WO2023228023A1 - Traitement du diabète de type 2 ou contrôle de la gestion du poids avec de l'acide 2-((4-((s)-2-(5-chloropyridin-2-yl)-2-méthylbenzo[d][1,3]dioxol-4-yl)pipéridin-1-yl)méthyl)-1-(((s)-oxétan-2-yl)méthyl)-1h-benzo[d]imidazole-6-carboxylique ou un sel pharmaceutique de celui-ci - Google Patents

Traitement du diabète de type 2 ou contrôle de la gestion du poids avec de l'acide 2-((4-((s)-2-(5-chloropyridin-2-yl)-2-méthylbenzo[d][1,3]dioxol-4-yl)pipéridin-1-yl)méthyl)-1-(((s)-oxétan-2-yl)méthyl)-1h-benzo[d]imidazole-6-carboxylique ou un sel pharmaceutique de celui-ci Download PDF

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Publication number
WO2023228023A1
WO2023228023A1 PCT/IB2023/055132 IB2023055132W WO2023228023A1 WO 2023228023 A1 WO2023228023 A1 WO 2023228023A1 IB 2023055132 W IB2023055132 W IB 2023055132W WO 2023228023 A1 WO2023228023 A1 WO 2023228023A1
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Prior art keywords
methyl
compound
oxetan
chloropyridin
methylbenzo
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PCT/IB2023/055132
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English (en)
Inventor
Clare BUCKERIDGE
Kai Teck LEE
Sweta MANTHENA
Ruchi Avinash THOMBRE
Hugh Michael VERRIER
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Pfizer Inc.
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Publication of WO2023228023A1 publication Critical patent/WO2023228023A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention provides a method for treating type 2 diabetes mellitus or for weight management control (e.g. treating obesity or overweight) by administering to a mammal (e.g. a human) in need thereof a pharmaceutical composition as an oral dosage form once-daily, wherein the pharmaceutical composition contains 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically salt thereof [such as its 2-amino-2- (hydroxymethyl)propane-1 ,3-diol salt, also known as its tris salt].
  • the invention provides oral compositions/formulations for the methods of treatment described herein.
  • Type 1 diabetes develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump.
  • Type 2 diabetes mellitus (referred to generally as T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.
  • Insulin secretogogues including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1 R) agonists (e.g., liraglutide, al biglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells.
  • sulphonyl-ureas e.g., glipizide, glimepiride, glyburide
  • Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia.
  • DPP-IV inhibitors have limited efficacy.
  • Marketed GLP-1R agonists are peptides primarily administered by subcutaneous injection. Semaglutide and liraglutide are additionally approved for the treatment of obesity.
  • Biguanides e.g., metformin
  • Biguanides are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis.
  • Inhibitors of alpha-glucosidase decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances.
  • Thiazolidinediones e.g., pioglitazone, rosiglitazone
  • act on a specific receptor peroxisome prol iterator-activated receptor-gamma
  • Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hypoglycemia.
  • SGLT2 sodium-glucose linked transporter cotransporter 2
  • inhibitors e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin
  • This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.
  • Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.
  • T2DM is most commonly associated with hyperglycemia and insulin resistance
  • diseases, disorders, and/or conditions associated with T2DM include, for example, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, NASH, fibrosis, cirrhosis and ultimately hepatocellular carcinoma.
  • NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids.
  • the severity of NAFLD/NASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with fatty liver disease (e.g. steatosis or NAFLD) progress to NASH, a substantial proportion do.
  • GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17 (2): 93-102).
  • GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).
  • GLP-1 receptor agonists such as GLP-1 , liraglutide and exendin-4
  • FPG and PPG fasting and postprandial glucose
  • Compound 1 is a GLP1 agonist.
  • Compound 1 was designated as 2-( ⁇ 4-[2-(5-chloropyridin-2-yl)-2-methyl- 1,3-benzodioxol-4-yl]piperidin-1-yl ⁇ methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6- carboxylic acid, DIAST-X2:
  • DIAST-X2 wherein the chiral center on the left part of the compound structure is marked as “abs” to indicate that chiral center has only one stereo-configuration (i.e. , not a racemate with respect to that chiral center).
  • WO2021116874 International Application No. PCT/IB2020/061585 filed December 07, 2020 reported a hydrate crystalline form (for example, a monohydrate crystalline form, such as Form 2 or Form 3) and an amorphous form of tris salt of Compound 1.
  • the present invention provides, in part, a method for treating type 2 diabetes mellitus (T2DM) comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((
  • the present invention further provides a method for weight management control (such as for treating obesity or overweight) comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-
  • the present invention further provides an immediate-release oral pharmaceutical composition (e.g. a tablet) comprising: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant.
  • This immediate-release oral pharmaceutical composition of the invention can also be used in the methods of treatment of the invention provided herein.
  • FIG. 1 shows a flow diagram of the preparation process of tris salt of Compound 1 immediate release tablets (strength equivalent to 1 mg, 10 mg, 20 mg, 60 mg, or 100 mg Compound 1) in Example 1.
  • FIG. 2 shows a diagram for the Compounding Process of tris salt of Compound 1 oral solutions in Example 2.
  • FIG. 3 shows overall study design with actual implementation of the clinical study in Example 3.
  • the present invention provides a method for treating T2DM comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1 -yl)methyl)-1-(((S)
  • Embodiment A2 is a further embodiment of Embodiment A1 , wherein the pharmaceutical composition is present in an oral solution form or in a solid oral dosage form.
  • Embodiment A3 is a further embodiment of Embodiment A1 or A2, wherein the pharmaceutical composition is present in a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.
  • a solid oral dosage form which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.
  • Embodiment A4 is a further embodiment of any one of Embodiments A1 to A3, wherein the pharmaceutical composition is in an immediate-release solid dosage form.
  • immediate release or its abbreviated term “IR” [for example, in “immediate release tablet”] corresponds to the definition provided in European Pharmacopeia 6.0, part 01/2008: 1502 as relating to "conventional-release dosage forms” or “immediate- release dosage forms” in the form of a tablet showing a release of the active substance, which is not deliberately modified by a special formulation design and/or manufacturing method, thereby being distinct from “modify-release", “prolong-release”, “delayed-release” and “pulsatile- release” dosage forms as defined in European Pharmacopeia 6.0. , part 01/2008: 1502.
  • immediate release or "IR” means a release quantity of the active pharmacological ingredient of at least 75% within 30 minutes, as determined according to the USP release method using apparatus 2 (paddle), i.e. having a Q value (30 minutes) of at least 75 %.
  • Embodiment A5 is a further embodiment of any one of Embodiments A1 to A4, wherein the pharmaceutical composition is in an immediate-release tablet dosage form.
  • Embodiment A6 is a further embodiment of any one of Embodiments A1 to A5, wherein the pharmaceutical composition includes one or more tablets.
  • Embodiment A7 is a further embodiment of any one of Embodiments A1 to A6, wherein the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, for example, about 20 mg to about 280 mg of Compound 1 , about 20 mg to about 260 mg of Compound 1 , about 20 mg to about 240 mg of Compound 1 , about 20 mg to about 220 mg of Compound 1 , about 20 mg to about 200 mg of Compound 1 , about 20 mg to about 180 mg of Compound 1 , about 20 mg to about 120 mg of Compound 1 , about 20 mg to about 100 mg of Compound 1 , about 20 mg to about 80 mg of Compound 1 , about 20 mg to about 60 mg of Compound 1 , about 20 mg to about 40 mg of Compound 1 , about 20 mg to about 30 mg of Compound 1 , about 30 mg to about 260 mg of Compound 1 , about 30 mg to about 240 mg of Compound 1 , about 30 mg to about 180 mg
  • the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, about 20 mg to about 260 mg of Compound 1 , or about 60 mg to about 200 mg of Compound 1. In some yet further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 20 mg to about 260 mg of Compound 1 , or about 60 mg to about 200 mg of Compound 1.
  • Embodiment A8 is a further embodiment of any one of Embodiments A1 to A7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, tris salt of Compound 1
  • Embodiment A9 is a further embodiment of any one of Embodiments A1 to A7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is tris salt of Compound 1.
  • Embodiment A10 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in a crystalline form.
  • Embodiment A11 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in a monohydrate crystalline form.
  • Embodiment A12 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in Form 3, wherein Form 3 is a monohydrate form which has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8; and Form 3 has a 13 C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ⁇ 0.2 ppm.
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined herein.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).
  • Embodiment A13 is a further embodiment of any one of Embodiments A1 to A12, wherein the method for treating T2DM includes improving glycemic control.
  • Embodiment A14 is a further embodiment of any one of Embodiments A1 to A13, wherein the method for treating T2DM includes reducing the fasting plasma glucose level of the human, for example, to about 126 mg/dL or lower.
  • Embodiment A15 is a further embodiment of any one of Embodiments A1 to A14, wherein the method treating T2DM includes reducing glycated hemoglobin (HbA1c), for example, to about 7.0 % or less, about 6.5% or less, or about 5.7% or less.
  • HbA1c glycated hemoglobin
  • Embodiment A16 is a further embodiment of any one of Embodiments A1 to A15, wherein the method treating T2DM includes reducing the mean daily glucose level to about 157 mg/dL or less.
  • Embodiment A17 is a further embodiment of any one of Embodiments A1 to A16, wherein the method for treating T2DM has low risk of hypoglycemia.
  • Embodiment A18 is a further embodiment of any one of Embodiments A1 to A17, wherein the method further includes administering to the human an additional therapeutic agent.
  • Embodiment A19 is a further embodiment of any one of Embodiments A1 to A18, wherein the method is an adjunct to a reduced-calorie diet and/or increased physical activity.
  • the invention provides a method for weight management control (including e.g.
  • a method for treating obesity or overweight comprising once-daily administering to a human in need thereof a pharmaceutical composition
  • the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 180 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1
  • Embodiment B2 is a further embodiment of Embodiment B1, wherein the pharmaceutical composition is present in an oral solution form or in a solid oral dosage form.
  • Embodiment B3 is a further embodiment of Embodiment B1 or B2, wherein the pharmaceutical composition is present in a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.
  • a solid oral dosage form which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.
  • Embodiment B4 is a further embodiment of any one of Embodiments B1 to B3, wherein the pharmaceutical composition is in an immediate-release solid dosage form.
  • Embodiment B5 is a further embodiment of any one of Embodiments B1 to B4, wherein the pharmaceutical composition is in an immediate-release tablet dosage form.
  • Embodiment B6 is a further embodiment of any one of Embodiments B1 to B5, wherein the pharmaceutical composition includes one or more tablets.
  • Embodiment B7 is a further embodiment of any one of Embodiments B1 to B6, wherein the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, for example, about 20 mg to about 280 mg of Compound 1 , about 20 mg to about 260 mg of Compound 1 , about 20 mg to about 240 mg of Compound 1 , about 20 mg to about 220 mg of Compound 1 , about 20 mg to about 200 mg of Compound 1 , about 20 mg to about 180 mg of Compound 1 , about 20 mg to about 120 mg of Compound 1 , about 20 mg to about 100 mg of Compound 1 , about 20 mg to about 80 mg of Compound 1 , about 20 mg to about 60 mg of Compound 1 , about 20 mg to about 40 mg of Compound 1 , about 20 mg to about 30 mg of Compound 1 , about 30 mg to about 260 mg of Compound 1 , about 30 mg to about 240 mg of Compound 1 , about 30 mg to about 180 mg
  • the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, about 20 mg to about 260 mg of Compound 1 , or about 80 mg to about 260 mg of Compound 1. In some yet further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 20 mg to about 260 mg of Compound 1 , or about 80 mg to about 260 mg of Compound 1.
  • Embodiment B8 is a further embodiment of any one of Embodiments B1 to B7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, tris salt of Compound 1
  • Embodiment B9 is a further embodiment of any one of Embodiments B1 to B7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is tris salt of Compound 1.
  • Embodiment B10 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in a crystalline form.
  • Embodiment B11 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in a monohydrate crystalline form.
  • Embodiment B12 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in Form 3, wherein Form 3 is a monohydrate form which has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8; and Form 3 has a 13 C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ⁇ 0.2 ppm.
  • Embodiment B12 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial body mass index (BMI) of the human is 24 kg/m 2 or greater (the initial BMI is the BMI when the weight management control starts). In some further embodiments, the initial BMI of the human is 24 kg/m 2 to 30 kg/m 2 .
  • BMI body mass index
  • Embodiment B13 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial BMI of the human is 27 kg/m 2 or greater.
  • Embodiment B14 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial BMI of the human is 30 kg/m 2 or greater. In some further embodiments, the initial BMI of the human is 30.0 kg/m 2 to 45 kg/m 2 .
  • a human with a BMI of 30 kg/m 2 or greater is obese (i.e. suffering from obesity).
  • a human with a BMI of 25.0 to 29.9 kg/m 2 is overweight (i.e. suffering from overweight/having the condition of overweight).
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined herein.
  • treating also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).
  • weight management control includes treating obsesity or overweight.
  • Embodiment B15 is a further embodiment of any one of Embodiments B1 to B14, wherein the human has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
  • weight-related comorbidity e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia.
  • Embodiment B16 is a further embodiment of any one of Embodiments B1 to B12, wherein the human is overweight and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
  • Embodiment B17 is a further embodiment of any one of Embodiments B1 to B12, wherein the human has obesity and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).
  • Embodiment B18 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.
  • Embodiment B19 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 5%, 6%, 7%, 8%, 9%, or 10%.
  • Embodiment B20 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 8%, 9%, 10%, 11 %, 12%, 13%, 14%, or 15%.
  • Embodiment B21 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 10%, 15%, 20%, 25%, or 30%.
  • Embodiment B22 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.
  • BMI body mass index
  • Embodiment B23 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 8%, 9%, 10%, 11 %, 12%, 13%, 14%, or 15%.
  • BMI body mass index
  • Embodiment B24 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 10%, 15%, 20%, 25%, or 30%.
  • BMI body mass index
  • Embodiment B25 is a further embodiment of any one of Embodiments B1 to B24, wherein the method further includes administering to the human an additional therapeutic agent.
  • Embodiment B26 is a further embodiment of any one of Embodiments B1 to B25, wherein the method is an adjunct to a reduced-calorie diet and/or increased physical activity.
  • the present invention provides an immediate- release oral pharmaceutical composition comprising:
  • Embodiment C2 is a further embodiment of Embodiment C1 , wherein the oral pharmaceutical composition comprises microcrystalline cellulose; lactose (e.g. in the form of lactose monohydrate); crospovidone (e.g. Crospovidone Type B); and a metallic stearate (such as magnesium stearate) or sodium stearyl fumarate.
  • lactose e.g. in the form of lactose monohydrate
  • crospovidone e.g. Crospovidone Type B
  • a metallic stearate such as magnesium stearate
  • sodium stearyl fumarate such as magnesium stearate
  • the oral pharmaceutical composition comprises microcrystalline cellulose; lactose (e.g. in the form of lactose monohydrate); Crospovidone Type B; and sodium stearyl fumarate.
  • Embodiment C3 is a further embodiment of Embodiment C1 or C2, wherein the oral pharmaceutical composition of the invention comprises:
  • Compound 1 1.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C4 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • Compound 1 1.0% to 30.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];
  • disintegrant e.g. sodium starch glycolate or croscarmellose sodium
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C5 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • Compound 1 1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1); 60% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C6 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • Compound 1 1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • disintegrant e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C7 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • tris salt of Compound 1 e.g. Form 3 of tris salt of Compound 1
  • filler e.g. a combination of microcrystalline cellulose and lactose (e.g. in the form of lactose monohydrate)];
  • disintegrant e.g. crospovidone such as Crospovidone Type B
  • crospovidone such as Crospovidone Type B
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C8 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • tris salt of Compound 1 e.g. Form 3 of tris salt of Compound 1
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof]; 2.0% to 4.0% by weight of disintegrant (e.g. crospovidone such as Crospovidone Type
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C9 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:
  • tris salt of Compound 1 e.g. Form 3 of tris salt of Compound 1
  • filler e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof];
  • disintegrant e.g. crospovidone such as Crospovidone Type B
  • crospovidone such as Crospovidone Type B
  • lubricant e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • Embodiment C10 is a further embodiment of any one of Embodiments C1 or C9, wherein the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is in an amount equivalent to about 1 .0 mg to about 300 mg of Compound 1 , for example, in an amount equivalent to about 1 .0 mg to about 260 mg of Compound 1 , about 1.0 mg to about 200 mg of Compound 1 , about 1.0 mg to about 180 mg of Compound 1 , about 1.0 mg to about 150 mg of Compound 1 , about 1.0 mg to about 125 mg of Compound 1 , about 1.0 mg to about 100 mg of Compound 1 , about 1 .0 mg to about 80 mg of Compound 1 , about 1 .0 mg to about 60 mg of Compound 1 , about 1 .0 mg to about 50 mg of Compound 1 , about 10 mg to about 100 mg of Compound 1 , about 10 mg to about 80 mg of Compound 1 , about 10 mg to about 60 mg of Compound 1 , about 10 mg to about 80 mg of Com
  • Compound 1 about 70 mg to about 130 mg of Compound 1 , about 70 mg to about 120 mg of Compound 1 , about 100 mg to about 140 mg of Compound 1 , about 110 mg to about 130 mg of Compound 1 , about 115 mg to about 125 mg of Compound 1 , about 1 mg of Compound 1 , about 10 mg of Compound 1 , about 20 mg of Compound 1 , about 30 mg of Compound 1 , about 40 mg of Compound 1 , about 50 mg of Compound 1 , about 60 mg of Compound 1 , about 70 mg of Compound 1 , about 80 mg of Compound 1 , about 90 mg of Compound 1 , about 100 mg of Compound 1 , about 120 mg of Compound 1 , about 140 mg of Compound 1 , about 150 mg of Compound 1 , about 160 mg of Compound 1 , about 180 mg of Compound 1 , or about 200 mg of Compound 1.
  • Embodiment C11 is a further embodiment of any one of Embodiments C1 or C9, wherein the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is in an amount equivalent to about 10 mg to about 200 mg of Compound 1 , about 10 mg to about 120 mg of Compound 1, about 1 mg to about 10 mg of Compound 1, about 10 mg to about 40 mg of Compound 1 , about 40 mg to about 70 mg of Compound 1 , about 70 mg to about 120 mg of Compound 1 , about 1 mg of Compound 1 , about 10 mg of Compound 1 , about 20 mg of Compound 1, about 50 mg of Compound 1, about 60 mg of Compound 1, about 80 mg of Compound 1, about 100 mg of Compound 1, about 120 mg of Compound 1, or about 150 mg of Compound 1.
  • Embodiment C12 is a further embodiment of any one of Embodiments C1 or C11 , wherein the immediate-release oral dosage form is a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, orally dispersible films.
  • the immediate-release oral dosage form is a tablet form.
  • Embodiment C13 is a further embodiment of any one of Embodiments C1 or C12, wherein the 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1 , 3]dioxol-4-yl)pi peridi n- 1 - yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is tris salt of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid.
  • Embodiment C14 is a further embodiment of any one of Embodiments C1 or C12, wherein the tris salt of Compound 1 is in a crystalline form, for example, a monohydrate form (e.g. Form 3, wherein Form 3 has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at
  • Form 3 has a 13 C ssNMR spectrum comprising chemical shifts at 54.7 and
  • Embodiment C15 is a further embodiment of any one of Embodiments C1 or C12, wherein the tris salt of Compound 1 is in an amorphous form.
  • the immediate-release oral pharmaceutical composition in any one of Embodiments C1 to C15 can be used in the method of any one of Embodiments A1 to A19.
  • the immediate-release oral pharmaceutical composition in any one of Embodiments C1 to C15 can be used in the method of any one of Embodiments B1 to B26.
  • trimer means 1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine, also known as THAM, tromethamine, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol, tris(hydroxymethyl)aminomethane.
  • Tris salt of Compound 1 means a salt of Compound 1 made using 1 ,3-dihydroxy-2- (hydroxymethyl)propan-2-amine.
  • the tris is associated with the carboxylic acid moiety of Compound 1.
  • the counterion and Compound 1 are in a stoichiometric ratio of about 1 :1 (i.e. from 0.9: 1.0 to 1.0:0.9, for example, from 0.95:1.00 to 1.00:0.95).
  • tris salt of Compound 1 is 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-((4-((S)-2-(5-Chloropyridin- 2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylate, which can also be represented, for example, by one of the following structures.
  • hydrate when used to describe a crystalline form of a compound (or a salt) means that the stoichiometric ratio of the hydrate water to the compound (or salt) is about 1 : 1 (for example, from 0.9 : 1.0 to 1.1 : 1.0).
  • the tris salt of Compound is present as a crystalline form, for example, a monohydrate crystalline form, such as Form 3.
  • a crystalline form for example, a monohydrate crystalline form, such as Form 3.
  • Preparation and characterization of Form 3 can be found in WO2021116874 (International Application No. PCT/IB2020/061585 filed December 07, 2020).
  • WO2021116874 International Application No. PCT/IB2020/061585 filed December 07, 2020.
  • Form 3 has a PXRD comprising at least one, two, three, or four peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6.
  • Form 3 has a PXRD comprising at least two or three peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8. In some embodiments, Form 3 has a PXRD comprising three peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, and 14.8. In some embodiments, Form 3 has a PXRD comprising four peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 14.8, and 20.6.
  • Form 3 has a PXRD comprising five peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 11.1 , 14.8, 18.2, 20.6, 23.5, 24.3, and 24.6. As reported in WO2021116874 (including information on sample preparation and NMR instrument and data collection), some characteristic 13 C ssNMR chemical shifts of Form 3, expressed as ppm, are at 42.8, 54.7, 128.2, 138.4 and 156.6 ⁇ 0.2 ppm.
  • Form 3 has a 13 C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ⁇ 0.2 ppm. In some embodiments, Form 3 has a 13 C ssNMR spectrum comprising chemical shifts at 54.7, 138.4 and 156.6 ppm ⁇ 0.2 ppm.
  • Pharmaceutically acceptable salts include acid addition and base salts.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-Amino-2-(hydroxymethyl)propane-1 ,3-diol (tris or tromethamine) and zinc salts.
  • bases include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-Amino-2-(hydroxymethyl)propane-1 ,3-diol (tris or tromethamine) and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
  • compositions may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • solvate is used herein to describe a molecular complex comprising a compound or its salt, and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent for example, ethanol.
  • hydrate is employed when said solvent is water.
  • a hydrate crystalline form of tris salt of Compound 1 disclosed herein refers to a crystalline material/complex that includes both tris salt of Compond 1 and water (hydrate water) in the crystal lattice of the crystalline material/complex.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • complexes of this type include clathrates (drughost inclusion complexes) and co-crystals.
  • the latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004).
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’).
  • crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’).
  • a compound may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’.
  • Some compounds may exhibit polymorphism and/or one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism).
  • the crystalline forms of the invnetions may also be isotopically labelled. Such variation is implicit to Compound 1 or its salt defined as they are by reference to their structural features and therefore within the scope of the invention.
  • tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Certain pharmaceutically acceptable salts of Compound 1 may also contain a counterion which is optically active (e.g. d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dl-arginine).
  • a counterion which is optically active (e.g. d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dl-arginine).
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • a racemic precursor containing a chiral ester may be separated by enzymatic resolution (see, for example, Int J Mol Sci 29682-29716 by A. C. L. M. Carvaho et. al. (2015)).
  • a salt may be formed with an optically pure base or acid such as 1 -phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by fractional crystallization and one or both of the diastereomeric salts converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • the racemate or a racemic precursor
  • a suitable optically active compound for example, an alcohol, amine or benzylic chloride.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization by means well known to a skilled person to give the separated diastereomers as single enantiomers with 2 or more chiral centers.
  • Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed.
  • racemic compounds such as the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labeled Compound 1 or a salt thereof wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, nitrogen, such as 13 N and 15 N, and oxygen, such as 15 0, 17 O and 18 O.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de- DMSO.
  • a compound of the invention is administered in an amount effective to treat a condition as described herein.
  • the compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.
  • the compounds of the invention may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the dosage regimen for the compounds of the invention and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Multiple doses per day may be used to increase the total daily dose, if desired.
  • compositions may be provided, for example, in the form of tablets containing the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • Suitable subjects according to the invention include mammalian subjects.
  • humans are suitable subjects. Human subjects may be of either sex and at any stage of development.
  • the invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition.
  • Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • pharmaceutically acceptable carriers include one or more components select from diluents/fi Ilers, disintegrants, binders, wetting agents, and lubricants.
  • diluent or filler refers to a substance that acts to dilute the active pharmacological agent to the desired dosage and/or that acts as a carrier for the active pharmacological agent.
  • examples of diluent or filler include mannitol, lactose (including e.g.
  • lactose monohydrate sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, and/or a metal aluminosilicate.
  • disintegrant refers to a substance that encourages disintegration in water (or water-containing fluid in vivo) of a pharmaceutical composition/formulation of the invention.
  • examples of disintegrant include croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, and/or calcium phosphate.
  • binder refers to a substance that increases the mechanical strength and/or compressibility of a pharmaceutical composition/formulation of the invention.
  • binder include polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, crosslinked poly(acrylic acid), gum arabic, gum acacia, gum tragacanath, lecithin, casein, polyvinyl alcohol, gelatin, kaolin, cellulose, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, methylhydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrins, microcrystalline cellulose, and/or sorbitol.
  • the term “wetting agent” refers to a substance that increases the water permeability of a pharmaceutical composition/formulation of the invention.
  • the term, “wetting agent” refers to a substance that increases dissolution of the active pharmacological agent in water (or water containing fluid in vivo).
  • the term “wetting agent” refers to a substance that increases the bioavailability of the active pharmacological agent after administration of a pharmaceutical composition/formulation of the invention.
  • wetting agent examples include metallic lauryl sulfate, polyethylene glycol, glycerides of fatty ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, metal alkyl sulfate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sugar ester of fatty acid, polyglycolized glyceride, quaternary ammonium amine compound, lauroyl macrogol glycerides, caprylocaproyl macrogolglycerides, stearoyl macrogol glycerides, linoleoyl macrogol glycerides, oleoyl macrogol glycerides, polyethoxylated vegetable oil, polyethoxylated sterol, polyethoxylated cholesterol, polyethoxylated glycerol fatty acid ester, polyethoxylated fatty acid ester, sulfosuccinate, taurate, and
  • lubricant refers to a substance that aids in preventing sticking to the equipment of the pharmaceutical formulations/composition during processing and/or that improves powder flow of the composition/formulation during processing.
  • examples of lubricant include stearic acid, metallic stearate (e.g. magnesium stearate), sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, polyalkylene glycol, and/or sodium chloride.
  • a composition of the invention comprises a filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof], a disintegrant (e.g. croscarmellose sodium, sodium alginate, potassium alginate, or sodium starch glycolate), and a lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].
  • a composition of the invention comprises microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), sodium starch glycolate, and sodium stearyl fumarate.
  • compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions, dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of a pharmacological active ingredient (API, for example, Compound 1 or a pharmaceutical acceptable salt thereof such as tris salt of Compound 1).
  • the oral administration may be in tablet form.
  • the oral administration may be in capsule form.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of the invention are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain an immediate release formulation.
  • such capsules or tablets may contain a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
  • compositions of the invention can be used alone, or in combination with other therapeutic agents.
  • the invention provides any of the uses, methods or compositions as defined herein wherein the compound of any embodiment herein, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, is used in combination with one or more other therapeutic agent discussed herein.
  • the administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time that each may generate a biological effect in the same time frame.
  • the presence of one agent may alter the biological effects of the other compound(s).
  • the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.
  • the invention provides methods of treatment that include administering compounds of the present invention in combination with one or more other pharmaceutical agents, wherein the one or more other pharmaceutical agents may be selected from the agents discussed herein.
  • the compounds of this invention are administered with an antidiabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildaglipt
  • glucose-dependent insulinotropic peptide GIP
  • an alpha glucosidase inhibitor e.g. voglibose, acarbose, or miglitol
  • an insulin or an insulin analogue including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.
  • the compounds of this invention are administered with an antiobesity or other agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g.
  • an antiobesity or other agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist,
  • obeticholic acid zonisamide
  • phentermine alone or in combination with topiramate
  • a norepinephrine/dopamine reuptake inhibitor e.g., buproprion
  • an opioid receptor antagonist e.g., naltrexone
  • a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist e.g., a combination of bupropion and naltrexone
  • a GDF-15 analog sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin)
  • a serotonergic agent e.g., lorcaserin
  • a methionine aminopeptidase 2 (MetAP2) inhibitor e.g., beloranib or ZGN-1061
  • the compounds of this invention are administered in combination with one or more of the following: an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a/5 agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., pumpuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor 21 (FGF21) agonist (e.g., BMS
  • Some specific compounds that can be used in combination with the compounds of the present invention for treating diseases or disorders described herein include:
  • Crystal forms of 4-(4-(1- lsopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin- 2-yl)benzoic acid including an anhydrous mono-tris form (Form 1) and a trihydrate of the monotris salt (Form 2), are described in International PCT Application No. PCT/IB2018/058966, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes;
  • [(1 R,5S,6R)-3- ⁇ 2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl ⁇ -3- azabicyclo[3.1.0]hex-6-yl]acetic acid, or a pharmaceutically acceptable salt thereof, (including a crystalline free acid form thereof) is an example of a ketohexokinase (KHK) inhibitor and is described in Example 4 of U.S. Patent No. 9,809,579, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes; and the FXR agonist Tropifexor or a pharmaceutically acceptable salt thereof is described in Example 1-1 B of U.S. Patent No. 9,150,568, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.
  • KHK ketohexokinase
  • agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like.
  • the particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or Igs; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspara
  • Liposomes containing these agents and/or compounds of the invention are prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.
  • PEG-PE PEG-derivatized phosphatidylethanolamine
  • agents and/or the compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing Compound 1 or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and 7 ethyl-L-glutamate copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as those used in LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3- hydroxybutyric acid.
  • LUPRON DEPOTTM injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • sucrose acetate isobutyrate sucrose acetate isobutyrate
  • poly-D-(-)-3- hydroxybutyric acid poly-D-(-)-3- hydroxybutyric acid.
  • the formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes.
  • Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • Suitable emulsions may be prepared using commercially available fat emulsions, such as IntralipidTM, LiposynTM, InfonutrolTM, LipofundinTM and LipiphysanTM.
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water.
  • an oil e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil
  • a phospholipid e.g., egg phospholipids, soybean phospholipids or soybean lecithin
  • other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emul
  • Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.
  • the emulsion compositions can be those prepared by mixing a compound of the invention with IntralipidTM or the components thereof (soybean oil, egg phospholipids, glycerol and water).
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • kits comprising a pharmaceutical composition of the invention.
  • a kit may include, in addition to a pharmaceutical composition of the invention, diagnostic or therapeutic agents.
  • a kit may also include instructions for use in a diagnostic or therapeutic method.
  • the kit includes a pharmaceutical composition of the invention and a diagnostic agent.
  • the kit includes a pharmaceutical composition and instructions for use in a therapeutic method.
  • the invention comprises kits that are suitable for use in performing the methods of treatment described herein.
  • the kit contains one or more of solid forms of the invention in quantities sufficient to carry out the methods of the invention.
  • the kit comprises one or more solid forms of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage.
  • compositions of these tablets are shown in Tables 1-1 to 1-5.
  • Blend approximately half of the microcrystalline cellulose 2. Add tris salt of Compound 1 to the microcrystalline cellulose, followed by the lactose monohydrate and crospovidone type B and mix.
  • Table 2-1 Formulation Details for tris salt of Compound 1 Oral Solutions a. the dosage strength weight expressed in milligram is the weight equivalent to Compound 1 The required quantity of tris salt of Compound was weighed and dissolved in 0.1 % Polysorbate 80 in sterile water for irrigation vehicle to provide the final stock solution volume. Appropriate aliquots of the solutions were dispensed into a suitable drinking vessel to achieve the desired doses. The aliquots were administered without further dilution.
  • Example 3 A clinical study (dose escalating study) of Compound 1 (in the form of its tris salt)
  • Part A 4 cohorts were enrolled to participate in Part A, with approximately 10 participants (8 Compound 1 : 2 placebo) per cohort. Participants in Part A were admitted to a clinical research unit 2 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 31.
  • Part B adult participants with Obesity (without diabetes) received Compound 1 (as its tris salt) or placebo daily for 42 days. As shown in Figure 3, 1 cohort, with approximately 15 participants (12 Compound 1 : 3 placebo), was enrolled to participate in Part B. Participants in Part B were admitted to a clinical research unit 3 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 45.
  • Part C adult participants with T2DM inadequately controlled on metformin received Compound 1 (as its tris salt) or placebo daily for 42 days.
  • 1 cohort with approximately 10 participants (8 Compound 1 : 2 placebo), was enrolled to participate in Part C. Participants in Part C were admitted to a clinical research unit 2 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 45. For all participants (Parts A, B and C), there was a planned follow-up period of at least 28 days post last-dose.
  • T2DM with an HbAlc of >7.0% and ⁇ 10.5%, receiving a stable dose of metformin of at least 500 mg per day and use of no other medications for glycemic control and Participants were required to have a BMI of >24.5 to ⁇ 45.5 kg/m 2 and total body weight of >50 kg.
  • Part B Key criteria for participants enrolling with Obesity (Part B): BMI of >30.5 to ⁇ 45.5 kg/m 2 . Participants did not have diabetes as indicated by laboratory tests including HbA1c of less than 6.5% .
  • the investigator determined the appropriate times during the day to administer those doses.
  • the timing of administration should have been the same between inpatient days, and care should have been taken to minimize changes to the participants’ stable medication routine.
  • the investigational product was Compound 1 (as its tris salt), or matching placebo. Study intervention information is provided in Table 3-1. Compound 1 and matching placebo were supplied as tablets to the CRU in bulk along with individual dosing containers for unit dosing.
  • Table 3-1 A dose titration approach was taken in this study. Within a given cohort, the daily dose administered increased at set intervals over the dosing period up to a planned target dose. The target dose level for each cohort was adjusted based on data emerging from prior cohorts, in dose escalation fashion (Table 3-2 and Table 3-3).
  • a total of 66 participants (51 with T2DM and 15 with obesity) were assigned to treatment and received at least 1 dose of study intervention; of these, 61 participants completed the blinded treatment.
  • 3 were due to treatment-related AEs: 1 participant from Part A Compound 1 60 mg group discontinued on Day 13 at a dose of 40 mg due to nausea; this participant did not complete the follow-up visit due to withdrawal by participant.
  • One participant from Part A Compound 1 120 mg group discontinued on Day 5 at a dose of 40 mg due to hypoglycemia.
  • One participant from Part B Compound 1 180 mg group discontinued study drug on Day 32 at a dose of 150 mg due to upper abdominal pain; this participant continued in the study.
  • 1 participant from Part A placebo group and 1 participant from Part C Compound 1 180 mg group discontinued during the treatment phase due to other reasons.
  • Demographic characteristics were generally comparable across groups.
  • the gender distribution of the 66 participants was well-balanced, with 53% male and 47% female.
  • the majority (more than 80%) of the participants were White, and a majority had Hispanic or Latino ethnicity (approximately 75% of participants with T2DM, and 87% of participants with Obesity).
  • the mean age of participants was 57.4 years (range: 29 to 70 years), with generally similar average age and range across the populations studied.
  • the mean weight and BMI for participants enrolling with T2DM were 89.7 kg (range: 52 to 152 kg) and 32.7 kg/m 2 (range: 25 to 45 kg/m 2 ), respectively.
  • the mean duration of T2DM for participants with T2DM was 10.7 years (range: 1.6 to 22.8 years) and the median HbA1c at Screening in these participants was 8.4% (range: 7.0% to 10.5 %).
  • the mean weight and BMI for participants enrolling with Obesity was 98.2 kg (range: 74 to 122 kg) and 35.1 kg/m 2 (range: 31 to 44 kg/m 2 ), respectively.
  • TEAEs treatment-emergent adverse events
  • Compound 1 in the form of its tris salt plasma pharmacokinetic parameters (Table 3-4) area under the plasma concentration time profile from time 0 to time 24 hours (AIIC24), maximum observed concentration over a 24-hour interval (C m ax), and time for C m ax (T m ax) were calculated for each participant and treatment following Day 1 and multiple dose administration, using noncompartmental analysis of concentration-time data.
  • Cmax was observed at 1 to 2 hours on Day 1 , and 2 to 8 hours following last dose on Day 28 or 42.
  • Exposure (Cmax and ALICtau) generally increased in an approximately dose proportional manner across the dose range studied.
  • CFB Change From Baseline (CFB) in Mean Daily Glucose (MDG), Fasting Plasma Glucose (FPG), and HbA1c in participants with T2DM CFB in MDG
  • Mean daily glucose (MDG) was assessed following MMTT (mixed meal tolerance test) in participants with T2DM at baseline at end of treatment (Day 28 or Day 42).
  • Baseline mean values were generally similar across treatment groups.
  • the observed mean CFB in MDG increased with Compound 1 dose are shown in Table 3-5, ranging from -41.9 mg/dL (10 mg, Day 28) to -89.4 mg/dL (120 mg, Day 28), and -110.6 mg/dL (180 mg, Day 42).
  • Baseline is defined as the value on Day -1 .
  • Mean Daily Glucose is defined as AUC24/24.
  • Table 3-6 Change from Baseline for Fasting Plasma Glucose in Participants with T2DM a. Maximum mean decline observed during dosing period.
  • N number of participants randomized
  • n number of participants analyzed
  • Mean CFB for the placebo groups as assessed in Part A on Day 28 and in Part C on Day 42 were -0.60 % and -0.61%, respectively.
  • Baseline is defined as the measurement collected at Day -1 OH. Unplanned readings have been excluded from the presentation. ANCOVA or MMRM model, used as appropriate
  • Baseline is defined as the value on Day -1.

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Abstract

L'invention concerne une méthode de traitement du diabète sucré de type 2, de l'obésité ou du surpoids ou de contrôle de la gestion du poids par l'administration à un mammifère (par exemple un être humain) qui en a besoin d'une composition pharmaceutique une fois par jour sous une forme galénique orale, la composition pharmaceutique contenant de l'acide 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-méthylbenzo[d][1,3]dioxol-4-yl)pipéridin-1-yl)méthyl)-1-(((S)-oxétan-2-yl)méthyl)-1H-benzo[d]imidazole-6-carboxylique, ou un sel pharmaceutiquement acceptable de celui-ci (tel que son sel tris). De plus, l'invention concerne des compositions/formulations orales pour les méthodes de traitement selon la présente divulgation.
PCT/IB2023/055132 2022-05-23 2023-05-18 Traitement du diabète de type 2 ou contrôle de la gestion du poids avec de l'acide 2-((4-((s)-2-(5-chloropyridin-2-yl)-2-méthylbenzo[d][1,3]dioxol-4-yl)pipéridin-1-yl)méthyl)-1-(((s)-oxétan-2-yl)méthyl)-1h-benzo[d]imidazole-6-carboxylique ou un sel pharmaceutique de celui-ci WO2023228023A1 (fr)

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