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WO2009005672A1 - Azaindoles et diazaindoles antidiabétiques - Google Patents

Azaindoles et diazaindoles antidiabétiques Download PDF

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Publication number
WO2009005672A1
WO2009005672A1 PCT/US2008/007919 US2008007919W WO2009005672A1 WO 2009005672 A1 WO2009005672 A1 WO 2009005672A1 US 2008007919 W US2008007919 W US 2008007919W WO 2009005672 A1 WO2009005672 A1 WO 2009005672A1
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group
optionally substituted
phenyl
alkyl
pharmaceutically acceptable
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Inventor
Sheryl D. Debenham
Kun Liu
Weiguo Liu
Peter T. Meinke
Harold B. Wood
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the instant invention is concerned with azaindoles and diazaindoles having an aromatic substituent, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders.
  • Diabetes is a disease derived from multiple causative factors and characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test.
  • type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin-dependent diabetes mellitus
  • Type 2 diabetes or noninsulin-dependent diabetes mellitus (NIDDM)
  • insulin is still produced in the body.
  • Patients having type 2 diabetes often have hyperinsulinemia (elevated plasma insulin levels); however, these patients are insulin resistant, which means that they have a resistance to the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues.
  • Type 2 diabetes Patients who are insulin resistant but not diabetic compensate for the insulin resistance by secreting more insulin, so that serum glucose levels are not elevated enough to meet the criteria of Type 2 diabetes. In patients with Type 2 diabetes, even elevated plasma insulin levels are insufficient to overcome the pronounced insulin resistance. Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease.
  • diabetes mellitus Patients with type 2 diabetes mellitus have a significantly increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity, and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
  • syndrome X A patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic.
  • Each of these symptoms is defined in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670.
  • Patients with metabolic syndrome whether or not they have or develop overt diabetes mellitus, have an increased risk of developing the macro vascular and microvascular complications that are listed above that occur with type 2 diabetes, such as atherosclerosis and coronary heart disease.
  • Insulin resistance is not primarily caused by a diminished number of insulin receptors but by a post-insulin receptor binding defect that is not yet completely understood. This lack of responsiveness to insulin results in insufficient insulin-mediated activation of uptake, oxidation and storage of glucose in muscle and inadequate insulin-mediated repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • a widely used drug treatment involves the administration of meglitinide or a sulfonylurea (e.g. tolbutamide or glipizide), which are insulin secretagogues. These drugs increase the plasma level of insulin by stimulating the pancreatic ⁇ cells to secrete more insulin.
  • meglitinide or a sulfonylurea e.g. tolbutamide or glipizide
  • the biguanides are another class of drugs that are widely used to treat type 2 diabetes.
  • the two best known biguanides, phenformin and metformin cause some correction of hyperglycemia without risk of causing hypoglycemia.
  • the biguanides can be used either with insulin or with an insulin secretagogue without increasing the risk of hypoglycemia.
  • phenformin and metformin can induce lactic acidosis and nausea/diarrhea. Metformin has a lower risk of side effects than phenformin and is widely prescribed for the treatment of Type 2 diabetes.
  • the glitazones are a newer class of compounds that can ameliorate hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes, resulting in partial or complete correction of elevated plasma glucose levels without the occurrence of hypoglycemia.
  • the glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype.
  • PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones.
  • New PPAR agonists are being developed for the treatment of Type 2 diabetes and/or dyslipidemia. Many of the newer PPAR compounds are agonists of one or more of the PPAR alpha, gamma and delta subtypes. Compounds that are agonists of both the PPAR alpha and PPAR gamma subtypes (PPAR alpha/gamma dual agonists) are promising because they reduce hyperglycemia and also improve lipid metabolism.
  • PPAR agonists and particularly glitazones, have had shortcomings which have so far detracted from their attractiveness. Some of the compounds, especially troglitazone, have exhibited liver toxicity. Troglitazone was eventually withdrawn from the marketplace because of hepatotoxicity. Another weakness in the currently marketed PPAR agonists is that monotherapy for type 2 diabetes produces only modest efficacy - a reduction in average plasma glucose of ⁇ 20% and a decline from -9.0% to -8.0% in HemoglobinAlC. The currently marketed compounds also do not greatly improve lipid metabolism, and may actually have a negative effect on the lipid profile. These shortcomings have provided an incentive to develop better insulin sensitizers for Type 2 diabetes which function via similar mechanism(s) of action.
  • WOO 1/30343 describes a specific compound that is a PPAR gamma partial agonist/antagonist that is useful for the treatment of obesity and Type 2 diabetes.
  • WO02/08188, WO2004/020408, WO2004/020409, WO2004/019869, WO 2006/014262, and WO 2006/022954 disclose classes of PPAR agonists and partial agonists that are indole or benzourea derivatives and that are useful in the treatment of Type 2 diabetes, with reduced side effects relating to body and heart weight gain.
  • PPAR agonists and partial agonists having an azaindole central ring have not been described.
  • the class of compounds described herein is a new class of PPAR-gamma agonists and partial agonists.
  • the compounds are potent ligands of the PPAR gamma nuclear receptor.
  • the class of compounds comprises primarily PPAR ⁇ partial agonists, but also may include PPAR ⁇ full agonists and/or PPAR ⁇ antagonists. Some compounds may also have PP ARa activity in addition to PPAR ⁇ activity.
  • the compounds are useful in the treatment and control of hyperglycemia and insulin resistance.
  • the compounds are efficacious in the treatment of non- insulin dependent diabetes mellitus (NIDDM) in human and other mammalian patients, particularly in the treatment of hyperglycemia, and in the treatment of conditions associated with NIDDM, including hyperlipidemia, dyslipidemia, obesity, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, inflammatory conditions, and other PPAR mediated diseases, disorders and conditions.
  • NIDDM non- insulin dependent diabetes mellitus
  • the compounds are also useful in the treatment of one or more lipid disorders, including mixed or diabetic dyslipidemia, isolated hypercholesterolemia, which may be manifested by elevations in LDL-C and/or non-HDL-C, hyperapoBlipoproteinemia, hypertriglyceridemia, elevated triglyceride-rich-lipoproteins, and reduced HDL cholesterol. They are also useful in the treatment or amelioration of atherosclerosis, obesity, vascular restenosis, inflammatory conditions, psoriasis, polycystic ovary syndrome, and other PPAR mediated diseases, disorders and conditions.
  • lipid disorders including mixed or diabetic dyslipidemia, isolated hypercholesterolemia, which may be manifested by elevations in LDL-C and/or non-HDL-C, hyperapoBlipoproteinemia, hypertriglyceridemia, elevated triglyceride-rich-lipoproteins, and reduced HDL cholesterol.
  • lipid disorders including mixed or diabetic dyslipidemia, isolated hypercholesterolemia
  • Aryl is phenyl or naphthyl
  • HET is a 5-membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O and S;
  • X is selected from the group consisting of a bond, CH2, CH(CH3), and C(CH3)2-
  • Y and Z have 3 alternative definitions as follows:
  • Y is selected from the group consisting of -OCR ⁇ R ⁇ -, -SCR7R8- 5 and -CR5R6CR7R8- ; and Z is selected from the group consisting of -CO2H and -CO2Ci-C5alkyl;
  • Rl is -X-HET-Y-Z
  • -Y-Z is optionally H, -CR5R6CO2H, or -CO2H.
  • each R 9 is independently selected from the group consisting of Ci-C4alkyl, C2-C4alkenyl, C2-C3alkynyl, -C ⁇ C-Phenyl, -OCi-C4alkyl, -OH, halogen, and -CN, wherein Ci-C4alkyl, C2-C4alkenyl, C2-C3alkynyl, and -OCi_C4alkyl are each optionally substituted with 1-5 halogens, and Phenyl of -C ⁇ C-Phenyl is optionally substituted with 1-3 substitutents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen;
  • R5, R6 S R7 5 and R8 are each independently selected from the group consisting of H, halogen, C1-C5 alkyl, -OC1-C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl, wherein C1-C5 alkyl, -OC1-C5 alkyl, C2-C5 alkenyl, and -OC2-C5 alkenyl are optionally substituted with 1-5 halogens;
  • R2 is selected from the group consisting of H, -CH2S(O)2Ci-C3alkyl,
  • Ci-C3alkyl wherein Ci-C3alkyl in all uses is optionally substituted with 1-3 halogens;
  • Each R4 is independently selected from H, halogen, C1-C5 alkyl and -OC1-C5 alkyl, wherein C1-C5 alkyl and -OC1-C5 alkyl are optionally substituted with 1-5 halogens; n is an integer from 0-2; and p is an integer from 1 to 3.
  • alkyl groups may be either linear or branched, unless otherwise specified.
  • the invention has numerous embodiments. It provides compounds of Formula I, including pharmaceutically acceptable salts of these compounds, prodrugs of these compounds, and pharmaceutical compositions comprising these compounds and a pharmaceutically acceptable carrier.
  • Aryl is Phenyl
  • HET is isoxazolyl, pyrazolyl, or tetrazolyl.
  • Y is selected from the group consisting of -OCR ⁇ R ⁇ -, -SCR7R.8-, and -CR5R6CR7R8-.
  • Z is CO2H.
  • R2 is selected from H and C1-C3 alkyl, which is optionally substituted with 1-3 halogens.
  • each R4 is independently selected from H, halogen, C1-C3 alkyl and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-3 F.
  • n is an integer from 0-2.
  • p is an integer from 1 to 3.
  • p is an integer from 1-2. In other embodiments, p is 1.
  • Rl is -X- Aryl- Y-Z, wherein Aryl is phenyl which is optionally substituted with 1-3 groups independently selected from R9.
  • each R9 is independently selected from the group consisting of C1-C3 alkyl, C2-3 alkenyl, C2-3alkynyl, -OH, -CN, CF3, -OCH3, -OCF3, halogen, and -C ⁇ C-Phenyl in which the phenyl group is optionally substituted with 1-3 substituents independently selected from CH3, CF3, -OCH3, -OCF3, and halogen.
  • Y is -OCR7R.8-; R7 i s selected from the group consisting of H and C1-C3 alkyl; and R.8 is selected from the group consisting of H, C1-C3 alkyl, and OC1-C3 alkyl, wherein Ci- C3 alkyl and OC1-C3 alkyl in all uses are optionally substituted with 1-3 F.
  • Y is -CR5R.6CHR8-; wherein R.5 and R.6 are each independently selected from H and CH3; and R.8 is selected from the group consisting of H, Ci_C3alkyl and -OC1-C3 alkyl, wherein Cl-C3alkyl and -OCl-C3alkyl are each optionally substituted with 1-3 F.
  • X is CH2 or a bond.
  • X is a bond.
  • X is CH2.
  • R.4 is selected from the group consisting of H, CH3, CF3, -OCH3, -OCF3, and halogen.
  • R.2 is CH3.
  • Rl is selected from -X-Aryl-Y-Z and -X-HET-Y-Z, wherein Aryl and HET are optionally substituted with 1-2 groups independently selected from R 9 ;
  • Aryl is Phenyl
  • HET is a 5-membered heteroaromatic ring selected from the group consisting of isoxazolyl, pyrazolyl, and tetrazolyl;
  • X is selected from the group consisting of a bond and CH2-
  • Y and Z have alternative definitions, as follows:
  • Y is selected from the group consisting of -OCR ⁇ R ⁇ -, -SCR7R8- 5 and -CR5R6CR7R8- ; and Z is -CO2H or -CO2CH3;
  • Rl is -X-HET-Y-Z
  • -Y-Z is optionally H, -CR5R6CC>2H, or -CO2H.
  • each R 9 is independently selected from the group consisting of
  • Ci_C3alkyl C2-C3alkenyl, C2-C3alkynyl, -C ⁇ C-Phenyl, -OCH3, CF3, -OCF3, -OH, halogen, and -CN;
  • R5 and R6 are each independently selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms;
  • R7 is selected from the group consisting of H and Ci-C3alkyl, wherein Ci-C3alkyl is optionally substituted with 1-3 F atoms
  • R.8 is selected from the group consisting of H, Ci-C3alkyl, and -OCi-C2alkyl, wherein Ci-C3alkyl and -OCi-C2alkyl are optionally substituted with 1-3 F atoms;
  • R2 is selected from the group consisting of H, -CH2S(O)2CH3, -CH2SCH3, and CH3;
  • Each R4 is independently selected from H, CH3, CF3, -OCH3, -OCF3, and halogen; and p is an integer from 1 to 2.
  • Rl is -X-HET-Y-Z, wherein HET is optionally substituted with 1-2 groups independently selected from R9;
  • X is selected from the group consisting of a bond and CH2;
  • Y and Z have alternative definitions, as follows:
  • Y is selected from the group consisting of -OCR ⁇ R ⁇ -, -SCR7R8-, and -CR5R6CR7R8-; and Z is -CO2H;
  • Y and Z together optionally represent a substituent selected from the group consisting of H, -CR5R6C02H, and -CO2H.
  • each R9 is independently selected from the group consisting of halogen, CH3, -OCH3, CF3, and -OCF3;
  • R2 is CH3.
  • Rl is -X-Phenyl-Y-CO2H, wherein Phenyl is optionally substituted with 1-2 groups independently selected from R.9.
  • each R.9 is independently selected from the group consisting of C 1.3 alkyl, C2-3alkenyl, C2-3alkynyl, -OCi -3 alkyl, -OH, halogen, and -CN, wherein alkyl, alkenyl, alkynyl, and -Oalkyl are each optionally substituted with 1-3 F.
  • Y is -OCR7R8-, wherein R7 is selected from the group consisting of H and CH3, and R8 is selected from the group consisting of C1-C3 alkyl and -OC1-C2 alkyl.
  • Tables 1 and 2 Structures of specific compounds are provided in Tables 1 and 2.
  • the syntheses of the specific compounds in Table 1 are provided hereinafter in the Examples.
  • the compounds in Table 2 were made by generally following the methods disclosed herein, which were varied to adjust for structural differences. These compounds can readily be made by a practitioner of synthetic organic chemistry using the techniques disclosed herein. Mass spectral data are also included in Table 2.
  • the compounds of this invention can be used in pharmaceutical compositions comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compounds of this invention can be used in pharmaceutical compositions in which a compound of Formula I or a pharmaceutically acceptable salt thereof is the only active ingredient, or in compositions that also include additional active ingredients.
  • the compounds of the invention and pharmaceutically acceptable salts thereof can be used in the manufacture of medicaments for the treatment of type 2 diabetes mellitus in a human or other mammalian patient, and in the manufacture of medicaments for other diseases described herein that are treated by the compounds.
  • the compounds as defined above may be used in any of the following methods to treat or control diseases, as well as methods to treat other diseases not listed below, in a mammalian patient, especially a human, by administering to the patient a therapeutically effective amount of a compound of Formula I:
  • non-insulin dependent diabetes mellitus type 2 diabetes
  • hypertriglyceridemia and/or (7) one or more lipid disorders, including mixed or diabetic dyslipidemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
  • the compounds may also be used in a method for reducing the risks of adverse sequelae associated with metabolic syndrome in a human or other mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I.
  • the compounds may also be used in a method for treating atherosclerosis, for reducing the risk of developing atherosclerosis, for delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis in a human or other mammalian patient in need of such treatment or at risk of developing atherosclerosis or sequelae of atherosclerosis, which comprises administering to the patient a therapeutically effective amount of a compound of Formula I.
  • Sequelae of atherosclerosis include for example angina, claudication, heart attack, stroke, etc.
  • PPAR agonists are potentially useful in the treatment of Alzheimer's disease.
  • These compounds may therefore also have utility in treating Alzheimer's disease.
  • the compounds are especially useful in the treatment of the following diseases, by administering a therapeutically effective amount to a patient in need of treatment:
  • type 2 diabetes and especially hyperglycemia resulting from type 2 diabetes
  • Ac is acetyl, which is CH3C(O)-.
  • Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, and the like.
  • alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic saturated or partially unsaturated carbocyclic rings, each having from 3 to 10 carbon atoms, unless otherwise stated. The term also includes a monocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • a cycloalkylidene group is a divalent cycloalkane radical in which both attachments are at the same carbon.
  • the cyclopropyl group of 1,1- dimethylcyclopropane is a cyclopropylidene group.
  • Aryl when used to describe a substituent or group in a structure means a monocyclic or bicyclic compound in which all the rings are aromatic and which contains only carbon ring atoms.
  • aryl can also refer to an aryl group that is fused to a cycloalkyl or heterocycle. More specifically, Aryl means phenyl or naphthyl. The most preferred Aryl group is phenyl.
  • Heteroaryl (and heteroarylene) means a mono- or fused bicyclic aromatic ring system containing 1-4 heteroatoms selected from N, O and S, including -S(O)- and -S(O)2-, with each ring containing 5 to 6 atoms.
  • HET in this application is a 5-membered aromatic ring containing 1-4 heteroatoms independently selected from N, O, and S, wherein the ring does not contain any carbonyl, sulfoxide, or sulfone groups.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, azoxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • HET examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, azoxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, and thienyl.
  • Preferred HET groups include tetrazolyl, isoxazolyl, and pyrazolyl.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Me represents methyl.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • tetrazole means a 2//-tetrazol-5-yl substituent group and tautomers thereof.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • keto-enol tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers.
  • An example is a ketone and its enol form, known as keto-enol tautomers.
  • keto-enol tautomers The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
  • enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • Therapeutically active metabolites of other compounds where the metabolites themselves fall within the scope of the claimed invention, are also compounds of the current invention.
  • Prodrugs which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient, are also compounds of this invention.
  • Compounds of the present invention are potent ligands having agonist, partial agonist or antagonist activity on one or more of the various peroxisome proliferator activated receptor subtypes, particularly PPAR ⁇ .
  • the compounds may also be ligands or agonists, partial agonists or antagonists of the PPAR ⁇ subtype as well as the PPAR ⁇ subtype, resulting in mixed PPAR ⁇ / ⁇ agonism or in agonism of mainly the PPAR ⁇ subtype.
  • Some compounds may also be PPAR ⁇ ligands and have PPAR ⁇ activity in addition to their other PPAR activity.
  • the compounds of this invention are useful in treating or controlling diseases, disorders or conditions which are mediated by one or more ligands of the individual PPAR subtypes (eg ⁇ or ⁇ ) or a combination of PPAR subtypes (e.g. ⁇ / ⁇ ).
  • One aspect of the present invention provides a method for the treatment and control of diseases that can be mediated by administration of a PPAR agonist or partial agonist, particularly a PPAR ⁇ agonist or partial agonist, such as type 2 diabetes, by administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I.
  • Compounds of the present invention may be useful in treating or controlling many PPAR mediated diseases and conditions, including, but not limited to, (1) diabetes mellitus, and especially non-insulin dependent diabetes mellitus (NIDDM), (2) hyperglycemia, (3) low glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDL levels, (12) high LDL levels, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) irritable bowel syndrome, (16) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neurodegenerative disease, (21) retinopathy, (22) psoriasis, (23) metabolic syndrome, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is
  • They may also have utility in treating high blood pressure, neoplastic conditions, adipose cell tumors, adipose cell carcinomas, such as liposarcoma, prostate cancer and other cancers, including gastric, breast, bladder and colon cancers, angiogenesis, and Alzheimer's disease.
  • the present compounds can be used to lower glucose, lipids, and insulin in non- diabetic patients that have impaired glucose tolerance and/or are in a pre-diabetic condition.
  • the present compounds can be used to treat obesity in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1.
  • the present compounds can be used to treat or reduce the risk of developing atherosclerosis in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1.
  • the present compounds can be used to treat or reduce hyperglycemia in a patient in need of such treatment by administering to the patient a therapeutically effective amount of a compound of Formula 1.
  • the compounds may have utility in treating osteoporosis.
  • the compounds of this invention may treat osteoporosis or reduce the risk of developing osteoporosis by slowing or stopping the loss of bone density in a patient who has osteoporosis or is at risk of developing osteoporosis.
  • the compounds of this invention may also reverse the loss of bone mass in patients who have already begun to lose bone mass.
  • One aspect of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I.
  • the compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, or itavastatin.
  • the compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors, niacin, niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors.
  • cholesterol absorption inhibitors for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe
  • ACAT inhibitors such as avasimibe
  • CETP inhibitors such as avasimibe
  • niacin niacin receptor agonists
  • bile acid sequestrants bile acid sequestrants
  • microsomal triglyceride transport inhibitors microsomal t
  • Another aspect of the invention provides a method of treating inflammatory conditions, including inflammatory bowel disease, Crohn's disease, and ulcerative colitis by administering an effective amount of a compound of this invention to a patient in need of treatment.
  • Additional inflammatory diseases that may be treated with the instant invention include gout, rheumatoid arthritis, osteoarthritis, multiple sclerosis, asthma, ARDS, psoriasis, vasculitis, ischemia/reperfusion injury, frostbite, and related diseases.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • When treating or controlling diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which compounds of Formula I are indicated generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, including humans (e.g.
  • the total daily dosage is from about 0.1 milligrams to about 1000 milligrams, is likely to be from about 0.5 milligrams to about 350 milligrams, and is often from about 1 milligram to about 50 milligrams.
  • the dosage for an adult human may be as low as 0.1 mg.
  • Examples of daily dosages for a 70 kg adult human are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg per day.
  • the daily dosage regimen may be adjusted within the above ranges or even outside of these ranges to provide the optimal therapeutic response.
  • Oral administration will usually be carried out using tablets.
  • Examples of doses in tablets which may be administered once a day or more than once a day are 0.1 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 350 mg, and 500 mg.
  • Other oral forms e.g. capsules or suspensions
  • compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts of pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous), hi preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds of Formula I may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of
  • the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
  • PPAR gamma agonists and partial agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like), and PPAR gamma agonists and partial agonists that do not have a glitazone structure such as T- 131 ;
  • glitazones e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, netoglitazone, and the like
  • PPAR gamma agonists and partial agonists that do not have a glitazone structure such as T- 131 ;
  • dipeptidyl peptidase FV (DP-FV) inhibitors such as sitagliptin, vildagliptin, saxigliptin, and NN-7201.
  • ⁇ -glucosidase inhibitors such as acarbose
  • agents which improve a patient's lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) niacin receptor agonists, (v) PP ARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (vi) cholesterol absorption inhibitors, such as for example ezetimibe, (vii) acyl CoAxholesterol acyl
  • PPAR ⁇ / ⁇ dual agonists such as KRP-297, muraglitazar, tesaglitazar, naveglitazar (LY-818), TAK-559, LY-929, and the like
  • PPAR ⁇ agonists such as GW501516 and compounds disclosed in
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4r agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, and ⁇ 3 adrenergic receptor agonists; (1) ileal bile acid transporter inhibitors;
  • agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors;
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • Non-limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-IB inhibitors, DP-IV inhibitors, and anti-obesity compounds.
  • Compounds of the present invention can be used to treat one or more diseases or conditions selected from hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia by administering a therapeutically effective amount of a compound of Claim 1 in combination with an HMG-CoA reductase inhibitor to a patient in need of such treatment.
  • Statins are the preferred HMG-CoA reductase inhibitors for use in this combination therapy.
  • Preferred statins include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522, rivastatin, and rosuvastatin. This combination treatment may be particularly desirable for treating or reducing the risk of developing atherosclerosis.
  • the resuspended pellet was broken in a French press and debris was removed by centrifugation at 12,000 X g.
  • Recombinant human PPAR receptors were purified by affinity chromatography on glutathione sepharose. After application to the column, and one wash, receptor was eluted with glutathione. Glycerol (10%) was added to stabilize the receptor and aliquots were stored at -80 0 C.
  • TEGM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamidine and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 10 nM [ 3 H2] AD5075, (21 Ci/mmole), ⁇ test compound as described in Berger et al (Novel peroxisome proliferator- activated receptor (PPAR ⁇ ) and PPAR ⁇ ligands produce distinct biological effects.
  • TEGM 10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithioth
  • TEGM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 2.5 nM [ 3 H2]L-783483, (17 Ci/mmole), ⁇ test compound as described in Berger et al (Novel peroxisome proliferator-activated receptor ⁇ (PPAR ⁇ ) and PPAR ⁇ ligands produce distinct biological effects.1999 J Biol Chem 274: 6718- 6725).
  • L-783483 is 3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-benz-[4,5]- isoxazoloxy)propylthio)phenylacetic acid, Ex. 20 in WO 97/28137).
  • Assays were incubated for — 16 hr at 4°C in a final volume of 150 ⁇ L. Unbound ligand was removed by incubation with 100 ⁇ L dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifugation at 3000 rpm for 10 min at 4°C, 50 ⁇ L of the supernatant fraction was counted in a Topcount.
  • TEGM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamide and 0.5 mM PMSF) containing 0.1% non-fat dry milk and 5.0 nM [ 3 H2]L-797773, (34 Ci/mmole), ⁇ test compound.
  • TEGM 10 mM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benz
  • the specific compounds in this application exhibit IC50 values for PPAR gamma using this assay in the range of 390OnM to ⁇ 0.5nM, and preferred compounds have IC50 values in the range of 50OnM to ⁇ 0.5nM.
  • the chimeric receptor expression constructs pcDNA3-hPPAR ⁇ /GAL4, pcDNA3- hPPAR ⁇ /GAL4, pcDNA3-hPPAR ⁇ /GAL4 were prepared by inserting the yeast GAL4 transcription factor DBD adjacent to the ligand binding domains (LBDs) of hPPAR ⁇ , hPPAR ⁇ , hPPAR ⁇ , respectively.
  • the reporter construct, pUAS(5X)-tk-luc was generated by inserting 5 copies of the GAL4 response element upstream of the herpes virus minimal thymidine kinase promoter and the luciferase reporter gene.
  • pCMV-lacZ contains the galactosidase Z gene under
  • COS-I cells were seeded at 12 X 10 cells/well in 96 well cell culture plates in high glucose Dulbecco's modified Eagle medium (DMEM) containing 10% charcoal stripped fetal calf serum (Gemini Bio-Products, Calabasas, CA), nonessential amino acids, 100 units/ml Penicillin G and 100 mg/ml Streptomycin sulfate at 37 °C in a humidified atmosphere of 10% CO2- After 24 h, transfections were performed with
  • Lipofectamine (GIBCO BRL, Gaithersburg, MD) according to the instructions of the manufacturer. Briefly, transfection mixes for each well contained 0.48 ⁇ l of Lipofectamine, 0.00075 ⁇ g of pcDNA3-PPAR/GAL4 expression vector, 0.045 ⁇ g of pUAS(5X)-tk-luc reporter vector and 0.0002 ⁇ g of pCMV-lacZ as an internal control for transactivation efficiency. Cells were incubated in the transfection mixture for 5 h at 37° C in an atmosphere of 10% CO2.
  • the cells were then incubated for -48 h in fresh high glucose DMEM containing 5% charcoal stripped fetal calf serum, nonessential amino acids, 100 units/ml Penicillin G and 100 mg/ml Streptomycin sulfate ⁇ increasing concentrations of test compound. Since the compounds were solubilized in DMSO, control cells were incubated with equivalent concentrations of DMSO; final DMSO concentrations were ⁇ 0.1%, a concentration which was shown not to effect transactivation activity. Cell lysates were produced using Reporter Lysis Buffer (Promega, Madison, WI) according to the manufacturer's instructions.
  • Reporter Lysis Buffer Promega, Madison, WI
  • Luciferase activity in cell extracts was determined using Luciferase Assay Buffer (Promega, Madison, WI) in an ML3000 luminometer (Dynatech Laboratories, Chantilly, VA).
  • ⁇ -galactosidase activity was determined using ⁇ -D-galactopyranoside (Calbiochem, San Diego, CA).
  • Agonism is determined by comparison of maximal transactivation activity with a full PPAR agonist, such as rosiglitazone. Generally, if the maximal stimulation of transactivation is less than 50% of the effect observed with a full agonist, then the compound is designated as a partial agonist. If the maximal stimulation of transactivation is greater than 50% of the effect observed with a full agonist, then the compound is designated as a full agonist.
  • the compounds of this invention have EC50 values in the range of InM to 3000 nM.
  • mice Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar Harbor, ME) are housed 5/cage and allowed ad lib. access to ground Purina rodent chow and water. The animals, and their food, are weighed every 2 days and are dosed daily by gavage with vehicle (0.5% carboxymethylcellulose) ⁇ test compound at the indicated dose. Drug suspensions are prepared daily. Plasma glucose, and triglyceride concentrations are determined from blood obtained by tail bleeds at 3-5 day intervals during the study period.
  • Glucose and triglyceride determinations are performed on a Boehringer Mannheim Hitachi 911 automatic analyzer (Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 1 :6 (v/v) with normal saline. Lean animals are age-matched heterozygous mice maintained in the same manner.
  • the compounds in the Examples and Table 1 were generally analyzed by NMR and tandem high pressure liquid chromatography - mass spectrometry (LC-MS).
  • the compounds in Table 2 were analyzed by LC-MS, as well as NMR or other methods for many of the compounds.
  • LC-MS samples were analyzed using an Agilent 1 100 Series high pressure liquid chromatograph coupled to a Waters Micromass ZQ mass spectrometer.
  • the column used was a Waters XTerra and compounds were eluted using a gradient elution program (10% B to 100% B in 4.5 min) with a flow rate of 2.5 mL/min; Solvent A: water containing 0.05% trifluoroacetic acid; Solvent B: acetonitrile containing 0.05% trifluoroacetic acid. Retention times are given in minutes.
  • Method A XTerra MS-C 18, 4.5 x 50 mm, 10 - 100% B in 4.5 min, flow rate 2.5 ml/min.
  • Method B XTerra Cl 8, 3 x 50 mm, 10 - 98% in 3.75 min, then 98% for 1 min, flow rate 1 ml/min.
  • Step 1 The first step in this synthesis was published in a methodology paper in
  • (2S)-2-(3- ⁇ [3-(4-chlorobenzoyl)-2,6-dimethyl-lH-pyrrolo[2,3-b]pyridin-l- yl]methyl ⁇ phenoxy)propanoic acid was isolated as a lyophilized powder.
  • the starting material was prepared using the procedure described by Lang, F.; Zewge, D.; Houpis, I.N.; Volante, R.P. Tetrahedron Lett., 42, 3251-3254, 2001.
  • Step l A solution of 2-methoxy-5-aminopyridine (1 g, 8.1 mmol) in EtOAc (2 ml) was added to a solution of BoC 2 O (1.6 eq, 2.8 g) in hexanes (7 niL) at reflux. After 1 hour, the reaction was cooled to 25 °C and concentrated. Purification via flash chromatography eluding with a gradient of 0 to 25% EtOAc/hexanes provided tert-butyl (6-methoxypyridin-3- yl)carbamate.
  • the sodium salt was prepared upon treatment of the free acid with NaHCO 3 (0.95eq).
  • Step l
  • Step 1 A solution of 5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (75mg, 0.51mmol), Cs 2 CO 3 (3eq, 500mg), and 3-methoxybenzyl bromide (1.2eq, 0.087mL) in DMF (6mL) was stirred at 25°C for 15h. The reaction was diluted with EtOAc and washed with p ⁇ 7 buffer (2x). The organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified via flash chromatography eluding with a gradient of 0 - 100% EtOAc/hexanes.
  • Step 2 To a solution of 5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7- carbaldehyde (113mg, 0.423mmol) in T ⁇ F (2.2mL) at 0 0 C was added p-chlorophenylmagnesium bromide (IM soln, l.leq, 0.466mL). After 30min, the reaction was quenched with IM HCl, neutralized to p ⁇ 6 and extracted with EtOAc. The organic layer was concentrated then purified via flash chromatography eluding with a gradient of 0 tol00% EtOAc/hexanes. (4- chlorophenyl)[5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]methanol was isolated as a mixture of product and starting material.
  • Step 3 A solution of TPAP (0.2eq, 26mg), NMO (64mg, 1.5eq), 4A molecular sieves and (4-chlorophenyl)[5-(3-methoxybenzyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl]methanol (138mg, 0.364mmol) in DCM (ImL) and MeCN (ImL) were stirred at 25°C for lhr. The mixture was filtered through silica gel and concentrated. The filtrated was concentrated and purified via prep TLC (50% EtOAc/hexanes). (4-chlorophenyl)[5-(3-methoxybenzyl)-5H- pyrrolo[2,3-b]pyrazin-7-yl]methanone was isolated as a colorless film.
  • Step 4 To a solution of (4-chlorophenyl)[5-(3-methoxybenzyl)-5//-pyrrolo[2,3- b]pyrazin-7-yl]methanone (30mg, 0.08mmol) in DCM (0.5mL) at 0°C was added BBr 3 (IM soln, 1.2eq, 0.095mL). After 30min, the reaction was warmed to 25°C and stirred for lhr. More BBr 3 (2eq) was added over the next 2h. The reaction was quenched with pH7 buffer and extracted with DCM (2x) and EtOAc (Ix). The organic layers were dried over Na 2 SO 4 and concentrated.
  • BBr 3 IM soln, 1.2eq, 0.095mL
  • Step 5 To a solution of (4-chlorophenyl)[5-(3-hydroxybenzyl)-5H-pyrrolo[2,3- b]pyrazin-7-yl]methanone (20mg, 0.055mmol), R-methyl lactate (1.5eq, 7.9uL) and PPh 3 (1.5eq, 22mg) in DCM (55uL) and T ⁇ F (55uL) was added DEAD (1.5eq, 13.IuL). After 4h at 25 0 C, more DEAD (0.5eq) was added. The reaction stirred for 15h then diluted with EtOAc, washed with p ⁇ 7 buffer (2x). The organic layer was dried over Na 2 SO 4 and concentrated.
  • Step 6 Methyl 2-(3- ⁇ [7-(4-chlorobenzoyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl]methyl ⁇ phenoxy)propanoate (30.6mg, 0.068mmol), IM KOH (2eq, 0.136mL) and aqueous MeOH (ImL) were stirred at 25°C for 4h. The mixture was concentrated and purified via preparatory LC. The product 2-(3- ⁇ [7-(4-chlorobenzoyl)-5H-pyrrolo[2,3-b]pyrazin-5- yl] methyl ⁇ phenoxy)propanoic acid was isolated as a white lyophilized powder.
  • p-Chlorophenylmagnesium bromide (1.0M, 2eq, 0.6mL) was added to a solution of 5-(2-chloro-5-methoxybenzyl)-iV-methoxy-N,6-dimethyl-5H-pyrrolo[2,3-6]pyrazine-7- carboxamide (113mg, 0.30 mmol) in T ⁇ F (3mL) at -78°C. After 2 hr, more p- chlorophenylmagnesium bromide (leq) was added. After 2 hr, reaction was quenched with IM HCl. Stir 5 min before dilution with EtOAc and washed with p ⁇ 7 buffer, brine.
  • BBr 3 (IM, 3eq, 0.6mL) was added to a solution of [5-(2-chloro-5- methoxybenzyl)-6-methyl-5H-pyrrolo[2,3-Z)]pyrazin-7-yl](4-chlorophenyl)methanone (86mg, 0.2mmol) in CH 2 Cl 2 (2mL). After 2 hr, diluted with CH 2 Cl 2 and washed with pH7 buffer and water. The organic layers were dried over Na 2 SO 4 and concentrated.

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Abstract

L'invention porte sur des azaindoles et des diazaindoles comportant des substituants aromatiques sur le cycle à 5 éléments qui sont des agonistes ou des agonistes partiels du récepteur PPAR et qui sont utiles dans le traitement et le contrôle du diabète de type 2 et des symptômes du diabète, comprenant l'hyperglycémie, la dyslipidémie, l'hyperlipidémie, l'hypercholestérolémie, l'hypertriglycéridémie et l'obésité, qui sont souvent associés au diabète de type 2.
PCT/US2008/007919 2007-06-29 2008-06-25 Azaindoles et diazaindoles antidiabétiques Ceased WO2009005672A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
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WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012164071A1 (fr) * 2011-06-02 2012-12-06 Intervet International B.V. Dérivés d'imidazole
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
JP2015503609A (ja) * 2012-01-13 2015-02-02 ノバルティス アーゲー 肺動脈高血圧症（ｐａｈ）および関連障害の治療のためのｉｐ受容体アゴニストとしての縮合ピロール
US9522134B2 (en) 2014-10-24 2016-12-20 Orca Pharmaceuticals Limited Compounds
WO2023155871A1 (fr) * 2022-02-18 2023-08-24 Insilico Medicine Ip Limited Inhibiteurs de la kinase inhibitrice de cdc2 spécifique de la tyrosine/thréonine associée aux membranes (pkmyt1) et leurs utilisations
US12435090B2 (en) * 2021-10-04 2025-10-07 Repare Therapeutics Inc. Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006112828A1 (fr) * 2005-04-15 2006-10-26 Scios, Inc. Derives d’azaindole en tant qu’inhibiteurs de kinase p38
US20070027140A1 (en) * 2003-11-24 2007-02-01 Novo Nordisk A/S N-heteroaryl indole carboxamides and analogues thereof, for use as glcokinase activators in the treatment of diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070027140A1 (en) * 2003-11-24 2007-02-01 Novo Nordisk A/S N-heteroaryl indole carboxamides and analogues thereof, for use as glcokinase activators in the treatment of diabetes
WO2006112828A1 (fr) * 2005-04-15 2006-10-26 Scios, Inc. Derives d’azaindole en tant qu’inhibiteurs de kinase p38

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WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
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WO2012164071A1 (fr) * 2011-06-02 2012-12-06 Intervet International B.V. Dérivés d'imidazole
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2013068486A1 (fr) 2011-11-08 2013-05-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le diagnostic et le traitement de l'infertilité masculine
JP2015503609A (ja) * 2012-01-13 2015-02-02 ノバルティス アーゲー 肺動脈高血圧症（ｐａｈ）および関連障害の治療のためのｉｐ受容体アゴニストとしての縮合ピロール
US9522134B2 (en) 2014-10-24 2016-12-20 Orca Pharmaceuticals Limited Compounds
US9861612B2 (en) 2014-10-24 2018-01-09 Orca Pharmaceuticals Limited Indolyl-containing RORγt inhibitors
US12435090B2 (en) * 2021-10-04 2025-10-07 Repare Therapeutics Inc. Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use
WO2023155871A1 (fr) * 2022-02-18 2023-08-24 Insilico Medicine Ip Limited Inhibiteurs de la kinase inhibitrice de cdc2 spécifique de la tyrosine/thréonine associée aux membranes (pkmyt1) et leurs utilisations

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