Formulations of farnesol X receptor agonists

Abstract

This article describes pharmaceutical formulations of the farnesol X receptor agonist 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester, and methods of using such pharmaceutical formulations to treat conditions, diseases, or symptoms associated with farnesol X receptor activity.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 991,216, filed March 18, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article describes spray-dried solid dispersions of farnesol X receptor agonists, pharmaceutical formulations comprising such spray-dried solid dispersions, and methods of treating conditions, diseases, or ailments related to farnesol X receptor activity using such spray-dried solid dispersions and pharmaceutical formulations. Background Technology

[0004] The farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver, intestine, kidney, adrenal glands, and adipose tissue. FXR regulates multiple target genes involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis. FXR agonism is a therapeutic approach for many metabolic disorders, liver diseases or conditions, inflammatory conditions, gastrointestinal diseases, or cell proliferation disorders. Summary of the Invention

[0005] In one aspect, this document provides a spray-dried solid dispersion comprising: (a) 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester and (b) a pharmaceutically acceptable polymer; wherein 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester is dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M. In some embodiments, the weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester to a pharmaceutically acceptable polymer is from 9:1 to 1:9. In some embodiments, the weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester to a pharmaceutically acceptable polymer is from 3:1 to 1:3. In some embodiments, the weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester to a pharmaceutically acceptable polymer is about 2:1.In some embodiments, the weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester to a pharmaceutically acceptable polymer is about 1.5:1. In some embodiments, the weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester to a pharmaceutically acceptable polymer is about 1:1. In some embodiments, the spray-dried solid dispersion also contains a non-aqueous solvent. In some embodiments, the non-aqueous solvent is selected from tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments of the spray-dried solid dispersion, 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester is substantially amorphous. In some embodiments of the spray-dried solid dispersion, 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester is substantially crystalline.

[0006] In another embodiment, this document provides a pharmaceutical formulation comprising the spray-dried solid dispersion described herein, further comprising one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more flow aids, and one or more surfactants. In some embodiments, one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silica, mannitol, crospovidone, and sodium stearoyl fumarate. In some embodiments, one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silica. In some embodiments, the pharmaceutical formulation is in tablet form. In some embodiments, the tablet comprises about 1% to about 30% by weight of the spray-dried solid dispersion. In some embodiments, the tablet comprises about 5% to about 25% by weight of the spray-dried solid dispersion. In some embodiments, the tablets comprise about 1% to about 20% by weight of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester. In some embodiments, the tablets comprise about 1 mg, about 5 mg, about 12 mg, or about 25 mg of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester. In some embodiments, the pharmaceutical formulation is in capsule form.

[0007] On the other hand, this document provides a method for treating or preventing liver diseases or conditions in mammals, the method comprising administering to the mammal in need a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the disease or condition is a metabolic condition. In some embodiments, the disease or condition is a liver condition.

[0008] In some embodiments, the spray-dried solid dispersions described herein are administered to mammals via intravenous, subcutaneous, oral, inhalation, nasal, skin, or ocular administration. In some embodiments, the pharmaceutical formulations described herein are administered to mammals via intravenous, subcutaneous, oral, inhalation, nasal, skin, or ocular administration.

[0009] On the other hand, this article describes a method for treating or preventing any of the diseases or conditions described herein, the method comprising administering a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical preparation described herein to a mammal in need.

[0010] On the other hand, this document describes a method for treating or preventing metabolic or hepatic conditions in mammals, comprising administering to the mammal in need a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein. In other embodiments, the metabolic or hepatic condition is suitable for treatment with an FXR agonist. In some embodiments, the method further includes administering to the mammal a second therapeutic agent in addition to the spray-dried solid dispersion described herein or a pharmaceutically acceptable salt or solvate thereof.

[0011] In another embodiment, this document describes a method for treating or preventing liver diseases or conditions in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the liver disease or condition is alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the alcoholic liver disease or condition is fatty liver (steatohepatitis), cirrhosis, or alcoholic hepatitis. In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) accompanied by liver fibrosis. In some implementations, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) without liver fibrosis. In some implementations, the non-alcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis. In some implementations, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrotic liver disease, hepatitis, primary biliary cholangitis, biliary atresia, Alagille syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNALD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof.

[0012] On the other hand, this document describes a method for treating or preventing liver fibrosis in mammals, comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH).

[0013] On the other hand, this document describes a method for treating or preventing liver inflammation in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). In some embodiments, liver inflammation is associated with inflammation in the gastrointestinal tract. In some embodiments, the mammal is diagnosed with inflammatory bowel disease.

[0014] On the other hand, this document describes a method for treating or preventing gastrointestinal diseases or conditions in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric cancer, graft-versus-host disease, or any combination thereof. In some embodiments, the gastrointestinal disease is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), undifferentiated IBS (IBS-U), or bile acid diarrhea (BAD).

[0015] On the other hand, this document describes a method for treating or preventing kidney diseases or conditions in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the kidney disease or condition is renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis / nephropathy, glomerulonephritis / nephropathy, or a combination thereof.

[0016] On the other hand, this document describes a method for treating or preventing metabolic inflammation-mediated diseases or conditions in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the metabolic inflammation-mediated disease or condition is diabetes.

[0017] On the other hand, this document describes a method for treating or preventing lipid diseases or conditions in mammals, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the lipid disease or condition in the mammal is dyslipidemia.

[0018] On the other hand, this document describes a method for treating or preventing cancer in mammals, comprising administering to a mammal the spray-dried solid dispersion or pharmaceutical preparation described herein. In some embodiments, the cancer is prostate cancer, colorectal cancer, or hepatocellular carcinoma.

[0019] On the other hand, this document describes a method for treating or preventing diseases or conditions in mammals that would benefit from treatment with an FXR agonist, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, in addition to the spray-dried solid dispersion or pharmaceutical formulation described herein, the method herein further comprises administering at least one additional therapeutic agent.

[0020] Incorporation

[0021] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. Attached Figure Description

[0022] Figure 1 The pharmacokinetic curves of compound 1 tablets A and C in monkeys are described.

[0023] Figure 2 Release profiles for 12 mg tablets of compounds containing 5% and 10% croscarmellose sodium were described. Detailed Implementation

[0024] The nuclear hormone receptor farnesol X receptor (also known as FXR or nuclear receptor subfamily 1, H group, member 4 (NR1H4)) (OMIM: 603826) functions as a regulator of bile acid metabolism. FXR is a ligand-activated transcriptional receptor expressed in various tissues, including the adrenal glands, kidneys, stomach, duodenum, jejunum, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissue. FXR is highly expressed in tissues involved in bile acid metabolism, such as the liver, intestine, and kidneys. Bile acids act as endogenous ligands of FXR, causing intestinal and systemic release of bile acids to induce FXR-directed alterations in the gene expression network. Bile acids are the main oxidation products of cholesterol and, in some cases, regulators of cholesterol absorption during secretion into the intestine. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by the cytochrome p450 enzyme cholesterol 7-α-hydroxylase (CYP7A1) and occurs in the liver. Cytochrome p450 steroid 12-α-hydroxylase (CYP8B1) mediates the production of bile acids and determines the relative amounts of the two main bile acids—cholic acid and chenodeoxycholic acid. Activation of the FXR can inhibit the transcription of CYP7A1 and CYP8B1 by increasing the expression levels of the hepatic small heterodimer chaperone (SHP) (also known as nuclear receptor subfamily O, B group, member 2; or NROB2) and the intestinal expression of fibroblast growth factor 15 (FGF15) and human fibroblast growth factor 19 (FGF19) in mice. SHP inhibits the liver receptor homologue (LRH-1) and hepatocyte nuclear factor 4α (HNFα4), transcription factors that regulate the expression of CYP7A1 and CYP8B1 genes. FXR inhibition of CYP8B1 can be species-specific, and FXR activation can increase the expression of human CYP8B1 in some cases (Sanyal et al., PNAS, 2007, 104, 15665). In some cases, FGF15 / 19 released from the intestine then activates fibroblast growth factor receptor 4 in the liver, leading to activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which inhibits CYP7A1 and CYP8B1.

[0025] In some implementations, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance sometimes leads to reduced blood glucose uptake and increased de novo glucose production in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting the secretion of glucagon-like peptide-1 (GLP-1) by intestinal L-cells. GLP-1 is an intestinal hypoglycemic agent derived from the transcript of the proglucagon gene. It is released in response to food intake and controls appetite and gastrointestinal function, and promotes insulin secretion from the pancreas. The biologically active forms of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH2, which are produced by the selective cleavage of the proglucagon molecule. In this case, FXR activation, which leads to reduced bile acid production, is associated with reduced insulin resistance.

[0026] In some implementations, FXR activation is also associated with the secretion of pancreatic polypeptide folds such as peptide YY (PYY or PYY3-36). In some cases, peptide YY is a gastrointestinal hormone peptide that regulates neuronal activity in brain regions involved in reward processing—the hypothalamus and brainstem. In some cases, decreased PYY levels are associated with increased appetite and weight gain.

[0027] In some cases, activation of FXR indirectly leads to a decrease in plasma triglycerides. The clearance of triglycerides from the bloodstream is due to lipoprotein lipase (LPL). LPL activity is enhanced by induction of its activator, apolipoprotein CII, and the inhibition of its inhibitor, apolipoprotein CIII, in the liver occurs upon FXR activation.

[0028] In some cases, activation of the FXR further regulates energy expenditure, such as adipocyte differentiation and function. Adipose tissue includes adipocytes (or fat cells). In some cases, adipocytes further differentiate into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to generate body heat, while the function of WAT is fat storage tissue.

[0029] In some cases, FXR is widely expressed in the gut. In others, activation of FXR has been shown to induce the expression and secretion of FGF19 (or FGF15 in mice) in the gut. FGF19 is a hormone that regulates bile acid synthesis and plays a role in glucose metabolism, lipid metabolism, and energy expenditure. In some cases, FGF19 has also been observed to regulate adipocyte function and differentiation. Indeed, one study showed that administering FGF19 to mice fed a high-fat diet increased energy expenditure, regulated adipocyte differentiation and function, reversed weight gain, and improved insulin resistance (see Fu et al., “Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes” Endocrinology 145:2594-2603 (2004)).

[0030] In some cases, intestinal FXR activity has also been shown to participate in reducing microbial overgrowth, for example, during eating (Li et al., Nat Commun 4:2384, 2013). For instance, studies have shown that FXR activation is associated with increased expression of several genes in the ileum, such as Ang2, iNos, and Il18, which have been identified as having antimicrobial effects (Inagaki et al., ProcNatl Acad Sci USA 103:3920-3925, 2006).

[0031] In some cases, FXR is involved in barrier function and immune regulation in the gut. FXR regulates the transcription of genes involved in bile salt synthesis, transport and metabolism in the liver and gut, and has been shown in some cases to lead to improved intestinal inflammation and prevent bacterial translocation into the gut (Gadaleta et al., Gut. 2011 Apr; 60(4):463-72).

[0032] In some cases, excessive production of bile acids or improper transport and recycling of bile acids can lead to diarrhea. FXR regulates the transcription of genes involved in bile salt synthesis, transport and metabolism in the liver and intestine, and may improve diarrhea in some cases. Camilleri, Gut Liver. 2015 May; 9(3):332–339.

[0033] G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, membrane receptor for bile acids, or M-BAR or TGR5) is a cell surface receptor for bile acids. Upon activation with bile acids, TGR5 induces the production of intracellular cAMP, which then triggers an increase in triiodothyronine due to activation by deiodinase (DIO2) in bile acids, leading to increased energy expenditure.

[0034] Therefore, in some embodiments, the regulation of metabolic processes such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism, or insulin sensitivity is modulated through activation of FXR. Furthermore, in some embodiments, dysregulation of metabolic processes such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism, or insulin sensitivity leads to metabolic diseases such as diabetes or diabetes-related conditions, alcoholic or non-alcoholic liver disease or conditions, intestinal inflammation, or proliferative disorders.

[0035] In some embodiments, compounds having activity as FXR agonists are disclosed herein. In some embodiments, the FXR agonists described herein are structurally different from bile acids, other synthetic FXR ligands, and other natural FXR ligands.

[0036] In some embodiments, this document also discloses methods for treating or preventing metabolic conditions such as diabetes, obesity, impaired glucose tolerance, dyslipidemia, or insulin resistance by administering a therapeutically effective amount of an FXR agonist. In some cases, the compound is administered to the gamma tract of the subject.

[0037] In other embodiments, this document discloses methods for treating or preventing alcoholic or non-alcoholic liver diseases or conditions (e.g., cholestasis, primary biliary cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), or elevated liver enzymes) by administering a therapeutically effective amount of an FXR agonist to a subject in need (e.g., via the GI pathway). In other embodiments, this document discloses methods for treating or preventing cholestasis, cirrhosis, primary biliary cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis (PSC) by administering a therapeutically effective amount of an FXR agonist to a subject in need. In some embodiments, this document discloses methods for treating or preventing cholestasis by administering a therapeutically effective amount of an FXR agonist to a subject in need. In some embodiments, the present invention discloses methods for treating or preventing primary biliary cirrhosis by administering a therapeutically effective amount of an FXR agonist to a subject in need. In some embodiments, the present invention discloses methods for treating or preventing NASH by administering a therapeutically effective amount of an FXR agonist to a subject in need. In some embodiments, the present invention discloses methods for treating or preventing NAFLD by administering a therapeutically effective amount of an FXR agonist to a subject in need.

[0038] In further embodiments, the methods disclosed herein include treating or preventing intestinal inflammation and / or proliferative disorders such as cancer by administering a therapeutically effective amount of an FXR agonist to a subject in need, for example, via the GI pathway.

[0039] In a further embodiment, the present invention discloses FXR agonists that regulate one or more proteins or genes associated with metabolic processes such as bile acid synthesis, glucose metabolism, lipid metabolism, or insulin sensitivity such as increased activity of FGF19 (FGF15 in mice), increased secretion of GLP-1, or increased secretion of PYY.

[0040] 3-Hydroxyazine-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester (Compound 1)

[0041] This article describes the FXR agonist compound 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester (compound 1). "Compound 1" or "3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester" refers to a compound having the following structure:

[0042]

[0043] In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 is a free base. Furthermore, compound 1 can exist in a non-solventized form and in a solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of compound 1 provided herein are also considered to be disclosed herein. In some embodiments, compound 1 is solvated. In some embodiments, compound 1 is non-solventized. In some embodiments, compound 1 is crystalline. In some embodiments, compound 1 is amorphous.

[0044] Compound 1 has a non-bile acid chemical structure. In some embodiments, compound 1 provides continuous exposure when administered to mammals. In some embodiments, compound 1 exhibits continuous target engagement with FXR. In some embodiments, compound 1 is suitable for once-daily oral administration.

[0045] Obeticholic acid (OCA) is an FXR agonist containing a bile acid chemical structure. In published clinical studies, OCA has demonstrated clinical efficacy as an FXR agonist, but at higher doses it has been associated with adverse side effects such as itching, increased LDL cholesterol, and hepatotoxicity. In some embodiments, compound 1 has shown at least 30 times the potency of OCA in appropriate in vitro assays evaluating the binding of FXR agonists to FXR. In some embodiments, the increased potency of compound 1 indicates a wider potential therapeutic window relative to OCA.

[0046] In some embodiments, compound 1 has demonstrated sustained FXR engagement in preclinical animal models based on pharmacokinetic and pharmacodynamic markers. In some embodiments, compound 1 has demonstrated sustained FXR engagement that allows for once-daily administration of compound 1.

[0047] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, i.e., that the material is applied to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0048] The term "pharmaceutically acceptable salt" refers to a form of therapeutically active agent consisting of a cationic form of the therapeutically active agent combined with a suitable anionic combination, or, in an alternative embodiment, a anionic form of the therapeutically active agent combined with a suitable cationic combination. (See Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SMBerge, LDBighley, DCMonkhouse, J. Pharm. Sci. 1977, 66, 1-19. Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by PHStahl and CGWermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002.) Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than nonionic substances, and therefore can be used in solid dosage forms. Furthermore, because their solubility is generally a function of pH, selective dissolution in one or more parts of the digestive tract is possible, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Moreover, because salt-forming molecules can balance with the neutral form, they can regulate channels through biological membranes.

[0049] It should be understood that references to pharmaceutically acceptable salts include solvation forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during the separation or purification of the compound using a pharmaceutically acceptable solvent such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is an alcohol. The solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. Furthermore, the compounds provided herein are optionally present in both non-solventized and solvated forms.

[0050] certain terms

[0051] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term "including" and other forms such as "include," "includes," and "included" is not restrictive. When referring to a number or range of values, the term "about" means that the mentioned number or range of values ​​is an approximation within experimental variability (or within statistical experimental error), and therefore the number or range of values ​​may vary between 1% and 15% of that number or range of values. Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0052] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it has no lasting harmful effects on the general health of the person being treated.

[0053] As used herein, the term “modulate” means to interact with a target directly or indirectly to alter the target’s activity, including (by way of example only) enhancing, inhibiting, limiting, or prolonging the target’s activity.

[0054] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions between agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0055] As used herein, the terms "administer," "administering," "administration," etc., refer to methods that can be used to deliver a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0056] As used herein, the term "co-administration" and the like are intended to cover the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agent is administered via the same or different routes of administration or at the same or different times.

[0057] As used herein, the term "effective amount" or "therapeutic effective amount" refers to an adequate amount of a drug or compound administered that will, to a certain extent, alleviate one or more symptoms of the disease or condition being treated. Results include reduction and / or relief of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. In any individual case, the appropriate "effective" amount may optionally be determined using techniques such as dose escalation studies.

[0058] As used herein, the term "enhance" or "enhancing" refers to increasing or prolonging the potency or duration of a desired effect. Therefore, regarding the effect of enhancing a therapeutic agent, the term "enhancement" refers to the ability of another therapeutic agent to increase or prolong its effect on the system in terms of potency or duration. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent on the desired system.

[0059] As used herein, the term "drug combination" refers to a product resulting from a mixture or combination of more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of the active ingredient (e.g., compound 1 or a pharmaceutically acceptable salt thereof) and the co-medicine to a patient as a single entity or dose. The term "non-fixed combination" refers to the simultaneous, parallel, or sequential administration of the active ingredient (e.g., compound 1 or a pharmaceutically acceptable salt thereof) and the co-medicine to a patient as separate entities without a specific time interval, wherein such administration provides effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.

[0060] The terms “kit” and “product” are used as synonyms.

[0061] The terms "object" or "patient" include mammals. Examples of mammals include, but are not limited to, any member of the mammal class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one implementation, the object is a human being.

[0062] The term “treatment” as used herein includes relieving, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, for example, preventing the development of a disease or condition, alleviating a disease or condition, causing the remission of a disease or condition, relieving symptoms caused by a disease or condition, or preventing and / or therapeutically stopping the symptoms of a disease or condition.

[0063] Pharmaceutical Composition

[0064] In some embodiments, the spray-dried solid dispersion of Compound 1 described herein is formulated into a pharmaceutical composition. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Remington's Pharmaceutical Sciences, Hoover, John E., Mack Publishing Co., Easton, Pennsylvania 1975; Pharmaceutical Dosage Forms, eds. Liberman, HA and Lachman, L., Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), all of which are incorporated herein by reference.

[0065] In some embodiments, the spray-dried solid dispersion of Compound 1 described herein is administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. The administration of the spray-dried solid dispersion of Compound 1 described herein and its pharmaceutical composition may be affected by any method capable of delivering the compound to the site of action. These methods include, but are not limited to, oral administration.

[0066] In some embodiments, the pharmaceutical composition of compound 1 suitable for oral administration exists in discrete units, such as capsules, caches, or tablets, each containing a predetermined amount of the active ingredient; powders or granules.

[0067] Orally administered pharmaceutical compositions include tablets, push-in capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powders or granules optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. In some embodiments, tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be at a dose suitable for such administration. Push-in capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The dragee core has a suitable coating. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the coating of the tablet or dragee for the identification or characterization of different combinations of active compound dosages.

[0068] Conventional techniques for manufacturing solid oral dosage forms include, but are not limited to, one or a combination of the following methods: (1) dry mixing; (2) direct compression; (3) grinding; (4) dry granulation or non-aqueous granulation; or (5) wet granulation. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, etc.

[0069] It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other conventional pharmaceutical agents in the art that take into account the types of formulations discussed, such as those suitable for oral administration, which may include flavoring agents.

[0070] This document provides tablets comprising compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet comprises: compound 1 dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids; and optionally one or more film coating agents.

[0071] In some embodiments, a spray-dried solid dispersion is described herein comprising (a) compound 1; and (b) a pharmaceutically acceptable polymer; wherein compound 1 is dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer.

[0072] In some embodiments, tablets prepared using the spray-dried solid dispersions described herein are described.

[0073] Compound 1 spray-dried solid dispersion formulation

[0074] In some embodiments described herein, the pharmaceutical composition of Compound 1 is a spray-dried solid dispersion formulation. In some embodiments, a spray-dried solid dispersion comprising: (a) 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester and (b) a pharmaceutically acceptable polymer; wherein 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester is dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Soluplus. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP 30. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-L. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-H. In some embodiments, the pharmaceutically acceptable polymer is Eudragit L100-55. In some embodiments, the pharmaceutically acceptable polymer is Eudragit L100. In some embodiments, the pharmaceutically acceptable polymer is Eudragit EPO. In some embodiments, the pharmaceutically acceptable polymer is HPMC E15. In some embodiments, the pharmaceutically acceptable polymer is HPMC E3. In some embodiments, the pharmaceutically acceptable polymer is HPMC E5. In some embodiments, the pharmaceutically acceptable polymer is HPMC-HP55. In some embodiments, the pharmaceutically acceptable polymer is Soluplus. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 9:1 to 1:9. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 7:1 to 1:7.In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 5:1 to 1:5. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 4:1 to 1:4. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 3:1 to 1:3. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 2:1 to 1:2. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 4:1. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 3:1. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 2:1. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 1.5:1. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 1:1. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 1:1.5. In some embodiments, the weight ratio of compound 1 to the pharmaceutically acceptable polymer is 1:2. In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is selected from tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 15 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 14 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 13 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 12 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 11 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 10 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 9 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 8 / 1.In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 7 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 6 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 5 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 4 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 3 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 2 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 1 / 1. In some embodiments of the spray-dried solid dispersion, compound 1 is substantially amorphous.

[0075] On the other hand, this document provides a pharmaceutical formulation comprising the spray-dried solid dispersion described herein, further comprising one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more flow aids, and one or more surfactants. In some embodiments, one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silica, mannitol, crospovidone, and sodium stearoyl fumarate. In some embodiments, one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silica. In some embodiments, the pharmaceutical formulation is in tablet form. In some embodiments, the pharmaceutical formulation is in capsule form.

[0076] In one aspect, this article describes a tablet comprising: compound 1 or a pharmaceutically acceptable salt thereof, dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids; and optionally one or more film coating agents.

[0077] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, dispersed in a polymer matrix formed of a pharmaceutically acceptable polymer, is a spray-dried solid dispersion as described herein.

[0078] In some embodiments, the tablet comprises about 1% to about 15% by weight of compound 1. In some embodiments, the tablet comprises about 1% to about 20% by weight of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0079] In some embodiments, the tablet comprises about 1% to about 15% by weight of compound 1, which is dispersed in about 0.5% to about 10% by weight of a polymer matrix formed of a pharmaceutically acceptable polymer.

[0080] In some embodiments, the tablet comprises about 1% to about 15% of compound 1 dispersed in about 0.5% to about 10% of a polymer matrix formed of a pharmaceutically acceptable polymer; about 70% to about 99% of one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids; and optionally less than about 2% of one or more film coating agents.

[0081] In some embodiments, the tablet comprises about 1% to about 30% by weight of a spray-dried solid dispersion. In some embodiments, the tablet comprises about 5% to about 25% by weight of a spray-dried solid dispersion. In some embodiments, the tablet comprises about 5% to about 20% by weight of a spray-dried solid dispersion. In some embodiments, the tablet comprises about 5% to about 15% by weight of a spray-dried solid dispersion. In some embodiments, the tablet comprises about 5% to about 10% by weight of a spray-dried solid dispersion.

[0082] In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablet include one or more diluents, one or more disintegrants, one or more lubricants, one or more flow aids, or any combination thereof. In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablet include microcrystalline cellulose, mannitol, cropovidone, colloidal silica, and magnesium stearate.

[0083] In some embodiments, the tablet comprises one or more fillers / binders / diluents. The fillers / binders / diluents are selected from cellulose (e.g., microcrystalline cellulose, carboxymethyl cellulose, ethyl cellulose, and methyl cellulose), starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, mannitol, and lactose), natural and synthetic gums (e.g., acacia, sodium alginate, panwart gum, and solanum), polyvinylpyrrolidone, polyethylene glycol, waxes, and any combination thereof. In some embodiments, the tablet comprises microcrystalline cellulose and lactose monohydrate.

[0084] In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 40% to about 95% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 60% to about 95% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 65% to about 95% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 75% to about 95% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 58% of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents account for less than 95% by weight, less than 85% by weight, less than 75% by weight, less than 65% by weight, or less than 60% by weight of the total tablet weight.

[0085] In some embodiments, the tablet comprises one or more disintegrants. The disintegrants are selected from croscarmellose sodium, crospovidone, sodium starch glycolate, magnesium aluminum silicate (HV), methylcellulose, agar, bentonite, cellulose, carboxymethyl cellulose, and any combination thereof. In some embodiments, the tablet comprises croscarmellose sodium.

[0086] In some embodiments, one or more disintegrants in the tablets described herein account for about 2% to about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein account for about 5% to about 10% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein account for about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein account for about 5% by weight of the total tablet weight. In some embodiments, one or more disintegrants in the tablets described herein account for about 10% by weight of the total tablet weight. In some embodiments, one or more disintegrants account for less than 20% by weight of the total tablet weight.

[0087] In some embodiments, the tablet comprises one or more lubricants. The lubricant is selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearoyl fumarate, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and any combination thereof. In some embodiments, the tablet comprises magnesium stearate.

[0088] In some embodiments, one or more lubricants in the tablets described herein account for about 0.1% to about 5% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.1% to about 2% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.1% to about 1% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 1% of the total weight of the tablets. In some embodiments, one or more lubricants account for less than 2% of the total weight of the tablets.

[0089] In some embodiments, the tablet contains one or more flow aids. A flow aid is a substance added to a powder to improve its flowability. Examples of flow aids include magnesium stearate, colloidal silica, starch, and talc. In some embodiments, the tablet contains colloidal silica.

[0090] In some embodiments, one or more lubricants in the tablets described herein account for about 0.1% to about 5% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.1% to about 2% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.5% to about 1.5% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% of the total weight of the tablets. In some embodiments, one or more lubricants in the tablets described herein account for about 1% by weight of the total tablet weight. In some embodiments, one or more lubricants account for less than 2% by weight of the total tablet weight.

[0091] Additional excipients

[0092] In some embodiments, the tablets described herein contain additional excipients, including but not limited to buffers, flow aids, preservatives, and colorants. Additional excipients such as fillers, tensioners, and chelating agents are within the scope of these embodiments.

[0093] Non-limiting examples of buffers include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitates, mixtures of amino acids and buffers, mixtures of aluminum glycinate and buffers, mixtures of acidic salts of amino acids and buffers, and mixtures of basic salts of amino acids and buffers. Other buffers include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0094] In some embodiments, the tablets described herein contain preservatives. Preservatives include antimicrobial agents, antioxidants, and agents that improve sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, isoascorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl, ethyl, butyl), benzoic acid, potassium sorbate, vanillin, etc.

[0095] In some embodiments, the tablets described herein contain a colorant for identity and / or aesthetic purposes in the resulting liquid form. Suitable colorants include, exemplarily, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, iron oxide, and mixtures thereof.

[0096] Additional excipients are considered in the tablet formulations. These additional excipients are selected based on their functionality and compatibility with the tablet compositions described herein, and may be found, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Remington's Pharmaceutical Sciences by Hoover and John E. (Easton, PA: Mack Publishing Co., 1975); Pharmaceutical Dosage Forms, edited by Liberman, HA and Lachman, L. (Marcel Decker, New York, NY, 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), all of which are incorporated herein by reference in their entirety.

[0097] In other embodiments, the tablets described herein are coated tablets, such as enteric-coated tablets, sugar-coated tablets, or film-coated tablets.

[0098] In one embodiment, the individual unit dose further includes a film coating that disintegrates upon oral ingestion or contact with a diluent. In one embodiment, these formulations are prepared using conventional techniques.

[0099] Compressed tablets are solid dosage forms prepared by compressing the aforementioned bulk blend formulation. In various embodiments, the compressed tablets, designed to dissolve in the mouth, will contain one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, film coating helps patient compliance (e.g., Coated or sugar-coated). Contains The film coating is typically from about 1% to about 5% of the tablet weight. In other embodiments, the compressed tablet contains one or more excipients.

[0100] This article provides a film-coated tablet form comprising an active ingredient (e.g., compound 1 or a pharmaceutically acceptable salt thereof) and one or more tableting excipients to form a tablet core, which is then coated. The tablet core is prepared using conventional tableting methods and subsequent compression and coating.

[0101] Enteric coatings are coatings that resist the action of gastric acid but dissolve or disintegrate in the intestines.

[0102] In one aspect, the oral solid dosage forms disclosed herein include enteric coatings. Enteric coatings include one or more of the following: cellulose acetate phthalate; methyl acrylate-methacrylic acid copolymer; cellulose acetate succinate; hydroxypropyl methyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate (hydroxypropyl methyl cellulose acetate succinate); polyvinyl acetate phthalate (PVAP); methyl methacrylate-methacrylic acid copolymer; methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate forms); styrene-maleic acid copolymer; polymethacrylic acid / acrylic acid copolymer; hydroxyethyl ethyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; tetrahydrophthalate; acrylic resin; shellac.

[0103] Enteric coating is a coating placed on tablets, pills, capsules, granules, beads, pellets, particles, etc., so that it does not dissolve until it reaches the small intestine.

[0104] Sugar-coated tablets are compressed tablets covered in a sugar coating, which helps to mask unpleasant tastes or odors and protect the tablets from oxidation.

[0105] Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general properties as sugar coating. Multiple-compression tablets are compressed tablets prepared through more than one compression cycle, including layered tablets and compressed-coated or dry-coated tablets. In some embodiments, the tablets are coated with a water-soluble, pH-independent film coating that allows for rapid disintegration for rapid activity release (e.g., Opadry products).

[0106] Dosage in tablets

[0107] In some embodiments, the amount of compound 1 in the tablet is from about 1 mg to about 25 mg. In some embodiments, the amount of compound 1 in the tablet is about 1 mg. In some embodiments, the amount of compound 1 in the tablet is about 5 mg. In some embodiments, the amount of compound 1 in the tablet is about 12 mg. In some embodiments, the amount of compound 1 in the tablet is about 25 mg.

[0108] Administration method and treatment regimen

[0109] In one embodiment, the compound 1 described herein or a pharmaceutically acceptable salt thereof is used to prepare a medicament for treating a disease or condition in mammals that would benefit from administration of an FXR agonist. A method of treating any of the diseases or conditions described herein in mammals requiring such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition (i.e., a formulation) comprising the compound 1 described herein or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate.

[0110] This document discloses a method of administering an FXR agonist in combination with an adjunct therapy. In some embodiments, the adjunct therapy includes a therapeutic agent for treating diabetes or diabetes-related conditions, alcoholic or non-alcoholic liver disease, inflammatory bowel conditions, or proliferative disorders.

[0111] In some embodiments, a composition containing the compounds described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective amount for this use depends on the severity and duration of the disease or condition, prior treatment, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may optionally be determined through methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0112] In prophylactic applications, a composition containing the compounds described herein is administered to a patient who is susceptible to or at risk of a particular disease, condition, or illness. Such an amount is defined as a “preventative effective amount or dose.” In this application, the precise amount also depends on the patient’s health condition, weight, etc. When used on a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or illness, prior treatment, the patient’s health status and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition containing compound 1 or a pharmaceutically acceptable salt thereof to a mammal who has previously experienced at least one symptom of a treated disease and is currently in remission, to prevent recurrence of the symptoms of the disease or illness.

[0113] In some implementations where the patient’s condition does not improve, compound 1 is administered long-term, i.e., for an extended period of time, including throughout the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the physician’s judgment.

[0114] In some implementations where the patient's condition does improve, the dosage of the administered medication is temporarily reduced or temporarily discontinued for a certain period of time (i.e., a "medication holiday"). In specific implementations, the length of the medication holiday is between 2 days and 1 year, including, for example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example only, the dosage reduction during the medication holiday is 10%–100%, including, for example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0115] Once the patient's condition improves, a maintenance dose may be administered if necessary. Subsequently, in specific implementation schemes, the dose or frequency, or both, may be reduced to the level required to maintain improvement in the disease, condition, or illness, depending on the symptoms. However, in some implementation schemes, the patient requires long-term intermittent treatment whenever any symptoms recur.

[0116] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the person or host requiring treatment (e.g., weight, sex), but is still determined based on the specific circumstances surrounding the case, including, for example, the specific drug administered, the route of administration, the condition being treated, and the person or host being treated.

[0117] However, generally, the dosage for adult treatment is typically from 0.01 mg to 500 mg daily. In one aspect, the dosage for adult treatment is from about 1 mg to about 500 mg daily. In one embodiment, the desired dosage is conveniently presented as a single dose or as separate doses administered simultaneously or at appropriate intervals, for example, as sub-dose twice, three, four or more times daily.

[0118] In one embodiment, the daily dose suitable for compound 1 described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg body weight. In some embodiments, the daily dose or amount of active ingredient in the dosage form is lower or higher than the range shown herein, based on numerous variables relating to individual treatment regimens. In various embodiments, the daily dose and unit dose vary according to numerous variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the method of administration, the individual subject's needs, the severity of the disease or condition to be treated, and the physician's judgment.

[0119] The toxicity and efficacy of such treatment regimens are determined using standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining LD50. 50 and ED 50The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as LD50. 50 and ED 50 The ratio between. In some embodiments, data obtained from cell culture experiments and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range of ED with minimal toxicity. 50 Within the cyclic concentration range. In some embodiments, the daily dose range and / or unit dose vary within this range, depending on the dosage form and route of administration used.

[0120] In any of the foregoing aspects, further embodiments are provided in which an effective amount of the compound 1 described herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered locally to a mammal; and / or (f) administered neither systemically nor locally to a mammal.

[0121] Any of the foregoing aspects is a further implementation, including a single application of an effective amount of compound 1, including a further implementation wherein (i) the compound is applied once daily; or (ii) the compound is applied multiple times to mammals over a daily time span.

[0122] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of compound 1, including further embodiments in which (i) the compound is administered continuously or intermittently as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to mammals every 8 hours; (iv) the compound is administered to mammals every 12 hours; (v) the compound is administered to mammals every 24 hours. In further or alternative embodiments, the method includes a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; administration of the compound is resumed at the end of the drug holiday. In one embodiment, the length of the drug holiday is from 2 days to 1 year.

[0123] In some cases, it is appropriate to administer compound 1 or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

[0124] In one embodiment, the therapeutic efficacy of compound 1 is enhanced by the administration of an adjuvant (i.e., the adjuvant itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes treatment regimens) that also has therapeutic benefit.

[0125] In one specific implementation, compound 1 or a pharmaceutically acceptable salt thereof is administered co-administered with a second therapeutic agent, wherein compound 1 or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease, symptom, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent alone.

[0126] Example

[0127] List of abbreviations

[0128] As used above and throughout the description of this invention, unless otherwise specified, the following abbreviations shall be understood to have the following meanings:

[0129] ACN or MeCN acetonitrile

[0130] Bn benzyl

[0131] BOC or Boc tert-butylcarbamate

[0132] t-Bu tert-butyl

[0133] Cyclohexyl

[0134] DCE (dichloroethane) (ClCH2CH2Cl)

[0135] DCM (dichloromethane (CH2Cl2))

[0136] DIPEA or IEA (diisopropylethylamine)

[0137] DMAP 4-(N,N-dimethylamino)pyridine

[0138] DMF (dimethylformamide)

[0139] DMA N,N-dimethylacetamide

[0140] DMSO (dimethyl sulfoxide)

[0141] equivalent

[0142] Et Ethyl

[0143] Et2O diethyl ether

[0144] EtOH (ethanol)

[0145] EtOAc (ethyl acetate)

[0146] HPLC (High Performance Liquid Chromatography)

[0147] Me methyl

[0148] MeOH (methanol)

[0149] MS mass spectrometry analysis

[0150] NMR (Nuclear Magnetic Resonance)

[0151] RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography)

[0152] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-Trioxatriphosphacyclohexane-2,4,6-trioxide

[0153] TBME Methyl tert-butyl ether

[0154] TFA (trifluoroacetic acid)

[0155] THF Tetrahydrofuran

[0156] TLC (Thin Layer Chromatography)

[0157] I. Chemical Synthesis

[0158] Unless otherwise specified, reagents and solvents should be used as is, from the commercial supplier. Anhydrous solvents and dried glassware are used for synthetic transformations sensitive to moisture and / or oxygen. Yields are not optimized. Reaction times are approximate and not optimized. Unless otherwise specified, column chromatography and thin-layer chromatography (TLC) are performed on silica gel.

[0159] Example 1: Preparation of 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxaldehyde (intermediate 1)

[0160]

[0161] Step 1: 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-8-ol

[0162] Three batches were run in parallel: n-BuLi (762 mL, 1.90 mol, 2.5 M n-hexane solution) was added dropwise to a solution of 4-bromo-1-methoxy-2-toluene (333 g, 1.66 mol) and anhydrous THF (2 L) over 1 h at -60 °C in N2. The reaction was stirred at -60 °C for 1 h, followed by the dropwise addition of a solution of 1,4-dioxaspiro[4.5]dec-8-one (284.53 g, 1.82 mol) and anhydrous THF (1 L) over 45 min. The reaction was stirred at -60 °C for 1 h, and then the three batches were poured into a saturated aqueous solution of NH4Cl (3 L). The mixture was extracted with EtOAc (5 L × 2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then ground overnight in n-hexane (1.2 L) at room temperature. The mixture was filtered, the filter cake was washed with cold n-hexane (200 mL × 2), and then dried under vacuum to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxane[4.5]dec-8-ol (1100 g, 82%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.30-7.20(m,2H),6.74(d,1H),4.02-3.87(m,4H),3.78(s,3H) ),2.18(s,3H),2.15-2.00(m,4H),1.82-1.73(m,2H),1.68-1.60(m,2H),1.48(s,1H).

[0163] Step 2: 8-Allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane

[0164] Four batches were run in parallel: BF3·Et2O (376.95 g, 2.65 mol) was added to a solution of 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-8-ol (275 g, 0.99 mol), allyltrimethylsilane (180.62 g, 1.58 mol), and anhydrous DCM (3 L) at -65 °C in N2. The reaction mixture was stirred at -65 °C for 1 h, and then the four batches were carefully poured into a saturated aqueous solution of NaHCO3 (10 L). The mixture was extracted with DCM (5 L × 3). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, and concentrated to give 1350 g of 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane as a yellow oil. 1H NMR (400MHz, CDCl3): δ7.17-7.01(m,2H),6.85-6.75(m,1H),5.53-5.37(m,1H),5.01-4.85(m,2H),3.99-3.87(m, 4H),3.82(s,3H),2.37-2.29(m,1H),2.28-2.21(m,5H),2.20-2.10(m,2H),1.82-1.71(m,2H),1.70-1.52(m,3H).

[0165] Step 3: 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone

[0166] Three batches were run in parallel: Water (450 mL) and formic acid (285.95 g, 5.95 mol) were added sequentially to a solution of 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (450 g) and THF (1.8 L) at room temperature. The reaction mixture was refluxed overnight and cooled to room temperature, then the three batches were poured into a saturated aqueous solution of NaHCO3 (3 L). The mixture was extracted with EA (3 L × 3). The combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0-50 / 1) to give a yellow oily 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (800 g, 69.3%, in two steps). 1 H NMR (400MHz, CDCl3): δ7.16-7.06(m,2H),6.80-6.73(m,1H),5.48-5.30(m,1H),4.96 -4.79(m,2H),3.77(s,3H),2.48-2.35(m,2H),2.32-2.05(m,9H),1.89-1.77(m,2H).

[0167] Step 4: 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile

[0168] Three batches were run in parallel: t-BuOK (299.69 g, 2.67 mol) was added in portions to a solution of 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (230 g, 890.25 mmol), Tos-MIC (260.72 g, 1.34 mol), and DME (2 L) in N2 at 0 °C for 1 h (while maintaining an internal temperature <5 °C). The mixture was stirred at room temperature for 2 h, and then poured into a saturated NH4Cl aqueous solution (5 L) in three batches. The mixture was extracted with EtOAc (5 L × 2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether / EtOAc = 1 / 0-50 / 1) to give a yellow oily 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (508 g, 70.6%). 1 H NMR (400MHz, CDCl3): δ7.13-6.99(m,2H),6.83-6.75(m,1H),5.51-5.31(m,1H),5.03-4.85(m,2H),3.84 (s,3H),2.58-2.48(m,1H),2.38-2.02(m,7H),1.98-1.79(m,2H),1.78-1.56(m,3H),1.54-1.40(m,1H).

[0169] Step 5: 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile

[0170] Three batches were run in parallel: NMO (242.66 g, 2.07 mol) and subsequently K₂O₄·2H₂O (7.63 g, 20.71 mmol) were added to a solution of 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (186 g, 690.47 mmol), acetone (2 L), and H₂O (250 mL) at 0 °C. The reaction was heated to room temperature and stirred for 2 h. The three batches were poured into a saturated aqueous solution of Na₂SO₃ (4 L), and the mixture was extracted with EtOAc (3 L × 2). The combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether / EtOAc = 5 / 1-1 / 2) to give 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (600 g, 95.4%) as a yellow oil. 1HNMR (400MHz, CDCl3): δ7.21-7.01(m,2H),6.87-6.74(m,1H),3.83(s,3H),3.65-3.49(m,1H), 3.35-3.17(m,2H),2.60-2.45(m,1H),2.41-2.11(m,5H),2.01-1.81(m,4H),1.79-1.38(m,6H).

[0171] Step 6: 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanenitrile

[0172] Three batches were run in parallel: NaIO4 (169.20 g, 791.05 mmol) was added in portions (keeping the internal temperature <5 °C) to a solution of 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (200 g, 659.21 mmol), THF (2 L), and H2O (1 L) for 30 min at 0 °C. The mixture was stirred at room temperature for 3 h, and then the three batches were poured into water (2 L). The mixture was extracted with EtOAc (2 L × 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated to give 510 g of 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanenitrile as a colorless oil. 1 HNMR (400MHz, CDCl3): δ9.43-9.22(m,1H),7.20-6.99(m,2H),6.87-6.71(m,1H),3.82(s,3H), 2.63-2.48(m,2H),2.46-2.36(m,1H),2.33-2.13(m,4H),2.02-1.71(m,5H),1.71-1.57(m,2H).

[0173] Step 7: 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile

[0174] Three batches were run in parallel: NaBH4 (35.55 g, 939.73 mmol) was added to a solution of 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanenitrile (170 g) and THF (1.7 L) at 0 °C in N2. The mixture was stirred at room temperature for 3 h, and then the three batches were poured into ice water (3 L). The mixture was extracted with EtOAc (1.5 L × 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated to give 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (495 g) as a colorless oil. 1H NMR (400MHz, CDCl3): δ7.18-6.97(m,2H),6.88-6.71(m,1H),3.85-3.78(m,3H),3.76-3.70(m,1H),3.44-3.33(m,2H),2.71-2.69(m,0.5H), 2.60-2.48(m,0.5H),2.37-2.35(m,0.5H),2.27-2.19(m,3H),2.14-2. 12(m,0.5H),1.96-1.79(m,5H),1.78-1.61(m,3H),1.58-1.45(m,1H).

[0175] Step 8: 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile

[0176] Three batches were run in parallel: a solution of PPh3 (316.62 g, 1.21 mol) and DCM (1 L) was added dropwise to a solution of 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (165 g), CBr4 (300.24 g, 905.37 mmol), and DCM (1.5 L) for 1 h in N2 at 0 °C. The mixture was stirred at room temperature for 1.5 h, combined with two other batches, and concentrated. The crude product was milled overnight in MTBE (5 L) at room temperature. The solid was removed by filtration, the filter cake was washed with MTBE (500 mL × 2), the filtrate was concentrated, and then purified by silica gel chromatography (petroleum ether / EtOAc = 30 / 1) to give 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanenitrile (530 g, 80%) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.11-6.96(m,2H),6.86-6.73(m,1H),3.87-3.73(m,3H),3.09-2.93(m,2H),2.78-2.68(m,0.5H),2.62-2 .50(m,0.5H),2.38-2.34(m,1H),2.28-2.18(m,3H),2.17-2.10(m,2H),2.08-1.99(m,1H),1.99-1.79(m,3H),1.77-1.45(m,3H).

[0177] Step 9: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxynitrile

[0178] Three batches were run in parallel: LDA (420 mL, 840 mmol, 2 M THF solution) was added dropwise to a solution of 4-(2-bromoethyl)-4-(4-methoxy-3-methyl-phenyl)cyclohexanenitrile (143 g, 425.26 mmol), HMPA (381.03 g, 2.13 mol), and THF (1430 mL) for 1 h at -65 °C in N2. The mixture was stirred at -65 °C for 3 h, and then poured into saturated NH4Cl aqueous solution (5 L) in three batches. The mixture was extracted with EtOAc (3 L × 2). The combined organic layers were washed with water (3 L), washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then ground overnight at room temperature in EA:hexane (1:30, 775 mL). The mixture was filtered, and the filter cake was washed with EA:hexane (1:30, 150 mL) and dried under vacuum to give 240 g, 73% of 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxylonite as a yellow solid. 1 H NMR (400MHz, CDCl3): δ7.13-6.98(m,2H),6.83-6.73(m,1H),3.82(s,3H),2.22(s,3H),2.12-1.98(m,6H),1.94-1.80(m,6H).

[0179] Step 10: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxaldehyde

[0180] Three batches were run in parallel: DIBAL-H (1M PhMe, 830 mL, 830 mmol) was added to a DCM (1 L) solution of 4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-carboxylonitrile (106 g, 415.11 mmol) at -65 °C in N2. The mixture was stirred at -65 °C for 1 h, and then poured into saturated NaK tartrate aqueous solution (3 L) in three batches and diluted with DCM (1.5 L). The mixture was stirred at room temperature for 3 h. The organic layer was separated, and the aqueous phase was extracted with DCM (2 L × 2). The organic layers were combined, washed with brine (3 L), dried over Na2SO4, filtered, and concentrated to give 336 g of 4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-carboxaldehyde as a yellow solid. 1H NMR (400MHz, DMSO-d6): δ9.50-9.43(m,1H),7.11-7.00(m,2H),6.83-6.79(m,1 H),3.77-3.68(m,3H),2.18-2.02(m,3H),1.82-1.72(m,6H),1.71-1.60(m,6H).

[0181] Step 11: Potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methanesulfonate

[0182] Six batches were run in parallel: a 2M, 54mL, 108mmol aqueous solution of potassium metabisulfite was added to a 300mL THF solution of 56g of 4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-carboxaldehyde at 45°C for 10min. The mixture was stirred at 45°C for 3.5h, cooled to room temperature, and then stirred overnight at room temperature. The six batches were filtered, and the filter cakes were washed with PE (400mL) and dried under vacuum to give potassium hydroxy(4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-yl)methanesulfonate (381g, 81%, in two steps) as a white solid. 1 H NMR (400MHz, DMSO-d6)7.12-6.97(m,2H),6.88-6.71(m,1H),4.51(d,1H),3.73(s,3H),3.56(d,1H),2.11(s,3H),1.88-1.56(m,12H).

[0183] Step 12: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxaldehyde

[0184] Six batches were run in parallel: 300 mL of saturated Na₂CO₃ aqueous solution was added to a mixture of potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methanesulfonate (63.5 g, 167.76 mmol) and DCM (300 mL) at room temperature in N₂. The mixture was stirred for 1 h, and then the six batches were poured into a mixture of DCM (1500 mL) and H₂O (1500 mL). The organic layers were separated, and the aqueous phase was extracted with DCM (1500 mL × 3). The combined organic layers were washed with brine (2 L), dried over Na₂SO₄, filtered, and concentrated to give 240.3 g, 92%, of 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxaldehyde as a white solid. 1H NMR (400MHz, DMSO-d6): δ9.52-9.41(m,1H),7.14-7.02(m,2H),6.84-7.80(m,1H), 3.73(s,3H),2.12(s,3H),1.83-1.72(m,6H),1.71-1.56(m,6H); LCMS:259.1[M+H] + .

[0185] Example 2: Preparation of 4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-amine (intermediate 2)

[0186]

[0187] 2-Methyltetrahydrofuran (10 mL), Pd(dppf)Cl2, and subsequently an aqueous solution of K2CO3 (3 M, 10 mL, 30 mmol) were added to a 40 mL vial containing 4-bromopyridine-2-amine (1.87 g, 10.8 mmol) and 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (2.50 g, 10.0 mmol). The reaction was degassed with three vacuum / N2 cycles, heated at 50 °C for 21 h, and then cooled to room temperature. The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaK tartrate (25 mL), followed by a wash with brine (25 mL). The aqueous layer was back-extracted with 2-methyltetrahydrofuran (25 mL). The combined organic matter was dried (MgSO4), filtered, concentrated, and then dried under vacuum for 1 h. The suspension of crude material and MTBE (25 mL) was refluxed for 2 h, cooled to room temperature overnight, and then filtered. The filter cake was washed with MTBE (2 × 3 mL) and then dried under vacuum to give 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine-2-amine (1.15 g, 53%). 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.86-7.82(m,2H),6.74(d,1H),6.61(s,1H),5.77(s,2H),1.54(s,9H); LCMS:217.1[M+H] + .

[0188] Example 3: Preparation of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (intermediate 3)

[0189]

[0190] Step 1: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate tert-butyldimethylsilyl ester

[0191] In N2 at room temperature, tert-butyldimethylchlorosilane (31.47 g, 208.8 mmol) was added to a mixture of trans-4-hydroxycyclohexanecarboxylic acid (10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol), and DMF (140 mL) (the reaction was exothermic to 32 °C). The reaction mixture was stirred at room temperature for 2 h, then diluted with diethyl ether (300 mL). The organic layer was washed (2 × 300 mL 1N HCl, then 300 mL brine), dried (Na2SO4), filtered, and concentrated to give a clear, oily tert-butyldimethylsilyl ester of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (31.5 g). 1 H NMR (400MHz, DMSO-d6): δ3.61-3.53(m,1H),2.26-2.18(m,1H),2.04-1.96(m,2H),1.92-1.85(m ,2H),1.51-1.39(m,2H),1.39-1.27(m,2H),0.94(s,9H),0.89(s,9H),0.26(s,6H),0.06(s,6H).

[0192] Step 2: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid

[0193] In nitrogen at room temperature, a solution of potassium carbonate (58.01 g, 419.7 mmol) in H₂O (300 mL) was added to a mixture of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate tert-butyldimethylsilyl ester (31.5 g crude, 69.6 mmol), ethanol (1000 mL), and THF (300 mL). The reaction mixture was stirred at room temperature for 3 h, concentrated to a final volume of 300 mL, diluted with brine (600 mL), and then acidified to pH 2–3 with 20% NaHSO₄ (550 mL). The aqueous layer was extracted with diethyl ether (800 mL). The organic layer was washed (800 mL brine), dried (Na2SO4), filtered, concentrated, and dried under high vacuum (to remove silanol byproducts) to obtain trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (17.3 g, 96%, in 2 steps) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.30 (br s,1H),3.59-3.51(m,1H),2.15-2.05(m,1H),1.88-1.74(m,4H),1.41-1.29(m,2H),1.28-1.16(m,2H),0.84(s,9H),0.02(s,6H).

[0194] Example 4: Preparation of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4- (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclo Hexyl ester (compound 1)

[0195]

[0196] Step 1: 4-(1-(tert-butyl)-1H-pyrazole-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)pyridine-2-amine

[0197] A mixture of intermediate 1 (1.0 equivalent) and intermediate 2 (1.1 equivalent) in methanol (7.5 v / L) and acetic acid (0.33 equivalent) was heated at 55 °C for at least 3 h. The reaction mixture was cooled to room temperature, and a solid 2-methylpyridineborane complex (1.0 equivalent) was added over at least 20 min. The reaction was stirred overnight at room temperature, and water (12.0 v / L) was added over at least 60 min. The suspension was stirred for at least 2 h. The solid was collected by filtration, washed with water / methanol (2:1) (2 × 1 v / L), TBME (2 × 2 v / L), and heptane (2 × 2 v / L), and dried in a rotary evaporator at 50 °C to give 4-(1-(tert-butyl)-1H-pyrazole-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)pyridine-2-amine.

[0198] Steps 2 and 3: trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)cyclohexaneformamide

[0199] A solution of T3P in dichloromethane (2.0 equivalents) was added to a mixture of 4-(1-(tert-butyl)-1H-pyrazole-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridine-2-amine (1.0 equivalents) and intermediate 3 (1.2 equivalents) in dichloromethane (7.5 volumes) and triethylamine (4.0 equivalents) for 0.5 h at 0 °C. The reaction mixture was warmed to room temperature and stirred for at least 12 h. The reaction mixture was cooled to 5 °C and quenched by adding 2 parts of water (0.05 volumes and 6.0 volumes). The mixture was warmed to room temperature and stirred for at least 2 h. The organic layer was collected and washed with water. The dichloromethane solvent was replaced with 2-methyltetrahydrofuran (5.4 volumes) under vacuum. Methanol (2.4 volumes) and water (2 volumes) were added to the solution, followed by an aqueous solution of HCl (32%) (1.9 equivalents). The reaction mixture was stirred at room temperature for at least 2 hours. A 9.5% NaHCO3 aqueous solution (4 volumes) was added to the mixture. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated. The filtrate was concentrated under vacuum and TBME (9 volumes) was added. The solid was collected by filtration, washed with TBME and heptane, and dried under vacuum at 60 °C to give trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)cyclohexaneformamide.

[0200] Step 4: 3-Hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester (Compound 1)

[0201] Add 1,1'-carbonyldiimidazole (1.5 equivalents) to a dichloromethane (8.0 v / v) solution of trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)cyclohexanecarboxamide. Stir the mixture at room temperature for at least 3.5 h. Add 3-hydroxyazacyclobutane hydrochloride (3.0 equivalents) to the solution at room temperature, followed by iPr2NEt (7.0 equivalents). Stir the reaction mixture at room temperature for at least 2.5 h. Quench the reaction with 4.5% NaHCO3 aqueous solution (6.0 v / v). Collect the organic layer, and extract the aqueous layer once with dichloromethane (2.0 v / v). Add methanol (0.8 v / v), wash the combined organic layers twice with 20% NH4Cl solution (4.0 v / v), and wash twice with water (4.0 v / v). Dry the organic layers (Na2SO4) and replace the dichloromethane solvent with ethyl acetate (4 v / v). Slowly add heptane (4 v / v). Collect the crude product by filtration and wash with ethyl acetate:heptane (1:1). Dry the crude product under vacuum at 55 °C. Purify the crude product in a hot ethyl acetate slurry (5 v / v) and collect by filtration. Wash the product with ethyl acetate and dry under vacuum at 55 °C to give 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester (compound 1).

[0202] II. Spray-dried dispersion of compound 1

[0203] Example 5: Screening of Compound 1 / Polymer Combinations

[0204] Polymer-based spray-dried dispersions of Compound 1 were developed. Several Compound 1 / polymer combinations were screened and evaluated using computational models. The evaluated polymers were PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMCE5, HPMCP-HP55, and Soluplus. Evaluation of the Compound 1 / polymer combinations included: 1) miscibility assessment – ​​computer simulations were performed under different stable carriers and drug loadings to assess phase separation tendency; 2) API / polymer solubility confirmation – a range of compatible solvent systems were tested for each lead condition; 3) solvent casting – solvent casting experiments were conducted under different stable carriers and drug loadings to further narrow down formulation variables; and 4) supersaturation studies – precipitation inhibition of different stable carriers was evaluated using solvent displacement methods. Based on screening studies, compound 1 and PVP / VA 64 60% (w / w) and compound 1 and HPMCAS-M 60% (w / w) were scaled up proportionally.

[0205] Example 6: Laboratory-scale prototype fabrication of compound 1 / polymer combination

[0206] Spray drying. The feed solution was dried using a laboratory-scale spray dryer (Buchi B-290 spray dryer). This unit was equipped with a dual-fluid nozzle with nozzle tips and caps of 0.7 mm and 1.5 mm, respectively. The spray dryer operated in an open-loop configuration under nitrogen (i.e., without recirculation of the drying nitrogen) and the suction pump was blown at 100% capacity.

[0207] Secondary drying. A laboratory-scale vacuum disc dryer was used to reduce the residual solvent content of the wet spray-dried dispersion. A secondary drying process was performed at 50°C for 48 hours under vacuum and nitrogen purging.

[0208] Solution preparation. Solutions for manufacturing spray-dried dispersions using the PVP / VA 64 and HPMCAS-M prototypes were prepared according to the following general procedure: the total amount of solvent was loaded into an empty container; the total amount of polymer was slowly added while stirring; stirring was continued until the polymer was completely dissolved; the total amount of Compound 1 was slowly added while stirring; and stirring was continued until Compound 1 was completely dissolved. Representative solutions of Compound 1 and HPMCAS-M and Compound 1 and PVP / VA 64 were prepared according to the amounts and ratios in Table 1 below (where “C_feed” = solids content in the feed mixture [% w / w], and “C_compound 1” = content of Compound 1 in the feed mixture [% w / w]):

[0209] Table 1. Solutions used for prototype fabrication of spray-dried dispersions

[0210] Quantity and ratio Compound 1 / (HPMCAS-M) Compound 1 / (PVP / VA 64) 1 g of compound 19 24 HPMCAS M g 12.66 - PVP / VA 64g - 16 dichloromethane g 254.4 324 methanol g 28.5 36 Total solids (g) 31.66 40.0 Total liquid g 284.9 360 Compound 1 loading % w / w 60 60 C_feed%w / w 10 10 C compound 1% w / w 6 6

[0211] result

[0212] The main process data and analysis results are summarized in Table 2 below (where “T_feed” = temperature of feed solution [°C], “F_drying” = flow rate of drying gas in spray dryer [kg / h], “F_atomizing” = flow rate of atomizing gas [g / min], “T_outlet” = temperature of drying gas at the outlet of drying chamber [°C], “F_feed” = flow rate of feed solution in spray dryer [kg / h], “GC” = gas chromatography, “KF” = Karl Fischer, “TFN” = two-fluid nozzle, and “PSD” = particle size distribution):

[0213] Table 2. Key process data and analysis results from the prototype manufacturing of spray-dried dispersions

[0214]

[0215] Both spray-dried dispersions (compound 1: HPMCAS-M and compound 1: PVP / VA 64) were amorphous after secondary drying, as indicated by the absence of crystallization peaks (XRPD) and the endothermic melting characteristics (DSC) of crystalline materials.

[0216] Example 7: Stability study of spray-dried dispersion of compound 1

[0217] Both spray-dried dispersions of Compound 1 (Compound 1: HPMCAS-M and Compound 1: PVP / VA 64) were stored in capped vials at 40°C / 75% RH for one month. No chemical degradation was observed in either spray-dried dispersion. Furthermore, the amorphous state of each spray-dried dispersion was maintained.

[0218] Example 8: Development of a tablet formulation of compound 1SDI

[0219] First, the compatibility of compound 1API (amorphous form) with various excipients was evaluated. These compatibility studies were conducted for one month in a closed container at 40°C / 75% RH. At the end of the studies, no detectable changes in assays, related substances, or appearance were observed. Compound 1API was determined to be compatible with the following: Avicel (microcrystalline cellulose), Tablettose (lactose monohydrate), Pearlitol (mannitol), Compitrol (glyceryl behenate), Acdisol (crosslinked sodium carboxymethyl cellulose), Polyplasdone XL (crosspovidone), magnesium stearate, and Cab-o-sil (colloidal silica).

[0220] As outlined in Table 3, four compound 1 formulation matrices were prepared using spray-dried intermediates (SDI) PVP / VA and HPMCAS. Tablet formulation blends and tablets were prepared, and their tabletability profile, compressibility profile, disintegration time, friability, and biorelevant dissolution were evaluated. The only difference between the two formulations tested with each SDI was the disintegrant. The disintegrant is an important component in SDI-containing tablets because the SDI polymer can also be used as a binder. The disintegrant may be key to overcoming the binder effect of the SDI polymer to facilitate drug release.

[0221] Table 3. Formulation matrix of Compound 1 tablet formulation

[0222]

[0223] SDI: Spray-dried intermediate; API: Active pharmaceutical ingredient

[0224] Compressibility and compressibility profiles were obtained for each of the four formulations. All four formulations were produced using typical compression pressures such as 100-200 MPa to produce tablets with high tensile strength (e.g., hardness ≥ 1.7 MPa). Biorelevant dissolution profiles for the four tablet formulations showed that all formulations could be compressed into high-quality tablets.

[0225] Two prototype 5 mg tablets were prepared from tablet formulations A and C. These tablets were used for pharmacokinetic studies in monkeys (n = 12 / formulation). Compound 1 was adequately absorbed from both tablet formulations. Figure 1 ).

[0226] Example 9: Compound 1 SDI tablet formulation – 5 mg and 25 mg tablets

[0227] The ingredients in Formulation A of Example 8 were increased by 5 times to produce 25mg tablets.

[0228] Table 4. Formulations of Compound 1 tablets (5 mg and 25 mg)

[0229]

[0230] API: Active pharmaceutical ingredient

[0231] Example 10: Compound 1 SDI tablet formulation – 1 mg tablet

[0232] Since the amount of compound 1SDI in 1 mg of the blend is less than 2%, the blend is prepared by a three-stage geometric dilution to provide a homogeneous mixture. This method requires the following steps:

[0233] 1. Pre-blend #1: Sift the required amount of compound 1SDI for the batch and double the amount of microcrystalline cellulose (MCC). Mix pre-blend #1.

[0234] 2. Premix #2: Add MCC equivalent to twice the weight of premix #1, and then mix.

[0235] 3. Pre-blend #3: Add MCC equivalent to twice the weight of pre-blend #2 to the blend and then mix.

[0236] 4. Add the remaining required amounts of MCC, lactose monohydrate, croscarmellose sodium, and colloidal silica to the blend and mix. Evaluate the blend using blend homogeneity analysis (BUA).

[0237] 5. Once BUA meets the requirements, sieve half of the batch of magnesium stearate, add it to the blend from step 4, and mix.

[0238] 6. Granulate the blend from step 5 by roll pressing. Remove a sample to measure bulk density (BD), tap density (TD), and particle size distribution (PSD). Then, add the remaining half of the required batch of magnesium stearate to the dry-granulated blend and mix.

[0239] 7. Compress the blend from step 6 into tablets (round; 100 mg target weight).

[0240] 8. Coat the compressed tablets in a pot coating machine.

[0241] 9. Take samples of the final coated sheets for quality and stability testing, and bottle and cap the remaining bulk portion.

[0242] Table 5. Formulation of Compound 1 tablet (1 mg)

[0243]

[0244] Example 11: Compound 1 SDI tablet formulation – 12mg tablet

[0245] When tablet strength increased beyond 5 mg of Compound 1 and 3.3 mg PVP / VA per 100 mg tablet, the increased amount of polymer inhibited drug release by acting as a binder. As a result, increasing the amount of cross-linked sodium carboxymethyl cellulose from 5% to 10% and decreasing the percentages of microcrystalline cellulose and lactose monohydrate resulted in an improved release profile for Compound 1. Figure 2 ).

[0246] Table 6. Formulation of Compound 1 tablet (12 mg)

[0247]

[0248] III. Compound 1 FXR Activity

[0249] Example 12: In vitro FXR assay (TK)

[0250] Seeding

[0251] CV-1 cells were seeded at a density of 2,000,000 cells in T175 flasks with DMEM and 10% carbon double-peeled FBS and incubated at 37°C in 5% CO2 for 18 h (O / N).

[0252] transfection

[0253] After 18 hours of culture, the culture medium in the T175 flask was replaced with fresh DMEM + 10% activated charcoal to remove serum. In a polypropylene tube, 2500 μL of OptiMEM (Life Technologies, Cat#31985-062) was combined with expression plasmids of hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP. The tube was then briefly vortexed and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP, Roche, catalog number 06366236001) was added to the vortexed OptiMEM / plasmid mixture and incubated at room temperature for 20 minutes. After incubation, the transfection reagent / DNA mixture complex was added to the cells in the T175 flask, and the cells were incubated at 37°C in 5% CO2 for 18 hours (O / N).

[0254] Add compound 1

[0255] Compound 1 was serially diluted in DMSO and added to transfected CV-1 cells. The cells were then incubated for 18 hours. Cells were lysed the next day and examined for luminescence. Compound 1 TK hFXR:EC 50 ≤0.01μM.

Claims

1. A spray-dried solid dispersion comprising: (a) 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester and (b) a pharmaceutically acceptable polymer; wherein 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl ester is dispersed in a polymer matrix formed of the pharmaceutically acceptable polymer; The pharmaceutically acceptable polymers mentioned therein are selected from PVP / VA 64 and HPMCAS-M; The weight ratio of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester to the pharmaceutically acceptable polymer is about 1.5:1, and the term "about" means that the numbers or numerical ranges mentioned are approximate values ​​within experimental variability or within statistical experimental error. Therefore, the range of numbers or values ​​may vary between 1% and 15% of that range.

2. The spray-dried solid dispersion according to claim 1, wherein the pharmaceutically acceptable polymer is PVP / VA 64.

3. The spray-dried solid dispersion according to claim 1, wherein the pharmaceutically acceptable polymer is HPMCAS-M.

4. The spray-dried solid dispersion according to any one of claims 1-3, further comprising a non-aqueous solvent.

5. The spray-dried solid dispersion according to claim 4, wherein the non-aqueous solvent is selected from tert-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof.

6. The spray-dried solid dispersion according to claim 5, wherein the non-aqueous solvent is selected from ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof.

7. The spray-dried solid dispersion according to claim 6, wherein the non-aqueous solvent is a mixture of dichloromethane and methanol.

8. The spray-dried solid dispersion according to any one of claims 1-3, wherein 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester is substantially amorphous.

9. The spray-dried solid dispersion according to any one of claims 1-3, wherein 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester is crystalline.

10. A pharmaceutical formulation comprising a spray-dried solid dispersion according to any one of claims 1-9 and optionally one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more flow aids, and one or more surfactants.

11. The pharmaceutical formulation of claim 10, wherein one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silica, mannitol, crospovidone, and sodium stearate fumarate.

12. The pharmaceutical formulation of claim 11, wherein one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silica.

13. The pharmaceutical formulation of claim 10, wherein the pharmaceutical formulation is in tablet form.

14. The pharmaceutical formulation of claim 13, wherein the tablet comprises 1% to 30% by weight of the spray-dried solid dispersion.

15. The pharmaceutical formulation of claim 14, wherein the tablet comprises 5% to 25% by weight of the spray-dried solid dispersion.

16. The pharmaceutical formulation of claim 13, wherein the tablet comprises 1% to 20% by weight of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester.

17. The pharmaceutical formulation of claim 13, wherein the tablet comprises about 1 mg, about 5 mg, about 12 mg, or about 25 mg of 3-hydroxyazacyclobutane-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)carbamoyl)cyclohexyl ester, wherein the term "about" means that the mentioned number or numerical range is an approximation within experimental variability or within statistical experimental error, and therefore the number or numerical range varies between 1% and 15% of that number or numerical range.

18. The pharmaceutical preparation of claim 10, wherein the pharmaceutical preparation is in capsule form.

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