WO2006014262A2 - Indoles having anti-diabetic activity - Google Patents
Indoles having anti-diabetic activity Download PDFInfo
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- WO2006014262A2 WO2006014262A2 PCT/US2005/022906 US2005022906W WO2006014262A2 WO 2006014262 A2 WO2006014262 A2 WO 2006014262A2 US 2005022906 W US2005022906 W US 2005022906W WO 2006014262 A2 WO2006014262 A2 WO 2006014262A2
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- 0 Cc1cc2ccc(*)cc2[n]1 Chemical compound Cc1cc2ccc(*)cc2[n]1 0.000 description 4
- QPPHQQNBHOJCQX-SRZZPIQSSA-N C/C(/COc(cc1)ccc1Cl)=N\Nc1cc(OC(F)(F)F)ccc1 Chemical compound C/C(/COc(cc1)ccc1Cl)=N\Nc1cc(OC(F)(F)F)ccc1 QPPHQQNBHOJCQX-SRZZPIQSSA-N 0.000 description 1
- WFWKNGZODAOLEO-UHFFFAOYSA-N CC(Cc(cc1)ccc1OC)=O Chemical compound CC(Cc(cc1)ccc1OC)=O WFWKNGZODAOLEO-UHFFFAOYSA-N 0.000 description 1
- LTCHEMBLTJETNF-ALGPSANZSA-M C[C@@](Cc1cc(CBr)ccc1)(C(N1[Tl])=O)OC1O Chemical compound C[C@@](Cc1cc(CBr)ccc1)(C(N1[Tl])=O)OC1O LTCHEMBLTJETNF-ALGPSANZSA-M 0.000 description 1
- QJQYAWXIDUHOOF-UHFFFAOYSA-N Cc([nH]c1c2)c(C(c(cc3)ccc3Cl)=O)c1ccc2OC(F)(F)F Chemical compound Cc([nH]c1c2)c(C(c(cc3)ccc3Cl)=O)c1ccc2OC(F)(F)F QJQYAWXIDUHOOF-UHFFFAOYSA-N 0.000 description 1
- LCRUFLJAUDGNCM-UHFFFAOYSA-N Cc([nH]c1cc(OC(F)(F)F)ccc11)c1-c(cc1)ccc1OC Chemical compound Cc([nH]c1cc(OC(F)(F)F)ccc11)c1-c(cc1)ccc1OC LCRUFLJAUDGNCM-UHFFFAOYSA-N 0.000 description 1
- NPBIVQLBZUOQIX-UHFFFAOYSA-N Cc([nH]c1cc(OC(F)(F)F)ccc11)c1-c1n[o]c2c1ccc(OC)c2 Chemical compound Cc([nH]c1cc(OC(F)(F)F)ccc11)c1-c1n[o]c2c1ccc(OC)c2 NPBIVQLBZUOQIX-UHFFFAOYSA-N 0.000 description 1
- PGUYGXWLFYYEFI-UHFFFAOYSA-N NNc1cc(OC(F)(F)F)ccc1 Chemical compound NNc1cc(OC(F)(F)F)ccc1 PGUYGXWLFYYEFI-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- 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
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- 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
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- 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
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- 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
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
-
- 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
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- 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
-
- 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
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Definitions
- the instant invention is concerned with indoles having a thiazolidine-2,4-dione or oxazolidine-2,4-dione 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
- 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.
- 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.
- 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. 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.
- 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 HI, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670.
- 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 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 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.
- 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 selected from
- Aryl is phenyl or naphthyl
- Heteroaryl is a monocyclic or fused bicyclic aromatic ring containing 1-4 heteroatoms independently selected from N, O and S, including -S(O)- and -S(O)2-, wherein each ring contains 5 to 6 atoms;
- X and Y are independently selected from the group consisting of a bond and -CR R -;
- Q is selected from the group consisting of S and O;
- A is selected from C1-C4 alkyl, C2-C4 alkenyl, -OQ-C4 alkyl, and halogen, wherein alkyl, alkenyl, and -Oalkyl are each optionally substituted with 1-5 halogens;
- R2 is C1-C4 alkyl, which is optionally substituted with 1-5 halogens;
- R3 is selected from (a) Benzisoxazolyl
- R ⁇ is optionally substituted with 1-3 substituent groups independently selected from halogen, Q- C3 alkyl, and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-5 halogens;
- R4, R5, and R ⁇ are each independently selected from hydrogen, halogen, C1-C3 alkyl, and -OC1-C3 alkyl, wherein C1-C3 alkyl and -OC1-C3 alkyl are optionally substituted with 1-5 halogens;
- R7 is selected from H, C1-C3 alkyl, and halogen, wherein C1-C3 alkyl is optionally substituted with 1-3 F;
- R8 is selected from the group consisting of H and CH3;
- 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.
- R.8 is H.
- R 1 is -X-phenyl-YZ.
- X and Y are each independently a bond or -CH2-.
- A is selected from the group consisting of halogen, -CF3 , -OCF3 , -CH3 , and -OCH3 .
- R2 is Ci-3 alkyl or -CF3.
- R ⁇ is -CH3.
- R4 is selected from the group consisting of -OCH 3 , - OCF 3 , -CH 3 and -CF 3 ; and p is 1.
- R3 is selected from the group consisting of:
- R 1 is -X-phenyl-YZ or -X-tetrazolyl-YZ, where phenyl is optionally substituted with 1-2 groups independently selected from A;
- a preferred subgroup comprises compounds in which R 1 is -X-phenyl-YZ, where phenyl is optionally substituted with 1-2 groups independently selected from A;
- X and Y are independently selected from a bond and -CH2-;
- A is selected from the group consisting of F, Cl, I, -CF3, -OCF3, -CH3, and -OCH3;
- R2 is -CH3 ;
- R4 is selected from the group consisting of Cl, -CF3, -OCF3, -CH3, and -OCH3;
- R7 is selected from the group consisting of H, CH3, and CF3;
- R8 is H
- p is 0 or 1, and is more preferably 1.
- Q is O
- X and Y are -CH2-.
- Q is O
- X is -CH2-
- Y is a bond
- Heteroaryl is pyridyl, quinolyl, furyl, tetrazolyl, isoxazolyl, oxazolyl, azoxazolyl, pyrazolyl, or thiazolyl.
- Compounds in which Heteroaryl is tetrazolyl have desirable properties.
- 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, and can readily be made by a practitioner of synthetic chemistry.
- Mass spectral data for the compounds in Table 2 are also provided in Table 2A, which follows 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: (1) non-insulin dependent diabetes mellitus (type 2 diabetes);
- hypercholesterolemia (6) hypertriglyceridemia; and/or
- 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
- Ac is acetyl, which is CH3CXO)-.
- 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 (and “arylene") 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 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.
- 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.
- heterocycles include tetrahydrofuran, piperazine, and morpholine.
- Preferred aryl groups are phenyl or naphthyl. Phenyl is generally the most preferred.
- 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.
- 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.
- Preferred heteroaryl groups include pyridyl, quinolyl, furyl, tetrazolyl, isoxazolyl, oxazolyl, azoxazolyl, pyrazolyl, and thiazolyl.
- 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 as arg
- 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.
- Metabolites - Prodrugs 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 PP ARa subtype as well as the PPAR ⁇ subtype, resulting in mixed PPAR ⁇ / ⁇ agonism or in agonism of mainly the PP ARa 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
- 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, 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.
- Administration and Dose Ranges 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 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).
- 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 such as T- 131;
- biguanides such as metformin and phenformin;
- dipeptidyl peptidase IV (DP-IV) inhibitors such as LAF-237, MK-0431, and NN- 7201;
- DP-IV dipeptidyl peptidase IV
- ⁇ -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) cholesterol absorption inhibitors, such as for example ezetimibe, (vii) acyl CoAxhol
- 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 WO97/28149;
- 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 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.
- 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 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
- 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 0 C in an atmosphere of 10% CO2. The cells were then incubated for
- 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.
- 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-C 18, 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.
- Schemes 1-9 General and specific procedures for making the compounds of this invention and synthetic intermediates are summarized in Schemes 1-9.
- 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.
- Step 1 l-(3-Hvdroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-6-trifluoromethoxyindole (3): Step 1: l-(3-methoxy)phenyl-2-methyl-6-trifluoromethoxyindole (I): 2-Methyl-6- trifluoromethoxyindole (645 mg, 3.0 mmole), 3-bromoanisole (0.456 ml, 3.6 mmole), sodium t-butoxide (404 mg, 4.2 mmole), trisdibenzylidine dipalladium (206 mg, 0.225 mmole) and 2-di-t- butylphosphinobiphenyl (201 mg, 0.675 mmole) were stirred in toluene at 80 0 C and monitored by TLC (3/1 hexanes/methylene chloride) or reversed phase HPLC until complete. The reaction mixture was ,then cooled, filtered
- Step 2 1 -(3-hydroxy)phenyl-2-methyl-6-trifluoromethoxyindole (2): 460 mg (1.43 mmole) of (1) was dissolved in 7 mL of dichloromethane at O 0 C. Boron tribromide (1.0 N, 2.86 mL) in dichloromethane was added, the cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was then quenched with ice for 30 minutes and partitioned. The organic was washed with water and dried over sodium sulfate. After filtering the drying agent, the filtrate was evaporated and the residue chromatographed over silica gel to give the title compound.
- Step 3 l-(3-Hvdroxy)phenyl-2-methyl-3-(4-methoxy)benzoyl-6-trifluoromethoxyindole (3): 242 mg (0.788 mmole) of (2) was dissolved in methylene chloride (4 ml) and cooled to -2O 0 C. A solution of diethylaluminum chloride in toluene (1.8M, 1.23 ml) was added slowly (over 1-2 minutes) and stirred for 5-15 minutes. Then a solution of 4-methoxybenzoyl chloride (377mg, 2.21 mmole) in methylene chloride (1 mL) was added, followed by overnight stirring while the reaction slowly reached room temperature.
- pH 7.0 buffer was added dropwise until gas evolution ceased, then the layers were partitioned. The aqueous layer was extracted twice more with methylene chloride, and then the combined organic layers were washed twice with saturated NaCl solution, dried over sodium sulfate, filtered and evaporated. The crude isolate was then dissolved in methanol (5 mL) and sodium hydroxide solution (1.0 M, 1.6 mL) was added. The reaction was monitored by TLC for disappearance of diacyl indole, then was neutralized with HCl (1.0 M, 1.6 mL). The reaction mixture was then diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, evaporated and the residue was chromatographed by silica gel chromatography to give the title compound.
- Ketone 2 A suspension of chloroacetone (6.00 gr, 65 mmol), which was filtered through basic alumina prior to use, phenol 1 (10.00 gr, 65 mmole) and potassium carbonate (8.96gr, 65 mmol) was stirred in DMF at room temperature under nitrogen atmosphere for 1 h. After this time the reaction was diluted with ethyl acetate/H2 ⁇ and the layers were separated. The aqueous layer was acidified with IN HCl and extracted with ethyl acetate (3X).
- Indole 3 Ketone 2 (1.84 gr, 8.75 mmol) and 4-trifluoromethoxy phenylhydrazine hydrochloride (2.00 gr, 4.76 mmol) were stirred at 100 0 C in acetic acid (40 ml, 0.22M) for 1 hour under nitrogen atmosphere to give a 1:2 mixture of 4- and 6-trifluoromethoxy indoles (desired 6-substituted indole is slightly less polar by TLC). The reaction was cooled to room temperature, the acetic acid was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with water (IX) and brine (IX).
- 3-H indole 4 A solution of indole 3 (0.29 gr, 0.78 mmol) and thiosalicylic acid (0.12 gr, 0.78 mmol) in trifluoroacetic acid (3mL, 0.26M) was heated to 5O 0 C under nitrogen atmosphere for 2 hr. The reaction then was cooled to room temperature, diluted with ethyl acetate and washed with IN NaOH (2X), and brine (IX).
- 3-Acylindole 5 Zinc chloride (0.23 gr, 1.66 mmol) and ethyl magnesium bromide (0.29 ml of a 3M solution in ether, 0.87 mmol) were added to a solution of indole 4 (0.16 gr, 0.74 mmol) in CH 2 Cl 2 . The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hr. 4-Chlorobenzoyl chloride (0.21 gr, 1.18 mmol) was then added and stirring was continued for 1 hr. Finally, aluminum chloride (0.053 gr, 0.39 mmol) was added and the reaction mixture was stirred for 3 hr.
- R3 is phenoxy or thiophenoxy
- R3 is phenoxy or thiophenoxy
- indole intermediate having a phenoxy or thiophenoxy substituent in the 3-position.
- the synthesis of such an intermediate is shown in the scheme below, which is followed by a detailed description of the synthetic steps.
- Other compounds in Table 1 having phenoxy or thiophenoxy substituents in the R3 position can be synthesized by one of ordinary skill in the art by using similar synthetic strategies and readily available materials.
- ketone (12.89 g) and 3-trifluoromethoxyphenyl hydrazine (12.22 g) were dissolved in benzene (50 mL).
- the reaction mixture was heated at 60 0 C for 45 min, cooled to room temperature, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give the phenylhydrazone, which was used immediately without further purification.
- aldehyde 8 (19.3 g, 86 mmol). The reaction was stirred for 1.5 h at 50 0 C, then cooled to O 0 C. Et 2 O (100 mL) was added, followed by a suspension of NaCN (4.66 g) in water (100 mL). After 2 h at 0°C, the layers were separated. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give the cyanohydrin product as an oil.
- Cyclic diketal 26 was prepared based on literature procedure. To a solution of 26 (3 g, 16.85 mmol) in THF (30 mL) at - 78 °C was added LiHMDS (1.0 M in THF, 17.7 mL). After 10 min, the enolate solution thus formed was transferred via a canula to a solution of MeI (3.15 mL, 50.6 mmol) in THF (50 mL) at - 78 °C. The reaction was allowed to slowly warm to O 0 C over 3 h, quenched with saturated aqueous NH 4 Cl, and then partitioned between water and diethyl ether. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. Purification by flash chromatography gave the methylated product.
- Cyclic diketal 34 was prepared according to literature procedures. To a solution of 34 (1.77 g, 9.3 mmol) in THF (20 mL) at -78 0 C, was added a 1 M solution of lithium bis(trimethylsilyl)amide (9.3 mL). Ten minutes later, methyl iodide (0.58 mL, 9.3 mmol) was added in a single portion. The mixture was allowed to slowly warm to O 0 C over 2 h.
- the resulting nitrile (900mg, 2.32mmol) was dissolved in dry THF (23.2mL). Azidotrimethyltin (1.43g, 6.96mmol) was added to this solution. The reaction mixture was heated to reflux under N 2 overnight. The solvent was then evaporated on vacuo. The tetrazole thus prepared was purified by column chromatography on silica gel using gradient elution (5% to 100% ethyl acetate in hexane).
Abstract
Description
Claims
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JP2007519355A JP2008505091A (en) | 2004-07-02 | 2005-06-28 | Indole with anti-diabetic activity |
CA002571789A CA2571789A1 (en) | 2004-07-02 | 2005-06-28 | Indoles having anti-diabetic activity |
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Cited By (5)
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GB2431927A (en) * | 2005-11-04 | 2007-05-09 | Amira Pharmaceuticals Inc | 1,2-Disubstituted indoles & derivatives thereof as therapeutic 5-lipoxygenase-activating protein (flap) inhibitors |
WO2008116141A1 (en) | 2007-03-21 | 2008-09-25 | Emisphere Technologies, Inc. | Allylqxy and alkyloxy benzoic acid delivery agents |
US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
US7994331B2 (en) | 2005-07-13 | 2011-08-09 | Msd K.K. | Heterocycle-substituted benzimidazole derivative |
US8546431B2 (en) | 2008-10-01 | 2013-10-01 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
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US8399666B2 (en) | 2005-11-04 | 2013-03-19 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
TW200920369A (en) | 2007-10-26 | 2009-05-16 | Amira Pharmaceuticals Inc | 5-lipoxygenase activating protein (flap) inhibitor |
WO2010068311A1 (en) | 2008-05-23 | 2010-06-17 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein inhibitor |
JP2013100235A (en) * | 2010-03-08 | 2013-05-23 | Dainippon Sumitomo Pharma Co Ltd | Novel indole derivative |
US11235893B2 (en) | 2013-12-05 | 2022-02-01 | The Boeing Company | End effector for cleaning objects having multiple surfaces |
US9802894B2 (en) | 2015-09-29 | 2017-10-31 | King Saud University | α-glucosidase inhibitors |
DE102017129780A1 (en) | 2017-12-13 | 2019-06-13 | Delo Industrie Klebstoffe Gmbh & Co. Kgaa | Light-fixable and thermosetting compounds based on epoxy resins and thiols |
CN113527174B (en) * | 2021-09-16 | 2021-12-03 | 青州市立医院 | Compound with alpha-glucosidase inhibitory activity and preparation method and application thereof |
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WO2004020409A1 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
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WO2002008188A1 (en) | 2000-07-25 | 2002-01-31 | Merck & Co., Inc. | N-substituted indoles useful in the treatment of diabetes |
JP4340232B2 (en) | 2002-08-29 | 2009-10-07 | メルク エンド カムパニー インコーポレーテッド | Indoles having anti-diabetic activity |
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WO2004020409A1 (en) * | 2002-08-29 | 2004-03-11 | Merck & Co., Inc. | Indoles having anti-diabetic activity |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US7994331B2 (en) | 2005-07-13 | 2011-08-09 | Msd K.K. | Heterocycle-substituted benzimidazole derivative |
GB2431927A (en) * | 2005-11-04 | 2007-05-09 | Amira Pharmaceuticals Inc | 1,2-Disubstituted indoles & derivatives thereof as therapeutic 5-lipoxygenase-activating protein (flap) inhibitors |
GB2431927B (en) * | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
US7977359B2 (en) | 2005-11-04 | 2011-07-12 | Amira Pharmaceuticals, Inc. | 5-lipdxygenase-activating protein (FLAP) inhibitors |
US8710081B2 (en) | 2005-11-04 | 2014-04-29 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
WO2008116141A1 (en) | 2007-03-21 | 2008-09-25 | Emisphere Technologies, Inc. | Allylqxy and alkyloxy benzoic acid delivery agents |
EP2136624A1 (en) * | 2007-03-21 | 2009-12-30 | Emisphere Technologies, Inc. | Allylqxy and alkyloxy benzoic acid delivery agents |
EP2136624A4 (en) * | 2007-03-21 | 2011-11-30 | Emisphere Tech Inc | Allylqxy and alkyloxy benzoic acid delivery agents |
US8546431B2 (en) | 2008-10-01 | 2013-10-01 | Panmira Pharmaceuticals, Llc | 5-lipoxygenase-activating protein (FLAP) inhibitors |
Also Published As
Publication number | Publication date |
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CN1980659A (en) | 2007-06-13 |
CA2571789A1 (en) | 2006-02-09 |
EP1765329A2 (en) | 2007-03-28 |
JP2008505091A (en) | 2008-02-21 |
US20080119531A1 (en) | 2008-05-22 |
AU2005270201A1 (en) | 2006-02-09 |
US7625933B2 (en) | 2009-12-01 |
WO2006014262A3 (en) | 2006-08-03 |
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