EP1753423A2 - Benzoureas having anti-diabetic activity - Google Patents
Benzoureas having anti-diabetic activityInfo
- Publication number
- EP1753423A2 EP1753423A2 EP05812065A EP05812065A EP1753423A2 EP 1753423 A2 EP1753423 A2 EP 1753423A2 EP 05812065 A EP05812065 A EP 05812065A EP 05812065 A EP05812065 A EP 05812065A EP 1753423 A2 EP1753423 A2 EP 1753423A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- alkyl
- group
- compounds
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- the instant invention is concerned with benzoureas 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.
- Type 2 diabetes mellitus Patients with type 2 diabetes mellitus have a significantly increased risk of macrovascular 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. Many patients who have insulin resistance or Type 2 diabetes often have several symptoms that together are referred to as syndrome X, or the metabolic syndrome.
- syndrome X or the metabolic syndrome.
- 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 HI, or ATP HI), 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 macrovascular 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.
- meglitinide or a sulfonylurea e.g. tolbutamide or glipizide
- these drugs increase the plasma level of insulin by stimulating the pancreatic ⁇ -cells to secrete more insulin.
- the amount of insulin in the body can be supplemented by the injection of insulin so that insulin concentrations are high enough to stimulate even the very insulin-resistant tissues.
- dangerously low levels of plasma glucose can result from administration of insulin and/or insulin secretagogues, and an increased level of insulin resistance due to the even higher plasma insulin levels can occur.
- 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 i.e.
- 5-benzylthiazolidine-2,4-diones 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 current 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.
- WO01/30343 describes a specific compound that is a PPAR partial agonist/antagonist that is useful for the treatment of obesity and Type 2 diabetes.
- WO02/08188, WO2004/020408, WO2004/020409, and WO2004/019869 disclose classes of PPAR agonists and partial agonists that are indole derivatives and that are useful in the treatment of Type 2 diabetes, with reduced side effects relating to body and heart weight gain. Benzoureas have not been disclosed as having anti-diabetic activity. SUMMARY OF THE INVENTION
- 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 includes many compounds that are 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 expected to be 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 may also be 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, hyperapoBliproteinemia, hypertriglyceridemia, an increase in triglyceride-rich-lipoproteins, and low HDL cholesterol concentrations. They may also be 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, hyperapoBliproteinemia, hypertriglyceridemia, an increase in triglyceride-rich-lipoproteins, and low HDL cholesterol concentrations.
- lipid disorders including mixed or diabetic
- the present invention is directed to compounds having formula I:
- Rl is -X-Aryl-Y-Z, and Aryl is optionally substituted with 1-3 groups independently selected from A;
- Aryl is phenyl or naphthyl; X and Y are each independently selected from a bond and -CR R -;
- Q is selected from S and O;
- A is selected from C1-C4 alkyl, C2-C4 alkenyl, -OC1-C4 alkyl, and halogen, wherein alkyl, alkenyl, and -Oalkyl are each optionally substituted with 1-5 halogens;
- R2 is selected from:
- R ⁇ is optionally substituted with 1-3 substituent groups which are independently selected from halogen, Ci -C3 alkyl, and -OC1 -C3 alkyl, wherein C1-C3 alkyl and -OC1 -C3 alkyl are optionally substituted with 1-5 halogens;
- R3, R4, and R5 are each independently selected from hydrogen, halogen, Ci- C3 alkyl, and -OC1-C3 alkyl, where C1 -C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-5 halogens;
- R6 is selected from H, C1 -C3 alkyl, and halogen, where C1 -C3 alkyl is optionally substituted with 1-3 F;
- p is an integer from 0 to 4.
- alkyl groups may be either linear or branched, unless otherwise specified.
- the invention has numerous embodiments, as set forth below. All embodiments also include pharmaceutically acceptable salts of the compounds that are defined.
- One embodiment comprises compounds having Formula I, wherein R 1 is -X-phenyl-YZ.
- X and Y each independently can be a bond or -CH2-.
- Aryl is optionally substituted with 1-2 groups A, where each group A can be halogen, -CF3 , -OCF3 , -CH3 , or -OCH3 .
- R3 is -CH3, -OCH 3 ,
- R6 is H, CH3 5 or CF3.
- R2 is 3- benzisoxazolyl, which is optionally substituted with 1-2 groups independently selected from halogen, -OCH3, -OCF3, CH3, and CF3.
- R2 is 2- benzothiazolyl, which is optionally substituted with 1-2 groups independently selected from halogen, -OCH3, -OCF3, CH3, and CF3.
- R 1 is -X-phenyl-YZ, where phenyl is optionally substituted with 1-2 groups independently selected from A; X and Y are each independently selected from a bond and -CH2-;
- A is selected from halogen, -CF3, -OCF3, -CH3, and -OCH3;
- R3 is selected from -CF3, -OCF3, -CH3, and -OCH3;
- R6 is selected from H, -CH3, and -CF3; and p is 0 or 1.
- a subset of the compounds of Formula I, or of any of the embodiments described above, includes compounds in which Q is O, X is a bond, and Y is -CH2--
- Another subset of the compounds of Formula I, or of any of the embodiments described above, includes compounds in which Q is O, X is -CH2-, and Y is a bond.
- Another subset of the compounds of Formula I, or of any of the embodiments described above, includes compounds in which Q is O and X and Y are each -CH2--
- Another subset of the compounds of Formula I, or of any of the embodiments described above, includes compounds in which Q is O and X and Y are each a bond.
- the invention includes 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.
- 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 also be used in pharmaceutical compositions in which a compound of Formula I or a pharmaceutically acceptable salt thereof is the only active ingredient.
- 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
- hyperglycemia hyperglycemia
- 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.
- 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
- metabolic syndrome
- 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.
- Heterocyclyl “heterocycle,” and “heterocyclic” means a fully or partially saturated monocyclic or bicyclic ring system containing 1-4 heteroatoms independently selected from N, S and O, each of said rings having from 3 to 8 atoms. Examples of aryl substitiuents include phenyl and naphthyl.
- Aryl rings fused to cycloalkyls are found in indanyl, indenyl, and tetrahydronaphthyl.
- Examples of aryl fused to heterocyclic groups are found in 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, and the like.
- Examples of heterocycles include tetrahydrofuran, piperazine, and morpholine.
- Preferred aryl groups are phenyl and naphthyl. Phenyl is generally the most preferred.
- Heteroaryl (and heteroarylene) means a mono- or 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.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, 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.
- Preferred heteroaryl groups include pyridyl (2-, 3-, and 4-pyridyl) and quinolyl.
- 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 2H-tetrazol-5-yl substituent group and tautomers thereof.
- Optical Isomers - Diastereomers - Geometric Isomers - Tautomers 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.
- 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.
- the individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
- Compounds of Formula I having one or more asymmetric centers may be separated into diastereoisomers, enantiomers, and the like by methods well known in the art.
- 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 1 N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-mo ⁇ holine, 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.
- 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 PP ARa subtype as well as the PPAR ⁇ subtype, resulting in mixed PPAR ⁇ / ⁇ agonism.
- 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.
- 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.
- a PPAR agonist or partial agonist particularly a PPAR ⁇ agonist or partial agonist, such as type 2 diabetes.
- One aspect of the present invention provides a method for the treatment and control of such diseases, disorders, or conditions in a mammal which comprises administering to such mammal 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 (NEDDM), (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
- the present compounds 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 diabetic 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, itavastatin, or ZD-4522.
- 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.
- 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.
- 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.
- 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 prepared from 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).
- 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.
- 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 Formula I.
- a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
- 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.
- 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;
- 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
- PTP-IB protein tyrosine phosphatase- IB
- DP-IV dipeptidyl peptidase IV
- oc-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, ZD-4522 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)
- 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;
- agents intended for use in inflammatory conditions such as aspirin, non ⁇ steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors;
- agents intended for use in inflammatory conditions such as aspirin, non ⁇ steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors;
- glucagon receptor antagonists such aspirin, non ⁇ steroidal 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 i.e.
- compounds having Formula I) 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 full length human cDNA for PPARy 2 was subcloned into the pGEX-2T expression vector (Pharmacia).
- the full length human cDNAs for PPAR ⁇ and PPAR ⁇ were subcloned into the pGEX-KT expression vector (Pharmacia).
- E. coli containing the respective plasmids were propagated, induced, and harvested by centrifugation. 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°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
- 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 benzamidine and 0.5 mM PMSF
- 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 benzamide and 0.5 mM PMSF
- 0.1% non-fat dry milk and 2.5 nM [ 3 H2]L-783483
- 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
- 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 the regulation of the cytomegalovirus promoter.
- 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.
- 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.
- 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 generally 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.
- Table 1 further illustrate compounds of this invention that were made or can be made using the methods disclosed herein.
- LC-MS tandem high pressure liquid chromatography - mass spectrometry
- proton NMR proton NMR
- LC- MS samples were analyzed using an Agilent 1100 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 0.06% trifluoroacetic acid;
- Solvent B acetonitrile containing 0.05% trifluoroacetic acid. Retention times are given in minutes.
- Method A XTerra MS-C18, 4.5 x 50 mm, 10 - 100% B in 4.5 min, flow rate 2.5 ml/min.
- Method B XTerra C18, 3 x 50 mm, 10 - 98% in 3.75 min, then 98% for 1 min, flow rate 1 ml/min.
- General and specific procedures for making the compounds of this invention and synthetic intermediates are summarized below.
- Other compounds claimed herein can readily be made by a practitioner of medicinal and/or synthetic organic chemistry by adapting the procedures disclosed herein to the specific compound.
- l-r(6-methoxy)-benzisoxazol-3-yll-6-trifluoromethoxylbenzimidazole-2-one To a solution of l-[3-(6-chloro)-benzisoxazoyl]-6-trifluoromethoxylbenzimidazole-2-one (1.2 g, 3.25 mmol) in DMF (5 ml) was added NaOMe solution in methanol (30% wt/wt, 20 ml). The mixture was heated to 8O 0 C under vacuum to remove residual methanol and then stirred at 11O 0 C under nitrogen overnight.
- l-(4-trifluoromethoxyphenyl)-5-trifluoromethylbenzimidazole-2-one To the solution of l-Boc-5-trifluoromethylbenzimidazole-2-one (870 mg, 2.88 mmol) in methylene chloride (100 ml) was added Cu(OAc) 2 (521 mg, 2.88 mmol), triethylamine (0.94 ml, 14 mmol), and molecular sieves (200 mg). The mixture was stirred at room temperature under open air overnight, and filtered. The filtrate was concentrated to dryness. The residue was dissolved in TFA (5 ml), stirred at room temperature for 3 hours and concentrated to dryness.
- l-r(6-chloro)benzothiazol-2-yll-5-trifluoromethylbenzimidazole-2-one To the solution of l-Boc-5-trifluoromethylbenzimidazole-2-one (500 mg, 1.65 mmol) in DMF (5 ml) was added 2,6-dichlorobenzothiazole (336 mg, 1.65 mmol) and Cs 2 CO 3 (1.2 g, 3.68 mmol). The mixture was heated in an oil bath to 150 0 C, and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (2x20 ml).
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Child & Adolescent Psychology (AREA)
- Psychiatry (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US57514404P | 2004-05-28 | 2004-05-28 | |
PCT/US2005/018721 WO2006022954A2 (en) | 2004-05-28 | 2005-05-26 | Benzoureas having anti-diabetic activity |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1753423A2 true EP1753423A2 (en) | 2007-02-21 |
EP1753423A4 EP1753423A4 (en) | 2009-10-21 |
Family
ID=35967997
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05812065A Withdrawn EP1753423A4 (en) | 2004-05-28 | 2005-05-26 | Benzoureas having anti-diabetic activity |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1753423A4 (en) |
JP (1) | JP2008501027A (en) |
CN (1) | CN101076334A (en) |
AU (1) | AU2005278099A1 (en) |
CA (1) | CA2565803A1 (en) |
WO (1) | WO2006022954A2 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102006014685A1 (en) * | 2006-03-28 | 2007-10-04 | Sanofi-Aventis | New bicyclic imidazolone derivatives useful as endothelial lipase inhibitors, e.g. for treating disorders of fat metabolism or glucose utilization |
EP2100604B1 (en) * | 2008-03-10 | 2012-07-04 | Nestec S.A. | Medium chain dicarboxylic acids and their derivates and metabolic disorders |
JP6314142B2 (en) * | 2012-09-21 | 2018-04-18 | レオキシン ディスカバリーズ グループ,インコーポレイテッド | Cell for electrolyzing liquid |
JP2024515985A (en) * | 2021-04-27 | 2024-04-11 | メッドシャイン ディスカバリー インコーポレイテッド | Derivatives of six-membered aromatic heterourea rings and uses thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5624935A (en) * | 1994-04-11 | 1997-04-29 | Sankyo Company, Limited | Heterocyclic compounds having anti-diabetic activity and their use |
WO2004019869A2 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6653478B2 (en) * | 2000-10-27 | 2003-11-25 | Ortho-Mcneil Pharmaceutical, Inc. | Substituted benzimidazol-2-ones as vasopressin receptor antagonists and neuropeptide Y modulators |
-
2005
- 2005-05-26 CA CA002565803A patent/CA2565803A1/en not_active Abandoned
- 2005-05-26 AU AU2005278099A patent/AU2005278099A1/en not_active Abandoned
- 2005-05-26 CN CNA2005800171945A patent/CN101076334A/en active Pending
- 2005-05-26 WO PCT/US2005/018721 patent/WO2006022954A2/en not_active Application Discontinuation
- 2005-05-26 EP EP05812065A patent/EP1753423A4/en not_active Withdrawn
- 2005-05-26 JP JP2007515386A patent/JP2008501027A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5624935A (en) * | 1994-04-11 | 1997-04-29 | Sankyo Company, Limited | Heterocyclic compounds having anti-diabetic activity and their use |
WO2004019869A2 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
Non-Patent Citations (2)
Title |
---|
BRAJ B. LOHRAY ET AL: "Novel euglycemic and hypolipidemic agents. 1" JOURNAL OF MEDICINAL CHEMISTRY, vol. 41, no. 10, 1998, pages 1619-1630, XP002149048 ISSN: 0022-2623 * |
See also references of WO2006022954A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU2005278099A1 (en) | 2006-03-02 |
EP1753423A4 (en) | 2009-10-21 |
CN101076334A (en) | 2007-11-21 |
WO2006022954A2 (en) | 2006-03-02 |
WO2006022954A3 (en) | 2006-10-12 |
CA2565803A1 (en) | 2006-03-02 |
JP2008501027A (en) | 2008-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4377815B2 (en) | Indoles having anti-diabetic activity | |
US7393960B2 (en) | Indoles having anti-diabetic activity | |
US7625933B2 (en) | Indoles having anti-diabetic activity | |
EP1861382B1 (en) | Fused aromatic compounds having anti-diabetic activity | |
AU2001277056A1 (en) | N-substituted indoles useful in the treatment of diabetes | |
WO2002008188A1 (en) | N-substituted indoles useful in the treatment of diabetes | |
AU2005206540B2 (en) | Antidiabetic oxazolidinediones and thiazolidinediones | |
WO2008137105A1 (en) | Method of treatment using fused aromatic compounds having anti-diabetic activity | |
WO2009005672A1 (en) | Antidiabetic azaindoles and diazaindoles | |
WO2006022954A2 (en) | Benzoureas having anti-diabetic activity | |
US20090069385A1 (en) | Antidiabetic Oxazolidinediones and Thiazolidinediones | |
US7807692B2 (en) | Antidiabetic oxazolidinediones and thiazolidinediones | |
US20080076810A1 (en) | Benzoureas Having Anti-Diabetic Activity | |
EP1537078B1 (en) | Indoles having anti-diabetic activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA HR LV MK YU |
|
17P | Request for examination filed |
Effective date: 20070412 |
|
RAX | Requested extension states of the european patent have changed |
Extension state: LV Payment date: 20070412 |
|
RBV | Designated contracting states (corrected) |
Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR |
|
RAX | Requested extension states of the european patent have changed |
Extension state: LV Payment date: 20070412 |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20090923 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: A61P 3/10 20060101ALI20090917BHEP Ipc: A61K 31/428 20060101ALI20090917BHEP Ipc: A61K 31/42 20060101ALI20090917BHEP Ipc: C07D 417/14 20060101ALI20090917BHEP Ipc: C07D 413/10 20060101ALI20090917BHEP Ipc: C07D 413/14 20060101AFI20090917BHEP |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: MERCK SHARP & DOHME CORP. |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20091223 |