5° C. and stirred for 16 h. The mixture was cooled to 55° C., concentrated, and charged with DCM (5 vol) to provide a solution of compound 403, which was used in the next step without further purification.

[0204] Step 3

[0205]

[0206] A reaction vessel was charged with the compound of formula III (Example 1, Step 4, 1.0 equiv), 2,6-lutidine (1.5 equiv) and acetonitrile (5 vol). The mixture was cooled to 5±5° C. and a crude DCM solution of 403 (1.05 equiv) was added dropwise and stirred for 16 hours. A 5% aqueous NaHCO solution (6 vol) was added dropwise. The organic layer was separated and the aqueous layer was washed with DCM (3.5 vol). The combined organic layers were washed with water (6 vol) and separated again. The crude solution containing compound 404 was used in the next step without further purification.

[0207] Step 4

[0208]

[0209] Into a solution of compound 404 (step 3, 1.0 equivalents) was loaded monohydrated p-toluenesulfonic acid (0.05 equivalent), concentrated, loaded toluene (3 volumes), warmed to 90 ± 10 ° C, and stirred for 16 h. The reaction mixture was filtered, and DCM was loaded into the solid and stirred to clarify. The solution was washed with 5% NaHCO 3 , washed with water, concentrated, redissolved in hot ethanol, loaded with water, filtered, and dried under vacuum to provide the compound of formula XIV (98.88% purity) as a white solid.

[0210] HPLC Test Method Parameters for Identity and Impurity Analysis

[0211] The analytical testing procedure for testing the identity of the compounds and impurities used reverse phase HPLC with gradient elution. The method was validated and has been shown to be stability-indicating. Chromatographic separations were performed at 40° C. using a Waters Xterra RP18 column (150 x 4.6 mm, 5 μm, Waters Corporation, Milford, USA) and a Ghost-Sniper 4.6 x 50 mm ghost trapping column.

[0212] The mobile phase consisted of (A) sodium phosphate buffer, pH 7.0, and (B) acetonitrile. Samples were dissolved in a 50:50 mixture of A and B, with a 20 μL injection volume, and separated using the following gradient profile at a flow rate of 1.0 mL / min: (95% A, 5% B) linearly over 50 minutes to (30% A, 70% B); (30% A, 70% B) for 10 minutes; and (95% A, 5% B) for 5 minutes. Compounds were detected at a wavelength of 220 nm.

[0213] Other implementation plans

[0214] The above specific embodiments are provided to help those skilled in the art practice the present disclosure. However, the scope of the disclosure described and claimed herein is not limited by the specific embodiments disclosed herein, as these embodiments are intended to illustrate several aspects of the present disclosure. Any equivalent embodiments are intended to be within the scope of the present disclosure. In fact, various modifications of the present disclosure, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description, and these modifications do not deviate from the spirit or scope of the present invention. Such modifications are also intended to fall within the scope of the appended claims.

[0215] All references, patents, or applications in the United States or abroad cited in this application are incorporated herein by reference as if fully written herein. In the event of any inconsistency, the material disclosed in this text shall prevail.

Claims

1. A compound having structural formula II:

2. A compound having the structural formula XIII:

3. A compound having structural formula XIV:

4. A composition comprising a compound of formula I: or a salt thereof, wherein the composition contains an undetectable amount of a compound having structural formula II:

5. A composition comprising a compound having structural formula I: or a salt thereof, wherein the composition contains a detectable amount of about 0.20% or less of a compound having structural formula XIII:

6. A composition comprising a compound having structural formula I: or a salt thereof, wherein the composition contains a detectable amount of about 0.20% or less of a compound having structural formula XIV:

7. A pharmaceutical composition comprising the composition according to any one of claims 4 to 6, and a pharmaceutically acceptable carrier.

8. A method for treating an HSD-1 mediated disorder in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of the composition of any one of claims 4 to 6 or the pharmaceutical composition of claim 7.

9. a method for treating an experimenter who needs glucocorticoid excess or its illness, said method comprising the step of the compositions as described in any one in claim 4 to 6 or the pharmaceutical composition as claimed in claim 7 to said experimenter using a therapeutically effective amount.

10. The method of claim 9, wherein the glucocorticoid excess disorder is Cushing's syndrome.

11. The method of claim 9, wherein the glucocorticoid excess disorder is autonomous Cortisol secretion.

12. method as claimed in claim 9, the disease of wherein said glucocorticoid excess is caused by using one or more glucocorticoid drugs.

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