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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
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  • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
  • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
  • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D241/20—Nitrogen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• the present invention relates to certain novel compounds.
• the present invention relates to compounds that activate human peroxisome proliferator activated receptors ("hPPARs").
• the present invention also relates to method for preparing the compounds, their use in medicine, pharmaceutical compositions containing them and methods for the prevention or treatment of PPAR mediated diseases or conditions.
• HMG CoA reductase inhibitors are useful for treating conditions characterized by high LDL-c levels. It has been shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been totally successfully addressed by drug therapy
• Syndrome X is loosely defined as a collection of abnormalities including hyperinsulemia, obesity, elevated levels of the following:- triglycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
• abnormalities including hyperinsulemia, obesity, elevated levels of the following:- triglycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
• PAI-1 plasminogen activator inhibitor 1
• NIDDM is described as insulin resistance, which in turn causes anomalous glucose output and a decrease in glucose uptake, by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsulinemia.
• ITT impaired glucose tolerance
• Peroxisome Proliferator Activated Receptors are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T.M. and Wahli, W., Curr. Opin. Chem. Biol., 1 , pp235-241 (1997) and Willson T.M. et. al., J. Med. Chem., 43, p527-549 (2000). The binding of agonist ligands to the receptor results in changes in the expression level of mRNAs encoded by PPAR target genes.
• PPAR alpha Three mammalian Peroxisome Proliferator Activated Receptors have been isolated and termed PPAR alpha, PPAR gamma, and PPAR delta (also known as NUC1 or PPAR beta).
• PPAR response elements PPRE response elements
• Activators of the nuclear receptor PPAR ⁇ for example rosiglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E.
• VLDL very low density lipoproteins
• LPL lipoprotein lipase
• Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-
• PPAR ⁇ results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion.
• PPAR ⁇ activation decreases production of apoC-lll. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of
• VLDL VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel.), S29-S37, 124
• the invention provides a compound of formula (I) and pharmaceutically acceptable salts and solvates and hydrolysable esters thereof.
• R 1 and R z are independently hydrogen or C 1 . 3 alkyl
• X represents a bond, CH 2 or O;
• R 3 and R 4 are independently hydrogen, C 1-6 alkyl, OCH 3 , CF 3 , allyl or halogen;
• X I is CH 2 , S0 2 , or CO;
• R 5 is -C 1-6 alkyl (optionally substituted by C ⁇ alkoxy or C 1-6 alkylthio), -C 2-6 alkenyl, -C 0 - 6 alkyl phenyl (wherein the phenyl is optionally substituted by one or more CF 3 , halogen, C 1-3 alkyl, C 1-3 alkoxy), -COC 1-6 alkyl, -S0 2 C 1-6 alkyl ;
• R 6 is phenyl or a 6 membered heteroaryl group containing 1 , 2 or 3 N atoms wherein the phenyl or heteroaryl group is optionally substituted with 1 , 2 or 3 moieties selected from the group consisting of C ⁇ alkyl, halogen, -OC 1-6 alkyl, -S0 2 C 1-3 alkyl, phenyl (optionally substituted by one or more groups selected from halogen, CF 3 , C 1-3 alkyl, OC 1-3 al
• the present invention discloses a method for prevention or treatment of a disease or condition mediated by one or more human PPAR alpha, gamma or delta (“hPPARs") comprising administration of a therapeutically effective amount of a compound of this invention.
• hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hypertipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa, cancer, Alzheimers disease or other cognitive disorders.
• disorders such as obesity, anorexia bulimia, and anorexia nervosa
• cancer Alzheimers disease or other cognitive disorders.
• the compounds of this invention are useful in the treatment and prevention of diabetes, obesity and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.
• the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
• the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
• the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR mediated disease or condition.
• a compound of the invention means a compound of formula (I) or a pharmaceutically acceptable salt, or solvate, or hydrolysable ester thereof.
• hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyse that are the active compounds.
• Esters that hydrolyse readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind well but is active in the transient transfection assay presumably due to hydrolysis.
• Preferred hydrolysable esters are C 1-6 alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred.
• each R 1 and R z is independently H or methyl. More preferably R 1 and R 2 are both H or both methyl. Even more preferably, R 1 and R 2 are both H.
• X is O.
• R 3 and R 4 are independently H or C 1-3 alkyl. More preferably at least one of R 3 and R 4 is hydrogen and when one of R 3 and R 4 is hydrogen and the other is not, then the one that is not hydrogen is preferably ortho to the depicted moiety X. More preferably the one that is not hydrogen is methyl.
• X 1 is CH 2 .
• R 5 is butyl or methoxyethyl.
• R 6 is phenyl or a 6 membered heterocycle selected from pyrimidine, pyridine, pyridazine, pyrazine, each of which is substituted by phenyl (optionally substituted by one or more CF 3 , C 1-3 alkyl, halogen, CN) and optionally a further C 1-3 alkyl substituent.
• this phenyl substituent is meta to the depicted N. More preferably the substituent on the phenyl or 6 membered heterocycle is para C 6 H 4 CF 3 , C 6 H 4 Me or C 6 H 4 CI.
• Preferred compounds of the invention are: 2-Methyl-2- ⁇ 2-methyl-4-[([4-(trifluoromethyl)benzyl] ⁇ 6-[4-(trifluoromethyl)phenyl]pyridin-2- yi ⁇ amino)methyl]phenoxy ⁇ propanoic acid
• preferred compounds of this invention include those in which several or each variable in Formula (I) is selected from the preferred, more preferred, or most preferred groups for each variable. Therefore, this invention is intended to include all combinations of preferred and most preferred groups.
• the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but this invention is also intended to cover each of these isomers in their racemic, enriched, or purified forms.
• a compound of formula (I) When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis using an optically active catalyst or a catalytic system with optically active ligands or isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E.
• the present invention is intended to include all tautomeric forms of the compounds.
• the activities at the various PPAR receptors varies between the S and R isomers. Which of these isomers is preferred depends on the particular desired utility of the compound. In other words, even with the same compound, it is possible that the S isomer will be preferred for some uses, while the R isomer will be preferred for others.
• the hPPAR agonists of formula (I) may be agonists of only one type ("selective agonists"), agonists for two PPAR subtypes ("dual agonists"), or agonists for all three subtypes ("pan agonists”).
• agonist or “activating compound”, or “activator”, or the like, is meant those compounds which have a pKi of at least 6.0 preferably at least 7.0 to the relevant PPAR, for example hPPAR ⁇ , in the binding assay described below, and which achieve at least
• the compounds of formula (I) are hPPAR agonists. More preferably the compounds are hPPAR ⁇ agonists. More preferably they are selective hPPAR ⁇ agonists.
• the compounds of the present invention may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof.
• physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts.
• suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene- 2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
• acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
• suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyiglucamine and procaine salts.
• compositions are conveniently administered in the form of pharmaceutical compositions.
• Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
• compositions of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
• the formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate.
• binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, m
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
• the tablets may be coated according to methods well-known in the art.
• the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example.
• formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono- oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
• suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats
• emulsifying agents such as lecithin, sorbitan mono- oleate or acacia
• non-aqueous vehicles
• Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
• Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
• a sterile liquid carrier for example, water-for-injection
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
• Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
• the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
• treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
• amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
• doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day.
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
• the compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators.
• the compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonylureas and/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone).
• antidiabetic agents e.g. metformin, sulfonylureas and/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists
• thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone
• antihypertensive agents such as angio
• telmisartan calcium channel antagonists e.g. lacidipine and ACE inhibitors e.g. enalapril.
• the invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR mediated disease.
• the compounds of formula (I) When used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
• compositions comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
• the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
• the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
• each compound of formula (I) When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
• Intermediates (A) can be prepared by alkylating a suitable 4-hydroxybenzaldehyde to afford benzaldehydes (intermediate C), followed by reductive amination of the aldehyde moiety.
• Intermediates (B) can be prepared by reducing a suitable 4-hydroxybenzaldehyde to the alcohol. Alkylation of the phenol moiety with a suitable bromoacetate, followed by halogenation of the benzylic alcohol affords intermediates (B).
• Suitable halogenated-anilines can be coupled with boronic acids under Suzuki coupling conditions to afford coupled products (intermediate D).
• Reductive amination, or acylation and reduction, of the resulting compounds yield the secondary anilines (intermediate E) which are alkylated with halides (intermediate B).
• Hydrolysis of the carboxylic esters, under standard conditions yield the carboxylic acids.
• dichloropyrazine can be coupled with boronic acids using Suzuki coupling conditions.
• the resultant mono chloropyrazine can be converted to the bromide by treatment with phosphorus tribromide.
• Displacement of the bromide with an amine (intermediate A) in the presence of N,N-diisopropylethylamine yield the esters which are hydrolysed to the acids, under standard conditions.
• a suitable dichloropyrimidine can be coupled with boronic acids using Suzuki coupling conditions.
• the resultant mono-chloro pyrimidines can be treated with an amine (intermediate A) in the presence of N,N-diisopropylethylamine to yield the esters which are hydrolysed under standard conditions to the carboxylic acids.
• LC/MS refers to analysis by analytical HPLC which was conducted on a Supelcosil LCABZ+PLUS column (3 ⁇ m, 3.3cm x 4.6mm ID) eluting with 0.1% HCO z H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HC0 2 H in water (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0 ⁇ 100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 100 ⁇ 0%B at a flow rate of 3 ml/minute.
• MS mass spectra
• BiotageTM chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KP-SilTM silica.
• Mass directed auto-prep HPLC refers to the method where the material was purified by high performance liquid chromatography on a HPLCABZ+ 5 ⁇ m column (5cm x 10mm i.d.) with 0.1% HC0 2 H in water and 95% MeCN, 5% water (0.5% HC0 2 H) utilising the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5 ⁇ 30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30 ⁇ 95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95 ⁇ 0%B at a flow rate of 8ml/minute.
• the Gilson 202-fraction collector was triggered by a VG Platform Mass Spectrometer on detecting the mass of interest.
• Hydrophobic frits refers to filtration tubes sold by Whatman.
• SPE solid phase extraction
• TLC thin layer chromatography
• CDCI 3 deuterated chloroform
• the reaction mixture was stirred at -78°C for 20 mins, then treated with triethylamine (0.543 mL, 3.9 mmol) in anhydrous CH 2 CI 2 (3 mL). The resultant mixture was allowed to gradually warm to room temperature and stirred for 16 h.
• the reaction mixture was diluted with CH 2 CI 2 (10 mL) and water (5 mL) prior to the addition of 2M HCl (0.5 mL). The mixture was stirred vigorously for 20 mins, then passed through a hydrophobic frit. The organic solution was stood over molecular sieves for 2 h, then decanted into a clean flask.
• Th organic extract was separated by hydrophobic firt and evaporated. Purification by BiotageTM chromatography (Silica, 12 g) eluting 9:1-17:3 cyclohexane:EtOAc, afforded the title compound as a yellow solid (65 mg).
• Example 11 ⁇ -( ⁇ -Methoxyethy ⁇ -methyl- ⁇ -ttrifluoromethy -l.r-biphenyl-S- y]]amino ⁇ rnethyl)-2-methylphenoxy]acetic acid
• the organic solution was dried (MgS0 4 ) and the solvent was removed in vacuo. Purification by SPE (5 g aminopropyl cartridge), loading crude material in CH 2 CI 2 and then washing with MeOH, prior to eluting with 5% NH 3 in MeOH. The 5% NH 3 in MeOH extract was concentrated in vacuo and the residue was partitioned between CH 2 CI 2 (20 L) and 2M HCl (2 mL). The organic solution was dried (MgS0 ) and the solvent was removed in vacuo affording the title compound as a white solid (64.4 mg).
• Example 19 ⁇ 4-[((2-Methoxyethyl) ⁇ 4-[4-(trifluoromethyl)phenyl]pyrimidin-2- yl ⁇ amino)methyl]-2-methyIphenoxy ⁇ acetic acid
• Example 24 ⁇ 4-[((2-Methoxyethyl) ⁇ 6-[4-(trifluoromethyl)phenyl]pyrazin-2- yl ⁇ amino)methyl]-2-methylphenoxy ⁇ acetic acid
• Example 32 (4- ⁇ [(2-Methoxyethyl)(4'-methoxy-2 -methyl-1 ,1'-biphenyl-3- yl)amino]methyl ⁇ -2-methylphenoxy)acetic acid
• Example 36 (4- ⁇ [(4'-Fluoro-2-methyl-1,1'-biphenyl-3-yl)(propyl)amino]methyl ⁇ -2- methylphenoxy)acetic acid
• Example 37 (4- ⁇ [(4' -Cyano-2 -methyl-1, 1'-biphenyI-3-yl)(propyl)amino]methyl ⁇ -2- methylphenoxy)acetic acid
• Example 38 (4- ⁇ [(4'-Methoxy-2-methyI-1,1'-biphenyl-3-yl)(propyl)amino] methyl ⁇ -2- methylphenoxy)acetic acid
• Example 45 ⁇ 2-Methyl-4-[(propyI ⁇ 6-[4-(trifluoromethyl)phenyl]pyrazin-2- yl ⁇ amino)methyl]phenoxy ⁇ acetic acid
• Example 54 [2-Methyl-4-( ⁇ (propylsulfonyl)[4"-(trifluoromethyl)-1 ,1 '-biphenyl-3- yl]amino ⁇ methyl)pheoxy]acetic acid
• Example 58 ⁇ 2-Methyl-4-[(2-propen-1-yl ⁇ 6-[4-(trifluoromethyl)phenyl]pyridin-2- yl ⁇ arnino)methyl]phenoxy ⁇ acetic acid
• This compound was used as a PPAR delta reference in the transfection assays described below and was prepared according to the method reported in WO200100603-A1
• This compound was used as a PPAR alpha reference in the transfection assay described below and was prepared according to method reported in WO200140207-A1
• PPAR ligand binding domain (LBD) was expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD was then labelled with biotin and immobilised on streptavidin-modified scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand (3H-BRL 49653 for PPAR gamma, and labelled GW 2433 (see Brown, P. J et al . Chem. Biol., 4, 909-918 (1997).
• SPA Scintillation Proximity Assay
• Transfection assay Compounds were screened for functional potency in transient transfection assays in CV-1 cells for their ability to activate the PPAR subtypes (transactivation assay).
• transactivation assay A previously established chimeric receptor system was utilized to allow comparison of the relative transcriptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example,
• An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgammaj, J. Biol. Chem., 270, 12953-6 (1995).
• PPARgammaj peroxisome proliferator-activated receptor gamma
• the ligand binding domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to the yeast transcription factor GAL4 DNA binding domain.
• CV-1 cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placental alkaline phosphatase (SPAP) and beta-galactosidase.
• the medium was exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration.
• cell extracts were prepared and assayed for alkaline phosphatase and ⁇ -galactosidase activity. Alkaline phosphatase activity was corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S.
• Rosiglitazone (BRL 49653) was used as a positive control in the hPPAR gamma assay.
• the positive control in the hPPAR alpha assays was 2-methyl-2-[4- ⁇ [(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-yl-carbonyl)amino]methyl ⁇ - phenoxy]propionic acid.
• the positive control for PPAR delta assays was 2- ⁇ 2-methyl-4-[( ⁇ 4- methyl-2- ⁇ trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl ⁇ methyl)sulfanyl]phenoxy ⁇ acetic acid.

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