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WO2001060807A1 - Acides aryloxyacetiques utilises en cas de diabete et de troubles lipidiques - Google Patents

Acides aryloxyacetiques utilises en cas de diabete et de troubles lipidiques Download PDF

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WO2001060807A1
WO2001060807A1 PCT/US2001/004636 US0104636W WO0160807A1 WO 2001060807 A1 WO2001060807 A1 WO 2001060807A1 US 0104636 W US0104636 W US 0104636W WO 0160807 A1 WO0160807 A1 WO 0160807A1
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alkyl
compound
alkenyl
group
alkynyl
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Kun Liu
Libo Xu
A. Brian Jones
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Merck and Co Inc
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Merck and Co Inc
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Priority to CA002400021A priority Critical patent/CA2400021A1/fr
Priority to AU38214/01A priority patent/AU784722B2/en
Priority to JP2001560192A priority patent/JP2003523336A/ja
Priority to EP01910624A priority patent/EP1259494A4/fr
Publication of WO2001060807A1 publication Critical patent/WO2001060807A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P9/12—Antihypertensives

Definitions

  • the instant invention is concerned with aryloxyacetic acids and pharmaceutically acceptable salts and prodrugs thereof which are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, often referred to as non-insulin dependent diabetes (NIDDM), of conditions that are often associated with this disease, and of lipid disorders.
  • NIDDM non-insulin dependent diabetes
  • Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy.
  • diabetes mellitus There are two generally recognized forms of diabetes.
  • type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM noninsulin dependent diabetes mellitus
  • patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
  • Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.
  • the biguanides increase insulin sensitivity resulting in some correction of hyperglycemia.
  • the two biguanides, phenformin and metformin can induce lactic acidosis and nausea/diarrhea, respectively.
  • the glitazones are a more recently described class of compounds with potential for a novel mode of action in ameliorating many 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 the elevated plasma levels of glucose without occurrence of hypoglycemia.
  • Disorders of lipid metabolism or dyslipidemias include various conditions characterized by abnormal concentrations of one or more lipids (i.e.
  • apolipoproteins i.e., apolipoproteins A, B, C and E
  • lipoproteins i.e., the macromolecular complexes formed by the lipid and the apolipoprotein that allow lipids to circulate in blood, such as LDL, VLDL and IDL
  • Cholesterol is mostly carried in Low Density Lipoproteins (LDL), and this component is commonly known as the "bad" cholesterol because it has been shown that elevations in LDL-cholesterol correlate closely to the risk of coronary heart disease.
  • a smaller component of cholesterol is carried in the High Density Lipoproteins and is commonly known as the "good" cholesterol.
  • HDL coronary heart disease
  • HDL raising agent is nicotinic acid, a drug with limited utility because doses that achieve HDL raising are associated with undesirable effects, such as flushing.
  • Dyslipidemias were originally classified by Fredrickson according to the combination of alterations mentioned above. The Fredrickson classification includes 6 phenotypes (i.e., I, Eta, lib, HI, IN and N) with the most common being the isolated hypercholesterolemia (or type Ha) which is usually accompained by elevated concentrations of total and LDL cholesterol.
  • the initial treatment for hypercholesterolemia is often to modify the diet to one low in fat and cholesterol, coupled with appropriate physical exercise, followed by drug therapy when LDL- lowering goals are not met by diet and exercise alone
  • a second common form of dyslipidemia is the mixed or combined hyperlipidemia or type Hb and HI of the Fredrickson classification.
  • This dyslipidemia is often prevalent in patients with type 2 diabetes, obesity and the metabolic syndrome.
  • this dyslipidemia there are modest elevations of LDL-cholesterol, accompanied by more pronounced elevations of small dense LDL-cholesterol particles, NLDL and/or DDL (i.e., triglyceride rich lipoproteins), and total triglycerides.
  • concentrations of HDL are often low.
  • Peroxisome proliferators are a structurally diverse group of compounds that when administered to rodents elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes of the beta-oxidation cycle.
  • Compounds of this group include but are not limited to the fibrate class of lipid modulating drugs, herbicides and phthalate plasticizers.
  • Peroxisome proliferation is also triggered by dietary or physiological factors such as a high-fat diet and cold acclimatization.
  • PPAR peroxisome proliferator activated receptor alpha
  • PPAR ⁇ peroxisome proliferator activated receptor gamma
  • PPAR ⁇ peroxisome proliferator activated receptor delta
  • PPAR ⁇ is also associated with the activity of fibrates and fatty acids in rodents and humans.
  • Fibric acid derivatives such as clofibrate, fenofibrate, benzafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, each of which are PPAR ⁇ ligands and/or activators, produce a substantial reduction in plasma triglycerides as well as some increase in HDL.
  • the effects on LDL cholesterol are inconsistent and might depend upon the compound and/or the dyslipidemic phenotype.
  • this class of compounds has been primarily used to treat hypertriglyceridemia (i.e, Fredrickson Type IN and N) and/or mixed hyperlipidemia.
  • the PPAR ⁇ receptor subtypes are involved in activating the program of adipocyte differentiation and are not involved in stimulating peroxisome proliferation in the liver.
  • There are two known protein isoforms of PPAR ⁇ PPAR ⁇ l and PPAR ⁇ 2 which differ only in that PPAR ⁇ 2 contains an additional 28 amino acids present at the amino terminus.
  • the D ⁇ A sequences for the human isotypes are described in Elbrecht, et al., BBRC 224;431-437 (1996). In mice, PPAR ⁇ 2 is expressed specifically in fat cells.
  • PPAR ⁇ 2 regulates the expression of genes through interaction with other proteins and binding to hormone response elements, for example in the 5' flanking regions of responsive genes.
  • An example of a PPAR ⁇ 2 responsive gene is the tissue-specific adipocyte P2 gene.
  • prostaglandin J2 derivatives have been identified as potential natural ligands of the PPAR ⁇ subtype, which also binds thiazolidinedione antidiabetic agents with high affinity.
  • PPAR ⁇ The human nuclear receptor gene PPAR ⁇ (hPPAR ⁇ ) has been cloned from a human osteosarcoma cell cD ⁇ A library and is fully described in A. Schmidt et al., Molecular Endocrinology, 6 : 1634-1641 (1992). It should be noted that PPAR ⁇ is also referred to in the literature as PPAR ⁇ and as NUCl, and each of these names refers to the same receptor; in Schmidt et al. the receptor is referred to as NUCl.
  • hNUClB a human PPAR subtype, hNUClB.
  • the amino acid sequence of hNUClB differs from human PPAR ⁇ (referred to therein as hNUCl) by one amino acid, i.e., alanine at position 292.
  • hNUClB protein represses hPPAR ⁇ and thyroid hormone receptor protein activity.
  • WO97/28149 It has been disclosed in WO97/28149 that agonists of PPAR ⁇ are useful in raising HDL plasma levels.
  • WO97/27857, 97/28115, 97/28137 and 97/27847 disclose compounds that are useful as antidiabetic, antiobesity, anti- atherosclerosis and antihyperlipidemic agents, and which may exert their effect through activation of PPARs.
  • glitazones exert their effects by binding to the peroxisome proliferator activated receptor (PPAR) family of receptors, controlling certain transcription elements having to do with the biological entities listed above.
  • PPAR peroxisome proliferator activated receptor
  • glitazones that are PPAR agonists have been approved for use in the treatment of diabetes. These include troglitazone, rosiglitazone and pioglitazone, all of which are primarily or exclusively PPAR ⁇ agonists. Many of the newer PPAR agonists that are currently under development or are in clinical trials have dual PPAR ⁇ and ⁇ activity. These are expected to improve both insulin sensitivity and the lipid profile in patients having NIDDM.
  • glitazones are beneficial in the treatment of NIDDM, there have been some serious adverse events associated with the use of the compounds. The most serious of these has been liver toxicity, which has resulted in a number of deaths. The most serious problems have occurred using troglitazone. Because of the problems that have occurred with the glitazones, researchers in a number of laboratories have been investigating classes of PPAR agonists that are not glitazones and do not contain 1,3-thiazolidinedione moieties. Compounds that are not glitazones but are agonists of PPAR sub-types are expected to be useful in the treatment of diabetes and associated conditions.
  • PPAR ⁇ agonists should improve the lipid profile and alleviate dyslipidemias by reducing elevated LDL levels and elevated triglyceride levels and/or increasing HDL levels. PPAR ⁇ agonists should improve insulin sensitivity, reducing the need for insulin injections in patients with NTDDM. The role of PPAR ⁇ is less well defined.
  • the class of compounds described herein is a new class of PPAR agonists that do not contain a 1,3-thiazolidinedione moiety and therefore are not glitazones.
  • the class of compounds includes compounds that are primarily PPAR ⁇ agonists and compounds that are mixed PPAR ⁇ / ⁇ agonists.
  • These compounds are useful in the treatment, control and/or prevention of diabetes, hyperglycemia, mixed or diabetic dyslipidemia, and other lipid disorders (including isolated hypercholesterolemia as manifested by elevations in LDL-C and/or non-HDL-C and or hyperapoBliproteinemia, hypertriglyceridemia and/or increase in triglyceride- rich-lipoproteins, or low HDL cholesterol concentrations), atherosclerosis, obesity, vascular restenosis, inflammatory conditions, neoplastic conditions, and other PPAR ⁇ and/or ⁇ mediated diseases, disorders and conditions.
  • lipid disorders including isolated hypercholesterolemia as manifested by elevations in LDL-C and/or non-HDL-C and or hyperapoBliproteinemia, hypertriglyceridemia and/or increase in triglyceride- rich-lipoproteins, or low HDL cholesterol concentrations
  • atherosclerosis obesity
  • vascular restenosis inflammatory conditions
  • neoplastic conditions and other
  • the present invention provides compounds having the structure of Formula I, including pharmaceutically acceptable salts and prodrugs of these compounds:
  • Rl and R2 are each independently selected from the group consisting of H, F, Ci-5 alkyl, C2-5 alkenyl, and C2-5 alkynyl, wherein said alkyl, alkenyl, and alkynyl may be linear or branched and are optionally substituted with 1-3 halogen atoms; or optionally Rl and R2 together form a C3-6 cycloalkyl;
  • R3 and R4 are each independently selected from the group consisting of C1-C5 alkyl, C2-5 alkenyl, C2-5 alkynyl, and chlorine, provided that R3 and R4 are not both chlorine, wherein said alkyl, alkenyl, and alkynyl groups may be linear or branched and are optionally substituted with 1-5 fluorine atoms;
  • X is N or CR
  • Y is O, S, or NR
  • Z is O or S
  • Each R group is selected from the group consisting of H, Ci-5 alkyl, C2-5 alkenyl, and C2-5 alkynyl, wherein said alkyl, alkenyl, and alkynyl may be linear or branched and are optionally substituted with 1-5 fluorine atoms and/or one -OC ⁇ _ 3 alkyl, said -OC1-.3 alkyl being optionally substituted with 1-7 fluorine atoms; and
  • R5 is selected from the group consisting of H, Cl-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 Aryl, -OCi-6 alkyl, -OC2-6 alkenyl, -OC2-6 alkynyl, - OC6-10 Aryl, C3-6 Cycloalkyl, 5-6-membered Heterocyclyl, 5-6-membered Heteroaryl, -OC3-6 Cycloalkyl, -O 5-6-membered Heterocyclyl, -O 5-6 membered Heteroaryl, and a Ci-4 alkyl group which comprises at a position interrupting the chain or at the end of the chain a group selected from C6-10 Aryl, C3..6 Cycloalkyl, 5-6-membered Heterocyclyl, and 5-6-membered Heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, -Oalkyl,
  • NIDDM non-insulin dependent diabetes mellitus
  • the invention has numerous embodiments. Several subsets of compounds having different heterocyclic rings are included, as follows:
  • R5 is selected from the group consisting of H, Ci-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, OC ⁇ _5 alkyl, OC2-5 alkenyl, OC2-5 alkynyl, and phenyl; in these compounds, the alkyl, alkenyl, alkynyl, -Oalkyl, -Oalkenyl, and -Oalkynyl are optionally substituted with 1-5 fluorine atoms, and phenyl is optionally substituted with 1-5 halogens.
  • R5 is selected from the group consisting of H, Ci-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, OCi-5 alkyl, OC2-5 alkenyl, and OC2-5 alkynyl, where alkyl, alkenyl, alkynyl, -Oalkyl, -Oalkenyl, and -Oalkynyl are optionally substituted with 1-5 fluorine atoms.
  • Rl and R2 are each H or Ci-3 alkyl, and the number of carbon atoms in Rl and R2 together is 0-5.
  • R3 and R4 are each independently C ⁇ _5 alkyl.
  • one of R3 and R4 is C2-5 alkyl, and the other of R3 and R is C 1-5 alkyl.
  • both R and R4 are C2-5 alkyl.
  • one of R3 and R4 is Cl or C ⁇ _ alkyl, and the other of R and R4 is C2-5 alkyl.
  • the alkyl groups are linear or branched. In the most preferred compounds R and R4 are linear when they are alkyl.
  • R5 is selected from C ⁇ _5 alkyl and -OC ⁇ _5 alkyl, where the alkyl and -Oalkyl are optionally substituted with 1-5 fluorine atoms.
  • Z is O.
  • X is N and Y is O, so that the compounds are benzisoxazoles.
  • R5 is Ci-3 alkyl, -OCi - 3 alkyl, CF , C2F5, -OCF3 or -OC2F5; and R 3 and R 4 are each n-propyl-
  • the invention further includes pharmaceutical compositions comprising any of the compounds described above and a pharmaceutically acceptable carrier.
  • the compounds as defined above are useful in the following methods of treating, controlling, and preventing diseases, as well as other diseases not listed below:
  • a method for treating, controlling or preventing diabetes mellitus, and particularly non-insulin dependent diabetes mellitus, in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I;
  • a method for treating, controlling, or preventing hypercholesterolemia in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I;
  • (6) a method for treating, controlling, or preventing hypertriglyceridemia in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I;
  • a method for treating, controlling, or preventing dyslipidemia, including low HDL cholesterol, in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I;
  • a method for treating, controlling, or preventing atherosclerosis in a mammalian patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of Formula I. It is understood that the sequellae of atherosclerosis (angina, claudication, heart attack, stroke, etc.) are thereby treated.
  • Ac is acetyl, which is CH3C(O)-.
  • Alkyl as well as other groups having the prefix “alk”, such as alkoxy or alkanoyl, means 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- 1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each having from 3 to 10 carbon atoms. The term also includes a monocyclic ring fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Aryl (and “arylene”) means mono- or bicyclic aromatic rings containing only carbon ring atoms.
  • the term also includes an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclic group in which the point(s) of attachment is on the aromatic portion.
  • the preferred aryl is phenyl.
  • Heterocycle and “heterocyclic” means a fully or partially saturated monocyclic, bicyclic or tricyclic ring containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms. Examples of aryl include phenyl, naphthyl, indanyl, indenyl, and tetrahydronaphthyl.
  • aryl fused to heterocyclic groups examples include 2,3-dihydrobenzofuranyl, benzopyranyl, l,4-benzodioxanyl,and the like.
  • heterocycles include tetrahydrofuran, piperazine, and morpholine.
  • Heteroaryl (and heteroarylene) means a mono-, bi- or tricyclic aromatic ring containing at least one ring heteroatom selected from N, O and S (including SO and SO2), 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, dibenzofuran and the like.
  • "Halogen” includes fluorine, chlorine, bromine and iodine.
  • 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.
  • Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and 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.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be 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 the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent.
  • any enantiomer of a compound of the general Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials 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
  • 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 of the compounds of this invention that are therapeutically active also are within the scope of the claimed parent compound.
  • 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 within the scope of the claimed active compound.
  • a non-limiting example of a prodrug of the carboxylic acids of this invention would be an ester of the carboxylic acid group, for example a Cl to C6 ester, which may be linear or branched, or an ester which has functionality that makes it more easily hydrolyzed after administration to a patient.
  • Prodrugs of this class of compounds may be described as compounds having the Formula la:
  • R6 is a group that is easily removed under physiological conditions during or after administration to a mammalian patient to yield a compound having Formula I, or the carboxylate anion thereof (in solution), or a pharmaceutically acceptable salt thereof , where Rl, R2, R3 ; R4 ; R5 ; ⁇ ; ⁇ ; z, and R are as defined above for compounds having Formula I.
  • Examples of prodrugs of Formula la include compounds in which R6 is selected from the group consisting of -OR7, -OCH2ORV, -OCH(CH3)OR7, - OCH2 ⁇ C(O)RV, -OCH(CH3)OC(O)RV 5 -OCH2 ⁇ C(O)ORV, -OCH(CH3)OC(O)ORV, -NR8R8 ; and -ONR8R8, where each R7 is independently selected from Ci-6 alkyl optionally substituted with one or two groups selected from -CO2H, -CONH2 , - NH2, -OH, -OAc, NHAc, and phenyl; and wherein each R ⁇ is independently selected from H and R7.
  • Compounds of the present invention are potent agonists of varioius peroxisome proliferator activator receptor subtypes, particularly PPAR ⁇ and/or PPAR ⁇ .
  • Compounds of the present invention may be selective agonists of one receptor subtype, e.g. PPAR ⁇ or PPAR ⁇ agonists, or they may be agonists of more than one receptor subtypes, e.g. dual PPAR ⁇ agonists.
  • Compounds of the present invention are useful in treating, controlling or preventing diseases, disorders or conditions, wherein the treatment is mediated by the activation of an individual PPAR subtype ( ⁇ or ⁇ ), or a combination of PPAR subtypes (e.g. ⁇ / ⁇ ).
  • one aspect of the present invention provides a method for the treatment, control or prevention 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.
  • the diseases, disorders or conditions for which compounds of the present invention are useful in treating, controlling or preventing include, but are 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) inflamatory bowel disease, including Crohn's disease and ulcerative colitis, (17) other inflammatory conditions, (18) pancreatitis, (19) abdominal obesity, (20) neuro
  • Another aspect of the invention provides a method for the treatment, control, or prevention of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and/or dyslipidemia, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of an agonist of PPAR ⁇ and/or PPAR ⁇ or a PPAR ⁇ / ⁇ dual agonist.
  • the PPAR agonist may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522.
  • a cholesterol biosynthesis inhibitor particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, or ZD-4522.
  • the PPAR agonist 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), and with niacin, 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
  • niacin niacin
  • bile acid sequestrants bile acid sequestrants
  • microsomal triglyceride transport inhibitors microsomal triglyceride transport inhibitors
  • bile acid reuptake inhibitors bile acid reup
  • 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 PPAR agonist, which may be a PPAR ⁇ agonist, a PPAR ⁇ agonist, or a PPAR ⁇ / ⁇ dual agonist.
  • a PPAR agonist which may be a PPAR ⁇ agonist, a PPAR ⁇ agonist, or a PPAR ⁇ / ⁇ dual agonist.
  • 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,
  • 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 0.1 milligram to about 100 milligram 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 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • 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 or prodrug thereof 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.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • 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.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • 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 preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously 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.
  • a liquid carrier such as a fatty oil.
  • Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, 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 hydroxy-propylcellulose.
  • 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, prevention, suppression 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. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, 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.
  • compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
  • 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: (a) insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g.
  • troglitazone pioglitazone, englitazone, MCC-555, rosiglitazone, and the like), and compounds disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847;
  • biguanides such as metformin and phenformin;
  • PTP-1B protein tyrosine phosphatase-lB
  • DP-TV dipeptidyl peptidase IV
  • ⁇ -glucosidase inhibitors such as acarbose
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522 and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) PPAR ⁇ / ⁇ dual agonists, such as KRP-297, (vi) inhibitors of cholesterol absorption, such as for example
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors, and ⁇ 3 adrenergic receptor agonists;
  • an ileal bile acid transporter inhibitor (h) an ileal bile acid transporter inhibitor; and (i) agents intended for use in inflammatory conditions such as 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-1B inhibitors PTP-1B inhibitors, DP-TV inhibitors, and anti-obesity compounds.
  • Human PPAR ⁇ 2 Human PPAR ⁇ and human PPAR ⁇ were expressed as gst- fusion proteins in E. coli.
  • the full length human cDNA for PPAR ⁇ 2 was subcloned into the pG ⁇ X-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.
  • TEGM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM
  • PPAR ⁇ ligands produce distinct biological effects. J. Biol. Chem. (1999), 274: 6718-6725. Assays were incubated for -16 hr at 4°C in a final volume of 150 ⁇ L. Unbound ligand was removed by incubation with 100 ⁇ L dextran/gelatin-coated charcoal, on ice, for -10 min. After centrifugation at 3000 rpm for 10 min at 4°C, 50 ⁇ L of the supernatant fraction was counted in a Topcount.
  • TEGM Tris, pH 7.2, 1 mM EDTA, 10% glycerol, 7 ⁇ L/100 mL ⁇ -mercaptoethanol, 10 mM Na molybdate, 1 mM dithiothreitol, 5 ⁇ g/mL aprotinin, 2 ⁇ g/mL leupeptin, 2 ⁇ g/mL benzamide and 0.5 mM PMSF
  • 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 5.0 nM [ 3 H2]-Comp'd B, (34 Ci/
  • 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-1 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-PPAPJGAL4 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.
  • ⁇ -galactosidase activity was determined using ⁇ -D- galactopyranoside (Calbiochem, San Diego, CA).
  • mice Male db/db mice (10-11 week old C57B1/KFJ, Jackson Labs, Bar
  • mice were housed 5/cage and allowed ad lib. access to ground Purina rodent chow and water. The animals, and their food, were weighed every 2 days and were dosed daily by gavage with vehicle (0.5% carboxymethylcellulose) ⁇ test compound at the indicated dose. Drug suspensions were prepared daily. Plasma glucose, and triglyceride concentrations were determined from blood obtained by tail bleeds at 3-5 day intervals during the study period. Glucose, and triglyceride, determinations were 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 were age-matched heterozygous mice maintained in the same manner.
  • the crude starting material (2,278 g) was dissolved in 1,2-dichlorobenzene (11.4 L) in a 22 L 4-neck flask equipped with a mechanical stirrer, a thermocouple, a distillation condenser and a nitrogen inlet. A portion of the solvent (1.7 L) was distilled off at 187 °C before the distillation condenser was switched to a reflux condenser. The reaction was refluxed at 187 ° C overnight. Ice-water (4 L) was added, followed by NaOH (320 g). The mixture was poured into hexanes (12 L) and layers were separated. The organic layer was extracted with aqueous NaOH (2 N, 2 x 4 L).

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Abstract

La présente invention concerne une classe d'acides aryloxyacétiques, comprenant des composés qui sont de puissants agonistes du récepteur alpha et/ou gamma activé par les proliférateurs de peroxysomes (PPAR) et sont, par conséquent, utilisés dans le traitement, le contrôle ou la prévention du diabète non insulino-dépendant (DNID), de l'hyperglycémie, de la dyslipidémie, de l'hyperlipidémie, de l'hypercholestérolémie, de l'hypertriglycéridémie, de l'athérosclérose, de l'obésité, de la resténose vasculaire, de l'inflammation et d'autres maladies, troubles et pathologies induits par récepteur alpha et/ou gamma activé par les proliférateurs de peroxysomes.
PCT/US2001/004636 2000-02-18 2001-02-14 Acides aryloxyacetiques utilises en cas de diabete et de troubles lipidiques Ceased WO2001060807A1 (fr)

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AU38214/01A AU784722B2 (en) 2000-02-18 2001-02-14 Aryloxyacetic acids for diabetes and lipid disorders
JP2001560192A JP2003523336A (ja) 2000-02-18 2001-02-14 糖尿病及び脂質障害のためのアリールオキシ酢酸
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