WO2014074700A1 - Antagonists of gpr119 receptor and the treatment of disorders related thereto - Google Patents

Antagonists of gpr119 receptor and the treatment of disorders related thereto Download PDF

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Publication number
WO2014074700A1
WO2014074700A1 PCT/US2013/068924 US2013068924W WO2014074700A1 WO 2014074700 A1 WO2014074700 A1 WO 2014074700A1 US 2013068924 W US2013068924 W US 2013068924W WO 2014074700 A1 WO2014074700 A1 WO 2014074700A1
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Prior art keywords
test compound
disease
individual
obesity
antagonist
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PCT/US2013/068924
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French (fr)
Inventor
Robert M. Jones
Thue Walter SCHWARTZ
Line Vildbrad KRISTENSEN
Torben Andreas Nygaard MADSEN
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Arena Pharmaceuticals, Inc.
The University Of Copenhagen
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Application filed by Arena Pharmaceuticals, Inc., The University Of Copenhagen filed Critical Arena Pharmaceuticals, Inc.
Publication of WO2014074700A1 publication Critical patent/WO2014074700A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/554—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being a biological cell or cell fragment, e.g. bacteria, yeast cells
    • G01N33/555—Red blood cell
    • G01N33/556—Fixed or stabilised red blood cell
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the present invention relates to compounds of Formula 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are antagonists of GPR 119 useful in the treatment of, for example, a disorder selected from: obesity and diseases/conditions related to obesity such, as congestive heart failure, polycystic ovarian syndrome, infertility,
  • GPR119 gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • the present antagonists of GPR119 are useful for treating non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer (e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer).
  • GPCR G protein-coupled receptor
  • GPCRs are also known as seven-transmembrane domain receptors as they share a common structural motif, having seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane.
  • the transmembrane helices are joined by strands of amino acids between transmembrane-2 and transmembrane-3, transmembrane -4 and transmembrane-5, and transmembrane-6 and transmembrane-? on the exterior, or "extracellular" side, of the cell membrane.
  • transmembrane helices are also joined by strands of amino acids between transmembrane- 1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or "intracellular” side, of the cell membrane.
  • the "carboxy" (“C") terminus of the receptor lies in the intracellular space within the cell, and the “amino” (“N”) terminus of the receptor lies in the extracellular space outside of the cell.
  • G-protein a ligand binds with the receptor (often referred to as "activation" of the receptor), there is a change in the conformation of the receptor that facilitates coupling between the intracellular region and an intracellular "G-protein.”
  • G proteins include Gq, Gs, Gi, Gz, and Go. It has been reported that GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein.
  • Ligand- activated GPCR coupling with the G-protein initiates a signaling cascade process (referred to as Attorney Docket No. 22578-0029WO1 / 214.WOI
  • signal transduction The two principal signal transduction pathways involving the G protein- coupled receptors are the cAMP signal pathway and the phosphatidylinositoi signal pathway. Under normal conditions, signal transduction uitimately results in cellular activation or cellular inhibition.
  • GPCRs exist in the cell membrane in equilibrium between two different conformations; an "inactive" state and an “active” state.
  • a receptor in ait inactive state is unable to link to the intracellular signaling transduction pathway to in itiate signal transduction leading to a biological response.
  • Changing the receptor conformation to the active state allows linkage to the transduction pathway (via the G -protein) and produces a biological response.
  • a receptor may be stabilized in an active state by a iigand or a compound such as a drug.
  • GPCRs represent an important area for She development of pharmaceutical products. Drugs active at GPCRs have therapeutic benefit across a broad spectrum of human diseases as diverse as pain, cognitive dysfunction, hypertension, peptic ulcers, rhinitis, and asthma. In fact, GPCRs are the target of approximately 40% of all modem medicinal drags.
  • GPC G protein -coupled receptor 1 19
  • RUP3 G protein -coupled receptor 1 19
  • SNORF25 G protein -coupled receptor 1 19
  • OSGPR 1 16, 19AJ Glucose-Dependent Insulinotroptc Receptor
  • GDIR Glucose-Dependent Insulinotroptc Receptor
  • GPRl 19 Activation of GPRl 19 is known to lead to the secretion of the incretins (hormones that work to increase insulin secretion), glucagon-like peptide- 1 (GLP-i), peptide tyrosine tyrosine (PYY), and glucose-dependent insulinotropic peptide (GIP).
  • incretins hormones that work to increase insulin secretion
  • GLP-i glucagon-like peptide- 1
  • PYY peptide tyrosine tyrosine
  • GIP glucose-dependent insulinotropic peptide
  • GLP- 1 is an in cretin hormone derived from the post-translational modification of pro- glucagon and is secreted by gut endocrine cells. GLP-1 mediates its actions through a specific GPCR, namely glucagon-like peptide- 1 receptor (GLP-1 R). GLP-1 is best characterized as a hormone that regulates glucose homeostasis. GLP-1 has been shown to stimulate glucose- dependent insulin secretion and to increase pancreatic beta cell mass. GLP- 1 has also been shown to reduce the rate of gastric emptying and to promote satiety. GLP- 1 peptide agonists are effective in controlling blood glucose in Type 2 diabetics and in reducing body mass.
  • GLP- 1 receptor agonists are additionally useful in protecting against myocardial infarction and against cognitive and neurodegenerative disorders.
  • GLP-1 has been shown to be cardioprotective in a rat model of myocardial infarction
  • GLP-1R has been shown in rodent models to be involved in learning and neuroprotection.
  • PYY is a 36 amino acid peptide originally isolated from porcine intestine. PYY is secreted from enteroendocrine L-cells within both the large and small intestine. Attorney Docket No. 22578-0029WO1 / 214.WOI
  • Immunoreactive PYY are low in the duodenum and jejunum, high in the ileum and colon, and highest in the rectum.
  • PYY is released into the circulation as PYY ⁇ and PYY;.;;,.
  • PYY 3 ..36 is generated from PYY ; . ;6 by cleavage of the N-terminai Tyr and Pro residues by dipeptidyl peptidase IV.
  • PYY3.36 is the predominant form of PY Y in human postprandial plasma. PYY has been reported to reduce food intake, body weight gain and glycemic indices in diverse models of metabolic diseases.
  • GIF also known as gastric inhibitory polypeptide
  • GIP is a peptide incretin hormone of 42 amino acids that is released from duodenal endocrine K ceils after meal ingestion. The amount of GIP released is largely dependent on She amount of glucose consumed. GIP has been shown to stimulate glucose-dependent insulin secretion in pancreatic beta cells. GIP mediates its actions through a specific G protein-coupled receptor, namely glucose-dependent insulinotropic peptide receptor (GIPR). GIP is a substrate for dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating the degradation of GIP. Full-length GIP (1-42) is rapidly converted to bio-inactive GIP (3-42) within minutes of secretion from the gut K cell.
  • DPP-IV dipeptidyl peptidase-4
  • Inhibition of DPP-IV has been shown to augment GIP bioactivity.
  • GIP has been shown to activate osteoblastic receptors, resulting in increases in collagen type I synthesis and alkaline phosphatase activity, both associated with bone formation.
  • GIP has been shown to inhibit osteoclast activity and differentiation in vitro, GIP administration has been shown to prevent the bone loss due to ovariectomy.
  • GIPR knockout mice evidence a decreased bone size, lower bone mass, altered bone microarchitecture and biochemical properties, and altered parameters for bone turnover, especially in bone formation.
  • Regulating the levels of incretins can be useful in the treatment of numerous conditions or diseases. This application furthers that goal by the provision of novel antagonists of GPR1 19.
  • the present invention relates to, inter alia, certain piperidine derivatives and pharmaceutically acceptable salts, solvates, and hydrates thereof, which are useful, for example, in selectively lowering a post-prandial GIP level in an individual, and for treating diseases and disorders such as obesity and di eases/conditions related thereto, non-alcoholic fatty liver disease, food-dependent Cu string's syndrome, and cancer.
  • GPR119 While the activation of GPR119 is known to lead to the secretion of the incretins (hormones that work to increase insulin secretion), ghicagon-tike peptide- 1 (GLP-1 ), peptide tyrosine tyrosine (PYY), and glucose-dependent insulinotropic peptide (GIP), applicants have identified compounds that can act as antagonists of GPR119 which unexpectedly selectively reduce postprandial GIP secretion, but do not reduce postprandial GLP-1 secretion.
  • GLP-1 ghicagon-tike peptide- 1
  • PYYY peptide tyrosine tyrosine
  • GIP glucose-dependent insulinotropic peptide
  • One aspect of the present invention is directed to certain pipersdine derivatives selected from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R. 1 is selected from: CpCe alky], cyano, and halogen;
  • A is C3-C7 cycioalkyiene, or heteroaryiene, wherein the heteroaryiene is optionally substituted with a substituent selected from: Ci -C 6 aikoxy, C r C s alkyl, and halogen;
  • Q is O or NH
  • X and Y are each independently , or CH;
  • Z is N or CR ;
  • R 2 is H or C;-C,5 alkylsulfonyi.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula II and pharmaceutically acceptabie salts, solvates, and hydrates thereof:
  • R' is selected from: Ci-Ce alkyl, cyano, and halogen
  • X and Y are each independently , or CH;
  • Z is N or CR ;
  • R " is H or (. -t ,, alkylsulfonyi.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptabie salts, solvates, and hydrates thereof: Attorney Docket No. 22578-0029WO1 / 214.WO!
  • R 1 is selected from: Ci -C 6 alky], cyano, and halogen;
  • X and Y are each independently N, or CH;
  • Z is N or CR'
  • R 2 is H or CVC 6 alkylsulfonyl.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula 111 and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • Q is O or NH
  • X and Y are each independently N, or CH;
  • Z is o CR 2 ;
  • R " is H or C;-C, 5 alkylsulfonyl
  • R 5 is selected from: Cp-Q alkoxy, CpC ' e alkyl, and halogen.
  • One aspect of the present invention is directed to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention is directed to processes for preparing
  • compositions comprising admixing a compound of the present invention with a pharmaceutically acceptable earner.
  • compositions comprising a compound of the present invention and a pharmaceutically acceptable earner.
  • One aspect of the present invention is directed to processes for preparing compositions, comprising admixing a compound of the present invention with a pharmaceutically acceptable Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • One aspect of the present invention is directed to GPR119 antagonists, for use in a method for reducing a postprandial GIP level in an individual, or for the treatment of obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cusbing's syndrome, or cancer, in an individual.
  • compositions comprising a GPR1 19 antagonist of the present invention.
  • One aspect of the present invention is directed to pharmaceutical products selected from; a ph rmaceutical composition, a formulation, a dosage form, and a kit; comprising a GPR119 antagonist of the present invention.
  • One aspect of the present invention is directed to methods of reducing a postprandial
  • GiP level in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
  • One aspect of th e present invention is directed to methods of reducing a postprandial GIP level in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods of reducing postprandial GIP secretion in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 ! 9 antagonist of the present invention.
  • One aspect of the present invention is directed to methods of reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 1 antagonist of the present invention.
  • a postprandial level of GLP- 1 is not reduced in the individual. In some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual.
  • One aspect of the present invention is directed to methods for treating obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility in an Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • One aspect of the present invention is directed to methods for treating non-alcoholic fatty liver disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating food-dependent Cushing's syndrome in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagon ist of the present invention.
  • One aspect of the present invention is directed to methods treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
  • One aspect of She present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present in vention wherein the cancer is selected from; leukemia, multiple myeloma, oon-Hodgkin's lymphoma, and colorectal cancer.
  • One aspect of the present invention is directed to uses of GP 1 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GiP level in an individual.
  • One aspect of the present invention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GiP level in an individual following a meal comprising one or more lipids.
  • One aspect of the present invention is directed to uses of GPR1 19 antagonists of th e present invention in the manufacture of a medicament for reducing postprandial GiP secretion in an individual.
  • One aspect of the present invention is directed to uses of GPR1 19 antagon ists of the present invention in the manufacture of a medicament for reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids.
  • a postprandial level of GLP-i is not reduced in the individual.
  • postprandial secretion of GLP-1 is not reduced in the individual.
  • One aspect of the present invention is directed to uses of GPR 1 19 antagonists of the present invention in the manufacture of a medicament for the treatment of obesity.
  • One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity.
  • One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity selected from; congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • a disease or condition related to obesity selected from; congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.
  • One aspect of the present invention is directed to uses of GP l 19 antagonists of the present invention in the manufacture of a medicament for the treatment of food-dependent Cushsng ' s syndrome.
  • One aspect of the present invention is directed to uses of GP 1 19 antagonists of the present in vention in the manufacture of a medicament for the treatment of cancer.
  • One aspect of the present invention is directed to uses of GPR 1 19 antagonists of the present in vention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in th e manufacture of a medicament for the treatment of cancer, wherein th e cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC 50 of the test compound at GPRl 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPRl 19 is indicative of the test compound being a GPRl 19 antagonist; comparing GIF levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cu string's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, the methods comprising the steps of: comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR119 antagonist useful for the treatment of the disease or condition; and formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
  • a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cu string's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, and to reduce a GIP level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the TCjo of the test compound at GPR 1 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GP 119 is indicative of the test compound being a GPR1 19 antagonist; comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR119 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment ofa disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • antagonize functionality of GPRl 19 in an in viiro model comprising the steps of: comparing GiP levels in an in vivo model in th e presence and absence of th e test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in th e absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, and to reduce a GiP level in an in vivo model, the methods comprising She step of: producing or synthesizing the test compound.
  • the method further comprises the step of: comparing GLP-1 levels in an in vivo model in the presence and absence of the test compound, wherein a GLP- 1 level in the in vivo model that is not substantially reduced in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR l 19 antagonist useful for the treatment of the disease or condition.
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food -dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the method comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for identifying a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, comprising: comparing GIP levels in an in vivo model Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • compositions comprising a GPRl 19 antagonist identified using a method of the present invention.
  • Figure 1 shows the effect of the GPR l 19 antagonist Compound 4 on GLP- 1 following a 10 mL/kg lipid challenge in mice.
  • Figure 2 shows the effect of the GPRl 19 antagonist Compound 4 on GIF following a 10 mL/kg lipid challenge in mice.
  • Figure 3 shows a synthetic procedure for preparing an intermediate useful for preparin compounds of Formula ⁇ or Ila.
  • Figure 4 shows a general synthetic procedure for preparing compounds of Formula II or ila.
  • Figure 5 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is O.
  • Figure 6 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is O.
  • Figure 7 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is NH.
  • FIG. 8 shows the results ofcAMP accumulation assays of Compounds 2, 6, and 7.
  • agonist refers to a moiety that interacts with and activates a G-protein-coupled receptor, for instance GPR l 19, and ca thereby in itiate a physiological or pharmacological response characteristic of that receptor.
  • G-protein-coupled receptor for instance GPR l 19, and ca thereby in itiate a physiological or pharmacological response characteristic of that receptor.
  • an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding So a membrane.
  • antagonist encompasses neutral antagonists and inverse agonists.
  • neutral antagonist refers to a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist.
  • inverse agonist refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by th e active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50% and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • GP 119 includes the human nucleotide sequences found in
  • GenBank® accession number AY288416 GenBank® accession number AY288416, and naturally-occurring allelic variants thereof, and mammalian orthologs thereof.
  • An example of a human GPR119 for use in screening and testing of the compounds of the invention is provided in the nucleotide sequence of SEQ ID NO:l and the corresponding amino acid sequence in SEQ ID NO:2 found in PCX Application No.
  • the term "in need of treatment” and th e term "in need thereof when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the resuit of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • a caregiver e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • mice refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • modulate or modulating refers to an increase or decrease in the amount quality, response or effect of a particular activity, function or molecule.
  • composition refers to a compound, including but not limited to, salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component.
  • composition refers to a composition comprising at least one active ingredient, such as a compound as described herein; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes on e or snore of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual thai may be predisposed to She disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or
  • ameliorating the disease for example, ameliorating a disease, condition or disorder in an individ ual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology), CHEMICAL GROUP, MOIETY OR RADICAL
  • -Ce aikoxy refers to a radical comprising a Cj-Ce alkyl group attached to an oxygen atom, wherein Cj-Ce alkyl has She same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons. Examples include, but are not limited to methoxy, ethoxy, w-propoxy, isopropoxy, «-butoxy, fcri-butoxy, isobutoxy, and .yec-butoxy.
  • aryl refers to an aromatic ring radical containing 6 to 10 ring carbons. Examples include, but are not limited to, phenyl and naphthyl.
  • Q -Cg alkyl refers to a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.
  • alkyl group examples include, but are not limited to, methyl, ethyl, «-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, feri-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1 -methyl butyl [i.e., -CH(CH 3 )CH 2 CH 2 CH 3 ], 2-methylbutyl [i.e., -C I ! ⁇ !l C! h id ! ⁇ ! and w-hexyl.
  • Ci-C* alkylsulfonyl refers to a radical comprising a C]-C 6 alkyl group attached to the sulfur of a sulfonyl group, wherein CpCg alkyl has the same definition as Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, w-butyisulfonyl, see-butyisulfonyl, isohutylsuifonyl, and teri-butylsulfonyl.
  • C3 cycloalkylene refers to a saturated ring di-radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons.
  • Examples include cyclopropylene, cycloburylene, cyclopentylene, and cyclohexyleae.
  • cyano refers to the group -CN
  • halogen refers So a fluoro, chloro, bromo or iodo group.
  • heteroarylene refers to a di-radical ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, Ci -C, acyl, C1-C4 alkyl, or O (i.e., forming an N-oxide) and S is optionally substituted with one or two oxygens.
  • the ring system contains one heteroatom.
  • the ring system contains two heteroatoms.
  • the ring system contains three heteroatoms.
  • 5-membered heteroarylene rings examples include, but are not limited to, furanylene, thienylene, pyrrolylene, imidazolylene, oxazolylene, fliiazolyleoe, isoxazolylene, pyrazoSylene, isofliiazolyleoe, oxadiazolylene, ( riazolylene, tetrazolylene, and thiadiazolylene.
  • 6-membered heteroarylene rings examples include, but are not limited to, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, and triazinylene.
  • One aspect of the present invention encompasses, inter alia, certain heterocyclyl derivatives selected from compounds of Formula ⁇ and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R 1 , A, O, Q, X, Y, and Z have the same definitions as described herein, supra and infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g.
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non -hydrogen substituent or group, the non -hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1 , 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1 , 2, 3, 4, 5, 6, or 7 substituents, and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution, it is understood that She various tautomeric forms are within the scope of the compounds of the present invention.
  • One aspect of the present invention is directed to compounds of the present invention wherein the mesoisomer stereochemistry is (lr,4r).
  • One aspect of the present invention is directed to compounds of the present invention wherein the mesoisomer stereochemistry is (Lv v).
  • One aspect of the present invention is directed to certain piperidine derivatives selected from compounds of Formula I and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R" is selected from: Ci-Ce alkyl, cyano, and halogen
  • A is C3-C7 eyeloalkylene, or heteroarylene, wherein the heteroarylene is optionally substituted with a substituent selected from: Ci-Ce alkoxy, Ci-Ce alkyl, and halogen;
  • Q is O or NH
  • X and Y are each independently N, or CH;
  • Z is N or CR 3 ; and Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • R 2 is H or CrCe alkylsuifonyi.
  • R 1 is selected from: C] -C 6 alkyl, cyano, and halogen, in some embodiments, R 1 is CrQ alkyl,
  • R 1 is halogen
  • R 1 is selected from methyl, cyano, and fluoro.
  • R 1 is methyl
  • R 1 is cyano
  • R * is fluoro
  • A is C3-C7 cycloalkylene, or heteroarylene, wherein the heteroarylene is optionally substituted with a substituent selected from: Ci -Ce alkoxy, Cj -Cg alkyl, and halogen,
  • A is cyclohexyiene or pyrimidinylene, wherein the pyrimidinylene is optionally substituted w ith a substituent selected from: Cr-Ce alkoxy, Ci-Ce alkyl, and halogen,
  • A is cyclohexyiene or pyrimidinylene, wherein the pyrimidinylene is optionally substituted with a substituent selected from: methoxy, methyl, and fluoro.
  • A is 1,4-cycloliexyeiene.
  • A is 4,6-pyrimidinylene optionally substituted with a substituent selected from: Ci -Q alkoxy, Ci- alkyl, and halogen.
  • A is 4,0-pyrimidinylene optionally substituted with a substituent selected from: methoxy, methyl, and fluoro.
  • A is 5-methoxy-4,6-pyrimidinylene.
  • A is 5-methyl 4,0-pyrimidinylene
  • A is 5-fluoro-4,6-pyrimidin.ylene.
  • Q is O or NH.
  • Q is O
  • Q is INH.
  • X is N or CH.
  • X is N.
  • X is CH.
  • X is N or CH.
  • Y is N
  • Y is CH.
  • X is N or CR'.
  • Z is N.
  • Z is CR 2 ,
  • R' is H or Ci -C fl alkylsulfonyl.
  • R 2 is H, or methyisuifonyl.
  • R 2 is H.
  • R 2 is Ci-Cg alJkylsulfonyl.
  • R 2 is methyisuifonyl
  • X is CH
  • Y is CH
  • Z is N
  • X is N
  • Y is N
  • Z is CH
  • X is CH
  • Y is CH
  • Z is CR ⁇
  • X is CH
  • Y is N
  • Z is CR 2 .
  • One aspect of the present invention is directed to compounds selected from compounds of Formula ⁇ and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R 1 is selected from: C] -C 6 alkyl, cyano, and halogen; Attorney Docket No. 22578-0029WO1 / 2I4.W01
  • X and Y are each independently N, or CH;
  • Z is N or CR 2 ;
  • R 2 is H or Ci-C 6 alkylsuifonyl.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula II and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R 1 is cyano
  • X and Y are both ; and Z is CH; or
  • X and Y are both CH; and Z is N.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptabie salts, solvates, and hydrates thereof:
  • R 1 is selected from: C] -C 6 alkyl, cyano, and halogen
  • X and Y are each independently , or CH;
  • Z is N or CR 2 ;
  • R 2 is H or C -C, alkylsuifonyl.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • X and Y are both N; and Z is CH; or
  • X and Y are both CH; and Z is N.
  • One aspect of the present invention is directed to compounds selected from compounds of Formula ⁇ and pharmaceutically acceptable salts, sol vates, and hydrates thereof:
  • R 1 is selected from: Ci-C fl alkyl, cyano, and halogen
  • X and Y are each independently N, or CH;
  • R 2 is H or C Ce alkylsulfonyl
  • R 3 is selected from: Ci-Cs alkoxy, CpCe alkyl, and halogen.
  • One aspect of th e present invention is directed to compounds selected from compounds of Formula III and pharmaceutically acceptable salts, solvates, and hydrates thereof:
  • R' is methyl or fSuoro
  • Q is O or NH
  • X is CH
  • Y is N or CH
  • Z is methylsulfonyl
  • Some embodiments of the present invention include ever ⁇ ' combination of one or more compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof selected from the following group shown in Table A.
  • individual compounds and chemical genera of the present invention for example those compounds found in Table A including, isomers, diastereoisomers and eoaotiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and hydrates, thereof.
  • mesoisomers of individual compounds and chemical genera of the present Attorney Docket No. 22578-0029WO1 / 214.WOI
  • the compounds of the Formula 1 of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplar ⁇ ' reagents and procedures for these reactions appear hereinafter in the working Examples.
  • Protection and deprotectioo may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M,, Protecting Groups in Organic Synthesis, 3* d Edition, 1999 [Wiley]).
  • the present invention embraces, each isomer, each diastereoisomer, each eiiantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers and enantiomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers can be accomplished by application of various methods which are well known to practitioners in the art.
  • One aspect of the present invention is directed to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention is directed to processes for preparing
  • compositions comprising admixing a compound of the present invention with a pharmaceutically acceptable carrier.
  • compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention is directed to processes for preparing compositions, comprising admixing a compound of the present invention wilh a pharmaceutically acceptable carrier.
  • One aspect of the present invention is directed to compounds of the present invention for use in a method of treatment of a human or animal by therapy .
  • One aspect of the present invention is directed to GPR1 1 antagonists, for use in a method for reducing a postprandial GIP level in an indiv idual, or for the treatment of obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, or cancer, in an individual.
  • the GPR1 i 9 antagonist has an IC 50 at GPRl.19 of less than about
  • the GPRl i 9 antagonist has an IC 50 at GPRl.19 of less than about 100 nM
  • the GPRl 19 antagonist has an IC 50 at GPRl 19 of less than about
  • the GPRl 1 antagonist has an IC 50 at GPRl 19 of less than about
  • the GPR l 19 antagonist has an TC50 at GPRl 19 of less than about
  • the GPR l 19 antagonist has an TC50 at GPRl 19 of less than 1 ⁇ .
  • the GPRl 19 antagonist has an JC 5 o at GPRl 19 of less than 1 00 nM.
  • the GPRl 19 antagonist has an IC 50 at GPRl 19 of less than 55 nM.
  • the GPRl 19 antagonist has an 1(3 ⁇ 4 0 at GPRl 19 of less than 35 nM.
  • the GPRl 19 antagonist has an 1(3 ⁇ 4 0 at GPRl 19 of less than 15 nM.
  • the GPRl 19 antagonist is an antagonist of human GPRl 19. in some embodiments the GPRl 19 antagonist is a small molecule.
  • the GPRl 19 antagonist is orally active.
  • the GPRl 19 antagonist is a selective GPRl 19 antagonist.
  • the GPRl 19 antagonist is selected from: a compound of the present invention, a pharmaceutical composition of the present in vention, a composition of the present invention, and i -(4-floorobenzy])-3'-(3-rne(hoxyphenyl)spiro[indoline-3,2'- thiazolidine]-2,4'-dione and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the GPRl 19 antagonist is selected from: a compound of the present invention, and a pharmaceutical composition of the present invention.
  • the GPRl 19 antagonist is selected from: i-(4-fluorobenzyl)-3'- (3-methoxyphenyI)spiro[indoline-3,2'-t[iiazoiidine]-2,4 ! -dione and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the GPRl 19 antagonist is for use in a method for reducing a postprandial GIP level in an individual.
  • a postprandial level of GLP-1 is not reduced in the individual.
  • postprandial secretion of GLP-1 is not reduced in the individual.
  • the GPR l 19 antagonist is for use in a method for reducing postprandial GIP secretion in an individual
  • a postprandial level of GLP-1 is not reduced in the individual.
  • postprandial secretion of GLP-1 is not reduced in the individual.
  • the GPRl 19 antagonist is for use in a method for reducing a postprandial GIP level in an individual following a meal comprising one or more lipids.
  • a postprandial level of GLP- 1 is not reduced in the individual. In some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual.
  • the GPRl 19 antagonist is for use in a method for reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids.
  • a postprandial level of GLP- is not reduced in the individual.
  • postprandial secretion of GLP- 1 is not reduced in the individual, in some embodiments the GPRl 19 antagonist is for use in a method for the treatment of obesity.
  • the GPRl 19 antagonist is for use in a method for the treatment of a disease or condition related to obesity.
  • the disease or condition related to obesity is selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic Attorney Docket No. 22578-0029WO1 / 214.WOI
  • renal failure lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility,
  • the GP l 1 antagonist is for use in a method for the treatment of non-alcoholic fatty liver disease.
  • the GPRl 19 antagonist is for use in a method for the treatment of food-dependent Cushing's syndrome.
  • the GPRl 19 antagonist is for use in a method for the treatment of cancer.
  • the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • the cancer is selected from: leukemia, multiple myeloma, non- Hodgkin's lymphoma, and colorectal cancer.
  • compositions comprising a GPRl 19 antagonist of the present invention.
  • One aspect of the present invention is directed to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a dosage form, and a kit, comprising a GPRl 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods of reducing a postprandial GiP level in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
  • a postprandial level of GLP-1 is not reduced in She individual, in some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
  • One aspect of the present invention is directed to methods of treating obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
  • One aspect of the present invention is directed to methods of treating a disease or condition related to obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
  • One aspect of the present invention is directed to methods of treating a disease or condition related to obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention So the individual, wherein the disease or condition related to obesity is selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • a GPRl 19 antagonist of the present invention selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower
  • One aspect of the present invention is directed to methods of treating non-alcoholic fatty liver disease in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present inv ention to the individiial.
  • One aspect of the present inv enti on is directed to methods of treating food-dependent Cusbing's syndrome in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
  • One aspect of the present invention is directed to methods of treating cancer in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to She individual.
  • One aspect of the present invention is directed to methods of treating cancer in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual, wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
  • One aspect of the present invention is directed to uses of GPR i 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GIF level in an individual.
  • a posiprandial level of GLP-1 is not reduced in the individual.
  • postprandial secretion of GLP-1 is not reduced in the individual.
  • One aspect of the present inv ention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GTP level in an individual following a meal comprising one or more lipids.
  • a postprandial level of GLP- 1 is not reduced in the individual.
  • postprandial secretion of GLP- 1 is not reduced in the individual.
  • One aspect of the present invention is directed to uses of GPRl 19 antagon ists of the present invention in the manufacture of a medicament for reducing GTP secretion in an individual.
  • a postprandial level of GLP-1 is not reduced in the individual, in some embodiments, posiprandial secretion of GLP-1 is not reduced in the individual.
  • One aspect of the present invention is directed to uses of GP l 19 antagonists of the present invention in the manufacture of a medicament for reducing GIP secretion in an individual following a meal comprising one or more lipids.
  • a postprandial level of GLP-1 is not reduced in the individual.
  • postprandial secretion of GLP-1 is not reduced in the individual.
  • One aspect of the present invention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for the treatment of obesity.
  • One aspect of the present inv ention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity.
  • One aspect of the present invention is directed to uses of GPRi 19 antagon ists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • a disease or condition related to obesity selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • One aspect of the present invention is directed to uses of GPRI 19 antagonists of the present invention in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.
  • One aspect ofthe present invention is directed to uses of GP 1 19 antagonists of the present invention in the manufacture of a medicament for the treatment, of food-dependent Gushing 's syndrome.
  • One aspect ofthe present invention is directed to uses of GPR i 19 antagonists of the present invention in the manufacture of a medicament for the treatment, of cancer.
  • One aspect ofthe present invention is directed to uses of GPRI 19 antagonists of the present invention in She manufacture of a medicament for the treatment of cancer, wherein She cancer is selected from: cancers ofthe esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • One aspect of the present invention is directed to uses of GPRI 19 antagonists ofthe present invention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
  • One aspect ofthe present invention is directed to uses of GPRI i 9 antagonists of the present invention, in the manufacture of a medicament for weight management in an individual, in some embodiments, the weight management comprises weight loss,
  • the weight management comprises maintenance of weight loss, in some embodiments, the weight management further comprises a reduced-calorie diet.
  • the weight management further comprises a program of regular exercise.
  • the weight management further comprises both a reduced- calorie diet and a program of regular exercise.
  • the individual is an obese patient with an initial body mass index > 30 kg/ nr.
  • the individual is an overweight patient with an initial body mass index > 27 kg/m ' in the presence of at least one weight related comorbid condition.
  • the individual is an overweight patient with an initial body mass index > 27 kg ' m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual has an initial body mass index > 30 kg/ ' nr.
  • the individual has an initial body mass index > 27 kg/ ' rrr. In some embodiments, the individual has an initial body mass index > 27 kg/ ' rrr in the presence of at least one weight related comorbid condition.
  • the individual has an initial body mass index > 27 kg/ ' rrr in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual has an initial body mass index > 25 kg/rrr. In some embodiments, the individual has an initial body mass index > 25 kg/rrr in the presence of at least one weight related comorbid condition.
  • the individual has an initial body mass index > 25 kg/rrr in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management.
  • One aspect of the present invention is directed to GPRl 19 antagonists of th e present invention, for use in a method of weight loss.
  • One aspect of the present invention is directed to GPRl 19 antagonists of th e present invention, for use in a method of maintenance of weight loss.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a reduced-calorie diet
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a program of regular exercise.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a reduced-calorie diet and a program of regular exercise.
  • One aspect of the present invention is directed to GPR11 antagonists of the present invention, for use in a method of weight management in an obese patient with an initial body mass index > 30 kg/m .
  • One aspect of the present inv ention is directed to GPR11 antagonists of the present invention, for use in a method of weight management in an overweight patient with an initial body mass index > 27 kg/rrf in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention is directed to GPR1 19 antagonists of the present invention, for use in a method of weight iiianagernent in an overweight patient with an initial body mass index > 27 kg/ni' in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • She present invention is d irected to GPR119 antagonists of the present inv ention, for use in a method of weight management in an individual with an initial body mass index > 30 kg m ⁇
  • One aspect of the present invention is directed to GP 1 19 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 27 kg/rrT.
  • One aspect of the present invention is directed to GPR i 19 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 2.7 kg/rrT in the presence of at least one weigh t related co-morbid condition.
  • One aspect of the present invention is directed to GPR119 antagonists of the present invention, for use in a method of weight management in an individual with an initiai body mass index > 27 kgfwf in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention is directed to GPR1 1 9 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 25 kg/m 7' .
  • One aspect of the present invention is directed to GPR1 ! 9 antagonists of the present invention, for use in a method of weight iiianagernent in an individual with an initial body mass index > 25 kg/rri 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention is directed to GPR119 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 25 kg/m' in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the method of weight management further comprises gastric electrical stimulation.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual.
  • One aspect of the present inv ention is directed to GPRl 19 antagonists of the present invention, for use in a method of inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in preparation of the individual for bariatric surgery.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of maintaining w eight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual.
  • One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of maintaining weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual following bariatric surgery.
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushtng's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC 50 of the test compound at GPRl 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPR i 19 is indicative of the test compound being a GPRl 19 antagonist; comparing GiP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or condition; and formulating the test compound with a test compound useful for the treatment of the disease or condition; and formulating the test compound with a test compound useful for the treatment of the disease or condition; and formulating the test compound with a test compound useful for
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, the methods comprising the steps of: comparing GiP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or Attorney Docket No. 22578-0029WO1 / 214.WOI
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR.119 in an in vitro model, and to reduce a GIP level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC 50 of the test compound at GPR1 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPR 119 is indicative of the test compound being a GPR1 19 antagon ist; comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR 119 in an in vitro model, the methods comprising the steps of: comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to Attorney Docket No. 22578-0029WO1 / 214.WOI
  • the methods comprising the step of: producing or synthesizing the test compound.
  • the method further comprises the step of: comparing GLP-1 levels in an in vivo model in the presence and absence of the test compound, wherein a GLP-1 level in the in vivo model that is not substantially reduced in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 i 9 antagonist useful for the treatment of the disease or condition.
  • One aspect of the present invention is directed to methods for preparing a
  • composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Costing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
  • One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushtng's syndrome, and cancer in an individual, the test compound having been determined to antagon ize functionality of GPR119 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: producing or synthesizing the test compound.
  • One aspect of the present invention is directed to methods for identifying a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, comprising: comparing GIP levels in an in vivo model in the presence and absence of the test compound; and observing a reduced GIP level in the in vivo model in the presence of the test, compound as compared to in the absence of the test compound.
  • the method further comprises comparing GLP-1 levels in the in vivo model in the presence and absence of the test compound; and observing a GLP-1 level in the in vivo model in the presence of the test compound that is not substantially reduced as compared to in the absence of the test compound.
  • the method comprises determining a GIP level in a blood or plasma sample obtained from a mammal, the mammal having been administered food and a test compound, wherein the ability of the test compound to reduce a GIP level in the mammal is Attorney Docket No. 22578-0029WO1 / 214.WOI
  • test compound indicative of the test compound being useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food- dependent Cushing's syndrome, and cancer in an individual.
  • the mammal is a human.
  • the mammal is non-human.
  • the mammal is a rodent.
  • the mammal is a mouse.
  • the food comprises a lipid.
  • the food comprises a triglyceride.
  • the food comprises olive oil.
  • the food comprises a nutritional shake.
  • the disease or condition is obesity.
  • the disease or condition is a disease or condition related to obesity.
  • the disease or condition related to obesity is selected from: congestive beast failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • the disease or condition is non-alcoholic fatty liver disease.
  • the disease or condition is food-dependent Cushing's syndrome. In some embodiments, the disease or condition is cancer.
  • the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast,
  • the cancer is selected from: leukemia, multiple myeloma, non-
  • the GiP level in the presence of the test compound is reduced by at least 10% as compared to in the absence of the test compound.
  • the GIP level in the presence of the test compound is reduced by at least 20% as compared to in the absence of the test compound.
  • the GIP level in the presence of the test compound is reduced by at least 30% as compared to in She absence of the test compound.
  • the GIP level in the presence of the test compound is reduced by at least 40% as compared to in the absence of the test compound.
  • the GIP level in the presence of the test compound is reduced by at least 50% as compared to in the absence of the test compound.
  • the GiP level in the presence of the test compound is reduced by at least 60% as compared to in the absence of the test compound.
  • the GiP level in the presence of the test compound is reduced by at least 70% as compared to in the absence of the test compound.
  • the GiP level in the presence of the test compound is reduced by at least 80% as compared to in the absence of the test compound.
  • the GIP level in the presence of the test compound is reduced by at least 90% as compared to in the absence of the test compound.
  • the test compound is an antagonist of human GPRl 19.
  • the test compound has an IC o at GPRl 19 of less than about 1 ⁇ .
  • the test compound has an ICso at GPRl 19 of less than about 100 nM.
  • the test compound has an IC 50 at GPRl 19 of less than about 55 nM.
  • the test compound has an ICjo at GPRl 19 of less than about 35 nM.
  • the test compound has am IC 50 at GPR l 19 of less than about 15 nM.
  • the test compound is a small molecule.
  • test compound is orally active.
  • the test compound is a selective GPRl 19 antagonist.
  • the method further comprises the step of subsequently admixing the test compound with a pharmaceutical carrier to form a pharmaceutical composition.
  • compositions comprising a GPRl 19 antagonist identified using a method of the present invention.
  • Antagonists of GPR l 19 are useful in methods of treatment, alle viation, and pre vention of several diseases or disorders.
  • antagonists of GPRl 19 are useful for treating obesity and diseases/conditions related to obesity such as congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
  • antagonists of GPRl 19 are useful for treating, reducing the risk of developing, alleviating the symptoms of, or preventing non- Attorney Docket No. 22578-0029WO1 / 214.WOI
  • alcoholic fatty liver disease e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
  • the methods of treatment involve administering to a subject in need of such treatment an effective amount of an antagonist of GPR1 19 (or pharmaceutical compositions comprising same).
  • the GPR1 19 antagonist inhibits signaling through GPR1 19 thereby treating, reducing the risk of developing, alleviating the symptoms of, or preventing the disease/disorder.
  • the antagonists of GPR119 described herein are useful in prophylactic and therapeutic treatments, at least in part, because of their ability to reduce or inhibit the levels of the incretin GIP.
  • Obesity is a medical condition in which excess body fat has accumulated to such an extent that it may have an adverse effect on health, leading to reduced life expectancy, and/or increased health problems. Obesity puts people at increased risk for chronic diseases such as heart disease, type 2 diabetes, high blood pressure, and stroke. Obesity also increases the risk of developing other conditions such as polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis, hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, headache, asthma, and insulin resistance.
  • the incretin GIP has been linked to obesity based on several experimental observations. Consumption of high-fat diets induces K cell hyperplasia and increases GIP gene expression. In obese children, basal and postprandial GIP secretion was significantly decreased three to seven months after dieting as compared with GIP levels before the dietary restrictions. In obese adults compared to age-matched healthy individuals, postprandial GIP secretion was found to be increased.
  • Administration of the GTPR antagonist (Pro " *) GIP to ob/ob mice prevented the onset of many abnormalities of obesity, in addition, the targeted knockout of GIP-producing K cells reduced obesity in high-fat fed mice and GIPR. knock-out mice exhibited a suppression of body weight gain and reduced adiposity.
  • RYGB Roux-en-Y gastric surgery
  • GIPR is expressed in adipose tissue.
  • the GIPR ligand, GIP is a key regulator of adipocytes and lipid metabolism and facilitates efficient deposition of fat in body stores.
  • GIP's effects on adipocytes include increasing levels of lipoprotein lipase (LPL), stimulation of Attorney Docket No. 22578-0029WO1 / 214.WOI
  • GIP stimulates LPL activity, which hydrolyzes chylomicrons and very-low- density lipoproteins, thereby liberating fatty acids for uptake and incorporation by adipocytes, thereby exerting an anabolic function on adipose tissue.
  • TAG triacylglycerol
  • FFA free fatty acid
  • GIP has also been implicated in impairing the function of adipocytes by increased production of pro-inflammatory cytokines and chemokines (e.g., IL-6, TNF-a, MCP-1, MCP-2, MCP-3).
  • pro-inflammatory cytokines and chemokines e.g., IL-6, TNF-a, MCP-1, MCP-2, MCP-3.
  • the GTP-indoced inflammatory response leads to increased basal glucose uptake but inhibits insulin-stimulated glucose uptake.
  • Blocking the action of GIP by, for example, downregulating the levels of GIP can thus reduce body weight, reduce adiposity, and reduce or prevent obesity or conditions associated with obesity.
  • the antagonists of GPR119 described herein can achieve this goal.
  • the antagonists of GP 119 can be used to decrease: body weight, adipose tissue mass, levels of triglycerides in muscle and/or liver, and/or circulating lipids.
  • the antagonists of GPR11 can be used to treat, reverse or prevent obesity and many of the metabolic abnormalities associated with obesity.
  • the antagonists of GPR119 can increase the burning of fat and increase energy expenditure, while decreasing fat deposition and lipotoxictty. 2, Insis!in Resistance
  • Insulin resistance is a condition in which the body produces insulin but does not use it properly.
  • a person is insulin resistant, their muscle, fat, and liver cells do not respond properly to insulin.
  • the person's body needs more insulin to help glucose enter cells.
  • the pancreas tries to keep up with this increased demand for insulin by producing more insulin.
  • the pancreas fails to keep up with the body's need for insulin and excess glucose builds up in the bloodstream, setting the stage for diabetes.
  • Many people with insulin resistance have high levels of both glucose and insulin circulating in their blood at the same time. Insulin resistance increases the chance of developing type 2 diabetes and heart disease.
  • Decreasing GIP levels alleviates insulin resistance and restores glucose tolerance.
  • the two major abnormalities associated with insulin resistance are increased hepatic glucose output and decreased glucose uptake (mainly by skeletal muscle).
  • preferential oxidation and decreased deposition of fat, decreasing levels of GIP or blocking GIP action can clear triglyceride deposits from the liver and muscle thereby restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake.
  • Decreasing GIP levels also decreases corticosterone levels which beneficially impact insulin action.
  • the antagonists of GPR119 are useful in methods of ameliorating, treating, or preventing insulin resistance by, at least in part, decreasing levels of GiP. 3.
  • Non-alcoholic fatty liver disease is a term used to describe the accumulation of fat in the liver of people who drink little or no alcohol. The fat. that accumulates can cause inflammation and scarring in the liver. This more serious form of nonalcoholic fatty liver disease is sometimes called nonalcoholic steatohepatitis (NASH). At its most severe, nonalcoholic fatty liver disease can progress to liver failure, it is She most common liver disorder in developing countries.
  • NASH nonalcoholic steatohepatitis
  • antagonizing GIP has been shown to reverse liver, muscle, and adipose tissue triglyceride infiltration caused by consumption of a high-fat diet. Histological analyses of livers revealed fatty liver in normal mice fed a high- fat diet, but mice with inactive GIPR had normal liver structure, despite being fed a high-fat diet. These studies indicate that GiP has a role in fatty liver development.
  • the antagonists of GPR1 19 can be used to ameliorate, treat, or prevent NAFLD or NASH in a subject in need thereof by, at least, in part, decreasing levels of GiP.
  • Cushing's syndrome also referred So as hypercortisolism, is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone Cortisol.
  • Cortisol performs vital tasks in the body including: helping maintain blood pressure and cardiovascular function; reducing the immune system's inflammatory response; balancing the effects of insulin, which breaks down glucose for energy; regulating the metabolism of proteins, carbohydrates, and fats; and helping the body respond to stress.
  • Cushing ' s syndrome most commonly affects adults between the ages of 20 and 50 and is relatively rare. People who are obese and have type 2. diabetes have an increased risk of developing the disorder.
  • ACTH-independent Cushing's syndrome has also been identified, in ACTH -independent Cushing's syndrome, adrenal cells of a patient express aberrant hormone receptors, e.g., GIPR is overexpressed on adrenal cells of patients with ACTH-independent Cushing's syndrome, in patients with food-dependent Cushing's syndrome, the GiP that is released from endocrine K cells of the small intestine after meals binds the overexpressed GIPR on adrenal ceils resulting in postprandial increase in plasma Cortisol.
  • GIPR aberrant hormone receptors
  • GPRl 19 The antagonists of GPRl 19 described herein Eire useful in treatment of food-dependent Cusbing's syndrome by lowering the levels of GiP and thereby decreasing the amount of GIP that can bind GiPR on adrenal cells, thereby lowering Cortisol levels.
  • administration of the compounds described herein provides an alternative to adrenalectomy.
  • the antagon ists of GPRl 19 described herein are useful in the treatment of cancers, especially cancers linked to excess body fat.
  • cancers include cancers of the esophagus, uterine lining, ovary, endometrium, gall bladder, kidney, pancreas, colon, breast, and liver.
  • the antagonists of GPRl 19 described herein are also useful in the treatment of leukemia, multiple myeloma, and non-Hodgkin's lymphoma.
  • the antagonists of GPRl 19 decrease the levels of GIP and also the levels of insulin, both of which have been implicated in promoting cancer growth.
  • the antagonists of GPRl 19 described herein are useful in the treatment of colorectal cancer.
  • Colorectal cancer also known as colon cancer or bowel cancer, is prevalent in obese individuals. This cancer results from uncontrolled cell growth in the colon, rectum, or appendix, and patients with this cancer present with rectal bleeding and anemia which are sometimes associated with weight loss and changes in bowel habits.
  • Colorectal cancer has been linked with GIP.
  • GIP is expressed on several human colorectal cancer cell lines and incubation of these ceil lines with GIP causes the ceil lines to proliferate in a concentration-dependent manner.
  • GIP induces the activity of protein kinase B (Akt), which causes a cascade of cellular responses, including attenuation of apoptosis and stimulation of cell proliferation.
  • Akt protein kinase B
  • GIP treatment of colorectal cancer cells promotes the phosphorylation of p70S6 , a major component of the mammalian target of rapamycin (mTOR) pathway.
  • mTOR is known to play a key role in several pathways that are in involved in human cancer, as well as in obesity and its associated disorders.
  • the antagonists of GPR l 19 described herein can be used in treatment of colorectal cancer (e.g., obesity-related colorectal cancer) by doworegulating levels of GIP.
  • One aspect of the present invention is directed to methods of reducing a postprandial
  • GIP level in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of She present invention.
  • One aspect of the present invention is directed to methods of reducing a postprandial GIP level in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods of reducing postprandial GiP secretion in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GP I 1 antagonist of the present invention.
  • One aspect of the present inventi on is directed to methods of reducing postprandial GiP secretion in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR i 19 antagonist of the present invention.
  • a postprandial level of GLP- i is not reduced in the individual.
  • postprandial secretion of GLP- i is not reduced in the individual.
  • One aspect of She present invention is directed to methods for treating obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating non-alcoholic fatty liver disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating food-dependent Cushing's syndrome in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • a GPRI 19 antagonist of the present invention wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
  • One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effectiv e amount of a GPRl 19 antagonist of the present invention wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
  • One aspect of the present invention is directed to methods for weight management in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of the present invention
  • the weight management comprises weight loss.
  • the weight management comprises maintenance of weight loss. in some embodiments, the weight management further comprises a reduced -calorie diet.
  • the weight management further comprises a program of regular exercise
  • the weight management further comprises both a reduced- calorie diet and a program of regular exercise.
  • the individual in need of weight management is an obese patient with an initial body mass index > 30 kg/m .
  • the individual in need of weight management is an overweight patient with an initial body mass index > 27 kg m 2 in the presence of at least one weight related co morbi d cond ttio .
  • the individual in need ofweight management is an overweight patient with an initial body mass index > 27 kg/m" in the presence of at least one weight related comorbid condition selected from: hypertension, dysltpidemia, cardiovascular disease, glucose intolerance and sleep apnea,
  • the individual in need ofweight management has an initial body mass index > 30 kg/m y' .
  • the individual in need of weight management has an initial body mass index > 27 kg ⁇ ' ,
  • the individual in need ofweight management has an initial body mass index > 27 kg m 2 in the presence of at least one weight related comorbid condition
  • the individual in need of weight management has an initial body mass index > 27 kg m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dysltpidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual in need of weight management has an initial body mass index > 25 kg m 2 .
  • the individual in need of weight management has an initial body mass index > 25 kg/m in the presence of at least one weight related comorbid condition. in some embodiments, the individual in need of weight management has an initial body mass index > 25 kg/m in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the method of weight management further comprises gastric electrical stimulation.
  • One aspect of the present invention is directed to methods for inducing weight loss, BMi loss, waist circumference loss, or body fat percentage loss in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
  • One aspect of th e present invention is directed to methods for inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in preparation of the individual for bariatric surgery in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for maint aining weigh t loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
  • One aspect of the present invention is directed to methods for maintaining weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual following bariatric surgery in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
  • a further aspect of the present: invention is directed to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising ⁇ compound of the present invention and a pharmaceutically acceptable carrier. Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein with a pharmaceutically acceptable carrier. Attorney Docket No. 22578-0029WO1 / 214.WOI
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • Con ventional excipients such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants may be used in tablets and capsules for oral administration.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another so liable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pbarmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro el al.)
  • a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption i an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the invention may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules tilled with the same, Attorney Docket No. 22578-0029WO1 / 214.WOI
  • compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as iactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as com starch, potato starch or sodium carboxymethyl-ce!hilose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient defined in the context of a "pharmaceutical composition' * , refers to a component of a. pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose wh en using the compounds of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It. depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether farther active compounds are administered i addition to the compounds of the present invention.
  • Representative doses of the present invention include, but not limited to, about 0,001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on. she weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • Representative factors include the type, age, weight, sex, diet and medical condition of She patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of She particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination.
  • the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in she art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present in vention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that, the following dosage forms may comprise, as She active component either a compound of the invention or a pharmaceutically acceptable salt, solvate, or hydrate of a compound of the invention.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances Attorney Docket No. 22578-0029WO1 / 214.WOI
  • the carrier in powders, is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component in tablets, is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of She active compound; however, an artisan would know when amounts outside of Shis range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylceilulose, sodium carboxymethylceliulose, a low melting wax, cocoa butter and the like.
  • the term "preparation” refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a Sow melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propy ene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injeetables.
  • the compounds according to the present invention may thus he formulated for parenteral administration (e.g. by injection, for example boius injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fumbled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilizatioa from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for orai use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyleeliulose, sodium carboxymethylcelMose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methyleeliulose, sodium carboxymethylcelMose, or other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanfh; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multi-dose form, in the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administratio to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitabie propellant. If the compounds of the present in vention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • compositions for administration of the compounds of the present invention as an aerosol can be prepared by processes well known to the person skilled in the art
  • solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitabie preservatives, absorption enhancers for increasing the bioavailability, soiubiiizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, diehiorodifluoromethane, trichlorofiuoromethane, or dtchlorotetrafluoroethane; and the like.
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound in formulations intended for administration to the respiratoiy tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by mtcrooization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the ph rmaceutical preparations are preferably in unit dosage forms, in such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such, as packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from Attorney Docket No. 22578-0029WO1 / 214.WOI
  • pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dtchloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
  • Certain compounds of the present invention which contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cation and cations derived from organic bases.
  • Representative metals include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, in some embodiments the pharmaceutically acceptable metal is sodium.
  • Organic bases include, but are not limited to, benzathine (N' ⁇ -dibenzylethane- 1 ,2-diamine), chloroprocaine (2- (diethylamino)ethyi 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2 i,3i?,4i?,5>S)-6-(methylamino)hexane-l,2,3,4,5-pentaol), procaine (2- (diethylamino)ethyl 4-aminobenzoate), and the like.
  • Certain pharmaceutically acceptable salts are listed in Berge, ei al., Journal of Pharmaceutical Sciences, 66: 1 -19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard Sow molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound.
  • Pro-drags can thus be viewed as compounds of the invention containing one or more speci lized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound.
  • the "pro-drag” approach is utilized to facilitate oral absorption .
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed, Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • Some embodiments of tlie present invention include a method of producing a pharmaceutical composition for "combination therapy" comprising admixing at least one compound according to any of th e compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • GPRl 19 antagonists when utilized as active ingredients in pharmaceutical compositions, these are not intended for use in humans only, but in non-human mammals as well.
  • active agents such as GPRl 19 antagonists
  • livestock animals e.g. , horses, cows, etc.
  • hydrate as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces.
  • solvate as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non- toxic, and/or acceptable for administration to humans in trace amounts.
  • the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate or hydrate thereof.
  • various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in; Polymorphism in Pharmaceutical Solids, ed. Harry G. England, Vol.
  • one aspect of the present invention is directed to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), Attorney Docket No. 22578-0029WO1 / 214.WOI
  • TGA-mass spectroscopy TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Kari Fisher titration, high resolution X-ray diffraction, and the like.
  • XRPD powder X-ray diffraction
  • Kari Fisher titration high resolution X-ray diffraction
  • Example companies offering these services include Wilmington PharmaTech (Wilmi gton, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).
  • Polymorphism is the ability of a substance to exis as two or more crystalline phases that have different arrangements and/or conformations of She molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they behave differently in She solid state.
  • drugs can also exist as salts and other multtcomponent crystalline phases.
  • solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests.
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocs stals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which, the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily and may be thermodynamically favored over anhydrous polymorphs.
  • Crystalline forms can be identified by their un ique solid state signatures with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms of the present inv ention can be gauged by any of the following methods for example, thermogravimetric analysis (TGA), DSC, and the like. For DSC, it is known that the temperatures corresponding to thermal events observed will depend upon sample purity, the Attorney Docket No. 22578-0029WO1 / 214.WOI
  • Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio- imaging but also in assays, both, in vitro and in vivo, for localizing and quantitating GPR ⁇ 19 in tissue samples, including human, and for identifying GPR 1 19 ligands by inhibition binding of a radio-labeled compound. It is a further object of Shis invention So develop novel GPRl 19 assays of which comprise such radio- labeled compounds.
  • the present disclosure includes ail isotopes of atoms occurring in the present compounds, intermediates, salts and crystalline forms thereof, isotopes include those atoms having the same atomic number but different mass numbers.
  • One aspect of the present invention includes every combination of one or more atoms in the present compounds, intermediates, salts, and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number.
  • One such example is the replacement of an atom that is the most naturally abundant isotope, such as ⁇ or 1 C, found in one the present compounds, intermediates, salts, and crystalline forms thereof, with a different atom that is not the most naturally abundant, isotope, such as 2 H or ⁇ (replacing 3 ⁇ 4), or H C, L, C, or M C (replacing U C).
  • a different atom that is not the most naturally abundant, isotope such as 2 H or ⁇ (replacing 3 ⁇ 4), or H C, L, C, or M C (replacing U C).
  • isotopic-labeling of the present compounds, intermediates, salts, and crystalline forms thereof can be accomplished using any one of a variety of different synthetic methods know to those of ordinary skill in the art and they are readily credited with understanding the synthetic methods and available reagents needed to conduct such isotopic-labeling.
  • isotopes of hydrogen include ⁇ (deuterium) and ⁇ (tritium).
  • isotopes of carbon include ' * C, 1 5 C, and ' ' C.
  • isotopes of nitrogen include l3 N and Lr N.
  • isotopes of oxygen include l5 0, "O, and 18 C.
  • An isotope of fluorine includes 18 F,
  • An isotope of sulfur incl udes 35 S.
  • An isotope of chlorine includes 36 CS .
  • isotopes of bromine include 7j Br, 6 Br, ' 7 Br, and &i Br.
  • Isotopes of iodine include l2 % U4 I, and 13* I
  • Another aspect of the present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present compounds, intermediates, salts, and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed.
  • compositions and ph rmaceutical compositions comprising compounds as Attorney Docket No. 22578-0029WO1 / 214.WOI
  • the compound is enriched at one or more positions with an isotope other than the most naturally abundant isotope.
  • Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.
  • isotopically- labeled compounds of the present in vention are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or li C isotopes are useful in these studies.
  • substitution with heavier isotopes such, as deuterium (i.e., ⁇ ) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent. Other synthetic methods that are useful are discussed infra.
  • Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as follows:
  • Tritium Gas Exposure Labeling This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
  • Synthetic methods for incorporating activity levels of " 5 i into target molecules include: Attorney Docket No. 22578-0029WO1 / 214.WOI
  • This method is generally a two step process.
  • the first step is the conversion of the aryl or heteroarvi bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction ⁇ i.e. Pd(PlhP) 4 ] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhaiide or hexaalkylditin [e.g., A representative procedure was reported by Le Bas, M.-D. and co-workers in /. Labelled Compd. Radiopharm. 2001 , 44, 8280-S282.
  • a radiolabeled GPR119 compound of Formula 1 can be used in a screenin g assay to identify/evaluate compounds.
  • a newly synthesized or identified compound ⁇ i.e., test compound) can be evaluated for its ability to reduce binding of a radio-labeled compound of Formula I to a GPR 119.
  • the ability of a test compound to compete with a radiolabeled compound of Formula i for the binding to a GPR 1 19 directly correlates to its binding affinity.
  • the labeled compound has an IC 3 ⁇ 4 less than about 500 ⁇ . in one embodiment, the labeled compound has an ⁇ 3 ⁇ 4 ⁇ less than about 100 ⁇ , In one embodiment, the labeled compound has an ⁇ 3 ⁇ 4 0 less than about 10 ⁇ , In one embodiment, the labeled compound has an IC3 ⁇ 4! less than about 1 ⁇ . In one embodiment, the labeled compound has an IC 50 less than about 0.1 ⁇ . In one embodiment, the labeled compound has an IC 50 less than about 0.01 ⁇ . In one embodiment, the labeled compound has an IC 50 less than about 0,005 ⁇ ,
  • Example 1 Syntheses of Compounds of the Present Invention. Attorney Docket No. 22578-0029WO1 / 214.WOI
  • the compounds of the invention and their syntheses are farther illustrated by the following examples.
  • the following examples are provided to farther define the invention without, however, limiting the invention to the particulars of these examples.
  • the compounds described herein, supra and infra are named according to AutoNom version 2.2, AutoNom 2000, CS ChemDraw Ultra Version 7,0.1, or CS ChemDraw Ultra Version 9,0.7. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.
  • Microwave irradiations were carried out using a Smith SynthesizerTM or an Emrys OptimizerTM (Biotage® column chromatography) , Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0,200 mm (Merck),
  • LCMS spec HPLC-pumps: LC- iOAD VP, Shimadzu Inc.; HPLC system controller: SCL-iOA VP, Shimadzu fee; UV-Deteetor: SPD-iOA VP, Shimadzu fee; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.
  • Example 1.1 Preparation of 3-((lr,4r)-4-(l-(4-(Trifluoromethyl)py rimidin-2-yl)piperidin- 4-yIoxy)cyclohexyIoxy)pyrazine-2-carbonitrile (Compound 1).
  • Step 1 Preparation of fert-Butyl 4-((lr,4r)-4-(3-Cyanopyrazin-2- yioxy)cyclohexyioxy)piperidine-l-carboxylate.
  • Step B Preparation of 3-((lr,4r)-4-(Piperidm-4-yloxy)cyclohexyloxy)pyrazme-2- carbonitrile Hydrochloride.
  • Step C Preparation of 3-((lr,4r)-4-(l-(4-(TrifluoromethyI)pyriniidiii-2- yI)piperidia-4-yloxy)cycIohexyloxy)pyraziae-2-carboaitriIe (Compound 1).
  • Example 1.2 Preparation of 4-(2-Fluoro-4-(methylsulfonyi)phenoxy)-5-methyi-6-(l-(4- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidiiie (Compound 2).
  • Step A Preparation of l-(4-(Trif!uoromethyl)pyrimidin-2-yl)piperidm-4-ol. To a solution of piperidin-4-ol (0.50 g, 4.94 mmol) and 2-chloro-4-
  • Step B Preparation of 4-Chioro-5-naethyl-6-(l-(4-(trinuoromethyI)p rimidin-2- yi)piperidin-4-yloxy)pyrimidine.
  • Step C Preparation of 4-(2-Fluoro-4-(methyls «lfonyI)phenoxy)-5-methyi-6-(l-(4-
  • Example 1.3 Preparation of 5-Fliuoro-4 ⁇ (2 ⁇ metl!yI ⁇ 6-(ii!iiei3iiy!sulfo:isyI)pyrid:ffl-3 ⁇ yloxy)-6- (l-(4-(trMuoromethyl)pyrimidin-2-yi)piperidin-4-yloxy)pyriniidine (Compound 3).
  • Step A Preparation of fert-Butyl 4-(6-ChIoro-5-fluoropyrimidin-4- yioxy)piperidine-l-carboxylate.
  • Step C Preparation of 5-Fluoro-4-(2-niethyl-6-(methylsulfoayl)pyridin-3-yloxy)- 6-(piperidm-4-yIoxy)pyrimidine Hydrochloride.
  • Step D Preparation of 5-Fluoro-4-(2-methyi-6-(methylsulfonyi)pyridiii-3-yioxy)- 6-(l -(4-(trifliiorometlsyl)pyrsmidm-2-y!pipeiidi!i-4-yloxy)pyririsidm (Compound 3).
  • Step A Preparation of l-(4-(Trifiuoromethyl)pyriniidm-2-yl)piperidiii-4-ol.
  • Step B Preparation of 4-Chloro-5-methoxy-6-(l-(4-(trifluoromethyl)pyrimidiii-2- yi)piperidin-4-yloxy)pyrimidme.
  • Step C Preparation of 5-Methoxy-A-(2-methyl-6-(methylsuifonyl)pyridin-3-yi)-6- (l-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidm-4-amine (Compound 4).
  • Example 1.5 Synthesis of 4-((lr,4r)-4-(l-(4-(Tiiiluoromethyl)pyrimidm-2-yl)piperidin-4- yloxy)cyclohexyloxy)nicotinoiiitrile (Compound 5).
  • Step A Preparation of 4-(l,4-Dioxaspiro[4iijdecan-8-yIoxy)pyridine.
  • Step B Preparation of 4-(Pyridin-4-yloxy)cycIohexanone.
  • Step C Preparation of (ls,4s)-4-(Pyridm-4-yloxy)cyclohexanol and (lr,4r)-4- (Pyridin-4-yloxy)cyclohexanol.
  • Step D Preparation of (lr,4r)-4-(Piperidin-4-yioxy)cyclohexanol.
  • tetraborate decahydrate (4.05 g, 10.62 romoi) in IPA (200 mL) was filled with hydrogen to ca. 20 bar and stirred at 80 °C (oil bath).
  • the bomb was refilled with hydrogen to ca. 20 bar three times within 8 h. After stirring over night, the bomb was refilled again to 20 bar (and then again after 4 and 8 hours). After stirring over the weekend, the reaction was complete.
  • the mixture was filtered through Celite®, washing with additionai IPA, The filtrate was concentrated and dried under high vacuum to give the title compound as a white solid (20,6 g, 97.4%).
  • Step E terf-Butyl 4-((lr,4r)-4-Hydroxycyclohexyloxy)piperidine-l-carboxylate.
  • Step F Preparation of fert-Butyl 4-((lr,4r)-4-(3-Cyanopyridin-4- yioxy)cyclohexyioxy)piperidine-l-carboxylate.
  • Step G Preparation of 4-((lr,4r)-4-(Piperidin-4- y!oxy)cyclohexy!oxy)nicotraonilrile diliydrocliloride.
  • Step H Preparation of 4-((ir,4r) ⁇ 4-(l-(4-(Trifiiioro:nitethyt)pyrm!id!K-2 ⁇ yI)piperidin-4-yloxy)cycIohexyloxy)nicotinonitriie (Compound 5),
  • Example 2 Homogeneous Time-Resolved Fluorescence (HTRF®) Assay for Direct cAMP Measurement.
  • HTRF® Homogeneous Time-Resolved Fluorescence
  • GPRl 19 antagonists (Compounds 1-5) were evaluated in an HTRF® cAMP detection assay (Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ) according to She manufacturer's instructions using CHO-Kl cells stably expressing GPRl 19.
  • CHO-Kl cells were transduced with a lentiviral vector encoding the nucleotide sequence of GPRl 19 (NCBI mRNA and protein reference sequences: NM_ 178471.2 & NP 848566 (human) and NM_ 181770.1 & NP 861435.1 (rat)).
  • NCBI mRNA and protein reference sequences NM_ 178471.2 & NP 848566 (human) and NM_ 181770.1 & NP 861435.1 (rat)
  • the N-terminus of the GPRl 19 nucleotide sequence was modified to Attorney Docket No. 22578-0029WO1 / 214.WOI
  • test compounds were concurrently added to the cells with the GPR1 19 agonist, A 7 -(2-fluoro-4-(niethylsulfonyl)phenyl)-6-(4-(3-isopropyl-l ,2,4-oxadiazol-5- yl)piperidin-l -yl)-5-nitrop>'rimidin-4-aniine (Compound 7).
  • Test compounds were evaluated in triplicate, using 10-point, 5-fold serial dilutions starting at 10 , uL.
  • Compound 7 was dispensed with the test compounds at a final concentration of 60 iiM. The final DMSO concentration in the assay was 0.5%.
  • Assay buffer containing 0,5% DMSO was used as a positive control in each runset while N-(2-fluoro-4- (methylsulfonyl)phenyl)-6-(4-(3-isopropyl-l ,2,4-oxadtazol-5-yl)piperidtri- 1 -yl)-5- nitropyrimidia-4-amine was used as the negative control.
  • the HTRF® assay was used to determine ⁇ 3 ⁇ 4 values for GPR119 antagonists.
  • mice C57BL/6J male mice (Taconic) (approximate body weight 25g) were fasted overnight in new cages.
  • Test compound Compound 4, 100 mg/kg or vehicle (PEG400, 10 mJL/kg) was dosed at 2b prior to lipid.
  • an eye -blood sample was taken and subsequently lipid (olive oil, 10 mL kg) (Sigma-Aldrich) was orally dosed. Eye -blood samples were taken 30 and 60 min after lipid load, and animals were decapitated and trunk blood was collected 120 min Attorney Docket No. 22578-0029WO1 / 214.WOI
  • Example 4 cAMP Accumulation Assay.
  • GPR11 receptor cDNA was cloned into pcDNA3.1(+) and tagged with a FLAG sag.
  • a modified signal peptide from viral hemagglutinin was inserted in front of the FLAG tag to enhance surface expression (Guan et ah, 1992).
  • COS? cells were grown in Dulbecco's modified Eagle's medium 1885 supplemented with 10% fetal calf serum, 2 mM glutamine, and 0.01 mg/mL pen-strep at 37 °C and 10% C0 2 . Cells were transfected with 20 ⁇ 3 ⁇ 4''75 cm 2 DNA using a calcium phosphate precipitation method with chloroquine addition. An ELISA assay was performed to confirm surface expression of the receptor.

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Abstract

The present invention relates to compounds of Formula I and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are antagonists of GPR119 useful in the treatment of, for example, a disorder selected from: obesity and diseases/conditions related to obesity such as congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility. In addition, the present antagonists of GPR119 are useful for treating non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer (e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer).

Description

Attorney Docket No. 22578-0029WO1 / 214.WOI
ANTAGONISTS OF GPR1 19 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO
FIELD OF THE INVENTION
The present invention relates to compounds of Formula 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof, that are antagonists of GPR 119 useful in the treatment of, for example, a disorder selected from: obesity and diseases/conditions related to obesity such, as congestive heart failure, polycystic ovarian syndrome, infertility,
gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility. In addition, the present antagonists of GPR119 are useful for treating non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer (e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer).
BACKGROUND OF THE INVENTION
Although a number of receptor classes exist in humans, by far the most abundant and therapeutically relevant is represented by the G protein-coupled receptor (GPCR) class, it is estimated that approximately 4% of the protein-coding genome encodes GPCRs.
GPCRs are also known as seven-transmembrane domain receptors as they share a common structural motif, having seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane. The transmembrane helices are joined by strands of amino acids between transmembrane-2 and transmembrane-3, transmembrane -4 and transmembrane-5, and transmembrane-6 and transmembrane-? on the exterior, or "extracellular" side, of the cell membrane. The transmembrane helices are also joined by strands of amino acids between transmembrane- 1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or "intracellular" side, of the cell membrane. The "carboxy" ("C") terminus of the receptor lies in the intracellular space within the cell, and the "amino" ("N") terminus of the receptor lies in the extracellular space outside of the cell.
Generally, when a ligand binds with the receptor (often referred to as "activation" of the receptor), there is a change in the conformation of the receptor that facilitates coupling between the intracellular region and an intracellular "G-protein." Examples of such G proteins include Gq, Gs, Gi, Gz, and Go. It has been reported that GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein. Ligand- activated GPCR coupling with the G-protein initiates a signaling cascade process (referred to as Attorney Docket No. 22578-0029WO1 / 214.WOI
"signal transduction"). The two principal signal transduction pathways involving the G protein- coupled receptors are the cAMP signal pathway and the phosphatidylinositoi signal pathway. Under normal conditions, signal transduction uitimately results in cellular activation or cellular inhibition.
Under physiological conditions, GPCRs exist in the cell membrane in equilibrium between two different conformations; an "inactive" state and an "active" state. A receptor in ait inactive state is unable to link to the intracellular signaling transduction pathway to in itiate signal transduction leading to a biological response. Changing the receptor conformation to the active state allows linkage to the transduction pathway (via the G -protein) and produces a biological response. A receptor may be stabilized in an active state by a iigand or a compound such as a drug.
GPCRs represent an important area for She development of pharmaceutical products. Drugs active at GPCRs have therapeutic benefit across a broad spectrum of human diseases as diverse as pain, cognitive dysfunction, hypertension, peptic ulcers, rhinitis, and asthma. In fact, GPCRs are the target of approximately 40% of all modem medicinal drags.
One example of a GPC i s G protein -coupled receptor 1 19 (GPR l 19), which has also been referred to as RUP3, SNORF25, GPCR2, OSGPR 1 16, 19AJ, and as Glucose-Dependent Insulinotroptc Receptor (GDIR). The human GPR l 19 amino acid sequence can be found at GenBank® Accession No. AAP72.125, The activation of GPRl 19 by an agonist leads to elevation of the level of intracellular cAMP, consistent with GPR l 19 being coupled to Gs. Activation of GPRl 19 is known to lead to the secretion of the incretins (hormones that work to increase insulin secretion), glucagon-like peptide- 1 (GLP-i), peptide tyrosine tyrosine (PYY), and glucose-dependent insulinotropic peptide (GIP).
GLP- 1 is an in cretin hormone derived from the post-translational modification of pro- glucagon and is secreted by gut endocrine cells. GLP-1 mediates its actions through a specific GPCR, namely glucagon-like peptide- 1 receptor (GLP-1 R). GLP-1 is best characterized as a hormone that regulates glucose homeostasis. GLP-1 has been shown to stimulate glucose- dependent insulin secretion and to increase pancreatic beta cell mass. GLP- 1 has also been shown to reduce the rate of gastric emptying and to promote satiety. GLP- 1 peptide agonists are effective in controlling blood glucose in Type 2 diabetics and in reducing body mass. GLP- 1 receptor agonists are additionally useful in protecting against myocardial infarction and against cognitive and neurodegenerative disorders. GLP-1 has been shown to be cardioprotective in a rat model of myocardial infarction, and GLP-1R has been shown in rodent models to be involved in learning and neuroprotection.
PYY is a 36 amino acid peptide originally isolated from porcine intestine. PYY is secreted from enteroendocrine L-cells within both the large and small intestine. Attorney Docket No. 22578-0029WO1 / 214.WOI
Immunoreactive PYY are low in the duodenum and jejunum, high in the ileum and colon, and highest in the rectum. PYY is released into the circulation as PYY^ and PYY;.;;,. PYY3..36 is generated from PYY;.;6 by cleavage of the N-terminai Tyr and Pro residues by dipeptidyl peptidase IV. PYY3.36 is the predominant form of PY Y in human postprandial plasma. PYY has been reported to reduce food intake, body weight gain and glycemic indices in diverse models of metabolic diseases.
GIF (also known as gastric inhibitory polypeptide) is a peptide incretin hormone of 42 amino acids that is released from duodenal endocrine K ceils after meal ingestion. The amount of GIP released is largely dependent on She amount of glucose consumed. GIP has been shown to stimulate glucose-dependent insulin secretion in pancreatic beta cells. GIP mediates its actions through a specific G protein-coupled receptor, namely glucose-dependent insulinotropic peptide receptor (GIPR). GIP is a substrate for dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating the degradation of GIP. Full-length GIP (1-42) is rapidly converted to bio-inactive GIP (3-42) within minutes of secretion from the gut K cell. Inhibition of DPP-IV has been shown to augment GIP bioactivity. GIP has been shown to activate osteoblastic receptors, resulting in increases in collagen type I synthesis and alkaline phosphatase activity, both associated with bone formation. GIP has been shown to inhibit osteoclast activity and differentiation in vitro, GIP administration has been shown to prevent the bone loss due to ovariectomy. GIPR knockout mice evidence a decreased bone size, lower bone mass, altered bone microarchitecture and biochemical properties, and altered parameters for bone turnover, especially in bone formation.
Regulating the levels of incretins can be useful in the treatment of numerous conditions or diseases. This application furthers that goal by the provision of novel antagonists of GPR1 19.
SUMMARY OF THE INVENTION
The present invention relates to, inter alia, certain piperidine derivatives and pharmaceutically acceptable salts, solvates, and hydrates thereof, which are useful, for example, in selectively lowering a post-prandial GIP level in an individual, and for treating diseases and disorders such as obesity and di eases/conditions related thereto, non-alcoholic fatty liver disease, food-dependent Cu string's syndrome, and cancer.
While the activation of GPR119 is known to lead to the secretion of the incretins (hormones that work to increase insulin secretion), ghicagon-tike peptide- 1 (GLP-1 ), peptide tyrosine tyrosine (PYY), and glucose-dependent insulinotropic peptide (GIP), applicants have identified compounds that can act as antagonists of GPR119 which unexpectedly selectively reduce postprandial GIP secretion, but do not reduce postprandial GLP-1 secretion. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to certain pipersdine derivatives selected from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000005_0001
Formula I
wherein:
R.1 is selected from: CpCe alky], cyano, and halogen;
A is C3-C7 cycioalkyiene, or heteroaryiene, wherein the heteroaryiene is optionally substituted with a substituent selected from: Ci -C6 aikoxy, C rCs alkyl, and halogen;
Q is O or NH;
X and Y are each independently , or CH;
Z is N or CR ; and
R2 is H or C;-C,5 alkylsulfonyi.
One aspect of the present invention is directed to compounds selected from compounds of Formula II and pharmaceutically acceptabie salts, solvates, and hydrates thereof:
Figure imgf000005_0002
Formula Π
wherein:
R' is selected from: Ci-Ce alkyl, cyano, and halogen;
X and Y are each independently , or CH;
Z is N or CR ; and
R " is H or (. -t ,, alkylsulfonyi.
One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptabie salts, solvates, and hydrates thereof: Attorney Docket No. 22578-0029WO1 / 214.WO!
Figure imgf000006_0001
Formula lia
wherein:
R1 is selected from: Ci -C6 alky], cyano, and halogen;
X and Y are each independently N, or CH;
Z is N or CR'; and
R2 is H or CVC6 alkylsulfonyl.
One aspect of the present invention is directed to compounds selected from compounds of Formula 111 and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000006_0002
Formula III
wherein:
1 is selected from: C] -C6 alkyl, cyano, and halogen;
Q is O or NH;
X and Y are each independently N, or CH;
Z is o CR2;
R" is H or C;-C,5 alkylsulfonyl; and
R5 is selected from: Cp-Q alkoxy, CpC'e alkyl, and halogen.
One aspect of the present invention is directed to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention is directed to processes for preparing
pharmaceutical compositions, comprising admixing a compound of the present invention with a pharmaceutically acceptable earner.
One aspect of the present invention is directed to compositions comprising a compound of the present invention and a pharmaceutically acceptable earner.
One aspect of the present invention is directed to processes for preparing compositions, comprising admixing a compound of the present invention with a pharmaceutically acceptable Attorney Docket No. 22578-0029WO1 / 2I4.W01
One aspect of the present invention is directed to GPR119 antagonists, for use in a method for reducing a postprandial GIP level in an individual, or for the treatment of obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cusbing's syndrome, or cancer, in an individual.
One aspect of the present invention is directed to compositions comprising a GPR1 19 antagonist of the present invention.
One aspect of the present invention is directed to pharmaceutical products selected from; a ph rmaceutical composition, a formulation, a dosage form, and a kit; comprising a GPR119 antagonist of the present invention.
One aspect of the present invention is directed to methods of reducing a postprandial
GiP level in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of th e present invention is directed to methods of reducing a postprandial GIP level in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
One aspect of the present invention is directed to methods of reducing postprandial GIP secretion in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 ! 9 antagonist of the present invention.
One aspect of the present invention is directed to methods of reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 1 antagonist of the present invention.
In some embodiments, a postprandial level of GLP- 1 is not reduced in the individual. In some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual.
One aspect of the present invention is directed to methods for treating obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility in an Attorney Docket No. 22578-0029WO1 / 2I4.W01
individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating non-alcoholic fatty liver disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating food-dependent Cushing's syndrome in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagon ist of the present invention.
One aspect of the present invention is directed to methods treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of She present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present in vention wherein the cancer is selected from; leukemia, multiple myeloma, oon-Hodgkin's lymphoma, and colorectal cancer.
One aspect of the present invention is directed to uses of GP 1 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GiP level in an individual.
One aspect of the present invention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GiP level in an individual following a meal comprising one or more lipids.
One aspect of the present invention is directed to uses of GPR1 19 antagonists of th e present invention in the manufacture of a medicament for reducing postprandial GiP secretion in an individual.
One aspect of the present invention is directed to uses of GPR1 19 antagon ists of the present invention in the manufacture of a medicament for reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids.
in some embodiments, a postprandial level of GLP-i is not reduced in the individual. in some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
One aspect of the present invention is directed to uses of GPR 1 19 antagonists of the present invention in the manufacture of a medicament for the treatment of obesity. Attorney Docket No. 22578-0029WO1 / 2I4.W01
One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity.
One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity selected from; congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.
One aspect of the present invention is directed to uses of GP l 19 antagonists of the present invention in the manufacture of a medicament for the treatment of food-dependent Cushsng's syndrome.
One aspect of the present invention is directed to uses of GP 1 19 antagonists of the present in vention in the manufacture of a medicament for the treatment of cancer.
One aspect of the present invention is directed to uses of GPR 1 19 antagonists of the present in vention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in th e manufacture of a medicament for the treatment of cancer, wherein th e cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC50 of the test compound at GPRl 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPRl 19 is indicative of the test compound being a GPRl 19 antagonist; comparing GIF levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the Attorney Docket No. 22578-0029WO1 / 2I4.W01
treatment of the disease or condition; and formulating the test compound with a
pharmaceutically acceptable earner to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cu string's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, the methods comprising the steps of: comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR119 antagonist useful for the treatment of the disease or condition; and formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, and to reduce a GIP level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment ofa disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the TCjo of the test compound at GPR 1 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GP 119 is indicative of the test compound being a GPR1 19 antagonist; comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR119 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment ofa disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to Attorney Docket No. 22578-0029WO1 / 2I4.W01
antagonize functionality of GPRl 19 in an in viiro model, the methods comprising the steps of: comparing GiP levels in an in vivo model in th e presence and absence of th e test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in th e absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, and to reduce a GiP level in an in vivo model, the methods comprising She step of: producing or synthesizing the test compound. in one embodiment, the method further comprises the step of: comparing GLP-1 levels in an in vivo model in the presence and absence of the test compound, wherein a GLP- 1 level in the in vivo model that is not substantially reduced in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR l 19 antagonist useful for the treatment of the disease or condition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food -dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the method comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for identifying a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, comprising: comparing GIP levels in an in vivo model Attorney Docket No. 22578-0029WO1 / 2I4.W01
in the presence and absence of the test compound; and observing a reduced G1P level in the in vivo model in th e presence of the test compound as compared to in the absence of the test compound.
One aspect of the present invention is directed to compositions comprising a GPRl 19 antagonist identified using a method of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the effect of the GPR l 19 antagonist Compound 4 on GLP- 1 following a 10 mL/kg lipid challenge in mice.
Figure 2 shows the effect of the GPRl 19 antagonist Compound 4 on GIF following a 10 mL/kg lipid challenge in mice.
Figure 3 shows a synthetic procedure for preparing an intermediate useful for preparin compounds of Formula Π or Ila.
Figure 4 shows a general synthetic procedure for preparing compounds of Formula II or ila.
Figure 5 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is O.
Figure 6 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is O.
Figure 7 shows a general synthetic procedure for preparing compounds of Formula III, wherein Q is NH.
Figure 8 shows the results ofcAMP accumulation assays of Compounds 2, 6, and 7. DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
For clarity and consistency, the following definitions will be used throughout this patent document.
The term "agonist" as used herein refers to a moiety that interacts with and activates a G-protein-coupled receptor, for instance GPR l 19, and ca thereby in itiate a physiological or pharmacological response characteristic of that receptor. For example, an agonist may activate an intracellular response upon binding to a receptor, or enhance GTP binding So a membrane.
The term "antagonist" as used herein encompasses neutral antagonists and inverse agonists. The term "neutral antagonist" as used herein refers to a moiety that competitively binds to the receptor at the same site as an agonist (for example, the endogenous ligand), but which does not activate the intracellular response initiated by the active form of the receptor and can thereby inhibit the intracellular responses by an agonist or partial agonist. A neutral Attorney Docket No. 22578-0029WO1 / 2I4.W01
antagonist does not diminish the baseline intracellular response in the absence of an agonist or partial agonist. The term "inverse agonist" refers to a moiety that binds to the endogenous form of the receptor or to the constitutively activated form of the receptor and which inhibits the baseline intracellular response initiated by th e active form of the receptor below the normal base level of activity which is observed in the absence of an agonist or partial agonist, or decreases GTP binding to a membrane. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50% and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
The term "GP 119" as used herein includes the human nucleotide sequences found in
GenBank® accession number AY288416, and naturally-occurring allelic variants thereof, and mammalian orthologs thereof. An example of a human GPR119 for use in screening and testing of the compounds of the invention is provided in the nucleotide sequence of SEQ ID NO:l and the corresponding amino acid sequence in SEQ ID NO:2 found in PCX Application No.
WQ2005/007647.
The term "in need of treatment" and th e term "in need thereof when referring to treatment are used interchangeably and refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the resuit of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
The term "individual" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
The term "modulate or modulating" refers to an increase or decrease in the amount quality, response or effect of a particular activity, function or molecule.
The term "composition" refers to a compound, including but not limited to, salts, solvates, and hydrates of a compound of the present invention, in combination with at least one additional component.
The term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, such as a compound as described herein; including but not limited to, salts, solvates, and hydrates of compounds of the present invention, whereby the composition is Attorney Docket No. 22578-0029WO1 / 2I4.W01
amenable to in vestigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
The term "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes on e or snore of the following:
(1) preventing the disease, for example, preventing a disease, condition or disorder in an individual thai may be predisposed to She disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
(2) inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or
symptomatology); and
(3) ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individ ual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology), CHEMICAL GROUP, MOIETY OR RADICAL
The term " -Ce aikoxy" refers to a radical comprising a Cj-Ce alkyl group attached to an oxygen atom, wherein Cj-Ce alkyl has She same definition as found herein. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons. Examples include, but are not limited to methoxy, ethoxy, w-propoxy, isopropoxy, «-butoxy, fcri-butoxy, isobutoxy, and .yec-butoxy.
The term "aryl" refers to an aromatic ring radical containing 6 to 10 ring carbons. Examples include, but are not limited to, phenyl and naphthyl.
The term "Q -Cg alkyl" refers to a straight or branched carbon radical containing 1 to 6 carbons. Some embodiments contain 1 to 5 carbons. Some embodiments contain 1 to 4 carbons. Some embodiments contain 1 to 3 carbons. Some embodiments contain 1 or 2 carbons.
Examples of an alkyl group include, but are not limited to, methyl, ethyl, «-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, feri-butyl, pentyl, isopentyl, i-pentyl, neopentyl, 1 -methyl butyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -C I ! ·Π !l C! h id ! ·Π ! and w-hexyl.
The term "Ci-C* alkylsulfonyl" refers to a radical comprising a C]-C6 alkyl group attached to the sulfur of a sulfonyl group, wherein CpCg alkyl has the same definition as Attorney Docket No. 22578-0029WO1 / 2I4.W01
described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, w-butyisulfonyl, see-butyisulfonyl, isohutylsuifonyl, and teri-butylsulfonyl.
The term "C3 cycloalkylene" refers to a saturated ring di-radical containing 3 to 7 carbons. Some embodiments contain 3 to 4 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 4 to 6 carbons. Some embodiments contain 5 to 6 carbons.
Examples include cyclopropylene, cycloburylene, cyclopentylene, and cyclohexyleae.
The term "cyano" refers to the group -CN,
The term "halogen" refers So a fluoro, chloro, bromo or iodo group.
The term "heteroarylene" refers to a di-radical ring system containing 5 to 10 ring atoms, that may contain a single ring or two fused rings, and wherein at least one ring is aromatic and at least one ring atom of the aromatic ring is a heteroatom selected from, for example: O, S and N, wherein N is optionally substituted with H, Ci -C, acyl, C1-C4 alkyl, or O (i.e., forming an N-oxide) and S is optionally substituted with one or two oxygens. In some embodiments, the ring system contains one heteroatom. In some embodiments, the ring system contains two heteroatoms. In some embodiments, the ring system contains three heteroatoms. Some embodiments are directed to 5-membered heteroarylene rings. Examples of a 5- membered heteroarylene ring include, but are not limited to, furanylene, thienylene, pyrrolylene, imidazolylene, oxazolylene, fliiazolyleoe, isoxazolylene, pyrazoSylene, isofliiazolyleoe, oxadiazolylene, (riazolylene, tetrazolylene, and thiadiazolylene. Some embodiments are directed to 6-membered heteroarylene rings. Examples of a 6-membered heteroarylene ring include, but are not limited to, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, and triazinylene.
COMPOUNDS
One aspect of the present invention encompasses, inter alia, certain heterocyclyl derivatives selected from compounds of Formula ί and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000015_0001
Formul 1 Attorney Docket No. 22578-0029WO1 / 2I4.W01
wherein R1, A, O, Q, X, Y, and Z, have the same definitions as described herein, supra and infra. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g. , R1, R2, R% A, O, Q, X, Y, and Z) contained within the generic chemical formulae described herein, for example, Formulae I, Π, Ila, and, ΙΠ, are specifically embraced by the present invention just as if each and every combination was individually and explicitly recited, to the extent that such combinations embrace compounds that result in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity), in addition, all subcombinations of She chemical groups listed in the embodiments describing such variables, as well as ail subcombinations of uses and medical indications described herein, are also specifically embraced by the present invention just as if each and every subcombination of chemical groups and subcombination of uses and medical indications was individually and explicitly recited herein.
As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group is replaced by a non -hydrogen substituent or group, the non -hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1 , 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1 , 2, 3, 4, 5, 6, or 7 substituents, and the like. Likewise, "substituted with one or more substituents" refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution, it is understood that She various tautomeric forms are within the scope of the compounds of the present invention.
it is understood and appreciated that compounds of Formula 1 and formulae related thereto may have one or more chiral centers and therefore can exist as enantiomers and/or diastereoisomers. The invention is understood to extend to and embrace ail such enantiomers, diastereoisomers and mixtures thereof, including but not limited to racemates. it is understood Attorney Docket No. 22578-0029WO1 / 2I4.W01
that compounds of Formula I and formulae used throughout this disclosure represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise,
it is understood and appreciated that certain compounds of Formula I and formulae related thereto exist as mesoisomers. Such mcsoisomers may he referred to as cis and trans isomers. The cii-meso isomers of compounds of Formula ί are named herein using the designation (1Λ,4Λ) and the iraws-meso isomers of compounds of Formula I are named herein using the designation (! r.4r). By way of example, mesoisomers of compounds of Formula II
Figure imgf000017_0001
(! r,4r)- or ira¾s-mesoisomer (Is, 4s)- or cis-mesoisomer
One aspect of the present invention is directed to compounds of the present invention wherein the mesoisomer stereochemistry is (lr,4r).
One aspect of the present invention is directed to compounds of the present invention wherein the mesoisomer stereochemistry is (Lv v).
One aspect of the present invention is directed to certain piperidine derivatives selected from compounds of Formula I and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000017_0002
Formula I
wherein:
R" is selected from: Ci-Ce alkyl, cyano, and halogen;
A is C3-C7 eyeloalkylene, or heteroarylene, wherein the heteroarylene is optionally substituted with a substituent selected from: Ci-Ce alkoxy, Ci-Ce alkyl, and halogen;
Q is O or NH;
X and Y are each independently N, or CH;
Z is N or CR3; and Attorney Docket No. 22578-0029WO1 / 2I4.W01
R2 is H or CrCe alkylsuifonyi.
The Group R
in some embodiments, R1 is selected from: C] -C6 alkyl, cyano, and halogen, in some embodiments, R1 is CrQ alkyl,
in some embodiments, R1 is halogen,
in some embodiments, R1 is selected from methyl, cyano, and fluoro.
in some embodiments, R1 is methyl,
in some embodiments, R1 is cyano.
in some embodiments, R* is fluoro.
The Group A
in some embodiments, A is C3-C7 cycloalkylene, or heteroarylene, wherein the heteroarylene is optionally substituted with a substituent selected from: Ci -Ce alkoxy, Cj -Cg alkyl, and halogen,
in some embodiments, A is cyclohexyiene or pyrimidinylene, wherein the pyrimidinylene is optionally substituted w ith a substituent selected from: Cr-Ce alkoxy, Ci-Ce alkyl, and halogen,
in some embodiments, A is cyclohexyiene or pyrimidinylene, wherein the pyrimidinylene is optionally substituted with a substituent selected from: methoxy, methyl, and fluoro.
in some embodiments, A is 1,4-cycloliexyeiene.
in some embodiments, A is 4,6-pyrimidinylene optionally substituted with a substituent selected from: Ci -Q alkoxy, Ci- alkyl, and halogen.
in some embodiments, A is 4,0-pyrimidinylene optionally substituted with a substituent selected from: methoxy, methyl, and fluoro.
in some embodiments, A is 5-methoxy-4,6-pyrimidinylene.
in some embodiments, A is 5-methyl 4,0-pyrimidinylene,
in some embodiments, A is 5-fluoro-4,6-pyrimidin.ylene.
The Group Q
in some embodiments, Q is O or NH.
in some embodiments, Q is O.
in some embodiments, Q is INH.
The Groiip X Attorney Docket No. 22578-0029WO1 / 2I4.W01
in some embodiments, X is N or CH.
in some embodiments, X is N.
in some embodiments, X is CH.
Group Y
in some embodiments, X is N or CH.
in some embodiments, Y is N,
in some embodiments, Y is CH.
The Group Z
in some embodiments, X is N or CR'.
in some embodiments, Z is N.
in some embodiments, Z is CR2,
The Group R2
in some embodiments, R' is H or Ci -Cfl alkylsulfonyl.
in some embodiments, R2 is H, or methyisuifonyl.
in some embodiments, R2 is H.
in some embodiments, R2 is Ci-Cg alJkylsulfonyl.
in some embodiments, R2 is methyisuifonyl
Certain Combinations
in some embodiments, X is CH, Y is CH, and Z is N.
in some embodiments, X is N, Y is N, and Z is CH.
in some embodiments, X is CH, Y is CH, and Z is CR\
in some embodiments, X is CH, Y is N, and Z is CR2.
One aspect of the present invention is directed to compounds selected from compounds of Formula Π and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000019_0001
Formula Π
wherein:
R1 is selected from: C] -C6 alkyl, cyano, and halogen; Attorney Docket No. 22578-0029WO1 / 2I4.W01
X and Y are each independently N, or CH;
Z is N or CR2; and
R2 is H or Ci-C6 alkylsuifonyl.
One aspect of the present invention is directed to compounds selected from compounds of Formula II and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000020_0001
Formula Π
wherein:
R1 is cyano; and
X and Y are both ; and Z is CH; or
X and Y are both CH; and Z is N.
One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptabie salts, solvates, and hydrates thereof:
Figure imgf000020_0002
Formula lla
wherein:
R1 is selected from: C] -C6 alkyl, cyano, and halogen;
X and Y are each independently , or CH;
Z is N or CR2; and
R2 is H or C -C, alkylsuifonyl.
One aspect of the present invention is directed to compounds selected from compounds of Formula lla and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000020_0003
Formula ila Attorney Docket No. 22578-0029WO1 / 214.WOI
wherein:
1 is cyano; and
X and Y are both N; and Z is CH; or
X and Y are both CH; and Z is N.
One aspect of the present invention is directed to compounds selected from compounds of Formula ΠΤ and pharmaceutically acceptable salts, sol vates, and hydrates thereof:
Figure imgf000021_0001
Formula III
wherein:
R1 is selected from: Ci-Cfl alkyl, cyano, and halogen;
Q is O or H;
X and Y are each independently N, or CH;
Z i or CR2;
R2 is H or C Ce alkylsulfonyl; and
R3 is selected from: Ci-Cs alkoxy, CpCe alkyl, and halogen.
One aspect of th e present invention is directed to compounds selected from compounds of Formula III and pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000021_0002
Formula ΠΪ
wherein:
R' is methyl or fSuoro;
Q is O or NH;
X is CH;
Y is N or CH;
Z is methylsulfonyl; and
is selected from: methoxy, methyl, and Attorney Docket No. 22578-0029WO1 / 214.WOI
Some embodiments of the present invention include ever}' combination of one or more compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof selected from the following group shown in Table A.
Figure imgf000022_0001
Additionally, individual compounds and chemical genera of the present invention, for example those compounds found in Table A including, isomers, diastereoisomers and eoaotiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and hydrates, thereof. Further, mesoisomers of individual compounds and chemical genera of the present Attorney Docket No. 22578-0029WO1 / 214.WOI
invention, for example those compounds found in Table A, encompass all pharmaceutically acceptable salts, solvates and particularly hydrates, thereof.
The compounds of the Formula 1 of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplar}' reagents and procedures for these reactions appear hereinafter in the working Examples.
Protection and deprotectioo may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M,, Protecting Groups in Organic Synthesis, 3*d Edition, 1999 [Wiley]).
it is understood that the present invention embraces, each isomer, each diastereoisomer, each eiiantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers and enantiomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers can be accomplished by application of various methods which are well known to practitioners in the art.
The chemical name, l-(4-fl«orobenzyl)-3'-(3-methoxypheKyl)spirof ido]iae-3,2'- miazo!idioe]-2,4'-dione (Compound 6), as used herein, refers to the following chemical structure:
Figure imgf000023_0001
(ChemDiv, San Diego, USA).
The chemical name, A''-(2-fluoro-4-(methylsuiionyi)phenyi)-6-(4-(3-isopropyl- l,2,4- oxadiazol-5-yi)piperidm-l-yl)-5-nitropyrimidin-4-amine (Compound 7) as used herein, refers to the following chemic
Figure imgf000023_0002
(WO2004065380, which, is incorporated herein by reference in its entirety). Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention is directed to processes for preparing
pharmaceutical compositions, comprising admixing a compound of the present invention with a pharmaceutically acceptable carrier.
One aspect of the present invention is directed to compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention is directed to processes for preparing compositions, comprising admixing a compound of the present invention wilh a pharmaceutically acceptable carrier.
One aspect of the present invention is directed to compounds of the present invention for use in a method of treatment of a human or animal by therapy .
One aspect of the present invention is directed to GPR1 1 antagonists, for use in a method for reducing a postprandial GIP level in an indiv idual, or for the treatment of obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, or cancer, in an individual.
In. some embodiments the GPR1 i 9 antagonist has an IC50 at GPRl.19 of less than about
1 μΜ,
In. some embodiments the GPRl i 9 antagonist has an IC50 at GPRl.19 of less than about 100 nM,
In some embodiments the GPRl 19 antagonist has an IC50 at GPRl 19 of less than about
55 nM.
In some embodiments the GPRl 1 antagonist has an IC50 at GPRl 19 of less than about
35 nM.
In some embodiments the GPR l 19 antagonist has an TC50 at GPRl 19 of less than about
15 nM.
In some embodiments the GPR l 19 antagonist has an TC50 at GPRl 19 of less than 1 μΜ.
In some embodiments the GPRl 19 antagonist has an JC5o at GPRl 19 of less than 1 00 nM.
in some embodiments the GPRl 19 antagonist has an IC50 at GPRl 19 of less than 55 nM.
in some embodiments the GPRl 19 antagonist has an 1(¾0 at GPRl 19 of less than 35 nM.
In some embodiments the GPRl 19 antagonist has an 1(¾0 at GPRl 19 of less than 15 nM. Attorney Docket No. 22578-0029WO1 / 214.WOI
in some embodiments the GPRl 19 antagonist is an antagonist of human GPRl 19. in some embodiments the GPRl 19 antagonist is a small molecule.
in some embodiments the GPRl 19 antagonist is orally active.
in some embodiments the GPRl 19 antagonist is a selective GPRl 19 antagonist.
in some embodiments the GPRl 19 antagonist is selected from: a compound of the present invention, a pharmaceutical composition of the present in vention, a composition of the present invention, and i -(4-floorobenzy])-3'-(3-rne(hoxyphenyl)spiro[indoline-3,2'- thiazolidine]-2,4'-dione and pharmaceutically acceptable salts, solvates, and hydrates thereof. in some embodiments the GPRl 19 antagonist is selected from: a compound of the present invention, and a pharmaceutical composition of the present invention.
in some embodiments the GPRl 19 antagonist is selected from: i-(4-fluorobenzyl)-3'- (3-methoxyphenyI)spiro[indoline-3,2'-t[iiazoiidine]-2,4!-dione and pharmaceutically acceptable salts, solvates, and hydrates thereof.
in some embodiments the GPRl 19 antagonist is for use in a method for reducing a postprandial GIP level in an individual.
In some embodiments, a postprandial level of GLP-1 is not reduced in the individual.
In some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
In some embodiments the GPR l 19 antagonist is for use in a method for reducing postprandial GIP secretion in an individual,
I some embodiments, a postprandial level of GLP-1 is not reduced in the individual.
In some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
In some embodiments the GPRl 19 antagonist is for use in a method for reducing a postprandial GIP level in an individual following a meal comprising one or more lipids.
In some embodiments, a postprandial level of GLP- 1 is not reduced in the individual. In some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual.
In some embodiments the GPRl 19 antagonist is for use in a method for reducing postprandial GIP secretion in an individual following a meal comprising one or more lipids. in some embodiments, a postprandial level of GLP- is not reduced in the individual. in some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual, in some embodiments the GPRl 19 antagonist is for use in a method for the treatment of obesity.
in some embodiments the GPRl 19 antagonist is for use in a method for the treatment of a disease or condition related to obesity.
In some embodiments the disease or condition related to obesity is selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic Attorney Docket No. 22578-0029WO1 / 214.WOI
renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility,
in some embodiments the GP l 1 antagonist is for use in a method for the treatment of non-alcoholic fatty liver disease.
in some embodiments the GPRl 19 antagonist is for use in a method for the treatment of food-dependent Cushing's syndrome.
in some embodiments the GPRl 19 antagonist is for use in a method for the treatment of cancer.
in some embodiments the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
in some embodiments the cancer is selected from: leukemia, multiple myeloma, non- Hodgkin's lymphoma, and colorectal cancer.
One aspect of the present invention is directed to compositions comprising a GPRl 19 antagonist of the present invention.
One aspect of the present invention is directed to pharmaceutical products selected from: a pharmaceutical composition, a formulation, a dosage form, and a kit, comprising a GPRl 19 antagonist of the present invention.
One aspect of the present invention is directed to methods of reducing a postprandial GiP level in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
in some embodiments, a postprandial level of GLP-1 is not reduced in She individual, in some embodiments, postprandial secretion of GLP-1 is not reduced in the individual. One aspect of the present invention is directed to methods of treating obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
One aspect of the present invention is directed to methods of treating a disease or condition related to obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
One aspect of the present invention is directed to methods of treating a disease or condition related to obesity in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention So the individual, wherein the disease or condition related to obesity is selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to methods of treating non-alcoholic fatty liver disease in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present inv ention to the individiial.
One aspect of the present inv enti on is directed to methods of treating food-dependent Cusbing's syndrome in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual.
One aspect of the present invention is directed to methods of treating cancer in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to She individual.
One aspect of the present invention is directed to methods of treating cancer in an individual comprising administering a therapeutically effective amount of a GPRl 19 antagonist of the present invention to the individual, wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast.
One aspect of the present invention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
One aspect of the present invention is directed to uses of GPR i 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GIF level in an individual.
In some embodiments, a posiprandial level of GLP-1 is not reduced in the individual.
In some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
One aspect of the present inv ention is directed to uses of GPRl 19 antagonists of the present invention in the manufacture of a medicament for reducing a postprandial GTP level in an individual following a meal comprising one or more lipids.
in some embodiments, a postprandial level of GLP- 1 is not reduced in the individual. in some embodiments, postprandial secretion of GLP- 1 is not reduced in the individual.
One aspect of the present invention is directed to uses of GPRl 19 antagon ists of the present invention in the manufacture of a medicament for reducing GTP secretion in an individual.
in some embodiments, a postprandial level of GLP-1 is not reduced in the individual, in some embodiments, posiprandial secretion of GLP-1 is not reduced in the individual. One aspect of the present invention is directed to uses of GP l 19 antagonists of the present invention in the manufacture of a medicament for reducing GIP secretion in an individual following a meal comprising one or more lipids.
in some embodiments, a postprandial level of GLP-1 is not reduced in the individual. Attorney Docket No. 22578-0029WO1 / 214.WOI
in some embodiments, postprandial secretion of GLP-1 is not reduced in the individual.
One aspect of the present invention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for the treatment of obesity.
One aspect of the present inv ention is directed to uses of GPR119 antagonists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity.
One aspect of the present invention is directed to uses of GPRi 19 antagon ists of the present invention in the manufacture of a medicament for the treatment of a disease or condition related to obesity selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
One aspect of the present invention is directed to uses of GPRI 19 antagonists of the present invention in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.
One aspect ofthe present invention is directed to uses of GP 1 19 antagonists of the present invention in the manufacture of a medicament for the treatment, of food-dependent Gushing 's syndrome.
One aspect ofthe present invention is directed to uses of GPR i 19 antagonists of the present invention in the manufacture of a medicament for the treatment, of cancer.
One aspect ofthe present invention is directed to uses of GPRI 19 antagonists of the present invention in She manufacture of a medicament for the treatment of cancer, wherein She cancer is selected from: cancers ofthe esophagus, uterine lining, ovary, kidney, pancreas, and breast.
One aspect of the present invention is directed to uses of GPRI 19 antagonists ofthe present invention in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
One aspect ofthe present invention is directed to uses of GPRI i 9 antagonists of the present invention, in the manufacture of a medicament for weight management in an individual, in some embodiments, the weight management comprises weight loss,
in some embodiments, the weight management comprises maintenance of weight loss, in some embodiments, the weight management further comprises a reduced-calorie diet.
in some embodiments, the weight management further comprises a program of regular exercise. Attorney Docket No. 22578-0029WO1 / 214.WOI
in some embodiments, the weight management further comprises both a reduced- calorie diet and a program of regular exercise.
in some embodiments, the individual is an obese patient with an initial body mass index > 30 kg/ nr.
in some embodiments, the individual is an overweight patient with an initial body mass index > 27 kg/m' in the presence of at least one weight related comorbid condition.
in some embodiments, the individual is an overweight patient with an initial body mass index > 27 kg'm2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
In some embodiments, the individual has an initial body mass index > 30 kg/'nr.
In some embodiments, the individual has an initial body mass index > 27 kg/'rrr. In some embodiments, the individual has an initial body mass index > 27 kg/'rrr in the presence of at least one weight related comorbid condition.
In some embodiments, the individual has an initial body mass index > 27 kg/'rrr in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
In some embodiments, the individual has an initial body mass index > 25 kg/rrr. In some embodiments, the individual has an initial body mass index > 25 kg/rrr in the presence of at least one weight related comorbid condition.
In some embodiments, the individual has an initial body mass index > 25 kg/rrr in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management.
One aspect of the present invention is directed to GPRl 19 antagonists of th e present invention, for use in a method of weight loss.
One aspect of the present invention is directed to GPRl 19 antagonists of th e present invention, for use in a method of maintenance of weight loss.
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a reduced-calorie diet One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a program of regular exercise.
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of weight management further comprising a reduced-calorie diet and a program of regular exercise. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to GPR11 antagonists of the present invention, for use in a method of weight management in an obese patient with an initial body mass index > 30 kg/m .
One aspect of the present inv ention is directed to GPR11 antagonists of the present invention, for use in a method of weight management in an overweight patient with an initial body mass index > 27 kg/rrf in the presence of at least one weight related co-morbid condition.
One aspect of the present invention is directed to GPR1 19 antagonists of the present invention, for use in a method of weight iiianagernent in an overweight patient with an initial body mass index > 27 kg/ni' in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
One aspect of She present invention is d irected to GPR119 antagonists of the present inv ention, for use in a method of weight management in an individual with an initial body mass index > 30 kg m\
One aspect of the present invention is directed to GP 1 19 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 27 kg/rrT.
One aspect of the present invention is directed to GPR i 19 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 2.7 kg/rrT in the presence of at least one weigh t related co-morbid condition.
One aspect of the present invention is directed to GPR119 antagonists of the present invention, for use in a method of weight management in an individual with an initiai body mass index > 27 kgfwf in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
One aspect of the present invention is directed to GPR1 1 9 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 25 kg/m7'.
One aspect of the present invention is directed to GPR1 ! 9 antagonists of the present invention, for use in a method of weight iiianagernent in an individual with an initial body mass index > 25 kg/rri2 in the presence of at least one weight related co-morbid condition.
One aspect of the present invention is directed to GPR119 antagonists of the present invention, for use in a method of weight management in an individual with an initial body mass index > 25 kg/m' in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea. in some embodiments, the method of weight management further comprises gastric electrical stimulation. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual.
One aspect of the present inv ention is directed to GPRl 19 antagonists of the present invention, for use in a method of inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in preparation of the individual for bariatric surgery.
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of maintaining w eight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual.
One aspect of the present invention is directed to GPRl 19 antagonists of the present invention, for use in a method of maintaining weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual following bariatric surgery.
REPRESENTATIVE METHODS
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushtng's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC50 of the test compound at GPRl 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPR i 19 is indicative of the test compound being a GPRl 19 antagonist; comparing GiP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or condition; and formulating the test compound with a
pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, the methods comprising the steps of: comparing GiP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GiP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPRl 19 antagonist useful for the treatment of the disease or Attorney Docket No. 22578-0029WO1 / 214.WOI
condition; and formulating the test compound with a pharmaceutically acceptable earner to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR.119 in an in vitro model, and to reduce a GIP level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the methods comprising the steps of: measuring the IC50 of the test compound at GPR1 19 in an in vitro model, wherein the ability of the test compound to antagonize functionality of GPR 119 is indicative of the test compound being a GPR1 19 antagon ist; comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR 119 in an in vitro model, the methods comprising the steps of: comparing GIP levels in an in vivo model in the presence and absence of the test compound, wherein a lower GIP level in the in vivo model in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 19 antagonist useful for the treatment of the disease or condition; and producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, the test compound having been determined to Attorney Docket No. 22578-0029WO1 / 214.WOI
antagonize functionality of GPR119 in an in vitro model, and to reduce a GIP level in an in vivo model, the methods comprising the step of: producing or synthesizing the test compound. in some embodiment the method further comprises the step of: comparing GLP-1 levels in an in vivo model in the presence and absence of the test compound, wherein a GLP-1 level in the in vivo model that is not substantially reduced in the presence of the test compound as compared to in the absence of the test compound is indicative of the test compound being a GPR1 i 9 antagonist useful for the treatment of the disease or condition.
One aspect of the present invention is directed to methods for preparing a
pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Costing's syndrome, and cancer in an individual, the test compound having been determined to antagonize functionality of GPR119 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: formulating the test compound with a pharmaceutically acceptable carrier to form the pharmaceutical composition.
One aspect of the present invention is directed to methods for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushtng's syndrome, and cancer in an individual, the test compound having been determined to antagon ize functionality of GPR119 in an in vitro model, to reduce a GIP level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, the methods comprising the step of: producing or synthesizing the test compound.
One aspect of the present invention is directed to methods for identifying a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, comprising: comparing GIP levels in an in vivo model in the presence and absence of the test compound; and observing a reduced GIP level in the in vivo model in the presence of the test, compound as compared to in the absence of the test compound.
In some embodiments, the method further comprises comparing GLP-1 levels in the in vivo model in the presence and absence of the test compound; and observing a GLP-1 level in the in vivo model in the presence of the test compound that is not substantially reduced as compared to in the absence of the test compound.
In some embodiments, the method comprises determining a GIP level in a blood or plasma sample obtained from a mammal, the mammal having been administered food and a test compound, wherein the ability of the test compound to reduce a GIP level in the mammal is Attorney Docket No. 22578-0029WO1 / 214.WOI
indicative of the test compound being useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food- dependent Cushing's syndrome, and cancer in an individual.
in some embodiments, the mammal is a human.
in some embodiments, the mammal is non-human.
in some embodiments, the mammal is a rodent.
in some embodiments, the mammal is a mouse.
in some embodiments, the food comprises a lipid.
in some embodiments, the food comprises a triglyceride.
in some embodiments, the food comprises olive oil.
in some embodiments, the food comprises a nutritional shake.
in some embodiments, the disease or condition is obesity.
in some embodiments, the disease or condition is a disease or condition related to obesity.
in some embodiments, the disease or condition related to obesity is selected from: congestive beast failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility.
In. some embodiments, the disease or condition is non-alcoholic fatty liver disease.
In some embodiments, the disease or condition is food-dependent Cushing's syndrome. In some embodiments, the disease or condition is cancer.
in some embodiments, the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast,
In some embodiments, the cancer is selected from: leukemia, multiple myeloma, non-
Hodgkin's lymphoma, and colorectal cancer.
In some embodiments, the GiP level in the presence of the test compound is reduced by at least 10% as compared to in the absence of the test compound.
In some embodiments, the GIP level in the presence of the test compound is reduced by at least 20% as compared to in the absence of the test compound.
in some embodiments, the GIP level in the presence of the test compound is reduced by at least 30% as compared to in She absence of the test compound.
In some embodiments, the GIP level in the presence of the test compound is reduced by at least 40% as compared to in the absence of the test compound.
In some embodiments, the GIP level in the presence of the test compound is reduced by at least 50% as compared to in the absence of the test compound. Attorney Docket No. 22578-0029WO1 / 214.WOI
in some embodiments, the GiP level in the presence of the test compound is reduced by at least 60% as compared to in the absence of the test compound.
in some embodiments, the GiP level in the presence of the test compound is reduced by at least 70% as compared to in the absence of the test compound.
in some embodiments, the GiP level in the presence of the test compound is reduced by at least 80% as compared to in the absence of the test compound.
in some embodiments, the GIP level in the presence of the test compound is reduced by at least 90% as compared to in the absence of the test compound.
in some embodiments, the test compound is an antagonist of human GPRl 19.
in some embodiments, the test compound has an IC o at GPRl 19 of less than about 1 μΜ.
in some embodiments, the test compound has an ICso at GPRl 19 of less than about 100 nM.
in some embodiments, the test compound has an IC50 at GPRl 19 of less than about 55 nM.
In some embodiments, the test compound has an ICjo at GPRl 19 of less than about 35 nM.
In some embodiments, the test compound has am IC50 at GPR l 19 of less than about 15 nM.
In some embodiments, the test compound is a small molecule.
In some embodiments, the test compound is orally active.
In some embodiments, the test compound is a selective GPRl 19 antagonist.
In some embodiments, the method further comprises the step of subsequently admixing the test compound with a pharmaceutical carrier to form a pharmaceutical composition.
One aspect of the present invention is directed to compositions comprising a GPRl 19 antagonist identified using a method of the present invention.
INDICATIONS AND METHODS OF TREATMENT
Antagonists of GPR l 19 (and pharmaceutical compositions comprising the same) are useful in methods of treatment, alle viation, and pre vention of several diseases or disorders. For example, antagonists of GPRl 19 are useful for treating obesity and diseases/conditions related to obesity such as congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility. In addition, antagonists of GPRl 19 are useful for treating, reducing the risk of developing, alleviating the symptoms of, or preventing non- Attorney Docket No. 22578-0029WO1 / 214.WOI
alcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer (e.g., cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast; leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer). The methods of treatment involve administering to a subject in need of such treatment an effective amount of an antagonist of GPR1 19 (or pharmaceutical compositions comprising same). The GPR1 19 antagonist inhibits signaling through GPR1 19 thereby treating, reducing the risk of developing, alleviating the symptoms of, or preventing the disease/disorder. The antagonists of GPR119 described herein are useful in prophylactic and therapeutic treatments, at least in part, because of their ability to reduce or inhibit the levels of the incretin GIP.
1. Obesity
Obesity is a medical condition in which excess body fat has accumulated to such an extent that it may have an adverse effect on health, leading to reduced life expectancy, and/or increased health problems. Obesity puts people at increased risk for chronic diseases such as heart disease, type 2 diabetes, high blood pressure, and stroke. Obesity also increases the risk of developing other conditions such as polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis, hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, headache, asthma, and insulin resistance.
The incretin GIP has been linked to obesity based on several experimental observations. Consumption of high-fat diets induces K cell hyperplasia and increases GIP gene expression. In obese children, basal and postprandial GIP secretion was significantly decreased three to seven months after dieting as compared with GIP levels before the dietary restrictions. In obese adults compared to age-matched healthy individuals, postprandial GIP secretion was found to be increased. Administration of the GTPR antagonist (Pro"*) GIP to ob/ob mice prevented the onset of many abnormalities of obesity, in addition, the targeted knockout of GIP-producing K cells reduced obesity in high-fat fed mice and GIPR. knock-out mice exhibited a suppression of body weight gain and reduced adiposity. Furthermore, patients that have undergone Roux-en-Y gastric surgery (RYGB), which bypasses most of the stomach as well as the duodenum and some portions of the jejunum, lose weight In RYGB patients, plasma concentrations of GIP drop following surgery suggesting that surgical removal of the site of GIP synthesis (GIP secreting K cells of the upper small intestine) confers weight loss benefits.
GIPR is expressed in adipose tissue. The GIPR ligand, GIP, is a key regulator of adipocytes and lipid metabolism and facilitates efficient deposition of fat in body stores. GIP's effects on adipocytes include increasing levels of lipoprotein lipase (LPL), stimulation of Attorney Docket No. 22578-0029WO1 / 214.WOI
lipogenesis, enhancement of fatty acid uptake, and increased free fatty acid (FFA) re- esterification. GIP stimulates LPL activity, which hydrolyzes chylomicrons and very-low- density lipoproteins, thereby liberating fatty acids for uptake and incorporation by adipocytes, thereby exerting an anabolic function on adipose tissue. Besides increasing lipolysis of circulating triacylglycerol (TAG) and FFA uptake, GTP also enhances glucose uptake by adipocytes which can then be used for lipogenesis. GIP has also been implicated in impairing the function of adipocytes by increased production of pro-inflammatory cytokines and chemokines (e.g., IL-6, TNF-a, MCP-1, MCP-2, MCP-3). The GTP-indoced inflammatory response leads to increased basal glucose uptake but inhibits insulin-stimulated glucose uptake.
Blocking the action of GIP by, for example, downregulating the levels of GIP can thus reduce body weight, reduce adiposity, and reduce or prevent obesity or conditions associated with obesity. The antagonists of GPR119 described herein can achieve this goal. The antagonists of GP 119 can be used to decrease: body weight, adipose tissue mass, levels of triglycerides in muscle and/or liver, and/or circulating lipids. Thus, the antagonists of GPR11 can be used to treat, reverse or prevent obesity and many of the metabolic abnormalities associated with obesity. By decreasing the levels of GIP, the antagonists of GPR119 can increase the burning of fat and increase energy expenditure, while decreasing fat deposition and lipotoxictty. 2, Insis!in Resistance
Insulin resistance is a condition in which the body produces insulin but does not use it properly. When a person is insulin resistant, their muscle, fat, and liver cells do not respond properly to insulin. As a result, the person's body needs more insulin to help glucose enter cells. The pancreas tries to keep up with this increased demand for insulin by producing more insulin. Eventually, the pancreas fails to keep up with the body's need for insulin and excess glucose builds up in the bloodstream, setting the stage for diabetes. Many people with insulin resistance have high levels of both glucose and insulin circulating in their blood at the same time. Insulin resistance increases the chance of developing type 2 diabetes and heart disease.
Decreasing GIP levels alleviates insulin resistance and restores glucose tolerance. The two major abnormalities associated with insulin resistance are increased hepatic glucose output and decreased glucose uptake (mainly by skeletal muscle). Through increased energy expenditure, preferential oxidation and decreased deposition of fat, decreasing levels of GIP or blocking GIP action can clear triglyceride deposits from the liver and muscle thereby restoring mechanisms for suppression of hepatic glucose output and cellular glucose uptake. Decreasing GIP levels also decreases corticosterone levels which beneficially impact insulin action. Attorney Docket No. 22578-0029WO1 / 214.WOI
The antagonists of GPR119 (and pharmaceutical compositions comprising the same) described herein are useful in methods of ameliorating, treating, or preventing insulin resistance by, at least in part, decreasing levels of GiP. 3. Non- Alcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a term used to describe the accumulation of fat in the liver of people who drink little or no alcohol. The fat. that accumulates can cause inflammation and scarring in the liver. This more serious form of nonalcoholic fatty liver disease is sometimes called nonalcoholic steatohepatitis (NASH). At its most severe, nonalcoholic fatty liver disease can progress to liver failure, it is She most common liver disorder in developing countries.
in animal models, antagonizing GIP has been shown to reverse liver, muscle, and adipose tissue triglyceride infiltration caused by consumption of a high-fat diet. Histological analyses of livers revealed fatty liver in normal mice fed a high- fat diet, but mice with inactive GIPR had normal liver structure, despite being fed a high-fat diet. These studies indicate that GiP has a role in fatty liver development.
Thus, the antagonists of GPR1 19 (and pharmaceutical compositions comprising the same) described herein can be used to ameliorate, treat, or prevent NAFLD or NASH in a subject in need thereof by, at least, in part, decreasing levels of GiP.
4, Food-dependent Cushing's Syndrome
Cushing's syndrome, also referred So as hypercortisolism, is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone Cortisol. Cortisol performs vital tasks in the body including: helping maintain blood pressure and cardiovascular function; reducing the immune system's inflammatory response; balancing the effects of insulin, which breaks down glucose for energy; regulating the metabolism of proteins, carbohydrates, and fats; and helping the body respond to stress. Cushing's syndrome most commonly affects adults between the ages of 20 and 50 and is relatively rare. People who are obese and have type 2. diabetes have an increased risk of developing the disorder.
Cushing's is normally associated with increased adrenocorticotropic hormone (ACTH) secretion. However, ACTH-independent Cushing's syndrome has also been identified, in ACTH -independent Cushing's syndrome, adrenal cells of a patient express aberrant hormone receptors, e.g., GIPR is overexpressed on adrenal cells of patients with ACTH-independent Cushing's syndrome, in patients with food-dependent Cushing's syndrome, the GiP that is released from endocrine K cells of the small intestine after meals binds the overexpressed GIPR on adrenal ceils resulting in postprandial increase in plasma Cortisol. Thus, compounds that Attorney Docket No. 22578-0029WO1 / 214.WOI
inhibit levels of GiP secretion can be useful in treating food-dependent Gushing' s syndrome. The antagonists of GPRl 19 described herein Eire useful in treatment of food-dependent Cusbing's syndrome by lowering the levels of GiP and thereby decreasing the amount of GIP that can bind GiPR on adrenal cells, thereby lowering Cortisol levels. Thus, administration of the compounds described herein provides an alternative to adrenalectomy.
5. Cancers
The antagon ists of GPRl 19 described herein are useful in the treatment of cancers, especially cancers linked to excess body fat. Examples of such cancers include cancers of the esophagus, uterine lining, ovary, endometrium, gall bladder, kidney, pancreas, colon, breast, and liver. The antagonists of GPRl 19 described herein are also useful in the treatment of leukemia, multiple myeloma, and non-Hodgkin's lymphoma. The antagonists of GPRl 19 decrease the levels of GIP and also the levels of insulin, both of which have been implicated in promoting cancer growth.
in one embodiment, the antagonists of GPRl 19 described herein are useful in the treatment of colorectal cancer. Colorectal cancer, also known as colon cancer or bowel cancer, is prevalent in obese individuals. This cancer results from uncontrolled cell growth in the colon, rectum, or appendix, and patients with this cancer present with rectal bleeding and anemia which are sometimes associated with weight loss and changes in bowel habits.
Colorectal cancer has been linked with GIP. GIPR is expressed on several human colorectal cancer cell lines and incubation of these ceil lines with GIP causes the ceil lines to proliferate in a concentration-dependent manner. GIP induces the activity of protein kinase B (Akt), which causes a cascade of cellular responses, including attenuation of apoptosis and stimulation of cell proliferation. In addition to Akt, GIP treatment of colorectal cancer cells promotes the phosphorylation of p70S6 , a major component of the mammalian target of rapamycin (mTOR) pathway. mTOR is known to play a key role in several pathways that are in involved in human cancer, as well as in obesity and its associated disorders. The antagonists of GPR l 19 described herein can be used in treatment of colorectal cancer (e.g., obesity-related colorectal cancer) by doworegulating levels of GIP.
One aspect of the present invention is directed to methods of reducing a postprandial
GIP level in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of She present invention.
One aspect of the present invention is directed to methods of reducing a postprandial GIP level in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of the present invention. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to methods of reducing postprandial GiP secretion in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GP I 1 antagonist of the present invention.
One aspect of the present inventi on is directed to methods of reducing postprandial GiP secretion in an individual following a meal comprising one or more lipids, the method comprising administering to the individual in need thereof a therapeutically effective amount of a GPR i 19 antagonist of the present invention.
in some embodiments, a postprandial level of GLP- i is not reduced in the individual. in some embodiments, postprandial secretion of GLP- i is not reduced in the individual. One aspect of She present invention is directed to methods for treating obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating a disease or condition related to obesity in an individual selected from: congestive heart failure, polycystic ovarian syndrome, infertility, gastroesophageal reflux disease, cholelithiasis (gall stones), hernia, erectile dysfunction, urinary incontinence, chronic renal failure, lymphedema, osteoarthritis, hyperuricemia, lower back pain, stroke, headache, asthma, and immobility in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating non-alcoholic fatty liver disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating food-dependent Cushing's syndrome in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRI 19 antagonist of the present invention wherein the cancer is selected from: cancers of the esophagus, uterine lining, ovary, kidney, pancreas, and breast. Attorney Docket No. 22578-0029WO1 / 214.WOI
One aspect of the present invention is directed to methods for treating cancer in an individual comprising administering to the individual in need thereof a therapeutically effectiv e amount of a GPRl 19 antagonist of the present invention wherein the cancer is selected from: leukemia, multiple myeloma, non-Hodgkin's lymphoma, and colorectal cancer.
One aspect of the present invention is directed to methods for weight management in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist of the present invention,
in some embodiments, the weight management comprises weight loss.
in some embodiments, the weight management comprises maintenance of weight loss. in some embodiments, the weight management further comprises a reduced -calorie diet.
in some embodiments, the weight management further comprises a program of regular exercise,
in some embodiments, the weight management further comprises both a reduced- calorie diet and a program of regular exercise.
In some embodiments, the individual in need of weight management is an obese patient with an initial body mass index > 30 kg/m .
In some embodiments, the individual in need of weight management is an overweight patient with an initial body mass index > 27 kg m2 in the presence of at least one weight related co morbi d cond ttio .
In some embodiments, the individual in need ofweight management is an overweight patient with an initial body mass index > 27 kg/m" in the presence of at least one weight related comorbid condition selected from: hypertension, dysltpidemia, cardiovascular disease, glucose intolerance and sleep apnea,
in some embodiments, the individual in need ofweight management has an initial body mass index > 30 kg/my'.
in some embodiments, the individual in need of weight management has an initial body mass index > 27 kg< ',
in some embodiments, the individual in need ofweight management has an initial body mass index > 27 kg m2 in the presence of at least one weight related comorbid condition, in some embodiments, the individual in need of weight management has an initial body mass index > 27 kg m2 in the presence of at least one weight related comorbid condition selected from: hypertension, dysltpidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
In some embodiments, the individual in need of weight management has an initial body mass index > 25 kg m2. Attorney Docket No. 22578-0029WO1 / 214.WOI
in some embodiments, the individual in need of weight management has an initial body mass index > 25 kg/m in the presence of at least one weight related comorbid condition. in some embodiments, the individual in need of weight management has an initial body mass index > 25 kg/m in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
in some embodiments, the method of weight management, further comprises gastric electrical stimulation.
One aspect of the present invention is directed to methods for inducing weight loss, BMi loss, waist circumference loss, or body fat percentage loss in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR119 antagonist of the present invention.
One aspect of th e present invention is directed to methods for inducing weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in preparation of the individual for bariatric surgery in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for maint aining weigh t loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
One aspect of the present invention is directed to methods for maintaining weight loss, BMI loss, waist circumference loss, or body fat percentage loss in an individual following bariatric surgery in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a GPR1 19 antagonist of the present invention.
COMPOSITIONS AND FORMULATIONS
A further aspect of the present: invention is directed to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising ι compound of the present invention and a pharmaceutically acceptable carrier. Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein with a pharmaceutically acceptable carrier. Attorney Docket No. 22578-0029WO1 / 214.WOI
Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
Con ventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another so liable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pbarmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro el al.)
While it is possible that, for use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption i an efficient manner with minimal degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan.
The compounds of the invention, together with a con ventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules tilled with the same, Attorney Docket No. 22578-0029WO1 / 214.WOI
ali for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as iactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, com starch or gelatins; with disintegrators such as com starch, potato starch or sodium carboxymethyl-ce!hilose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
Compounds of the present invention or a solvate, hydrate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as GPR i 19 antagonists. The term "active ingredient", defined in the context of a "pharmaceutical composition'*, refers to a component of a. pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit.
The dose wh en using the compounds of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It. depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether farther active compounds are administered i addition to the compounds of the present invention. Representative doses of the present invention include, but not limited to, about 0,001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein. Attorney Docket No. 22578-0029WO1 / 214.WOI
The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on. she weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of She patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of She particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in she art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4 part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
The compounds of the present in vention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that, the following dosage forms may comprise, as She active component either a compound of the invention or a pharmaceutically acceptable salt, solvate, or hydrate of a compound of the invention.
For preparing pharmaceutical composition s from th e compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances Attorney Docket No. 22578-0029WO1 / 214.WOI
which may also act as diluents, flavoring agents, soiubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
in powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
in tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of She active compound; however, an artisan would know when amounts outside of Shis range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylceilulose, sodium carboxymethylceliulose, a low melting wax, cocoa butter and the like. The term "preparation" refers to the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a Sow melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propy ene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution, injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injeetables. Attorney Docket No. 22578-0029WO1 / 214.WOI
The compounds according to the present invention may thus he formulated for parenteral administration (e.g. by injection, for example boius injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fiiled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilizatioa from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
Aqueous suspensions suitable for orai use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyleeliulose, sodium carboxymethylcelMose, or other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanfh; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form, in the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. Attorney Docket No. 22578-0029WO1 / 214.WOI
Administratio to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitabie propellant. If the compounds of the present in vention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well known to the person skilled in the art For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitabie preservatives, absorption enhancers for increasing the bioavailability, soiubiiizers, dispersants and others and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, diehiorodifluoromethane, trichlorofiuoromethane, or dtchlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
in formulations intended for administration to the respiratoiy tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by mtcrooization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
The ph rmaceutical preparations are preferably in unit dosage forms, in such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such, as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions,
The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from Attorney Docket No. 22578-0029WO1 / 214.WOI
pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dtchloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, / toluenesulfonic and the lik e. Certain compounds of the present invention which contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cation and cations derived from organic bases. Representative metals include, but are not limited to, aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, in some embodiments the pharmaceutically acceptable metal is sodium. Representative organic bases include, but are not limited to, benzathine (N'^-dibenzylethane- 1 ,2-diamine), chloroprocaine (2- (diethylamino)ethyi 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2 i,3i?,4i?,5>S)-6-(methylamino)hexane-l,2,3,4,5-pentaol), procaine (2- (diethylamino)ethyl 4-aminobenzoate), and the like. Certain pharmaceutically acceptable salts are listed in Berge, ei al., Journal of Pharmaceutical Sciences, 66: 1 -19 (1977).
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard Sow molecular weight solvents using methods known to the skilled artisan.
Compounds of the present invention can be converted to "pro-drugs." The term "prodrugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drags can thus be viewed as compounds of the invention containing one or more speci lized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drag" approach is utilized to facilitate oral absorption . A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed, Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
Some embodiments of tlie present invention include a method of producing a pharmaceutical composition for "combination therapy" comprising admixing at least one compound according to any of th e compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier. Attorney Docket No. 22578-0029WO1 / 214.WOI
it is noted that when the GPRl 19 antagonists are utilized as active ingredients in pharmaceutical compositions, these are not intended for use in humans only, but in non-human mammals as well. Recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as GPRl 19 antagonists, for the treatment of a GPRl 19 associated disease or disorder in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g. , horses, cows, etc.) Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.
HYDRATES AND SOLVATES
The term "hydrate" as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non- covalent intermolecular forces. The term "solvate" as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non- toxic, and/or acceptable for administration to humans in trace amounts.
it is understood that when the phrase "pharmaceutically acceptable salts, solvates, and hydrates" or the phrase "pharmaceutically acceptable salt, solvate, or hydrate" is used when referring to compounds described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of the compounds, pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable solvates and/or hydrates of pharmaceutically acceptable salts of the compounds. It is also understood that when the phrase "pharmaceutically acceptable solvates and hydrates" or the phrase "pharmaceutically acceptable solvate or hydrate" is used when referring to salts described herein, it embraces pharmaceutically acceptable solvates and/or hydrates of such salts,
it will be apparent to those skilled in the art that the dosage forms described herein may comprise, as the active component, either a compound described herein or a pharmaceutically acceptable salt or as a pharmaceutically acceptable solvate or hydrate thereof. Moreover, various hydrates and solvates of the compounds described herein and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K.J. Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in; Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, inc., New York, 1999. Accordingly, one aspect of the present invention is directed to methods of administering hydrates and solvates of compounds described herein and/or their pharmaceutical acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), Attorney Docket No. 22578-0029WO1 / 214.WOI
TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Kari Fisher titration, high resolution X-ray diffraction, and the like. There are several commercial entities that provide quick and efficient services for identifying solvates and hydrates on a routine basis. Example companies offering these services include Wilmington PharmaTech (Wilmi gton, DE), Avantium Technologies (Amsterdam), and Aptuit (Greenwich, CT).
POLYMORPHS AND PSEUDOPOLYMORPHS
Polymorphism is the ability of a substance to exis as two or more crystalline phases that have different arrangements and/or conformations of She molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they behave differently in She solid state.
Besides single-component polymorphs, drugs can also exist as salts and other multtcomponent crystalline phases. For example, solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests. Analogously, when the guest compound is a solid at room temperature, the resulting form is often called a cocrystal. Salts, solvates, hydrates, and cocs stals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.
Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which, the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily and may be thermodynamically favored over anhydrous polymorphs.
By way of example, Stahly recently published a polymorph screen of 245 compounds consisting of a "wide variety of structural types" that revealed about 90% of the compounds exhibited multiple solid forms. Overall, approximately half the compounds were polymorphic, often having one to three forms. About one -third of the compounds formed hydrates, and about one -third formed solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026).
Crystalline forms can be identified by their un ique solid state signatures with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms of the present inv ention can be gauged by any of the following methods for example, thermogravimetric analysis (TGA), DSC, and the like. For DSC, it is known that the temperatures corresponding to thermal events observed will depend upon sample purity, the Attorney Docket No. 22578-0029WO1 / 214.WOI
rate of temperature change, as well as sample preparation technique and the particular instrument employed.
OTHER UTILITIES
Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio- imaging but also in assays, both, in vitro and in vivo, for localizing and quantitating GPR ί 19 in tissue samples, including human, and for identifying GPR 1 19 ligands by inhibition binding of a radio-labeled compound. It is a further object of Shis invention So develop novel GPRl 19 assays of which comprise such radio- labeled compounds.
The present disclosure includes ail isotopes of atoms occurring in the present compounds, intermediates, salts and crystalline forms thereof, isotopes include those atoms having the same atomic number but different mass numbers. One aspect of the present invention includes every combination of one or more atoms in the present compounds, intermediates, salts, and crystalline forms thereof that is replaced with an atom having the same atomic number but a different mass number. One such example is the replacement of an atom that is the most naturally abundant isotope, such as Ή or 1 C, found in one the present compounds, intermediates, salts, and crystalline forms thereof, with a different atom that is not the most naturally abundant, isotope, such as 2H or Ή (replacing ¾), or HC, L,C, or MC (replacing UC). A compound wherein such a replacement has taken place is commonly referred to as being an isotopicaliy-labeled compound, isotopic-labeling of the present compounds, intermediates, salts, and crystalline forms thereof can be accomplished using any one of a variety of different synthetic methods know to those of ordinary skill in the art and they are readily credited with understanding the synthetic methods and available reagents needed to conduct such isotopic-labeling. By way of general example, and without limitation, isotopes of hydrogen include Ή (deuterium) and Ή (tritium). Isotopes of carbon include ' *C, 1 5C, and ' 'C. isotopes of nitrogen include l3N and LrN. isotopes of oxygen include l50, "O, and 18C. An isotope of fluorine includes 18F, An isotope of sulfur incl udes 35S. An isotope of chlorine includes 36CS . isotopes of bromine include 7jBr, 6Br, '7Br, and &iBr. Isotopes of iodine include l2% U4I, and 13*I, Another aspect of the present invention includes compositions, such as, those prepared during synthesis, preformulation, and the like, and pharmaceutical compositions, such as, those prepared with the intent of using in a mammal for the treatment of one or more of the disorders described herein, comprising one or more of the present compounds, intermediates, salts, and crystalline forms thereof, wherein the naturally occurring distribution of the isotopes in the composition is perturbed. Another aspect of the present invention includes compositions and ph rmaceutical compositions comprising compounds as Attorney Docket No. 22578-0029WO1 / 214.WOI
described herein wherein the compound is enriched at one or more positions with an isotope other than the most naturally abundant isotope. Methods are readily available to measure such isotope perturbations or enrichments, such as, mass spectrometry, and for isotopes that are radio-isotopes additional methods are available, such as, radio-detectors used in connection with HPLC or GC.
Certain isotopically- labeled compounds of the present in vention are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or liC isotopes are useful in these studies. Further, substitution with heavier isotopes such, as deuterium (i.e., Ή) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent. Other synthetic methods that are useful are discussed infra.
Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or a scarcer radioisotope or nonradioactive isotope.
Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as follows:
A. Catalytic Reduction with Tritium Gas: This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.
B. Reduction with Sodium Borohydride | "Ή j: This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters and the like,
C. Reduction with Lithium Aluminum Hydride j i i j : This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such, as aldehydes, ketones, lactones, esters and the like,
D, Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
E. N-Methylation using Methyl iodide [Ή]: This procedure is usually employed to prepare O-methyt or A'-methyl (3//) products by treating appropriate precursors with high specific activity methyl iodide (3/ ). This method in general allows for higher specific activity, such as for example, about 70-90 Ci/mmol.
Synthetic methods for incorporating activity levels of "5i into target molecules include: Attorney Docket No. 22578-0029WO1 / 214.WOI
A. Sandmeyer and like reactions: This procedure transforms an aryl amine or a heteroarvi amine into a diazonium salt, such as a diazonium tetrafluoroborate salt and subsequently to , ¾I labeled compound using Nal2lL A represented procedure was reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67, 943-948.
B. Ortho 12-1 Iod ination of phenols: This procedure allows for the incorporation of ι2"Ί at the ortho position of a phenol as reported by Collier, T, L. and co-workers in J. Labelled Compd Radiopharm. , 3999, 42, S264-S266.
C. Aryi and heteroarvi bromide exchange with "5T: This method is generally a two step process. The first step is the conversion of the aryl or heteroarvi bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction {i.e. Pd(PlhP)4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhaiide or hexaalkylditin [e.g.,
Figure imgf000054_0001
A representative procedure was reported by Le Bas, M.-D. and co-workers in /. Labelled Compd. Radiopharm. 2001 , 44, 8280-S282.
A radiolabeled GPR119 compound of Formula 1 can be used in a screenin g assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound {i.e., test compound) can be evaluated for its ability to reduce binding of a radio-labeled compound of Formula I to a GPR 119. The ability of a test compound to compete with a radiolabeled compound of Formula i for the binding to a GPR 1 19 directly correlates to its binding affinity.
Certain labeled compounds of the present invention bind to GPR119. In one embodiment, the labeled compound has an IC¾ less than about 500 μΜ. in one embodiment, the labeled compound has an Κ¾β less than about 100 μΜ, In one embodiment, the labeled compound has an Κ¾0 less than about 10 μΜ, In one embodiment, the labeled compound has an IC¾! less than about 1 μΜ. In one embodiment, the labeled compound has an IC50 less than about 0.1 μΜ. In one embodiment, the labeled compound has an IC50 less than about 0.01 μΜ. In one embodiment, the labeled compound has an IC50 less than about 0,005 μΜ,
Other uses of the disclosed receptors and methods will become apparent to those skilled in the art based upon, inter alia, a review of this disclosure.
As will be recognized, the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and not intended to be limiting. EXAMPLES
Example 1 : Syntheses of Compounds of the Present Invention. Attorney Docket No. 22578-0029WO1 / 214.WOI
illustrated syntheses for compounds of the present invention are shown in Figures 3-7 wherein the variables R1, R , A, O, Q, X, Y, and Z have the same definitions as used throughout this disclosure.
The compounds of the invention and their syntheses are farther illustrated by the following examples. The following examples are provided to farther define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to AutoNom version 2.2, AutoNom 2000, CS ChemDraw Ultra Version 7,0.1, or CS ChemDraw Ultra Version 9,0.7. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art.
Proton nuclear magnetic resonance (Ή NMR) spectra were recorded on a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band inverse) and z- gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference, NMR abbreviations are used as follows: s = singlet, d = doublet, dd = doublet of doublets, ddd = doubl et of doublet of doublets, dt = doublet of triplets, t = triplet, td = triplet of doublets, tt = triplet of triplets, q = quartet, m = multiple!, bs = broad singlet, bt = broad triplet. Microwave irradiations were carried out using a Smith Synthesizer™ or an Emrys Optimizer™ (Biotage® column chromatography) , Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman) and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063-0,200 mm (Merck),
Evaporation was done under reduced pressure on a Buchi rotary evaporator.
LCMS spec: HPLC-pumps: LC- iOAD VP, Shimadzu Inc.; HPLC system controller: SCL-iOA VP, Shimadzu fee; UV-Deteetor: SPD-iOA VP, Shimadzu fee; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.
Example 1.1 : Preparation of 3-((lr,4r)-4-(l-(4-(Trifluoromethyl)py rimidin-2-yl)piperidin- 4-yIoxy)cyclohexyIoxy)pyrazine-2-carbonitrile (Compound 1).
Step 1: Preparation of fert-Butyl 4-((lr,4r)-4-(3-Cyanopyrazin-2- yioxy)cyclohexyioxy)piperidine-l-carboxylate.
To a solution of feri-butyl 4-((ir,4r)-4-hydroxycyclohexyloxy)piperidine-i -carboxylase (WO2011127051) (4 g, 13.36 mmol) in THF (10 mL) was added 1 M potassium tert-butoxide solution in THF (16.03 mL, 16.03 mmol) at 0 °C under nitrogen. After stirring for 10 min, a solution of 3~ehloropyrazine-2-carbonitriie (2.051 g, 14.70 mmol) in THF (6 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The mixture Attorney Docket No. 22578-0029WO1 / 214.WOI
was quenched with water and 1 N HCi (aq) and extracted with EtOAc. 'The organic layer was washed with brine, dried with anhydrous MgSO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (4.80 g, 11.9 mmol, 89,3%), Exact mass calculated for C21H30N4Q4: 402.2, found LCMS mlz = 403.2 [M+.HJ ; Ή NMR (CDCI3, 400 MHz) δ ppm 1 .46 (s, 9H), 1.46-1.58 (m, 4H), i .65-1.72 (m, 2H), 1.75-1.82 (m, 2H), 1.96-2.05 (m, 2H), 2.10-2.18 (m, 2H), 3.05-3.12 (m, 2H), 3.52-3.58 (m, 2H), 3.73-3.82 (m, 2H), 5.18-5.25 (m, 1H), 8.22 (d, /= 2.5 Hz, 1H), 8.29 (d, /= 2,5 Hz, 1H).
Step B: Preparation of 3-((lr,4r)-4-(Piperidm-4-yloxy)cyclohexyloxy)pyrazme-2- carbonitrile Hydrochloride.
To a solution of feri-butyl 4-((ir,4r)-4-(3-cyanopyrazin-2- yloxy)cyclohexyloxy)piperidine-l -carboxylase (4.80 g, 1 1.9 mmol) in anhydrous diethyl ether (20 mL) was added 4 M hydrogen chloride solution in dioxane (29.8 mL, 1 19 mmol). The reaction mixture was stirred at room temperature overnight. The light-yellow solid was collected by vacuum filtration, washed with dioxane and dried to afford the title compound (3.95 g, 1 1.7 mmol, 98.3%). Exact mass calculated for€ί6Η22ΝΛ¾: 302.2, found LCMS mlz = 303.4 j \ ! · ί Ι Γ .
Step C: Preparation of 3-((lr,4r)-4-(l-(4-(TrifluoromethyI)pyriniidiii-2- yI)piperidia-4-yloxy)cycIohexyloxy)pyraziae-2-carboaitriIe (Compound 1).
To a suspension of 3 -((lr,4r)-4-(piperidin-4-y!oxy)cyclohexyloxy)pyraziae-2- carbonitrile hydrochloride (150 mg, 0.443 mmol) in IPA (6 mL) under nitrogen was added diisopropyl ethyl amine (0,39 mL, 2.2 mmol) and 2-chioro-4-(triiluoromeShyi)pyrimidine (0, 11 mL, 0.89 mmol). The mixture was heated at 120 °C for 2 h under microwave irradiation. The mixture was concentrated under reduced pressure to dryness and the residue was purified by silica gel column chromatography and prep HPLC to afford the title compound (1 55.5 mg, 0.347 mmol, 78.3%) as a white solid. !H NMR (400 MHz, CDC13) δ ppm 1.51 -1.65 (m, 4H), 1.67-1 .75 (m, 2H), 1.87-1.93 (ro, 2H), 2.00-2.07 (m, 2H), 2.32-2.18 (m, 2H), 3.48-3.54 (ro, 2H , 3.59-3.65 (m, 1H), 3 ,67-3.73 (m, 1H), 4.26-4.32 (m, 2H), 5.20-5.26 (m, IH), 6.72 (d, ./=== 4.8 Hz, IH), 8.23 (d, /= 2.5 Hz, 1H), 8.29 (d, / = 2.5 Hz, 1H), 8.47 (d, ./ == 4.8 Hz, I H). Exact mass calculated for
Figure imgf000056_0001
448.18, found: LCMS mlz = 449.2 [M+H]÷.
Example 1.2: Preparation of 4-(2-Fluoro-4-(methylsulfonyi)phenoxy)-5-methyi-6-(l-(4- (trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidiiie (Compound 2).
Step A: Preparation of l-(4-(Trif!uoromethyl)pyrimidin-2-yl)piperidm-4-ol. To a solution of piperidin-4-ol (0.50 g, 4.94 mmol) and 2-chloro-4-
(trsfiuoromethyDpyrimidine (0.90 g, 4.94 mmol) in IPA (10 mL) was added TEA (1.38 mL, Attorney Docket No. 22578-0029WO1 / 214.WOI
9,89 mmol). The mixture was heated at 120 °C for 1 h. The solvent was removed under reduced pressure. The residue was purified by Biotage® column chromatography (0-100% EtO Ac Hex in 30 min) to give the title compound (1.01 g, 4,08 mmol, 82%). Exact mass calculated for C , Π ·;1· Λ :ί ): 247.1 , found ί IM S miz - 248.2 i M - i i i .
Step B: Preparation of 4-Chioro-5-naethyl-6-(l-(4-(trinuoromethyI)p rimidin-2- yi)piperidin-4-yloxy)pyrimidine.
To a solution of l -(4-(trifluoromethyl)pyTirnidin-2-yl)piperidin-4-ol (1.01 g, 4.08 mmol) and 4,6-dichloro-5-methylpyrimidine (0.66 g, 4,08 mmol) in THF (15 ml.) was added potassium er/-butoxide (0.50 g, 4.48 mmol) portion-wise at 0 °C. The reaction was then stirred at room temperature for 30 min. The crude reaction mixture was partitioned between
EtOAc/¾0. The organic layer was dried over MgS04, filtered, and concentrated. The residue was purified by Biotage® column chromatography (0-100% EtOAc/Hex in 30 mini to give the title compound (1.40 g, 3.73 mmol, 92%). Exact mass calculated for & ,Η15αΡ3Ν50: 373.1 , found LCMS miz = 374.2 [M+HJ\
Step C: Preparation of 4-(2-Fluoro-4-(methyls«lfonyI)phenoxy)-5-methyi-6-(l-(4-
(trifluoromethyl)pyrimidiii-2-yl)piperidin^-yloxy)pyrimidiiie (Compound 2).
A mixture of 4-chloro-5-methyl-6-(l -(4-(trifluoromethyl)pyrirnidin-2-yl)piperidin-4- yloxy)pyrimidine (0.50 g, 1.338 mmol), 2- iluoro-4-(methylsulfonyl)phenol (0.38 g, 2,01 mmol), and potassium carbonate (0.56 g, 4.01 mmol) in DMA (5 ml.) was heated at 150 °C for 4 h. The solvent was removed under reduced pressure and purified by Biotage® column chromatography (0-100% EtOAc/Hex in 30 min) to give the title compound (0.48 g, 0.907 mmol, 67.8%). Exact mass calculated for
Figure imgf000057_0001
527.1 , found LCMS miz - 528.4 [M+H]+; Ή NMR (400 MHz, CDCi3) δ ppm 1.87-1.91 (m, 2H), 2.07-2.12 (m, 2H), 2.22 (s, 3H), 3. 10 (s, 3H), 3.79-3.86 (m, 2H), 4.19-4.25 (m, 2H), 5.46-5.48 (m, 1 H), 6.76 (d, /= 4.80 Hz, 1 H), 7.42-7.46 (m, I H), 7.77-7.81 (m, 2H), 8.22 (s, 1 H), 8.50 (d, J = 4.80 Hz, 1H).
Example 1.3: Preparation of 5-Fliuoro-4~(2~metl!yI~6-(ii!iiei3iiy!sulfo:isyI)pyrid:ffl-3~yloxy)-6- (l-(4-(trMuoromethyl)pyrimidin-2-yi)piperidin-4-yloxy)pyriniidine (Compound 3).
Step A: Preparation of fert-Butyl 4-(6-ChIoro-5-fluoropyrimidin-4- yioxy)piperidine-l-carboxylate.
To a solution of 4,6-dichloro-5-fluoropyriinidine (1.00 g, 5.99 mmol) and teri-butyl 4- hydroxypiperidine-l -carboxylase (1 ,205 g, 5.99 mmol) in THF (10 mL) at -78 °C was added 1 M potassium reri-butoxide solution in THF (5.99 mL, 5.99 mmol) dropwise. The mixture became thick and thus more THF (10 mL) was slowly added. After stirring for 15 min, the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure and purified by Bsotage® column chromatography to Attorney Docket No. 22578-0029WO1 / 214.WOI
afford the title compoimd (1.9561 g, 5.90 mmoi, 98%) as a coioriess oil that slowly became a white solid. Exact mass calculated for
Figure imgf000058_0001
331.1, found: LCMS mlz = 332.4
[M+H]+; Ή NMR (400 MHz, CD<¾) δ ppm 1.45 (s, 9H), 1.75-1.85 (m, 2H), 1.98-2.04 (m, 2H), 3.28-3.36 (m, 2H), 3.75-3.81 (m, 2H), 5.30-5.39 (m, IH), 8.31 (s, 1H).
Step B: Preparation of totf-Butyl 4-(5-Fluoro-6-(2-methyl-6-
(metir lsiiIfonyl)pyridin-3-yIoxy)pyrimidm^
A suspension of fert-butyl 4-(6-chloro-5-fluoropyrimtdiii-4-yloxy)pi.periditie-l- carboxylate (1 ,47 g, 4.43 mmol.'), 2-met3iyl-6-(methylsulfonyl)pyridin-3 -oj (0.912 g, 4.87 mmoi), and potassium carbonate (1.225 g, 8.86 mmol) in DMF (30.0 ml_) was heated at 100 °C for 1 h. The mixture was filtered to remove inorganic base and the filtrate was concentrated under reduced pressure. The crude was purified by Biotage® column chromatography to afford the title compound (1.52 g, 3.15 mmol, 71.1%) as an off-white solid. Exact mass calculated for C2 IH27FN ¾S: 482.2, found: LCMS mlz - 483.4 [M+H]+; Ή NMR (400 MHz, CDCi3) 3 ppm 1.48 (s, 9H), 1.78-1.88 (m, 2H), 1 .99-2.07 (m, 2H), 2.55 (s, 3H), 3.25 (s, 3H), 3.29-3.36 (m, 2H), 3.77-3.85 (m, 2H), 5.35-5.42 (m, I H), 7.67 (d, J = 8.4 Hz, IH), 8.01 (d, /= 8.4 Hz, I H), 8.07 (s, I H).
Step C: Preparation of 5-Fluoro-4-(2-niethyl-6-(methylsulfoayl)pyridin-3-yloxy)- 6-(piperidm-4-yIoxy)pyrimidine Hydrochloride.
To a solution of fert-butyl 4-(5-fluoro-6-(2-methyl-6-(inethy]s«lfonyl)pyridiK-3- yloxy)pyrtmidiii-4-y]oxy)piper!dine- 1 -carboxylate (1.52 g, 3.15 mnrol) in DCM (5 mL) was added 4 N hydrogen chloride solution in dioxane (4.43 mL, 17.72 mmol). The mixture was stiiTed at room temperature for 1 h. The reaction was not complete and the mixture had two layers. Thus, more 4 N hydrogen chloride solution in dioxane (4.43 mL, 17.72 mmol) was added and the mixture was stirred at room temperature for an additional 1 h. The mixture was concentrated under reduced pressure and the concentrate was dried under reduced pressure at 50 °C to afford the title compound as a light-yellow solid (1.32 g, 3.15 mmoi, 100%). Exact mass calculated for C; 6H19F 404S: 382.2, found: LCMS mlz = 383.4 [M+H]+; !H NMR (400 MHz, CDC13) δ ppm 2.25-2.35 (m, 2H), 2,38-2.48 (m, 2H), 2.55 (s, 3H), 3.26 (s, 3H), 3 ,33- 3,48 (m, 4H), 5.52-5.57 (m, IH), 7,68 (d, /= 8.4 Hz, IH), 8.03 (d, /= 8,4 FIz, IH), 8.09 (s, IH), 9.85 (bs, 2H).
Step D: Preparation of 5-Fluoro-4-(2-methyi-6-(methylsulfonyi)pyridiii-3-yioxy)- 6-(l -(4-(trifliiorometlsyl)pyrsmidm-2-y!)pipeiidi!i-4-yloxy)pyririsidm (Compound 3).
To a solution of 5-fluoro-4-(2-methyi-6-(methylsulfonyl)pyridin-3-yloxy)-6-(piperidin- 4-yloxy)pyrimidine hydrochloride (0.075 g, 0.179 mmol) and 2-chloro-4- (ti-ifiuoromethyi)pyrimidine (0.036 g, 0.197 mmol) in IPA (2.0 mL) was added DIEA (0.31 mL, 1.79 mmoi). The reaction mixture was heated at 100 °C under microwave irradiation for 2 h Attorney Docket No. 22578-0029WO1 / 214.WOI
and then diluted with water. The water layer was extracted two times with EtOAc. The combined extracts were dried over anhydrous
Figure imgf000059_0001
filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (silica gel) to afford the title compound as a white solid (86.4 mg, 91%). Exact mass calculated for C21H20F 6O4S: 528.12, found: LCMS mlz - 529.0 [M+HJ ; Ή MR (400 MHz, CDC13) δ ppm 1 .88- 1 .99 (m, 2H), 2.09-2.19 (m, 2H), 2.56 (s, 3H), 3.26 (s, 3H), 3.73 -3.82 (m, 2H), 4.27-4.35 (m, 2H), 5.47-5.55 (m, 1H), 6.78 (d, J - 4.8 Hz, 1H), 7.69 (d, .7 - 8.6 Hz, 1H), 8.02 (d, J - 8.4 Hz, 1 H), 8.10 (s, 1H), 8.51 x. J 5.1 Hz, l i l i Example 1.4: Preparation of 5-Methoxy-A-(2-methyl-6-(meth lsuifonyl)pyridin-3-yi)-6-(l- (4-(trifluoromethyi)pyrimidm-2-yl)piperidin-4-yioxy)pyrimidin-4-amm (Compound 4).
Step A: Preparation of l-(4-(Trifiuoromethyl)pyriniidm-2-yl)piperidiii-4-ol.
Piperidin-4-οί (1.65 g, 16.3 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (2.98 g, 16.3 mmol), and triethylamine (4.5 mL, 32,7 mmol) were refluxed in isopropanol (60 mL) for 5 h. The reaction was cooled to room temperature and diluted with hexanes causing a white precipitate to form. The solids were removed by filtration, and the filtrate was passed through a plug of silica, washing with 1 : 1 EtOAc hexartes and then EtOAc, The combined filtrate and washings were concentrated to dryness to afford 3.89 g of the title compound. Exact mass calculated for C10H12F3N3O: 247.09, found: LCMS mlz - 248.2 [M+Hf.
Step B: Preparation of 4-Chloro-5-methoxy-6-(l-(4-(trifluoromethyl)pyrimidiii-2- yi)piperidin-4-yloxy)pyrimidme.
Potassium 2-methylpropan-2-olate (17.3 mL, 17.3 mmol) was added to a solution of 1 - (4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-ol (3.89 g, 15.7 mmol) and 4,6-dichloro-5- methoxypwsmidine (2.82 g, 15.7 mmol) in THF (58 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was concentrated to a yellow solid and triturated with EtOAc and hexanes to afford 6.07 g of the title compound. Exact mass calculated for ( ' · ! ! ,ί 'ϋ; :\,ί >·: 389.09, found: LCMS m/z - 390.4 [M+Hf; Ή NMR (400 MHz, CDCI3) δ ppm 1.86- i .96 (m, 2H), 2.08-2.17 (m, 2H), 3.75-3.84 (m, 2H), 3.92 (s, 3H), 4.21 -4.29 (m, 2H), 5.50 (septet, / = 3.8 Hz, 1H), 6.77 (d, /= 4,8 Hz, 1H), 8.2.9 (s, I H), 8,50 (d, ./ .K ! ! ·. I l ! i.
Step C. Preparation of 5-Methoxy-A-(2-methyl-6-(methylsuifonyl)pyridin-3-yi)-6- (l-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yloxy)pyrimidm-4-amine (Compound 4).
4-C¾loro-5-methoxy-6-(l -(4-(uifiuoromethyi)pyrimidin--2-yl)piperidin-4- yloxy)pyrimidine (6.07 g, 15.6 mmol), 2-methyi-6-(methylsulfonyl)pyridin-3-amine (2.90 g, 15,6 mmol), cesium carbonate (17.8 g, 54.5 mmol), diacetoxypalladium (0.70 g, 3.1 12 mmol), Attorney Docket No. 22578-0029WO1 / 214.WOI
and 1 ,1 '-bis(di-t-butytpbospbii3o)ferrocene (2.95 g, 6.22 mmol) were suspended in dioxane (52.0 mL) and stirred at reflux for 2 h. The solids were removed by filtration and the filtrate was concentrated and purified by column chromatography (silica gel, 50-70% EtOAc in hexanes). The purified material was reerystallized from MTBE/DCM/hexanes to afford 4.54 g of the title compound. Exact mass calculated for C22H2 F3N7O4S: 539.16, found: LCMS mlz = 540.4 [M+H]+; Ή NMR (400 MHz, CDCI3) δ ppm 1.86-1.96 (m, 2H), 2.09-2.1 8 (m, 2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.77-3.85 (m, 2H), 4.01 (s, 3H), 4.21 -4.31 (m, 2H), 5.48-5.55 (m, I B), 6.77 (d, /= 4.8 Hz, 1H), 7.33 (s, IH), 7.97 (d, ./ === 8.6 Hz, 1H), 8.22 (s, IH), 8.51 (d, 5.0 Hz, IH), 9.01 (d, J - 8.6 Hz, IH).
Example 1.5: Synthesis of 4-((lr,4r)-4-(l-(4-(Tiiiluoromethyl)pyrimidm-2-yl)piperidin-4- yloxy)cyclohexyloxy)nicotinoiiitrile (Compound 5).
Step A: Preparation of 4-(l,4-Dioxaspiro[4iijdecan-8-yIoxy)pyridine.
To a suspension of sodium 2-methylpropan-2-olate (238 g, 2,478 mmol) in DMSO (700 mL), a solution of l ,4-dioxaspiro[4.5]decan-8-ol (196 g, 1,239 mmol) in DMSO (300 mL) was added followed by 4-chioropyridine hydrochloride (186 g, 1 ,239 mmol) portion-wise while maintaining the temperature belo 40 °C with a water bath. The mixture was then heated at 80 °C for 4 h until the complete disappearance of the starting material. The mixture was then quenched with 100 mL of water and partially concentrated to remove most of the DMSO (water bath at 80 °C). The resulting viscous material was then diluted with water and extracted with EtOAc three times. The organic layers were combined and dried over MgSQ* and concentrated to afford 4-(l,4-dioxaspiro[4.5]decan-8-yloxy)pyridine as beige solid. The solid was transferred to a vacuum filter cup, washed with a minimum amount of MTBE twice at room temperature, and dried under reduced pressure to give the title compound as a light-brown solid (254,5 g, 87%). The mother liquor was concentrated to give a wet solid which was triturated with MTBE. The resulting solid was removed by filtration and washed with a minimum amount of MTBE to give a second crop of the title compound as a light-brown solid (14 g, 4.8%). Exact mass calculated for C,jH17N03: 235.3, found LCMS mlz = 236.0 [M+H]+.
Step B; Preparation of 4-(Pyridin-4-yloxy)cycIohexanone.
4-(l,4-Dioxasptro[4.5]decan-8-yloxy)pyridine (169.5 g, 720 mmol) was dissolved in
THF (1500 mL). Water (1500 mL) was then added, followed by 6 M HC1 solution in water (240 mL, 1 ,441 mmol). The reaction mixture was stirred at 50 °C overnight. Crude LCMS showed 95% conversion to the product and 5% starting material. The reaction mixture was cooled to 24 °C, most of the organic solvent was removed under reduced pressure at 30 °C to give an aqueous solution (1, 150 mL) to which water (650 mL) was added. 'The pH was adjusted to 6 by addition of solid potassium phosphate, tribasic (194 g, 914 mmol) at room temperature Attorney Docket No. 22578-0029WO1 / 214.WOI
portion- wise while stirring over 10 min to give a turbid mixture. The mixture was then adjusted to pH 7-8 by addition of solid potassium phosphate, dibasic (159 g, 914 mmoi) at room temperature portion-wise while stirring over about 10 min. The mixture was stirred for 20 min at room temperature then extracted with 12% IPA/DCM (3 x 900 mL, 1 x 450 mL). The organic extracts were combined, dried with powdered MgSO. , and the solvent was concentrated to give the title compound as a beige solid (140.03 g, 100%) which contained 5 mol% of the starting material. Exact mass calculated for CnH^NC^: 191 ,2, found LCMS mlz =
192.0 [M+Hf,
Step C: Preparation of (ls,4s)-4-(Pyridm-4-yloxy)cyclohexanol and (lr,4r)-4- (Pyridin-4-yloxy)cyclohexanol.
To a 3 -neck round bottom flask equipped with a mechanical stirrer, a thermometer, a nitrogen inlet, an addition funnel, and a gas outlet was added 4-(pyridin-4-yloxy)cyclohexanone (162 g, 847 mmoi) and MeOH (2,000 mL). The resulting solution was cooled to 11 °C. Sodium borohydride ( 8.46 g, 1 ,017 mmoi) was added in four portions while maintaining the temperature below 37 °C. The cooling bath was then removed, and the reaction mixture was stirred at 18 °C for 1 b. An LCMS of the reaction mixture showed the title compounds (cisitrans 57:42) and small amount of the corresponding boraoe complex. The reaction was diluted with water, acidified to pH 2-3 with 6 M HCI, and stirred for 30 min , Then roost of methanol was removed by evaporation. Solid KOH was added to adjust the mixture to pH 8, A white precipitate formed, which was collected to give cis enriched product (80-85% pure). This material was triturated several times with acetone to give (ls,4s)-4-(pyridin-4- yloxy)cyclohexanol (~87 g). The filtrate was extracted with IPA/DCM (1 :3), dried over anhydrous NajSO.i, filtered and concentrated to give the title compound as a mixture of cis and trans isomers. This material was triturated with acetone and filtered. The filtrate was concentrated and a precipitate formed. The precipitate was collected to give trans enriched product (70-80% pure), which was then triturated with acetone to give (lr,4r)-4-(pyridin-4- yloxy)cyclohexanol (~ 25 g). After separation, a mixture of the title compounds remained (~35 g). Total yield was -147 g, 89.6%. Exact mass calculated for C11H15NO2: 193.1, found: LCMS mlz = i 94.0 [M+Hf; Ή NMR for cis (400 MHz, CDC13) δ ppm i .62- 1.82 (m, 7H), 1.99-2.08 (m, 2H), 3.78-3.86 (m, 1H), 4.45-4.51 (m, !H), 6.78 (dd, / = 4.8, 1.5 Hz, 2H), 8.40 (dd, /= 4.8, 1.5 Hz, 2H); Ή NMR for trans (400 MHz, CDC13) δ ppm 1.42-1.54 (m, 2H), 1 ,55-1 ,65 (m, 3H), 2.00-2.08 (m, 2H), 2,08-2, 18 (m, 2H), 3.78-3.87 (in, 1H), 4.35-4.42 (m, ! ! l i. 6,77 (dd, ./ 4.8, 1.5 Hz, 2H), 8.40 (dd, ,7 - 4.8, 1.5 Hz, 2H).
Step D: Preparation of (lr,4r)-4-(Piperidin-4-yioxy)cyclohexanol.
A steel bomb containing a mixture of (lr,4r)-4-(pyridin-4-ytoxy)cyclohexanol (20.5 g,
106.1 mmoi), palladium on carbon (10%, 50% water, 22.5 g, 10.6 mmoi), and sodium Attorney Docket No. 22578-0029WO1 / 214.WOI
tetraborate decahydrate (4.05 g, 10.62 romoi) in IPA (200 mL) was filled with hydrogen to ca. 20 bar and stirred at 80 °C (oil bath). The bomb was refilled with hydrogen to ca. 20 bar three times within 8 h. After stirring over night, the bomb was refilled again to 20 bar (and then again after 4 and 8 hours). After stirring over the weekend, the reaction was complete. 'The mixture was filtered through Celite®, washing with additionai IPA, The filtrate was concentrated and dried under high vacuum to give the title compound as a white solid (20,6 g, 97.4%). Exact mass calculated for CnH2lN02: 199.2, found: LCMS mlz = 200.0 [M+Hf; ¾ NMR (400 MHz, CDCI3) δ ppm 1.25-1.5 1 (m, SH), 1.81 - 1 .90 i n:. 2H), 1.91-2.00 (m, 4H), 2.55-2.64 (m, 2H), 3.04-3.12 (dt, J = 13.14, 3.79 Hz, 2H), 3.34-3.47 (m, 2H), 3.63-3.71 (m, 1H).
Step E: terf-Butyl 4-((lr,4r)-4-Hydroxycyclohexyloxy)piperidine-l-carboxylate.
To a suspension of (ir,4r)-4-(piperidin-4-yloxy)cyclohexanol (13.45 g, 67.49 mmol) and triethylamine (11 mL, 78.92 mmol) in DCM (400 mL), di-fe/ -butyl dicarbonate (16.2 g, 74.23 mmol) was added in small portions. After stirring at room temperature for 1 h, the reaction mixture was washed with water. The organic phase was dried over MgSC^, filtered, and concentrated. The residue was purified by Biotage® column chromatography (SiC½, hexane/EtOAc gradient) to give the title compound as a white solid (19.61 g, 97.0%). Exact mass calculated for
Figure imgf000062_0001
299.21, found: LCMS mlz = 300.4 [M+Hf; Ή NMR (400 MHz, CDCI3) δ ppm 1.27-1.52 (m, 16H), 1.74-1 ,80 (m, 2H), 1.89-2.02 (m, 4H), 3.02-3.09 (m, 2H), 3.34-3.4 (m, 1H), 3.50-3.56 (m, !H), 3.65-3 ,81 (m, 3H).
Step F: Preparation of fert-Butyl 4-((lr,4r)-4-(3-Cyanopyridin-4- yioxy)cyclohexyioxy)piperidine-l-carboxylate.
To a solution of teri-butyl 4-((lr,4r)-4-hydroxycyclohexyioxy piperidirie-l -carboxyiate (20.00 g, 66.80 mmol) and 4-ehloronicotinonitrile (9.72 g, 70.1 mmol) in THF (200 mL) at 0 °C under nitrogen was added 1 M potassium feri-butoxide solution in THF (80.2 mL, 80.2 mmol) over 30 min. After stirring for 30 min, the mixture was quenched with water. The mixture was extracted twice with EtOAc, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as an off-wbite solid (25,94 g, 96.7%). Exact mass calculated for C22H31N3O4: 401.2, found: LCMS mlz = 402.6 : Ή NMR (400 MHz, CDCI3) δ ppm i .46 (s, 9H), 1.47-1.58 (m, 4H), 1.68-1.81 (m, 4H), 1.96-2.04 (m, 2H), 2.08-2.15 (m, 2H), 3.07-3.13 (m, 211), 3.52-3.63 (m, 2H), 3.73-3.79 (m, 2H), 4.56-4.62 (m, 1H), 6.88 id. ./ 6.1 Hz, ! ! i s. 8.58 (d, ./ 6.1 Hz, IH), 8.66 (s, 1H).
Step G: Preparation of 4-((lr,4r)-4-(Piperidin-4- y!oxy)cyclohexy!oxy)nicotraonilrile diliydrocliloride.
To teri-butyl 4-((l ,4r)-4-(3-cyanopyridin-4-yioxy)cyclohexyloxy)piperidine-l- carboxylate (25.94 g, 64.61 mmol) in a 1 -I. round-bottom flask was added dioxane (200 mL). Attorney Docket No. 22578-0029WO1 / 214.WOI
To this solution was added 4 N hydrogen chloride solution in dioxane (80.8 rnL, 323 mmol) over 45 min. After the addition of 15 raL of the HCt the mixture became too thick to stir and more dioxane (100 mL) was added. Upon completion of the addition further dioxane (50 mL) was added. The mixture was stirred at room temperature overnight. The reaction was incomplete (15% product) and so the mixture was transferred to a three-neck 2-L round-bottom flask with dioxane (75 mL). To this was added 4 N hydrogen chloride solution in dioxane (161 .5 rnL, 646.1 mmol). The mixture was stirred at room temperature for 1 h, at which point the reaction was (25% complete). The mixture was then heated at 40 °C for 3 h, at which point the reaction was complete. The warm (40 °C) mixture was filtered and washed with dioxane (2 x 100 mL) and hexanes (2 x 200 mL) So afford the title compound (22.57 g, 60.30 mmol,
93.3%) as an off-white solid. Exact mass calculated for the freebase C17H23N3O2: 301.2, found: LCMS m/z - 302.2 | 1 · i ! i : Ή NMR (400 MHz, CDC13) δ ppm 1.42-1.51 (m, 2H), 1.55-1.70 (m, 4H), 1.87-1.96 (m, 4H), 2.01-2.05 (m, 2H), 2.90-2.97 (m, 2H), 3.09-3.16 (m, 2H), 3.55- 3.61 (m, IH), 3.66-3.72 (m, 1H), 4.83-4.89 (m, 1H), 7.31 (bs, 1H), 7.53 (d, J - 6.3 Hz, 1 H), 8.72 (d, ./= 6.3 Hz, IH), 8.92 (s, IH), 8.99 (bs, 2.H).
Step H. Preparation of 4-((ir,4r)~4-(l-(4-(Trifiiioro:nitethyt)pyrm!id!K-2~ yI)piperidin-4-yloxy)cycIohexyloxy)nicotinonitriie (Compound 5),
A solution of 4-((lr,4r)-4-(piperidin-4-yloxy)cyclohexyloxy)nicotinonitrile dtliydrochloride (0,03 g, 80,2 μαιοΐ), 2-ch.loro-4-(triiluoromethyl)pyrimidine (19.0 μΐ, 0.16 mmol), and DIEA (0.124 mL, 0.80 mmol) in isopropanol (1.2 mL) were stirred at 3 00 °C for 3h. The reaction was cooled to room temperature and concentrated to dryness. The residue was purified by column chromatography (silica gel, 50-75% EtOAc in hexanes) and triturated with hexanes to afford the title compound (21.8 mg). Exact mass calculated for CJJHJ^F J JO?.: 447.19, found: LCMS m/z = 448.4 [ +HJ*; Ή NMR (400 MHz, CDC13) δ ppm 1 .52-1.66 (m, 4H), 1 .68-1.79 (m, 2H), 1.84-1.94 (m, 2H), 1.98-2.07 (m, 2H), 2.08-2.18 (m, 2H), 3.48-3.57 (m, 2H), 3.62-3.73 (m, 2H), 4.22-4.32 (m, 2H), 4.58-4.65 (m, IH), 6.72 (d, J= 4.S Hz, IH), 6.89 (d, J - 6.0 Hz, IH), 8.47 (d, .7 - 4.8 Hz, I H), 8.59 (d, ,/= 5.8 Hz, IH), 8.67 (s, IH).
Example 2: Homogeneous Time-Resolved Fluorescence (HTRF®) Assay for Direct cAMP Measurement.
GPRl 19 antagonists (Compounds 1-5) were evaluated in an HTRF® cAMP detection assay (Cisbio, cAMP Dynamic 2 Assay Kit; #62AM4PEJ) according to She manufacturer's instructions using CHO-Kl cells stably expressing GPRl 19. CHO-Kl cells were transduced with a lentiviral vector encoding the nucleotide sequence of GPRl 19 (NCBI mRNA and protein reference sequences: NM_ 178471.2 & NP 848566 (human) and NM_ 181770.1 & NP 861435.1 (rat)). The N-terminus of the GPRl 19 nucleotide sequence was modified to Attorney Docket No. 22578-0029WO1 / 214.WOI
replace the first methionine -coding codon with a nucleotide sequence coding for a standard, nine amino acid, hemagglutinin tag. Following transduction, cells expressing GPR119 were isolated and a single clone was isolated following standard dilution-cloning procedures. On the day of the assay, cultured CHO-GP 1 19 cells were harvested, suspended in assay buffer, and plated into 384-well assay plates (PerkinElrner® Proxiplate® #6008280) at a density of 2,000 cells per well, A cAMP standard curve was added to each plate. Test compounds were dissolved in DMSO, serially diluted in DMSO and then diluted in assay buffer before being added to the cells. The test compounds were concurrently added to the cells with the GPR1 19 agonist, A7-(2-fluoro-4-(niethylsulfonyl)phenyl)-6-(4-(3-isopropyl-l ,2,4-oxadiazol-5- yl)piperidin-l -yl)-5-nitrop>'rimidin-4-aniine (Compound 7). Test compounds were evaluated in triplicate, using 10-point, 5-fold serial dilutions starting at 10 ,uL. Compound 7 was dispensed with the test compounds at a final concentration of 60 iiM. The final DMSO concentration in the assay was 0.5%. Compounds and cells were incubated for 1 h at room temperature and then detection reagents were added to each well (cAMP-D2 in cell lysis buffer, followed by europium cryptate-labeled anti-cAMP antibody). Plates were then incubated at room temperature for 1 b prior to reading. Time-resolved fluorescence measurements were collected on PerkinElrner Envision™ or BMG Pherastar™ roicroplate readers. Assay buffer containing 0,5% DMSO was used as a positive control in each runset while N-(2-fluoro-4- (methylsulfonyl)phenyl)-6-(4-(3-isopropyl-l ,2,4-oxadtazol-5-yl)piperidtri- 1 -yl)-5- nitropyrimidia-4-amine was used as the negative control. The HTRF® assay was used to determine ΪΟ¾ values for GPR119 antagonists.
Certain compounds of the present invention and their corresponding observed IC<« values are shown in Table B.
Table B
Figure imgf000064_0001
Example 3: Lipid challenge with GPR119 Antagonis
C57BL/6J male mice (Taconic) (approximate body weight 25g) were fasted overnight in new cages. Test compound (Compound 4, 100 mg/kg) or vehicle (PEG400, 10 mJL/kg) was dosed at 2b prior to lipid. At time 0 an eye -blood sample was taken and subsequently lipid (olive oil, 10 mL kg) (Sigma-Aldrich) was orally dosed. Eye -blood samples were taken 30 and 60 min after lipid load, and animals were decapitated and trunk blood was collected 120 min Attorney Docket No. 22578-0029WO1 / 214.WOI
after lipid load. GLP-1 was measured with a tGLP-i v2 kit (Mesoscaie Discover}'), and GIP was measured with GIP EL1SA (Miliipore). Compound 4 did not reduce GLP-1 following the lipid challenge, when compared to vehicle alone (Figure 1). Compound 4 reduced GIP following the lipid challenge, when compared to vehicle alone (Figure 2).
Example 4: cAMP Accumulation Assay.
GPR11 receptor cDNA was cloned into pcDNA3.1(+) and tagged with a FLAG sag. A modified signal peptide from viral hemagglutinin was inserted in front of the FLAG tag to enhance surface expression (Guan et ah, 1992). COS? cells were grown in Dulbecco's modified Eagle's medium 1885 supplemented with 10% fetal calf serum, 2 mM glutamine, and 0.01 mg/mL pen-strep at 37 °C and 10% C02. Cells were transfected with 20 μ¾''75 cm2 DNA using a calcium phosphate precipitation method with chloroquine addition. An ELISA assay was performed to confirm surface expression of the receptor.
One day after transfection, cells were seeded in 12 well plates at a density of 2 x 105 cells/well in 0.5 mL medium supplemented with 2 \xlJm Adenine-[2,8 3FI] (PerkinElmer). Two days after tran fection, the cells were washed w ith HBS and incubated with I mM isobutylmethylxanthine in HBS for 30 min. at 37 °C. Ligands were added. To test the potential antagonistic properties of Compounds 2 and 6, fixed concentrations of each compound were added prior to treatment with increasing concentrations of Compound 7, The cells were incubated for another 30 min at 37 °C. The medium was removed, and the cells were lysed with 5% TCA containing 0.1 mM ATP and 0.1 mM cAMP. The lysate was transferred to Dowex® columns (50WX4, Sigma- Aldrich), which were washed with 2 mL j¼0 before they were eluted into Alumina columns (A9003, Sigma-Aldrich) with 10 mL H20, from where cAMP was eluted with 6 mL 0.1 M imidazole into vials. Scintillation liquid (Gold Star, Meridian) ( 15 mL) was added to the eluate and the radioactivity from the samples was measured on a scintillation counter. Compounds 2 and 6 were found to function as GPR1 9 antagonists (Figure 8).
Those skilled in the art will recognize that various modifications, additions, and substitution to the illustrative examples set forth herein can be made without departing from the spirit: of the invention and are, therefore, considered within the scope of the invention.
Citation of any reference throughout this application is not to be construed as an admission that such reference is prior art to the present application.

Claims

Attorney Docket No. 22578-0029WO1 / 214.WOI
claim:
A compound selected from compounds of Formula 1 and pharmaceutically acceptab! salts, solvates, and hydrates thereof:
Figure imgf000066_0001
Formula I
wherein:
R' is selected from: Ci-Ce alkyl, cyano, and halogen;
A is C3-C7 cycloalkylene, or heteroarviene, wherein the heteroarviene is optionally substituted with a substituent selected from: Ci -Cg alkoxy, Cj-Ce alkyl, and halogen;
Q is O or NH;
X and Y are each independently N, or CH;
Z is N o!- Hi : and
R7 is H O!- CrC6 alkylsulfonyl.
A compound according to claim 1, wherein: R1 is selected from: methyl, cyano, and fluoro,
A compound according to claim 1 or 2, wherein A is cyclohexylene or pyrimidinylene, and wherein the pyrimidinylene is optionally substituted with a substituent selected from: Cj-Cg alkoxy, Ci~C6 alkyl, halogen, methoxv, methyl, and fluoro.
A compound according to claim 1 or 2, wherein A is 1 ,4-cyclohexylene or 4,6- pyrimidinylene, and wherein the 4,6-pyrimidinylene is optionally substituted with a substituent selected from: methoxy, methyl, and fluoro.
A compound according to claim 1 or 2, wherein A is selected from: 5 -methoxv- 4,6- pyrimidinylene, 5-methyi-4,6-pyrimidinylene, and 5-iluoro-4,6-pyrimidinylene. Attorney Docket No. 22578-0029WO1 / 214.WO!
A compound according to any one of claims 1 to 5, wherein Z is CR2, and wherein R" is methylsulfonyl.
A compound according claim 1 selected from compounds of Formula II and
pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000067_0001
Formula Π
wherein:
R' is selected from: Ct-Cg alkyl, cyano, and halogen;
X and Y are each independently N, or CH;
Z is IN or CR2; and
R2 is H or Ci-Cs alkyisulfonyl.
A compound according claim 1 selected from coinpounds of Formul
pharmaceutically acceptable salts, solvates, and hydrates thereof:
Figure imgf000067_0002
Formul ITa
wherein:
R' is selected from: Ci-Ce alkyl, cyano, and halogen;
X and Y are each independently N, or CH;
Z is N or CR2; and
R3 is H or C C6 alkyisulfonyl.
A compound according claim I selected from compounds of Formula III and pharmaceutically acceptable salts, solvates, and hydrates thereof: Attorney Docket No. 22578-0029WO1 / 214.WOI
Figure imgf000068_0001
Formula 111
wherein:
R' is selected from: C\-C alkyl, cyano, and halogen;
Q is O or NH;
X and Y are each independently N, or CH;
Z is Is' or CR2;
R2 is H or CI-CG alkylsulfonyl; and
3 is selected from: Ci -Ce alkoxy, Ci-Cg alkyl, and halogen.
A compound according to any one of claims 1 to 9, selected from the following compounds and pharmaceutically acceptable salts, solvates, and hydrates thereof:
3- ((lr,4r)-4-(l-(4-(frifluoromethyl)p riraidui-2-yl)piperidin-4- yloxy)cyciohexyloxy)pyrazine-2-carboniSrile;
4- (2-fliioro-4-(methylsiilfonyl)phenoxy)-5-meihyl-6-(l -(4-
Figure imgf000068_0002
5- fluoro-4-(2-methyl-6-(rnethylsulfonyl)pyridin-3-yloxy)-6-(l -(4-
Figure imgf000068_0003
5-methoxy-A'-(2-methyl-6-(m
(triiluoromethyl)pyrimidin-2-yl)psper and
4-((l r,4r)-4-(3 -(4-(trifluoroiTiethyl)pyrimidir!-2-yl)piperidiri-4- yloxy)cyclohexyloxy) nicotinonitrile.
A pharmaceutical composition comprising a compound according So any one of cla 1 to 10 and a pharmaceutically acceptable carrier.
A process for preparing a pharmaceutical composition according to claim 1 1, comprising admixing a compound according to any one of claims 1 to 10 with a pharmaceutically acceptable carrier. Attorney Docket No. 22578-0029WO1 / 214.WOI
13. A composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
14. A process for preparing a composition according to claim 13, comprising admixing a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
15. A compound according to any one of claims 1 to i 0 for use in a method of treatment of a human or animal by therapy,
16. A GPRl 19 antagonist for use in a method for reducing a postprandial gastric
inhi bitor}' polypeptide (GIP) level in an individual, or for the treatment of obesity, a disease or condition related to obesity, non-alcoholic fatty iiver disease, food- dependent Gushing' s syndrome, or cancer, in an individual.
17. The GPRl 19 antagonist according to claim 16, wherein said GP 1 19 antagonist has an
IC50 at GP ! 19 of less than about 1 μΜ.
18. The GPRl 19 antagonist according to claim i 6 or 17, wherein said GPR 119 antagonist is a small molecule.
19. The GPRl 19 antagonist according to any one of claims 16 to 18, wherein said GPRl 19 antagonist is orally active. 20. The GPRl 19 antagonist according to any one of claims 16 to 19, wh erein said GPRl 19 antagonist is selected from: a compound according to any one of claims 1 to 10, a pharmaceutical composition according to claim 11 , a composition according to claim 1 , and l-(4-fluoroben2yl)-3'-(3-methoxyphenyl)spiro[mdob'ne-3,2'-thiazolidine]-2,4'- dione and pharmaceutically acceptable salts, solvates, and hydrates thereof.
21. The GPRl 19 antagonist according to any one of claims 16 to 20, for use in a method for reducing a postprandial GIP level in an individual, wherein a postprandial level of glucagon-like peptide- 1 (GLP-1) is not reduced in said individual. Attorney Docket No. 22578-0029WO1 / 214.WOI
A pharmaceutical product selected from: a pharmaceutical composition, a formulation, a dosage form, and a kit, comprising a GPR l 19 antagonist according to any one of claims 16 to 20.
A method of reducing a postprandial GiP level in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist according to any one of claims 16 to 20.
The method according to claim 23, wherein a postprandial level of GLP-1 is not reduced in said individual.
A method for treating obesity in an individual comprising administering to said individual in need thereof a therapeuticaliy effective amount of a GPRl 19 antagonist according to any one of claims 16 to 20,
A method for treating a disease or condition related to obesity in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist according to any one of claims 16 to 20.
A method for treating non-alcoholic fatty liver disease in an individual comprising administering to said individual in need thereof a therapeuticaliy effective amount of a GPRl 19 antagonist according to any one of claims 16 to 20.
A method for treating food-dependent Gushing' s syndrome in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a GPRl 19 antagonist according to any one of claims 16 to 20.
A method for treating cancer in an individual comprising administering to said individual in need thereof a therapeutically effective amount, of a GPR 1 19 antagonist according to any one of claims 16 to 20.
U se of a GPRl 19 antagonist according to any one of claims 16 to 20, in the manufacture of a medicament for reducing a postprandial G1P level in an individual.
The use according to claim 30, wherein a postprandial level of GLP-1 is not reduced in said individual. Attorney Docket No. 22578-0029WO1 / 214.WOI
Use of a GPR119 antagonist according to any one of claims 16 to 20, in the manufacture of a medicament for the treatment of a disease or condition selected fr< obesity, a disease or condition related to obesity, non-alcoholic fatty ver disease, food-dependent Cushing's syndrome, and cancer.
A method for preparing a pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, said method comprising the steps of: a. measuring the IC<« of said test compound at GPR119 in an in vitro model, wherein the ability of said test compound to antagonize functionality of GPR119 is indicative of said test compound being a GPRi 1 antagonist; b. comparing GIP levels in an in vivo model in the presence and absence of said test compound, wherein a lower GTP level in said in vivo model in the presence of said test compound as compared to in the absence of said test compound is indicative of said test compound being a GPRI i 9 antagonist useful for the treatment of said disease or condition; and
c. formulating said test compound with a pharmaceutically acceptable carrier to form said pharmaceutical composition.
A method for preparing a pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPRI 19 in an in vitro model, said method comprising the steps of:
a. comparing GIP levels in an in vivo model in the presence and absence of said test compound, wherein a lower GIP level in said in vivo model in the presence of said test compound as compared to in the absence of said test compound is indicative of said test compound being a GPRI 19 antagonist useful for the treatment of said disease or condition; and
b. formulating said test compound with a pharmaceutically acceptable earner to form said pharmaceutical composition. Attorney Docket No. 22578-0029WO1 / 214.WOI
A method for preparing a pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty iiver disease, food-dependent Gushing' s syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, and to reduce a GIF level in an in vivo model, said method comprising the step of: formulating said test compound with a pharmaceutically acceptable carrier to form said pharmaceutical composition .
A method for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, nonalcoholic fatty liver disease, food -dependent Gushing 's syndrome, and cancer in an individual, said method comprising the steps of:
a. measuring the IC50 of said test compound at GPRl 19 in an in vitro model, wherein the ability of said test compound to antagonize functionality of GPR 119 is indicative of said test compound being a GPRl 19 antagonist; b. comparing GIP le vels in an in vivo model in the presence and absence of said test compound, wherein a lower GIP level in said in vivo model in the presence of said test compound as compared to in the absence of said test compound is indicative of said test compound being a GPRl 19 antagonist useful for the treatment of said disease or condition; and
c. producing or synthesizing said test compound.
A method for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, nonalcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, said method comprising the steps of:
a. comparing GIP levels in an in vivo model in the presence and absence of said test compound, wherein a lower GIP level in said in vivo model in the presence of said test compound as compared to in the absence of said test compound is indicative of said test compound being a GPRl 19 antagonist useful for the treatment of said disease or condition; and
b. producing or synthesizing said test compound. Attorney Docket No. 22578-0029WO1 / 214.WOI
A method for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, nonalcoholic fatty liver disease, food-dependent Cusliing's syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, and to reduce a GIF level in an in vivo model, said method comprising the step of; producing or synthesizing said test compound.
The method according to any one of claims 33 to 38, further comprising the step of: comparing GLP-1 levels in an in vivo model in the presence and absence of said test compound, wherein a GLP-1 level in said in vivo model that is not substantially reduced in the presence of said test compound as compared to in the absence of said test compound is indicative of said test compound being a GPRl 19 antagonist useful for the treatment of said disease or condition.
A method for preparing a pharmaceutical composition comprising a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food -dependent Gushing' s syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPR 119 in an in vitro model, to reduce a G1P level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, said method comprising the step of: formulating said test compound with a pharmaceutically acceptable carrier to form said pharmaceutical composition.
A method for preparing a test compound useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, nonalcoholic fatty liver disease, food-dependent Gushing' s syndrome, and cancer in an individual, said test compound having been determined to antagonize functionality of GPRl 19 in an in vitro model, to reduce a G F level in an in vivo model, and to not substantially reduce a GLP-1 level in an in vivo model, said method comprising the step of: producing or synthesizing said test: compound.
A method for identifying a test compound useful for She treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, nonalcoholic fatty liver disease, food-dependent Cushing's syndrome, and cancer in an individual, said method comprising the steps of: Attorney Docket No. 22578-0029WO1 / 214.WOI
a. comparing GIP levels in an in vivo model in the presence and absence of said test compound; and
b. observing a reduced GIP level in said in vivo model in the presence of said test compound as compared to in the absence of said test compound.
43. The method according to claim 42. further comprising the steps of:
a. comparing GLP-1 levels in said in vivo model in the presence and absence of said test compound; and
b. observing a GLP- 1 level in said in vivo model in the presence of said test compound that is not substantially reduced as compared to in the absence of said test compound.
The method according to claim 42 or 43, comprising determining a GIP level in a blood or plasma sample obtained from a mammal, said mammal having been administered food and a test compound, wherein the ability of said test compound to reduce a GIP level in said mammal is indicative of said test compound being useful for the treatment of a disease or condition selected from: obesity, a disease or condition related to obesity, non-alcoholic fatty liver disease, food -dependent Gushing' s syndrome, and cancer in an individual
The method according to any one of claims 33 to 44, wherein said GIP level in the presence of said test compound is reduced by at least 10% as compared to in the absence of said test compound.
The method according to any one of claims 33 to 45, wherein said test compound has an IC-50 at GPR1 19 of less than about 1 μπι.
47. The GPR i 19 antagonist according to any one of claims 33 to 46, wherein said test compound is a small molecule,
48. The GPR119 antagonist according to any one of claims 33 to 47, wherein said test compound is orally active.
49. The method according to any one of claims 42 to 48, further comprising the step of subseq ently admixing said test compound with a pharmaceutical earner to form a pharmaceutical composition. Attorney Docket No. 22578-0029WO1 / 214.W01
A composition comprising a GPR11 antagonist identified using a method according to
PCT/US2013/068924 2012-11-08 2013-11-07 Antagonists of gpr119 receptor and the treatment of disorders related thereto WO2014074700A1 (en)

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