WO2003084916A2 - Compounds that modulate ppar activity and methods for their preparation - Google Patents

Compounds that modulate ppar activity and methods for their preparation Download PDF

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Publication number
WO2003084916A2
WO2003084916A2 PCT/IB2003/001121 IB0301121W WO03084916A2 WO 2003084916 A2 WO2003084916 A2 WO 2003084916A2 IB 0301121 W IB0301121 W IB 0301121W WO 03084916 A2 WO03084916 A2 WO 03084916A2
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WO
WIPO (PCT)
Prior art keywords
acetic acid
compound
methyl
trifluoromethyl
phenoxy
Prior art date
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PCT/IB2003/001121
Other languages
French (fr)
Other versions
WO2003084916A3 (en
Inventor
Gary Frederick Filzen
Bharat Kalidas Trivedi
Andrew George Geyer
Paul Charles Unangst
Larry Don Bratton
Bruce Jeffrey Auerbach
Original Assignee
Warner-Lambert Company Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MXPA04009727A priority Critical patent/MXPA04009727A/en
Priority to APAP/P/2004/003135A priority patent/AP1772A/en
Application filed by Warner-Lambert Company Llc filed Critical Warner-Lambert Company Llc
Priority to EA200401153A priority patent/EA009518B1/en
Priority to UA20041008021A priority patent/UA76838C2/en
Priority to AU2003212578A priority patent/AU2003212578A1/en
Priority to IL16401503A priority patent/IL164015A0/en
Priority to JP2003582115A priority patent/JP3816922B2/en
Priority to CA002481246A priority patent/CA2481246C/en
Priority to KR1020047015763A priority patent/KR100687166B1/en
Priority to YUP-829/04A priority patent/RS82904A/en
Priority to EP03708403A priority patent/EP1494989A2/en
Priority to BR0309169-4A priority patent/BR0309169A/en
Publication of WO2003084916A2 publication Critical patent/WO2003084916A2/en
Publication of WO2003084916A3 publication Critical patent/WO2003084916A3/en
Priority to IS7429A priority patent/IS7429A/en
Priority to TNP2004000191A priority patent/TNSN04191A1/en
Priority to HRP20040916 priority patent/HRP20040916A2/en
Priority to NO20044795A priority patent/NO20044795L/en

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Definitions

  • the present invention relates to compounds and pharmaceutical formulations that can be used to treat conditions mediated by nuclear hormone receptors, more specifically, to compounds and pharmaceutical formulations that modulate Peroxisome Proliferator Activation Receptor (PPAR) activity.
  • PPAR Peroxisome Proliferator Activation Receptor
  • Hypercholesterolemia, dyslipidemia, diabetes, and obesity are well- recognized risk factors in the onset of atherosclerosis and coronary heart disease.
  • the diseases are characterized by high levels of cholesterol and lipids in the blood.
  • the blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine, and from the biosynthesis of cholesterol throughout the body, especially the liver.
  • the majority of cholesterol in plasma is carried on apolipoprotein B- containing lipoproteins, such as low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL).
  • LDL low-density lipoproteins
  • VLDL very-low-density lipoproteins
  • statins represent perhaps the most important classlbf lipid-lowering drugs. These compounds inhibit HMG-CoA reductase which is implicated in the rate- limiting step in cellular cholesterol biosynthesis.
  • Representative statins include atorvastatin, lovastatin, pravastatin, and simvastatin. The effectiveness of these compounds depends on LDL receptor regulation.
  • Other important antilipidemia drugs include f ⁇ brates such as gemfibril and clofibrate, bile acid sequestrants such as cholestyramine and colestipol, probucol, and nicotinic acid analogs.
  • sulfonylureas are generally used to stimulate insulin.
  • the biguanide metformin is generally used to improve insulin sensitivity and to decrease hepatic glucose output.
  • Acarbose is used to limit postprandial hyperglycemia.
  • Thiazolidine 2,4 diones are used to enhance insulin action without increasing insulin secretion.
  • Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, thromboembolic disease, and coronary heart disease.
  • Treatment of obesity remains a problem and it is unclear whether dieting results in decreased long- term risk of early death.
  • a further important obesity intervention is physical activity. Exercise, however, in general, has been found to be only moderately successful in promoting weight loss. A program combining both dieting and exercise as well as behaviour modification is widely viewed as the optimal approach to weight loss.
  • PPAR Peroxisome Proliferator Activation Receptors
  • PPARs are activated by fatty acids and fatty acid metabolites.
  • Each receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds.
  • PPAR ⁇ for instance, is expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial and smooth muscle cells jas well as macrophages.
  • PPAR receptors are associated with regulation of insulin sensitivity and blood glucose levels, macrophage differentiation, inflammatory response, and cell differentiation. Accordingly, PPARs have been associated with obesity, diabetes, carcinogenesis, hyperplasia, atherosclerosis, dyslipidemia, and hypercholesterolemia.
  • PPAR ⁇ agonists lower plasma triglycerides and LDL cholesterol and are therefore useful in treating hypertriglyceridemia, dyslipidemia and obesity.
  • PPAR ⁇ is associated with the development of non-insulin-dependent diabetes mellitus (NJDDM), hypertension, coronary artery disease, dyslipidemia and certain malignancies.
  • NJDDM non-insulin-dependent diabetes mellitus
  • activation of PPAR ⁇ has been demonstrated to increase HDL levels.
  • a PPAR ⁇ selective agonist was reported to have shown a dose-related increase in sjerum HDL-C and decrease in LDL-C and VLDL-TG in insulin-resistant middle aged rhesus monkeys.
  • Antilipidemic, antidiabetic and anti-obesity agents are still considered to have non-uniform effectiveness.
  • the effectivieness of antidiabetic and antilipidemic therapies is limited, in part because of poor patient compliance due to unacceptable side effects. These side effects include diarrhea and gastrointestinal discomfort, and in the case of antidiabetics, edema, hypoglycemia and hepatoxicity. Furthermore, each type of drug does not work equally well in all patients.
  • nov ⁇ l antilipidemic, antidiabetic, and anti-obesity agents that can be used alone or in combination.
  • activation of multiple PPARs for instance, PPAR ⁇ alone or in combination with the simultaneous activation of PPAR ⁇ and/or PPAR ⁇ , may be desirable in formulating a treatment for dyslipidemia in which HDL is increased and LDL lowered.
  • the present invention provides compounds capable of modulating PPAR activity.
  • Compounds of the present invention are described by Formula I:
  • Ar 1 and Ar 2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar 1 is not thiazolyl or oxazolyl;
  • v - ⁇ is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
  • R 1 and R 2 are selected from hydrogen, lower alkyl, lov ⁇ er alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p aIkyl, S(O) p aryl, -
  • R 3 and R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p alkyl, S(O) p aryl, - (CH 2 ) m OR 5 , -(CH 2 ) m NR 6 R 7 , -COR 5 , -CO 2 H, -CO 2 R 5 , or -NR 6 R 7 ; provided that at least one of R 1 -R 4 is H, lower alkyl, lower alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p alkyl, S(O) p aryl, - (CH 2 ) m OR 5
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
  • R 6 and R 7 are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl,
  • -COaryl cycloalkyl, -CO 2 alkyl, -CO aryl, or R 6 and R 7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1, to 3 heteroatoms; m is 0 to 5; p is O, l, or 2; q is 0 to 6; and r is 0 to 6.
  • the invention also provides a compound of formula (II):
  • -- is absent; or when present, — is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
  • R 3 and R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p alkyl, S(O) p aryl, - (CH 2 ) m OR 5 , -(CH 2 ) m NR 6 R 7 , -COR 5 , -CO 2 H, -CO 2 R 5 , or-NR 6 R 7 ;
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
  • R 6 and R 7 are each independently hydrogen, alkyl, alkenyj, alkynyl, -COalkyl,
  • -COaryl cycloalkyl, -CO 2 alkyl, -CO 2 aryl, -SO 2 alkyl, -SO 2 aryl, or R 6 and R 7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms;
  • a mj ⁇ thod of treating, preventing or controlling hypercholesteremia and dyslipidemia iiti a mammal comprises administering to the mammal in need thereof a therapeutically effective amount of the compounds of the present invention.
  • the compounds of the present invention are also useful in the method of the present invention for treating, preventing, or controlling obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes.
  • the compounds of the present invention are also useful in the methods of supressing appetite in a mammal, modulating leptin levels in a mammal, and treating a patient exhibiting glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone.
  • a therapeutically effective amount of the compounds of the present invention are administered to the mammal in need thereof.
  • a method for preparing compounds with Formulae I-II, or a pharmaceutically acceptable salt thereof comprises reacting
  • is OH or SH
  • Ri-R have any of the meanings defined above, and R n is a lower alkyl with:
  • is a bond or is absent.
  • the double bond may optionally be removed, for instance, by hydrogenation and the resulting ester is preferably hydrolyzed to form the compounds of Formulas I or H.
  • the invention provides a process ⁇
  • R 2 is methoxy or together with R 1 forms a 5 membered carbocyclic ring
  • R 3 is hydrogen or methyl
  • R 4 is hydrogen
  • X 1 is absent or O; and r is 0 or 1.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denpte both straight and branched groups; but reference to an individual radical such as "propyl" embraces
  • I only the straight chain radical, a branched chain isomer such as I'isopropyl" being specifically referred to.
  • Preferred alkyl groups have from 1 to 6 carbon atoms (CrC 6 alkyl).
  • lower alkyl refers to a subset of alkyl which means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • alkenyl means a straight or branched unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethenyl, 1- propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1- decenyl, 1-undecenyl, 1-dodecenyl, and the like.
  • alkynyl means a straight or branched hydrocarbon radical having from 2 to 12 carbon atoms having at least one triple bond and includes, for example, 1-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, 3-methyl-3-butynyl, 1- hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1- dodecynyl, and the like.
  • alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1 ,2-ethylene, 1,1- ethylene, 1,3-propylene, 2,2- dimethylpropylene, and the like.
  • the alkylene groups of this invention can be optionally substituted.
  • alkylene groups have from 1 to 6 carbon atoms (C ⁇ -C 6 alkyl).
  • the cycloalkyl ring may be unsubstituted or substituted by 1 to 3 substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl and di alkylamino, formyl, carboxyl, CN, -NH-CO-R', -CO-NHR'-, -CO2R', -COR', aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein.
  • substituted cycloalkyl groups include fluorocyclopropyl, 2-iodocyclobutyl,
  • heteroatom as used herein represents oxygen, nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO 2 ) unless otherwise indicated.
  • heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups.
  • Typical substituted cyclic ethers include propyleneoxide, phenyloxirane (styrene oxide), cis- 2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofurani 2,6-dimethyl-l,4- dioxane, and the like.
  • Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-l-yl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro-1,3- dithiol-2-yl, and hexahydrothiepin-4-yl.
  • heterocycles include dihydro-oxathiol-4-yl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro- oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.
  • hydrocarbon chain refers to a straight hydrocarbon of from 2 to 6 carbon atoms.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to
  • aryl includes both monovalenjt species, for example where Ar 2 is aryl, and divalent species, for example where Ar 1 is aryl.
  • aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3- methylphenyl, 2-chloro-4-methylphenyl, 2 ⁇ chloro-5-methylphenyl, 3-chloro-2- methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3- methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-trifluoromethyl and the like.
  • heteroaryl means an aromatic mono-, bi-, or or polycyclic ring incorporating one or more (i.e. 1-4) heteroatoms selected from N, O, and S.
  • heteroaryl includes both monovalent species, for example where Ar 2 is heteroaryl, and divalent species, for example where Ar 1 is heteroaryl. It is understood that a heterocycle is optionally substituted with up to 4 groups selected from C]-C 6 alkyl, cycloalkyl, heteroaryl, dialkylaminoalkoxy, or those recited above as substituents for alkyl.
  • Preferred monocyclic diheterocycles include, but are not limited to 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 3-, 4-, or 5-isothiazolyl, 3-, 4-, or 5- isoxazolyl, 1 , 3-, or 5-triazolyl, 1-, 2-, or 3-tetrazolyl, 2-pyrazinyl, 2-, 4-, 1 or 5- pyrimidinyl, 1- or 2-piperazinyl, 2-, 3-, or 4-morpholinyl.
  • bicyclic and polyclic heteroaryl groups include, but are not limited to include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl,
  • Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 1-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 1-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-,l 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl..
  • hydrocarbon-heteroatom chain refers to a hydrocarbon chain wherein one or more carbon atoms are replaced with a heteroatom.
  • the hydrocarbon-heteroatom chain is optionally substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(C ⁇ 2 )o-
  • heteroalkylene refers to a aljkylene radical as defined above that includes one or more heteroatoms such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in thje carbon chain or terminating the carbon chain.
  • heteroatoms such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in thje carbon chain or terminating the carbon chain.
  • lower alkoxy and lower thioalkoxy refers to O- alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for “lower alkyl.”
  • cycloalkenyl means a cycloalkyl group having one or more carbon-carbon double.
  • Example includes cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and the like.
  • the symbol " ' ⁇ " means a bond to a group wherein a k to 8 membered ring is formed. Typically this symbol will appear in pairs.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
  • a pharmaceutically acceptable salt refers to the relatively non- toxic, inorganic and organic base or acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic base or acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, di ethylamine, trirnethylamine, triethylamine, ethylamine, and the like.
  • the free base form may be regenerated by contacting the salt form with a base. While the free base may] differ from the salt form in terms of physical properties, such as solubility, the salts ,are equivalent to their respective free bases for the purposes of the present invention.
  • Ar 1 and Ar 2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar 1 is not thiazolyl or oxazolyl; ' ⁇ '
  • % — is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
  • R 1 and R 2 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p alkyl, S(O) p aryl, - (CH 2 ) m OR 5 , -(CH 2 ) m NR 6 R 7 , -COR 5 , -CO 2 R 5 , or -NR 6 R 7 , or together with the atoms to which they are attached form a five to eight member ring; R 3 and R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,-
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl
  • R 6 and R 7 are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl, -COaryl, cycloalkyl, -CO 2 alkyl, -CO 2 aryl, or R 6 and R 7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms; m is 0 to 5; p is O, l, or 2; q is 0 to 6; and r is 0 to 6.
  • R 1 , R 2 , R 3 , and R 4 are preferably selected from hydrogen, alkyl, or alkoxy. More preferably, R 2 and R 3 are hyd gen; and R 1 and R 4 are alkyl or alkoxy. In a particularly preferred embodiment of Formula I, R 2 and R 3 are hydrogen; R 1 is alkyl; and R 4 is alkoxy. Preferred alkoxy include methoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, or isobutoxy. Similarly, preferred alkyl include methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl.
  • q is 1, Ar 1 is phenyl, X 1 is absent, r is 0, V 1 is absent, and Ar 2 is 4-trifluoromethylphenyl. V ⁇ 1 ⁇
  • ⁇ — is preferably (CHJ_) t wherein t is 1 to 4.
  • Ar 1 and Ar 2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar 1 is not thiazolyl or oxazolyl;
  • v -- is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from /'" v-' 1 ⁇
  • R and R 4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH 2 ) m CF 3 , halogen, nitro, cyano, -OH, -SH, -CF 3 , -S(O) p alkyl, S(O) p aryl, -
  • R 5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl; are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl, -COaryl, cycloalkyl, -CO 2 alkyl, -CO 2 aryl, -SO 2 alkyl, -SO 2 aryl, or R 6 and R 7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms;
  • ⁇ - is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carbon atom of position 3 to form a five to eight member ring; m is 0 to 5; p is 0 to 2; q is 0 to 6; and r is 0 to 6.
  • R 3 , and R 4 are preferably selected from
  • R 3 and R 4 are hydrogen; and is a saturated or unsaturated, unsubstituted hydrocarbon chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carbo ⁇ atom of position 3 to form a five to eight member ring such as a cyclopentyl or cyclohexyl ring.
  • q is 1, Ar 1 is phenyl, X 1 is ! ⁇ , r is 1, V 1 is absent, and Ar 2 is 4-trifluoromethylphenyl.
  • -— is preferably (CH 2 ) t wherein t is 1 to 4.
  • R' and R" are independently alkyl, akenyl, alkynyl, aryl,[ or joined together to form a 4 to 7 member ring.
  • a subset of exemplary compounds of Formula I and Formula II include
  • Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration.
  • the present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. Additionally, the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • E Electronic Data
  • compounds may exist as tautomers. All tautomers are included within Formulas I and II and are provided by this invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention includes all pharmaceutically acceptable, nonn-toxic esters of the compounds of Formulae I and II.
  • esters include C ⁇ -C 6 alkyl esters where the alkyl group is a straight or branched chain. Acceptable esters also include C 5 -G 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. d ⁇ C esters are preferred.
  • Esters of the compounds of the present invention may be prepared according to conventional methods.
  • the compounds of the present invention are suitable to be administered to a patient for the treatment, control, or prevention of hypercholesteremia, dyslipidemia, obesity, hyperglycemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, and hyperinsulinemia.
  • the compounds of the present invention are also suitable to be administered to a patient for the supression of appetite and modulation of leptin. Accordingly, the compounds may be administered to a patient alone or as part of a composition that contains other components such as excipients,
  • compositions can be administered to humans and/or animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polvethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example sugars, sodium chloride, and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosteara and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary ammonium compounds
  • wetting agents as for example, cetyl alcohol and glycerol monostearate
  • adsorbents as for example, kaolin and bentonite
  • lubricants as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
  • the dosage forms may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be
  • embedding compositionjs which can be used are polymeric substances and waxes.
  • the active compounds can also be in micro- encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and i sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylenegljycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragaca ⁇ th, or mixtures of these substances, and the like.
  • compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day.
  • dosage levels in the range of about 0.1 to about 2,000 mg per day.
  • a dosage in the range of about 0.01 to about 10 mg per kilogram of body weight per day is preferable.
  • the specific dosage used can vary.
  • the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well-known to those skilled in the art.
  • PREPARATION OF COMPOUNDS OF THE INVENTION The present invention contains compounds that can be synthesized in a number of ways familiar to one skilled in organic synthesis.
  • the compounds outlined herein can be synthesized according to the methods described below, along with methods typically utilized by a synthetic chemist, and combinations or variations of those methods, which are generally known to one skilled in the art of synthetic chemistry.
  • the synthetic route of compounds in the present invention is not limited to the methods outlined below. It is assumed one skilled in the art will be able to use the schemes outlined below to synthesize compounds claimed in this invention.
  • Individual compounds may require manipulation of the conditions in order to accommodate various functional groups. A variety of protecting groups generally known to one skilled in the art may be required. Purification, if necessary, can be accomplished on a silica gel column eluted with the appropriate organic solvent system. Also, reverse phase HPLC or recrystallization may be
  • n, R 1 , R 2 , R 3 , R 4 , X°, X ] , V 1 , Ar 1 , and Ar 2 are the same aj. defined above for Fo ⁇ nula I;
  • R n is a lower alkyl; and X is a halogen.
  • the resulting ester is then preferably hydrolyzed to form the compounds of Formulas I and II.
  • compounds of Formulas I and II can be prepared using the synthetic route outlined in Scheme 1-6.
  • is S, q is 0-3, ⁇ — is absent, X 1 is absent and r is 0..
  • Compounds of the general formula A are thiocyanated with a mixture of bromine and sodium thiocyanate to give compounds of the general formula B.
  • Compounds of the general formula B are then alkylated with an alkyl haloacarboxylate to give compounds of the general formula C.
  • the preferred alkyl haloacarboxylate is methyl bromoacetate.
  • Alternate routes to compounds of formula C will be readily apparent to a person skilled in the art of organic synthesis.
  • Compounds of the general formula D are then prepared by reduction of C with dithiothreitol in methanol.
  • Scheme 2 covers the preparation of compounds of Formula I-II wherein X° is
  • Scheme 5 covers the preparation of compounds of formula I-II wherein X° is
  • compounds of the general formula HH are prepared by reacting aryl bromide V with boronic acid FF to ⁇ ive GG.
  • Compounds of the general formula GG are then reacted with an alkyl lithiu
  • compounds of the general formula NN can be prepared by reacting an appropriately substituted aryl amine LL under Sandmeyer conditions followed by heating to give intermediate MM. The resulting intermediate MM is then reacted with methanesulfonyl chloride to give chlorides of the general fo ⁇ nula NN.
  • Example IA The product from Example IA (3.5 g, 25 mmol), sodium thiocyanate (6.48 g, 80 mmol), and sodium bromide (2.6 g, 25 mmol) were dissolved i]n 30 ml anhydrous methanol. Bromine (4.4 g, 28 mmol) was added drop wise over 15 minutes and allowed to stir at ambient temperature for 1 h. Brine was added (50 ml) and the crude product was extracted into ethyl acetate (3x100 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated to afford the title product in good purity.
  • Example IC The product from Example IC (1.1 g, 4.1 mmol) and dithiothreitol (824 mg, 5.4 mmol) were dissolved in 20 ml methanol with 2.5 ml water. The solution was refluxed for 4 h, cooled, concentrated, and purified by normal phase chromatography. 400 MHz ] H NMR (DMSO-d 6 ) ⁇ 7.02 (s, 1H), 6.54 (s, 1H), 4.79 (s, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 2.02 (s, 3H); MS m/z 243 (M+l).
  • Example ID 100 mg, 0.38 mmol
  • product from Example IE 92 mg, 0.38 mmol
  • cesium carbonate 250 mg, 0.76 mmol
  • the reaction was filtered through Celite ® , concentrated and purified through normal phase chromatography. MS m/z 409 (M+l).
  • Example 3A The product from Example 3A was dissolved in 10 ml methylene chloride. Triethylamine (468 mg, 4.62 mol) and methanesulfonyl chloride (422 mg, 3.68 mmol) were then added and sti ⁇ ed for 18 h. The reaction wasj poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the title compound that was used without further purification. MS m/z 235 (M-Cl+1).
  • Step 2 Preparation of [4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]- acetic acid (compound 13)
  • Example 18C The title compound was prepared from the product of Example 18C in the manner analogous to Example 1. mp 225 °C (dec); 400 MHz 1H NMR (DMSO-d 6 ) ⁇ 8.97 (s,
  • Example 19B The title compound was prepared from the product of Example 19B in the manner analogous to Example 1. mp 203 °C (dec); 400 MHz 1H NMR (DMSO-d 6 ) ⁇ 8.34 (d,
  • Example 29C The title compound was prepared from the product of Example 29C in the manner analogous to Example 1. mp 154 °C (dec); 400 MHz 1H NMR (DMSO-d 6 ) ⁇ 12.94 (s, IH), 7.46-7.34 (m, 5H), 7.27-7.15 (m, 4H), 7.06-6.99 (m, 2H), 6.52 (s, IH), 4.69 (s, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 2.00 (s, 3H), MS m/z 439 (M l).
  • Compound 37A was prepared in the manner analogous to Example IF using the products from Example 18B and Example 20C. MS m/z 482 (M+).
  • Step 2 Preparation of ⁇ 5-Methoxy-2-methyl-4-[3-(4-trifIupromethyl-phenyl)- isoxa ⁇ ol-5-ylmethylsulfanyI]-phenoxy ⁇ -acetic acid (compound 46)
  • the title compound was prepared in a manner analogous to Example 1 using 46A.

Abstract

This invention discloses compounds that alter PPAR activity. The invention also discloses pharmaceutically acceptable salts of the compounds, pharmaceutically acceptable compositions comprising the compounds or their salts, and methods of using them as therapeutic agents for treating or preventing hyperlipidemia, hypercholesteremia, obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes in a mammal as well as methods of suppressing appetite and modulating leptin levels in a mammal. The present invention also discloses methods for making the disclosed compounds.

Description

COMPOUNDS THAT MODULATE PPAR ACTIVITY AND METHODS FOR
THEIR PREPARATION
This application claims priority to U.S. Provisional Applications Serial Nos. 60/370,508, filed April 5, 2002 and 60/386,026, filed June 5, 2002.
FIELD OF THE INVENTION
The present invention relates to compounds and pharmaceutical formulations that can be used to treat conditions mediated by nuclear hormone receptors, more specifically, to compounds and pharmaceutical formulations that modulate Peroxisome Proliferator Activation Receptor (PPAR) activity.
BACKGROUND OF THE INVENTION
Hypercholesterolemia, dyslipidemia, diabetes, and obesity are well- recognized risk factors in the onset of atherosclerosis and coronary heart disease. The diseases are characterized by high levels of cholesterol and lipids in the blood. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine, and from the biosynthesis of cholesterol throughout the body, especially the liver. The majority of cholesterol in plasma is carried on apolipoprotein B- containing lipoproteins, such as low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). The risk of coronary artery disease in man increases when LDL and VLDL levels increase. Conversely, high levels of cholesterol carried in high-density lipoproteins (HDL) is protective against coronary artery disease (Am. J. Med., 1977;62:707-714). The statins represent perhaps the most important classlbf lipid-lowering drugs. These compounds inhibit HMG-CoA reductase which is implicated in the rate- limiting step in cellular cholesterol biosynthesis. Representative statins include atorvastatin, lovastatin, pravastatin, and simvastatin. The effectiveness of these compounds depends on LDL receptor regulation. Other important antilipidemia drugs include fϊbrates such as gemfibril and clofibrate, bile acid sequestrants such as cholestyramine and colestipol, probucol, and nicotinic acid analogs.
To date, a number of oral antidiabetic agents have been developed. The most commonly used hypoglygemic drugs are the sulfonylureas. Sulfonylureas are generally used to stimulate insulin. The biguanide metformin is generally used to improve insulin sensitivity and to decrease hepatic glucose output. Acarbose is used to limit postprandial hyperglycemia. Thiazolidine 2,4 diones are used to enhance insulin action without increasing insulin secretion.
Obesity is a chronic disease that is highly prevalent in modern society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, thromboembolic disease, and coronary heart disease. Rissanen et al, British Medical Journal, 301 :835-837 (1990). Treatment of obesity remains a problem and it is unclear whether dieting results in decreased long- term risk of early death. A further important obesity intervention is physical activity. Exercise, however, in general, has been found to be only moderately successful in promoting weight loss. A program combining both dieting and exercise as well as behaviour modification is widely viewed as the optimal approach to weight loss.
Studies have demonstrated that the combination of both food restriction and exercise promote a substantial loss of fat while maitaining lean tissue. Peroxisome Proliferator Activation Receptors (PPAR) are implicated in a number of biological processes and disease states including hypercholesterolemia, dyslipidemia, and diabetes. PPARs are members of the nuclear receptor superfamily of transcription factors that includes steroid, thyroid, and vitamin D receptors. They play a role in controlling expression of proteins that regulate lipid metabolism.
Furthermore, the PPARs are activated by fatty acids and fatty acid metabolites. There are three PPAR subtypes PPAR α, PPAR β (also referred to as PPAR δ), and PPAR γ. Each receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds. PPAR γ, for instance, is expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial and smooth muscle cells jas well as macrophages. PPAR receptors are associated with regulation of insulin sensitivity and blood glucose levels, macrophage differentiation, inflammatory response, and cell differentiation. Accordingly, PPARs have been associated with obesity, diabetes, carcinogenesis, hyperplasia, atherosclerosis, dyslipidemia, and hypercholesterolemia.
In addition, PPARα agonists lower plasma triglycerides and LDL cholesterol and are therefore useful in treating hypertriglyceridemia, dyslipidemia and obesity. PPAR γ is associated with the development of non-insulin-dependent diabetes mellitus (NJDDM), hypertension, coronary artery disease, dyslipidemia and certain malignancies. Finally, activation of PPAR β has been demonstrated to increase HDL levels. (Leibowitz, WO97/28149, Aug. 1997.) More recently, |a PPAR β selective agonist was reported to have shown a dose-related increase in sjerum HDL-C and decrease in LDL-C and VLDL-TG in insulin-resistant middle aged rhesus monkeys. (W. R. Oliver et al., PNAS, v. 98, pp. 5306-5311 , 2001)
Antilipidemic, antidiabetic and anti-obesity agents are still considered to have non-uniform effectiveness. The effectivieness of antidiabetic and antilipidemic therapies is limited, in part because of poor patient compliance due to unacceptable side effects. These side effects include diarrhea and gastrointestinal discomfort, and in the case of antidiabetics, edema, hypoglycemia and hepatoxicity. Furthermore, each type of drug does not work equally well in all patients.
For the reasons set forth above, there is a need for novέl antilipidemic, antidiabetic, and anti-obesity agents that can be used alone or in combination. Furthermore, activation of multiple PPARs, for instance, PPARβ alone or in combination with the simultaneous activation of PPAR α and/or PPAR γ, may be desirable in formulating a treatment for dyslipidemia in which HDL is increased and LDL lowered.
SUMMARY OF THE INVENTION
The present invention provides compounds capable of modulating PPAR activity. Compounds of the present invention are described by Formula I:
Figure imgf000005_0001
I
and pharmaceutically acceptable salts thereof, where: X° and X1 are independently absent, O, S, -CH2- -CH2-CH2- -CH=CH-, - CH≡CH- , -S(O)2-, or-S(O)-;
Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl;
/1 v-1
\ \ \
\ \ \ x — - is absent; or when present, v-~ is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
1 to 4 atoms so that
Figure imgf000006_0001
, Ar1, X1, (CH2)r, and Ar2, together form a five to eight membered ring;
R1 and R2 are selected from hydrogen, lower alkyl, lov^er alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)paIkyl, S(O)paryl, -
(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, or -NR6R7, or together with the atoms to which they are attached form a five to eight member ring;
R3 and R4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, or -NR6R7; provided that at least one of R1-R4 is H, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(C^JroNRV. or NRV;
R5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R6 and R7 are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl,
-COaryl, cycloalkyl, -CO2alkyl, -CO aryl, or R6 and R7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1, to 3 heteroatoms; m is 0 to 5; p is O, l, or 2; q is 0 to 6; and r is 0 to 6.
The invention also provides a compound of formula (II):
Figure imgf000007_0001
π
and pharmaceutically acceptable salts thereof, where:
X° and X1 are independently absent, O, S, -CH2-, -CH2-CH2-, -CH=CH-, - CH≡CH- , -S(O)2- or-S(O)-; Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl;
Figure imgf000007_0002
-- is absent; or when present, — is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
1 to 4 atoms so that
Figure imgf000007_0003
, Ar , X , (CH )r, and Ar , together form a five to eight member ring; R3 and R4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, or-NR6R7; R5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R6 and R7 are each independently hydrogen, alkyl, alkenyj, alkynyl, -COalkyl,
-COaryl, cycloalkyl, -CO2alkyl, -CO2aryl, -SO2alkyl, -SO2aryl, or R6 and R7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms;
Figure imgf000008_0001
is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carbon atom of position 3 to form a five to eight member ring; m is 0 to 5; p is 0 to 2; q is 0 to 6; and r is 0 to 6.
In still another embodiment of the present invention, a mj≥thod of treating, preventing or controlling hypercholesteremia and dyslipidemia iiti a mammal is provided. The method comprises administering to the mammal in need thereof a therapeutically effective amount of the compounds of the present invention. Additionally, the compounds of the present invention are also useful in the method of the present invention for treating, preventing, or controlling obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes. Furthermore, the compounds of the present invention are also useful in the methods of supressing appetite in a mammal, modulating leptin levels in a mammal, and treating a patient exhibiting glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone. For each disease state treatable, preventable, or controllable bjy the method of the present invention, a therapeutically effective amount of the compounds of the present invention are administered to the mammal in need thereof.
In yet another embodiment of the present invention, a method for preparing compounds with Formulae I-II, or a pharmaceutically acceptable salt thereof, is provided. The method of this embodiment comprises reacting
Figure imgf000009_0001
in a solvent in the presence of a base such as cesium carbonate: with
Figure imgf000009_0002
where
X° is OH or SH;
V1
n, q, r, R1, R2, R3, R4, X1, * »- , Ar1 and Ar2 are as'defined above for
Formula I; RRππ is a lower alkyl; and X is a halogen. In yet another embodiment of the present invention, an alternative method for preparing compounds with Formulae I-II, or a pharmaceutically acceptable salt thereof, is provided. The method of this embodiment comprises reacting
Figure imgf000010_0001
where X is a halide, Ri-R have any of the meanings defined above, and Rn is a lower alkyl with:
Figure imgf000010_0002
V i 1 \ \ \ \ where — is a bond or is absent and wherein n, q, r, X°, X1 , -— , Ar1 and Ar2 are as defined above for Formula I; in the presence of a catalyst such as a palladium catalyst to form
Figure imgf000010_0003
where — is a bond or is absent. The double bond may optionally be removed, for instance, by hydrogenation and the resulting ester is preferably hydrolyzed to form the compounds of Formulas I or H.
In still another embodiment, the invention provides a processι|for preparing the compound of formula 1-4 which is:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, comprising:
(a) conversion of phenol 1 A to the thiocyante 1 B;
Figure imgf000011_0002
IA IB (b) alkylation of phenol moiety of thiocyanatej IB to acetoxyester
Figure imgf000012_0001
IB IC
(c) reduction of the thiocyanate moiety in IC to form thiol ID;
Reduction
Figure imgf000012_0002
Figure imgf000012_0003
IC ID
(d) alkylation of thiol ID with chloride 3C tolform 4a;
Figure imgf000012_0004
(e) saponification of the ester moiety in 4a to form 1-4; where R1 is hydrogen or together with R2 forms a 5 membered carbocyclic ring;
R2 is methoxy or together with R1 forms a 5 membered carbocyclic ring;
R3 is hydrogen or methyl;
R4 is hydrogen;
X1 is absent or O; and r is 0 or 1.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. denpte both straight and branched groups; but reference to an individual radical such as "propyl" embraces
I only the straight chain radical, a branched chain isomer such as I'isopropyl" being specifically referred to.
The term "alkyl" as used herein refers to a straight or branched hydrocarbon of from 1 to 11 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents selected from lower alkoxy, lower thioalkoxy, -O(CH2)1-sCF3, halogen, nitro, cyano, =O, =S, -OH, -SH, -CF3, -OCF3, -CO2H, -CO2C C6 alkyl, -NH2, -NHCrC6 alkyl, -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, akeriyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. Preferred alkyl groups have from 1 to 6 carbon atoms (CrC6 alkyl).
The term "lower alkyl" as used herein refers to a subset of alkyl which means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. Optionally, herein lower alkyl is referred to as "d- alkyl." The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl, or 1,1,1-trifluoroethyl and the like;. Haloalkyl can also include perfluoroalkyl wherein all hydrogens of a loweralkyl|gϋoup are replaced with fluorine atoms.
The term "alkenyl" means a straight or branched unsaturated hydrocarbon radical having from 2 to 12 carbon atoms and includes, for example, ethenyl, 1- propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3- butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1- decenyl, 1-undecenyl, 1-dodecenyl, and the like.
The term "alkynyl" means a straight or branched hydrocarbon radical having from 2 to 12 carbon atoms having at least one triple bond and includes, for example, 1-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, 3-methyl-3-butynyl, 1- hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1- dodecynyl, and the like.
The term "alkylene" as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1 ,2-ethylene, 1,1- ethylene, 1,3-propylene, 2,2- dimethylpropylene, and the like. The alkylene groups of this invention can be optionally substituted. The alkylene group can also be substituted with one or more of the substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2-5CF3, halogen, nitro, cyano, =O, =S, -OH, -SH,
-CF3, -CO2H, -CO2Cι-C6 alkyl, -NH2, -NHC,-C6 alkyl, -CONR'R", or -N(Cι-C6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring. Preferred alkylene groups have from 1 to 6 carbon atoms (Cι-C6 alkyl). The term "cycloalkyl" means a hydrocarbon ring containing from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, decalinyl, norpinanyl, and adamantyl. Where possible, the cycloalkyl group may contain double bonds, for example, 3-cyclohexen-l-yl. The cycloalkyl ring may be unsubstituted or substituted by 1 to 3 substituents selected from alkyl, alkoxy, thioalkoxy, hydroxy, thiol, nitro, halogen, amino, alkyl and di alkylamino, formyl, carboxyl, CN, -NH-CO-R', -CO-NHR'-, -CO2R', -COR', aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined herein. Examples of substituted cycloalkyl groups include fluorocyclopropyl, 2-iodocyclobutyl,
2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl, and 3-phenylcyclopentyl.
The term "heteroatom" as used herein represents oxygen, nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO2) unless otherwise indicated.
The term "heterocycloalkyl" means a monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring systems. Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms, with from 1 to 5 heteroatoms selected from N, O, and S, and preferably from 3 to 7 member atoms, in the ring. Bicyclic heterocyclics contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclics contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocyclics rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and substituted cyclic ethers, wherein the substituents are those described above for the alkyl and cycloalkyl groups. Typical substituted cyclic ethers include propyleneoxide, phenyloxirane (styrene oxide), cis- 2-butene-oxide (2,3-dimethyloxirane), 3-chlorotetrahydrofurani 2,6-dimethyl-l,4- dioxane, and the like. Heterocycles containing nitrogen are groups such as pyrrolidine, piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine, 4-methylpiperazin-l-yl, and the like. Typical sulfur containing heterocycles include tetrahydrothiophene, dihydro-1,3- dithiol-2-yl, and hexahydrothiepin-4-yl. Other commonly employed heterocycles include dihydro-oxathiol-4-yl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro- oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothiophene.
The term "hydrocarbon chain" as used herein refers to a straight hydrocarbon of from 2 to 6 carbon atoms. The hydrocarbon chain is optionally substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, - O(CH2)o-2CF3, halogen, nitro, cyano, =O, =S, -OH, -SH, -CF3, -CO2H, -CO2(Cι-C6 alkyl), -NH2, -NH -Ce alkyl, -CONR'R", or -N(Cι-C6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.
The term "aryl" means a cyclic or polycyclic aromatic ring having from 5 to
12 carbon atoms, and being unsubstituted or substituted with up 4 groups selected from CpC6 alkyl, cycloalkyl, heteroaryl, dialkylaminoalkoxy, orlthose recited above as substituents for alkyl. The term aryl includes both monovalenjt species, for example where Ar2 is aryl, and divalent species, for example where Ar1 is aryl. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3- methylphenyl, 2-chloro-4-methylphenyl, 2~chloro-5-methylphenyl, 3-chloro-2- methylphenyl, 3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl, 4-chloro-3- methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-trifluoromethyl and the like.
The term "heteroaryl" means an aromatic mono-, bi-, or or polycyclic ring incorporating one or more (i.e. 1-4) heteroatoms selected from N, O, and S. The term heteroaryl includes both monovalent species, for example where Ar2 is heteroaryl, and divalent species, for example where Ar1 is heteroaryl. It is understood that a heterocycle is optionally substituted with up to 4 groups selected from C]-C6 alkyl, cycloalkyl, heteroaryl, dialkylaminoalkoxy, or those recited above as substituents for alkyl. Examples of suitable monocyclic heteroaryl include, but are not limited to substituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazoiyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oxetaryl. Preferred monocyclic diheterocycles include, but are not limited to 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 3-, 4-, or 5-isothiazolyl, 3-, 4-, or 5- isoxazolyl, 1 , 3-, or 5-triazolyl, 1-, 2-, or 3-tetrazolyl, 2-pyrazinyl, 2-, 4-,1 or 5- pyrimidinyl, 1- or 2-piperazinyl, 2-, 3-, or 4-morpholinyl. Examples of suitable bicyclic and polyclic heteroaryl groups include, but are not limited to include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl,
2_, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, !_, 3_) 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8- cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-,
2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2_, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,jor 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-j or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-fr]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 1 l-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]- pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5Η-pyrido[2,3- J-σ-oxazinyl, 1-, 3-, or 5-1H- ρyrazolo[4,3--/]-oxazolyl, 2-, 4-, or 5-4H-imidazo[4,5-JJthiazolyl, 3-, 5-, or 8- pyrazino[2,3-Opyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,l-t>]thiazoIyl, 1-, 3-, 6-, 1-, B-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 1 l-4H-pyrido[2,3- cjcarbazolyl, 2-, 3-, 6-, or 7-imidazo[l,2-b][l,2,4]triazinyl, 7-benzo[b]thienyI, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8- benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 1 l-lH-pyrrolo[l,2- b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 1-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 1-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-,l 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl..
The term "hydrocarbon-heteroatom chain" as used herein refers to a hydrocarbon chain wherein one or more carbon atoms are replaced with a heteroatom. The hydrocarbon-heteroatom chain is optionally substituted with one or more substituents selected from lower alkyl, lower alkoxy, lower thioalkoxy, -O(CΗ2)o-
2CF3, halogen, nitro, cyano, =O, =S, -OH, -SH, -CF3, -CO2H, -CO2CrC6 alkyl, -NH2, -NHCi-Cό alkyl, -CONR'R", or -N(Cι-C6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.
The term "heteroalkylene" as used herein, refers to a aljkylene radical as defined above that includes one or more heteroatoms such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in thje carbon chain or terminating the carbon chain. The terms "lower alkoxy" and "lower thioalkoxy" as used herein refers to O- alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for "lower alkyl."
The term "cycloalkenyl" means a cycloalkyl group having one or more carbon-carbon double. Example includes cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclobutadiene, cyclopentadiene, and the like.
The symbol " '~ " means a bond to a group wherein a k to 8 membered ring is formed. Typically this symbol will appear in pairs.
When a bond is represented by a line such as " — " this is meant to represent that the bond may be absent or present provided that the resultant compound is stable and of satisfactory valency.
The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
A "therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of dyslipidemia, non-insulin dependent diabetes mellitus, obesity, fiyperglycemia, hypercholesteremia, hyperlipidemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia, glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone. Additionally, a "therapeutically effective amount" is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of an eating disorder, suppresses appetite, or modulates leptin levels. The term "a pharmaceutically acceptable salt" refers to the relatively non- toxic, inorganic and organic base or acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These also include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, di ethylamine, trirnethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M., et al., "Pharmaceutical Salts," J. Pharm. SJci., 1977;66:1-19, which is incorporated herein by reference.) The free base form may be regenerated by contacting the salt form with a base. While the free base may] differ from the salt form in terms of physical properties, such as solubility, the salts ,are equivalent to their respective free bases for the purposes of the present invention.
Compounds of the present invention are described by Formula I:
Figure imgf000021_0001
and pharmaceutically acceptable salts thereof, where:
X° and X1 are independently absent, O, S, -CH2- -CH2-CH2- -CH=CH-, - CH≡CH- , -S(O)2-, or -S(O)-; Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl; ' ✓'
\/'1 v-1
» \ \ \
\ \ -~ is absent; or when present, % — is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from
1 to 4 atoms so that
Figure imgf000021_0002
, Ar , X , (CH2)r, and Ar , together form a five to eight membered ring; R1 and R2 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, or -NR6R7, or together with the atoms to which they are attached form a five to eight member ring; R3 and R4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,-
O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, or -NR6^7; , provided that at least one of Rj-Ri is H, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkiyl, S(O)paryl, - (CH^OR5, -(CH^^R^ or NR^7; !
R5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
R6 and R7 are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl, -COaryl, cycloalkyl, -CO2alkyl, -CO2aryl, or R6 and R7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms; m is 0 to 5; p is O, l, or 2; q is 0 to 6; and r is 0 to 6.
In compounds of Formula I, R1 , R2, R3, and R4 are preferably selected from hydrogen, alkyl, or alkoxy. More preferably, R2and R3 are hyd gen; and R1 and R4 are alkyl or alkoxy. In a particularly preferred embodiment of Formula I, R2 and R3 are hydrogen; R1 is alkyl; and R4 is alkoxy. Preferred alkoxy include methoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy, n-butoxy, or isobutoxy. Similarly, preferred alkyl include methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl.
In a most preferred embodiment of Formula I, q is 1, Ar1 is phenyl, X1 is absent, r is 0, V1 is absent, and Ar2 is 4-trifluoromethylphenyl. V \ 1 \
\ \
In compounds of Formula I, "~— is preferably (CHJ_)t wherein t is 1 to 4.
yl
\ \
\ \
Additionally, ^— is optionally substituted with at least one substituent, wherein the substituent include but are not limited to lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2)o-2CF3, halogen, nitro, cyano, =O, =S, -OH, -SH, -CF3, -OCF3, -CO2H, -CO2Cι-C6 alkyl, -NH2, -NHC C6 alkyl, -CONR'R", or -N(CrC6alkyl)2 where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or joined together to form a 4 to 7 member ring.
1
In a preferred embodiment of Formula I, R and R are joined together to form a five to eight member ring having Formula II. Such a ring includes, for example, cycloalkyl, aryl, heterocycloalkyl, or a heteroaryl rings where each such ring is optionally substituted as described above.
Figure imgf000023_0001
π and pharmaceutically acceptable salts thereof, where: X° and X1 are independently absent, O, S, -CH2-, -CH2-iCH2- -CH=CH- - CH≡CH- , -S(O)2-, or -S(O)-;
Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl;
\ \ -- is absent; or when present, v-- is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from /'" v-'1 \
1 to 4 atoms so that - , Ar1, X1, (CH2)r, and Ar2, togetheπtorm a five to eight member ring;
R and R4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, -
(CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, or-NR6R7; R5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
Figure imgf000024_0001
are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl, -COaryl, cycloalkyl, -CO2alkyl, -CO2aryl, -SO2alkyl, -SO2aryl, or R6 and R7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms;
^- is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carbon atom of position 3 to form a five to eight member ring; m is 0 to 5; p is 0 to 2; q is 0 to 6; and r is 0 to 6.
Preferably, ^ is -CH2CH2CO-O-, -CH2-CH2-O-CO-, -GH2-CH2-CH2-CH2-, -HC=CH-HC=CH-, -N=CH-HC=CH-, -HC=N-HC=CH-, -HC=CH-N=CH-, - HC=CH-HC=N-, -CH2-CH2-CH2-, -CH2-CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2- HC=CH-CH2-, -CH2-HC=CH-, -CH2CH2-N R4-CH2-, -COCH=CH-O-, -O-CH=CH- CO-, -CH=CH-NR4-, -NR4-CH=CH-, -CH=CH-CH2-, -CH2-CH2-NR4-, -NR4-CH2-
CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2.CO-, -CH2-CO-CH2-, -CO-CH2-CH2-, -CH2-CH2-CH2-CO-, -CO-CH2-CH2-CH2-, -CH2-CO-CH2-CH2-, -CH2-CH2-CO-CH2, -CH2-CH2-CH2-NR4-, -NR4-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-, -CO-NR4-CH2-CH2-, NR4CO-CH2-CH2-, -CH2-CH2.NR4-CO-, or -CH2-CH2-CO- NR4-. It will be understood that the left-most atom of these groups in attached to the atom labeled "3" in Formula I and the right-most atom of these groups is attached to the atom label "2" in Formula I.
In the present embodiment, ^- is optionally substituted! with 1 or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower thioalkoxy, -O(CH2-5CF3, halogen, nitro, cyano, =O, =S, -OH, -SH, -CF3, -CO2H,
-CO2C,-C6 alkyl, -NR,, -NHC,-C6 alkyl, -OCH2O-, and -N(CfC6alkyl)2.
In compounds of Formula π, R3, and R4 are preferably selected from
hydrogen, alkyl, or alkoxy. More preferably, R3 and R4 are hydrogen; and
Figure imgf000025_0001
is a saturated or unsaturated, unsubstituted hydrocarbon chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carboϋ atom of position 3 to form a five to eight member ring such as a cyclopentyl or cyclohexyl ring. In a most preferred embodiment of Formula II, q is 1, Ar1 is phenyl, X1 is !θ, r is 1, V1 is absent, and Ar2 is 4-trifluoromethylphenyl.
V1
\ \
Also in this embodiment, -— is preferably (CH2)t wherein t is 1 to 4.
\ \ \
Additionally, *--- is optionally substituted with at least one substituent, wherein
Figure imgf000026_0001
where R' and R" are independently alkyl, akenyl, alkynyl, aryl,[ or joined together to form a 4 to 7 member ring.
Examples of compounds of Formula I and Formula II include
[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;
[4-(Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid; [2-Methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]- acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(2',4',6'-trimethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid; [4-(4'-Chloro-3,-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2-methyl- phenoxyj-acetic acid;
[4-(2',4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl- phenoxyj-acetic acid;
[4-(3',4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl- phenoxy]-acetic acid; [5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid;
[4-(4'-FIuoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]- acetic acid;
[5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl- -ylmetriylsulfanyl)- phenoxyj-acetic acid;
[7-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid;
[4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid;
{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]- phenoxy} -acetic acid;
{ 2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulf anyl]-phenoxy } - acetic acid; [5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3-ylmethylsulfanyI)- phenoxyl-acetic acid;
[4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]-acetic acid; { { 5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridinf 2-yl)-benzylsulf anyl]- phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3- ylmethylsulfanyl]-phenoxy} -acetic acid; l
[5-Chloro-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid; [3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]- acetic acid;
{ 2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy } - acetic acid;
{5-Methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biphenyl-J4-yl)-ethylsulfanyl]- phenoxy} -acetic acid; {2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy}-acetic acid;
{2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-ethyl]-phenoxy}-acetic acid;
{7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;
{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4- yloxy} -acetic acid;
[5-Methyl-7-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]- acetic acid; (4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl- phenoxy)-acetic acid;
{2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsjulfanyl]-phenoxy}- acetic acid;
{4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid;
{4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid;
{4-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid;
{2-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)-benzylsulfanyl]-phenoxy}- acetic acid; {6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5- yloxy} -acetic acid;
{5-Chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]- phenoxy} -acetic acid;
[5-hydroxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxyj-acetic acid;
[5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid;
{ 7-[4-(4-trifluoromethyl-benzyl)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl- phenoxy} -acetic acid;
{2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]- phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfanyl]-phenoxy}-acetic cid; {7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3-ylmethyls lfanyl]-indan-4- yloxy} -acetic acid;
{2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]- phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyI-phenyl)-isoxazol-5- yl ethylsulfanylj-phenoxy }-acetic acid;
[2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid;
[7-(4'-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)- phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4!-ylmethanesulfonyl)- phenoxyj-acetic acid; [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethanesulfinyl)- phenoxy]-acetic acid;
[2-Propyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;
{7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid; (5-Methoxy-2-methyl-4-{2-[l-(4-trifluoromethyl-benzyl)-lH-indol-3-yl]- ethylsulfanyl } -phenoxy)-acetic acid;
[7-(4'-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid;
{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]- phenoxy} -acetic acid;
{ 4-[4-(4-Fluoro-benzyloxy)-benzylsulf anyl]-2-methyl-phenoxy } -acetic acid;
{4-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid;
4-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid;
{2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]-phenoxy}-acetic acid;
{5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]- phenoxy} -acetic acid;
{ 7-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{ 7-[4-(4-Trifiuoromethyl-benzyloxy)-benzylsulf anyl]-iη'dan-4-yloxy } -acetic acid;
{5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid; {7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy} -acetic acid;
{ 7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid; {7-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;
{ 7-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
[7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid;
{7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4-yl(j)xy}-acetic acid;
{ 7-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{7-[4-(3,4-Dichloro-beπzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;
{7-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy} -acetic acid;
{7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid;
{ 7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{7-[4-(4-Fluoro-2-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy} -acetic acid; (7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;
{7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid; { 7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{7-[3-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid;
{ 7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy } -acetic acid;
{7-[3,5-Dichloro-4-(4-trifluoromethyl-benzyloxy)-benzylsulfonyl]-indan-4- yloxyj-acetic acid;
{8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}- acetic acid; {8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}- acetic acid;
{8-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-chroman-5-yloxy}-acetic acid;
{ 8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5-yloxy } - acetic acid; {7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy}-acetic acid;
{7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethylsulfanyl]-indan-4- yloxy} -acetic acid;
{7-[3-(4-Trifluoromethyl-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4- yloxy} -acetic acid;
{7-[2-(4'-Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]7indan-4-yloxy}-acetic acid;
{ 7-[2-(4'-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan- -yloxy } -acetic acid;
{5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2, 3-dihydro- benzofuran-4-yloxy} -acetic acid;
[8-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5-yloxy]-acetic acid; {8-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-chroman-5-yloxy}- acetic acid;
{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}- acetic acid;
{ 7-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-indan-4-yloxy } -acetic acid;
{7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-indan-4-yloxy}-acetic acid;
{5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isΘxazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid; 2-[2-butyl-4-({4-[4- (trifluoromethyl)phenyl]phenyl } methylthio)phenoxy]acetic acid;
{6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzyl-sulfanyl]-chroman-5- yloxy} -acetic acid;
{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8- tetrahydro-naphthalen- 1 -yloxy } -acetic acid; (4- { 2-Butyl-5-chloro- 1 -[4-( 1 -cyano-cyclopentyl)-benzyl]- 1 H-imidazol-4- ylmethylsulfanyl }-2-methyl-phenoxy)-acetic acid;
[4-(5-Biphenyl-4-yl-2-thiophen-2-yl-4,5-dihydro-oxazp[l-4-ylmethylsulfanyl)- 5-methoxy-2-methyl-phenoxy]-acetic acid; '
{4-[2-(4-Bromo-phenoxy)-ethylsulfanyl]-2,6-dimethyl-phenoxy}-acetic acid;
[4-(3-{2-[4-(2-Diethylamino-ethoxy)-phenyl]-benzimidazol-l-yl}- propylsulfanyl)-5-methoxy-2-methyl-ρhenoxy]-acetic acid;
[4-(5-Biphenyl-4-yl-2-thiophen-2-yl-4,5-dihydro-oxazol-4-ylmethylsulfanyl)- 2-methyl-phenoxy]-acetic acid;
(4-{2-[3-(4-Ruoro-phenyl)-benzo[b]thiophen-7-yl]-ethylsulfanyl}-2-methyl- phenoxy)-acetic acid;
{ 2-Methyl-4-[2-(5-phenyl-naphthalen- 1 -yloxy )-ethylsulf anyl] -phenoxy } - acetic acid; [2-Methyl-4-(3-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid;
[2,5-Dimethyl-4-(5-p-tolyl-l,3,4-oxadiazol-2-ylmethylsulfanyl)-phenoxy]- acetic acid; [2-Methyl-4-(4-pyrazol-l -yl-benzylsulfanyl)-phenoxy]|acetic acid;
[2-Methyl-4-(5-methyl-3-phenyl-isoxazol-4-ylmethylsulfanyl)-phenoxy]- acetic acid; [4-(Biphenyl-2-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid;
{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}- acetic acid; [2-Methyl-4-(5-p-tolyl-l,3,4-oxadiazol-2-ylmethylsulfanyl)-phenoxy]-acetic acid;
{4-[3-(4-Chloro-phenyl)-l,2,4-oxadiazol-5-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid;
[2,5-Dimethyl-4-(4-pyrazol- 1 -yl-benzylsulfanyl)-phenox Jy]-acetic acid;
[4-(Biphenyl-2-ylmethylsulfanyl)-2,5-dimethyl-phenoxyJ-acetic acid;
[4-(4-Benzyloxy-benzylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-l-yloxy]- acetic acid;
[4-(4-Benzyloxy-benzylsulfanyl)-2,6-dimethyl-phenoxy]-acetic acid;
[4-(4-Benzyloxy-benzylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid;
[4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid; [4-(4-Benzyloxy-benzylsulfanyl)-phenoxy]-acetic acid;
[4-(Biphenyl-4-ylmethylsulfanyl)-5,6,7,8-tetrahydro-naphthalen-l-yloxy]- acetic acid; [4-(Biphenyl-4-ylmethylsulfanyl)-2,6-dimethyl-phenoxy]-acetic acid;
[4-(Biphenyl-4-ylmethylsulfanyl)-2,5-dimethyl-phenqxy -acetic acid;
[4-(Biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid;
{4-[3-(2-Fluoro-phenoxy)-benzylsulfanyl]-2,6-dimethyl phenoxy}-acetic acid;
[4-(2-{4-[2-(3-Chloro-4-cyclohexyl-phenyl)-ethyl]-piperazin-l-yl}- ethylsulfanyl)-2-methyl-phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(2-{4-[2-(3-phenyl-benzofuran-7-yl)-ethyl]- piperazin-1 -yl }-ethylsulfanyl)-phenoxy]-acetic acid; {4-[2-(2,6-Diphenyl-piperidin-l-yl)-ethylsulfanyl]-5-methoxy-2-methyJ- phenoxy} -acetic acid;
[2-Methyl-4-(2-{4-[2-(3-phenyl-benzofuran-7-yl)-ethyl]-piperazin-l-yl}- ethylsulfanyl)-phenoxy]-acetic acid; { 4-[2-(2,6-Diphenyl-piperidin- 1 -yl)-ethylsulf anyl]-2-methyl-phenoxy } -acetic acid; and pharmaceutically acceptable salts thereof.
A subset of exemplary compounds of Formula I and Formula II include
[4-(Biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid; [4-(2',4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl- phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxy]-acetic acid;
[4-(4'-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2fmethyl-phenoxy]- acetic acid;
[7-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-indan-4-yloxy]-acetic acid;
{5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]- phenoxy} -acetic acid; [5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)- phenoxy]-acetic acid;
{ {5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]- phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3- ylmethylsulfanylj-phenoxy} -acetic acid;
[3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]- acetic acid;
{5-Methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biph nyl-4-yl)-ethylsulfanyl]- phenoxy} -acetic acid; (4- { 4- [2-(3-Euoro-phenyl)- vinyl] -benzyl sulf anyl } -5-methoxy-2-methyl- phenoxy)-acetic acid;
[5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid; {4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-methoxy-2-methyl- phenoxy}-acetic acid;
{5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfanyl]-phenoxy}-acetic acid;
{ 5-Methoxy-2-methyl-4- [3-(4-trifluoromethyl-phenyl)-i|oxazol-5- ylmethylsulfanyl]-phenoxy}-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)- phenoxy]-acetic acid;
{7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid; { 5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-2, 3-dihydro- benzofuran-4-yloxy} -acetic acid; and pharmaceutically acceptable salts thereof.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
In some situations, compounds may exist as tautomers. All tautomers are included within Formulas I and II and are provided by this invention. In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The present invention includes all pharmaceutically acceptable, nonn-toxic esters of the compounds of Formulae I and II. Such esters include Cι-C6 alkyl esters where the alkyl group is a straight or branched chain. Acceptable esters also include C5-G7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. d~C esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
The compounds of the present invention are suitable to be administered to a patient for the treatment, control, or prevention of hypercholesteremia, dyslipidemia, obesity, hyperglycemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, and hyperinsulinemia. The compounds of the present invention ,are also suitable to be administered to a patient for the supression of appetite and modulation of leptin. Accordingly, the compounds may be administered to a patient alone or as part of a composition that contains other components such as excipients,| diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and/or animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polvethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosteara and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
(c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate;
(h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be |of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositionjs which can be used are polymeric substances and waxes. The active compounds can also be in micro- encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1 ,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and i sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylenegljycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacaπth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 2,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 10 mg per kilogram of body weight per day is preferable. However, the specific dosage used can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. PREPARATION OF COMPOUNDS OF THE INVENTION The present invention contains compounds that can be synthesized in a number of ways familiar to one skilled in organic synthesis. The compounds outlined herein can be synthesized according to the methods described below, along with methods typically utilized by a synthetic chemist, and combinations or variations of those methods, which are generally known to one skilled in the art of synthetic chemistry. The synthetic route of compounds in the present invention is not limited to the methods outlined below. It is assumed one skilled in the art will be able to use the schemes outlined below to synthesize compounds claimed in this invention. Individual compounds may require manipulation of the conditions in order to accommodate various functional groups. A variety of protecting groups generally known to one skilled in the art may be required. Purification, if necessary, can be accomplished on a silica gel column eluted with the appropriate organic solvent system. Also, reverse phase HPLC or recrystallization may be| employed.
Many of the compounds with Formulas I and II are preferably made by reacting:
Figure imgf000041_0001
in a solvent in the presence of a base such as cesium carbonate, with the aryl halide:
Figure imgf000042_0001
wherein: n, R1, R2, R3, R4, X°, X], V1, Ar1, and Ar2 are the same aj. defined above for Foπnula I;
Rn is a lower alkyl; and X is a halogen.
The resulting ester is then preferably hydrolyzed to form the compounds of Formulas I and II. Specifically, compounds of Formulas I and II can be prepared using the synthetic route outlined in Scheme 1-6.
Scheme 1 covers the preparation of compounds of Formulas I and II wherein
\ \
X° is S, q is 0-3, ~— is absent, X1 is absent and r is 0.. Compounds of the general formula A are thiocyanated with a mixture of bromine and sodium thiocyanate to give compounds of the general formula B. Compounds of the general formula B are then alkylated with an alkyl haloacarboxylate to give compounds of the general formula C. The preferred alkyl haloacarboxylate is methyl bromoacetate. Alternate routes to compounds of formula C will be readily apparent to a person skilled in the art of organic synthesis. Compounds of the general formula D are then prepared by reduction of C with dithiothreitol in methanol. Compounds of the general formula D are then alkylated with compounds of the general formula Y in the same manner as for B to give E. Compounds of the general formula Y are prepared as described in Scheme 7 (below) or are readily available from commercial sources. Compounds of the general formula E are then saponified with l iOH in the THF to give the final compound F.
Scheme 1
Figure imgf000043_0001
C D
Figure imgf000043_0002
Scheme 2 covers the preparation of compounds of Formula I-II wherein X° is
V1
O, q is 0-3, X is absent, "*-— is absent, and r is 0. Compounds of the general formula A are alkylated with an alkyl haloacarboxylate to give compounds of the general formula G. The preferred alkyl halocarboxylate is methyl bromoacetate. Alternate routes to compounds of formula G when Y is O will be readily apparent to a person skilled in the art of organic synthesis. Compounds of the general formula G are then acylated using Friedel-Crafts conditions to give compounds of the general formula H which are then oxidized with m-chloroperoxybenzoic acid followed by hydrolysis to give phenolic compounds of the general formula I. Compounds of the general formula I are then reacted in a similar manner as for D to give after saponification with LiOH in THF, compounds of the general formula K.
Scheme 2
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0003
Scheme 3 covers the preparation of compounds of formula I-II wherein X° is
v I'1' \ \ \ \
— CH2-CH2- _ — c=C— , q is 0-3, X1 is absent, "—- is absent, and r is 0. Compounds of the general formula A are brominated with bromine, using acetic acid as solvent to give L. Alternatively, N-bromosuccinimide may be used in place of bromine and dichloromethane in place of acetic acid as solvent.11 Compounds of the general formula L are then alkylated with an alkyl haloacarboxylate to give compounds of the general formula M. The prefened alkyl halocarboxylate is methyl bromoacetate. Alternate routes to compounds of formula M will be readily apparent to a person skilled in the art of organic synthesis. Compounds of the general foπnula M are then reacted in the presence of tetrakis (triphenylphosphine)palladium(O) and biphenyl compounds of the general formula EE to give compounds of the general formula N. Compounds of the general formula EE are prepared as described in Scheme 9 or are readily available from commercial sources. Compounds of the general formula N are then saponified with LiOH in THF to give the final compound O.
Scheme 3
R1i Cs2C03/CH3CN alkylation
Figure imgf000046_0002
Figure imgf000046_0001
L M
Figure imgf000046_0003
Scheme 4 covers the preparation of compounds of formula I-II wherein X° is
V1
CH2-CH2t q js 0-3, X1 is absent, ~— is absent, and r is 0. Accordingly, compounds of the general N can be reduced with hydrogen and palladium as catalyst to give compounds of the general formula P which are then saponified LiOH in THF to give the final compound Q.
Scheme 4
Figure imgf000047_0001
N P Q
Scheme 5 covers the preparation of compounds of formula I-II wherein X° is
V1
absent, q is 0, X1 is absent, "-— is absent, and r is 0 are prepared. Compounds of the general foπnula M are allowed to react with tetrakis (triphenylphosphine) palladium(O) and biphenyl compounds of the general formula HH to give compounds of the general formula R. Compounds of the general formula HH are prepared as described in Scheme 10 or are readily available from commercial sources. Compounds of the general formula R are then saponified with LiOH in THF to give the final compound S.
Scheme 5
Figure imgf000048_0001
M HH
Figure imgf000048_0002
With reference to Scheme 6, compounds of formula I-II wherein X is S or O, q is 1-3, X1 is O, and r is 1-3 are prepared using the same conditions utilized for the preparation of K.
Scheme 6
Figure imgf000048_0003
With reference to Scheme 7, compounds of the general formula X are prepared by reacting aryl boronic acid W with aryl bromide V in the presence of Pd(0) and cesium carbonate. Compounds of the general formula) X are then reacted with methanesulfonyl chloride to give chlorides of the general fojrmula Y.
Scheme 7
Figure imgf000049_0001
V W X Y
With reference to Scheme 8, compounds of the general formula CC are prepared wherein an appropriate hydroxy benzyl alcohol AA is alkylated with an appropriate bromide Z. The resulting compound BB is then reacted with methanesulfonyl chloride to give chlorides of the general formula CC.
Scheme 8
Figure imgf000049_0002
AA BB CC
With reference to Scheme 9, compounds of the general foπnula EE are prepared by reacting aryl boronic acid V with aryl bromide DD in the presence of Pd(0) and cesium carbonate. Scheme 9
Figure imgf000050_0001
DD EE
With reference to Scheme 10, compounds of the general formula HH are prepared by reacting aryl bromide V with boronic acid FF to εive GG. Compounds of the general formula GG are then reacted with an alkyl lithiu|m reagent and then quenched with a borate which is hydrolyzed to give compoundjs of the general foπnula HH.
Scheme 10
Figure imgf000050_0002
FF GG HH
With reference to Scheme 11 , compounds of formula I-II wherein X° is S or O, q is 1-3, X1 is absent, r is 0, and V1 is a saturated or unsaturjated hydrocarbon chain which is substituted or unsubstituted are prepared using theisajfne conditions utilized for the preparation of K. Compounds of the general formula PJiTN are prepared as described in Scheme 12 or are readily available from commercial sources. Scheme 11
Figure imgf000051_0001
With reference to Scheme 12, compounds of the general formula NN can be prepared by reacting an appropriately substituted aryl amine LL under Sandmeyer conditions followed by heating to give intermediate MM. The resulting intermediate MM is then reacted with methanesulfonyl chloride to give chlorides of the general foπnula NN.
Scheme 12
Figure imgf000051_0002
LL MM NI N
Not all compounds of Formulas I-II falling into a giveri| class, may be compatible with some of the reaction conditions described. Such restrictions are readily apparent to those skilled in the art of organic synthesis, and alternative methods must then be used.
The following non-limiting descriptions also demonstrate methods for the synthesis of compounds of Formulae I and II. Example 1
Synthesis of r4-(BiphenvI-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy1- acetic acid (compound 1)
Figure imgf000052_0001
Step 1. Preparation of 5-Methoxy-2-methyl-phenol (compound IA)
Figure imgf000052_0002
2-Hydroxy-4-methoxy-benzaldehyde (3 g, 19.7 mmol), ammonium formate (6.2 g, 99 mmol) and palladium/carbon (900 mg @ 10%) were added to 26 ml glacial acetic acid and heated at 110 °C for 1 h. The reaction was cooled, filtered, and diluted with water (100 ml). The crude product was extracted with chloroform (3x50 ml), washed with water, brine, and dried over anhydrous sodium sulfate. The resulting solution was concentrated and used for the next step without further purification. MS m/z 139 (M+l). Step 2. Preparation of 5-Methoxy-2-methyl-4-thiocyanato-phenoI (compound
IB)
Figure imgf000053_0001
IB
The product from Example IA (3.5 g, 25 mmol), sodium thiocyanate (6.48 g, 80 mmol), and sodium bromide (2.6 g, 25 mmol) were dissolved i]n 30 ml anhydrous methanol. Bromine (4.4 g, 28 mmol) was added drop wise over 15 minutes and allowed to stir at ambient temperature for 1 h. Brine was added (50 ml) and the crude product was extracted into ethyl acetate (3x100 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, decanted, and concentrated to afford the title product in good purity. 400 MHz 1H NMR (DMSO- ck) 5 30.13 (s, 1H), 7.25 (s, 1H), 6.54 (s, 1H), 3.77 (s, 3H), 2.0 (s, 3H); MS m z 196 (M+l).
Step 3. Preparation of (5-Methoxy-2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (compound IC)
Figure imgf000053_0002
IC
The product from Example IB (620 mg, 3.2 mmol), methyl bromoacetate (854 mg, 3.5 mmol), and cesium carbonate (3.1 g, 9.6 mmol) were stirred in 10 ml anhydrous acetonitrile at ambient temperature for 1 h. The reaction was filtered through Celite®, concentrated, and purified using normal phase chromatography. 400 MHz 1H NMR (DMSO- ) δ 7.33 (s, 1H), 6.72 (s, 1H), 4.93 (s, 2H), 3.84 (s, 3H), 3.66 (s, 3H), 2.09 (s, 3H); MS w z 268 (M+l).
Step 4. Preparation of (4-Mercapto-5-methoxy-2-methyJ-phenoxy)-acetic acid methyl ester (compound ID)
Figure imgf000054_0001
The product from Example IC (1.1 g, 4.1 mmol) and dithiothreitol (824 mg, 5.4 mmol) were dissolved in 20 ml methanol with 2.5 ml water. The solution was refluxed for 4 h, cooled, concentrated, and purified by normal phase chromatography. 400 MHz ]H NMR (DMSO-d6) δ 7.02 (s, 1H), 6.54 (s, 1H), 4.79 (s, 2H), 4.41 (s, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 2.02 (s, 3H); MS m/z 243 (M+l).
Step 5. Preparation of 4-Bromomethyl-biphenyl (compound IE)
Figure imgf000054_0002
IE
Biphenyl-4-yl-methanol (500 mg, 2.72 mmol) phosphorus tribromide (809 mg, 2.99 mmol), and lithium bromide (260 mg, 2.99 mmol) were dissolved in 10 ml DMF and stirred at ambient temperature for 1 h. Water (10 ml) was added and the crude product was extracted into dichloromethane, dried over anhydrous sodium sulfate, filtered through silica gel, and concentrated. MS m/z 167 (M+l-Br). Step 6. Preparation of [4-(Biphenyl-4-ylmethyIsuIfanyl)-5-methoxy-2-methyI- phenoxy]-acetic acid methyl ester (compound IF)
Figure imgf000055_0001
IF
The product from Example ID (100 mg, 0.38 mmol), the product from Example IE (92 mg, 0.38 mmol) and cesium carbonate (250 mg, 0.76 mmol) were added to 5 ml acetonitrile and stiπed at ambient temperature for 4 hr. The reaction was filtered through Celite®, concentrated and purified through normal phase chromatography. MS m/z 409 (M+l).
Step 7. Preparation of [4-(Biphenyl-4-ylmethylsulfanyl)-5-ιnethoxy-2-methyl- phenoxy]-acetic acid (compound 1)
The product from Example IF (101 mg) was dissolved in 10 ml THF /water solution
(10:1). Lithium hydroxide monohydrate (300 mg) was added and stirred for 30 minutes. 2 Normal aqueous HCl was added to pH<5 and then washed with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, decanted, and concentrated. The title product was recrystallized from chloroform/hexanes. mp 60- 62 °C; 400 MHz ]H NMR (DMSO-rf6) δ 12.94 (br(s), 1H), 7.58 (d, 2H, J = 8 Hz),
7.52 (d, 2H, J = 8 Hz), 7.39 (t, 2H, J = 7.2 Hz), 7.30 (m, 3H), 7.02 (s, 1H), 6.52 (s, 1H), 4.69 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z 393 (M-l). Anal. Calc'd for C32H22O4S-3H2O C, 69.05; H, 5.07; found: C, 69.04; H, 5.35. Example 2
Synthesis of r4-(Biphenyl-4-vImethylsu]fanyl)-2-methyl-phenoxy1-acetic acid (compound 2)
Figure imgf000056_0001
Step 1. Preparation of 2-Methyl-4-thiocyanato-phenol (compound 2A)
Figure imgf000056_0002
2A
The title compound was prepared in a manner analogous to Example IB from 2- methylphenol. 400 MHz 1H NMR (DMSO-ci6) δ 10.09 (s, IH), 7.36 (s, IH), 7.30 (d,
IH, J = 8.1 Hz), 6.83 (d, IH, = 8.1 Hz), 2.08 (s, 3H); MS m/z 166 (M+l).
Step 2. Preparation of (2-Methyl-4-thiocyanato-phenoxy)-ajcetic acid methyl ester (compound 2B)
Figure imgf000056_0003
2B
The title compound was prepared from 2 Example 2A in a manner analogous to Example IC. 400 MHz ]H NMR (DMSO-d6) δ 7.46 (s, IH), 6.95 (d, IH, J = 8.5 Hz), 6.80 (d, IH, J = 8.5 Hz), 4.86 (s, 2H), 3.65 (s, 3H), 2.17 (s, 3H); MS m/z 238 (M+l).
Step 3. Preparation of (4-Mercapto-2-methyl-phenoxy)-acetic acid methyl ester (compound 2C)
Figure imgf000057_0001
2C
The title compound was prepared from (2-methyl-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example ID. 400 MHz ]H NMR (DMSO-de) δ 7.05 (s, lH), 7.00 (d, 1H, 7 = 10.3 Hz), 6.70 (d, IH, J= 10.3 Hz), 5.00 (s, 1H), 4.73
(s, IH), 3.63 (s, 3H), 2.09 (s, 3H); MS m/z 213 (M+l).
Step 4. Preparation of [4-(BiphenyI-4-ylmethylsulfanyI)-2-methyl-phenoxy]- acetic acid methyl ester (compound 2D)
Figure imgf000057_0002
2D
The title compound was prepared in the manner analogous to Example IF using 2C and IE. MS m z 379 (M+l).
Step 5. Preparation of [4-(Biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]- acetic acid (compound 2)
The title compound was prepared in the manner analogous to Example 1. mp 138 °C; 400 MHz 1H NMR (DMSO-J6) δ 7.59 (d, 2H, J = 9.5 Hz); 7.53 (d, 2H, J = 9.5 Hz), 7.40 (m, 2H), 7.31 (m, 3H), 7.14 (d, IH, 7= 1.7 Hz), 7.09 (d, IH, J = 10.7 Hz), 6.70 (d, IH, J= 10.7 Hz), 4.62 (s, 2H), 4.11 (s, 2H), 2.09 (s, 3H); MS /z 363 (M-l).
Example 3
Synthesis of r2-Methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxyl-acetic acid (compound 3)
Figure imgf000058_0001
3 Step 1. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-ήιethanol (compound
3A)
Figure imgf000058_0002
3A
l-Bromo-4-trifluoromethyl -benzene (814 mg, 3.62 mmol), 4- hydroxymethylphenylboronic acid (600 mg, 3.98 mmol), cesium carbonate (2.36 g, 7.24 mmol), and PdCl2(dρpf) (132 mg, 0.181 mmol) were added to 10 ml of a 1:1 solution of DMF THF. The reaction was flushed with nitrogen and heated to 90°C for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2x50 ml), brine (1x50ml) and dried over anhydrous sodium sulfate. The crude product was filtered through silica gel, eluted with diethyl ethejr, and concentrated to provide the title compound. MS m/z 251 (M-l). Step 2. Preparation of 4-Chloromethyl-4'-trifluoromethyl-biphenyl (compound 3B)
Figure imgf000059_0001
3B
The product from Example 3A was dissolved in 10 ml methylene chloride. Triethylamine (468 mg, 4.62 mol) and methanesulfonyl chloride (422 mg, 3.68 mmol) were then added and stiπed for 18 h. The reaction wasj poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the title compound that was used without further purification. MS m/z 235 (M-Cl+1).
Step 3. Preparation of [2-Methyl-4-(4'-trifluoromethyl-biphenyl-4- yImethylsulfanyI)-phenoxy]-acetic acid methyl ester (compound 3C)
Figure imgf000059_0002
3C
The title compound was prepared in the manner analogous to|Example IF using 3B and 2C. MS m/z 447 (M+l).
Step 4. Preparation of [2-Methyl-4-(4'-trifluoromethyI-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 3)
The title compound was prepared in the manner analogous to Example 1 using 3C. mp 140-141 °C; 400 MHz 1H NMR (DMSO- ) δ 12.95 (br(s), IH), 7.82 (d, 2H, J ■ 8.4 Hz), 7.74 (d, 2H, J= 8.4 Hz), 7.61 (d, 2H, J = 8.4 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.10 (m, 2H), 6.70 (d, IH, 7= 8.4 Hz), 4.62 (s, 2H), 4.13 (s, 2H), 2.08 (s, 3H); MS m/z 431 (M-l). Anal. Calc'd for C23H,9F3O3S-0.7 H2O C, 62.07; H, 4.62; found: C, 61.98; H, 4.22.
Example 4
Synthesis of r5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanvD-phenoxyl-acetic acid (compound 4)
Figure imgf000060_0001
Step 1. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyI-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 4A)
Figure imgf000060_0002
4A
The title compound was prepared in the manner analogous to Example IF using ID and 3B. MS m/z 477 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 4) The title compound was prepared in the manner analogous to Example 1 using 4A. mp 170-171 °C; 400 MHz 1H NMR (DMSO- ) 67.81 (d, 2Kj J = 8 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.4 Hz), 7.02 (s, IH), 6.52 (s, llH), 4.70 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 2.00 (s, 3H). MS m/z 463 (M+l). Anal. Calc'd for C24H21F3NO4S -0.1 H2O C, 62.09; H, 4.60; found: C, 62.00; H, 4.36.
Example 5
Synthesis of r5-Methoxy-2-methyl-4-(2'.4'.6'-trimethyl-biphenyl-4- ylmethylsuIfanvP-phenoxyl-acetic acid (compound 5)
Figure imgf000061_0001
Step 1. Preparation of [5-Methoxy-2-methyl-4-(2',4',6'-trimethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 5A)
Figure imgf000061_0002
5A
2-Bromo-l,3,5-trimethyl-benzene (396 mg, 2mmol), 4-hydroxymethylphenylboronic acid (334 mg, 2.2 mmol), cesium carbonate (1.3 g, 4 mmol), and PdCI2(dppf) (82 mg,
0.1 mmol) were added to 5 ml of a 1:1 solution of DMF/THF. The reaction was
I ' j flushed with nitrogen and heated to 90°C for 1 h. The reaction was cooled, poured into diethyl ether and washed with water (2x10 ml), brine (lxl 0ml) and dried over anhydrous sodium sulfate. The organic solution was filtered through silica gel, eluted with diethyl ether, and concentrated. The crude product was dissolved in 10 ml dichloromethane. Added to this solution were triethylamine (202 mg, 2 mmol) then methanesulfonyl chloride (184 mg, 1.6 mmol) and allowed to stir at ambient temperature for 18 h. The reaction was poured into water and extracted with methylene chloride. The organic solution was dried over anhydrous sodium sulfate, decanted and concentrated to provide the crude alkyl chloride. The product from Example ID (387 mg, 1.6 mmol), the crude 4'-chloromethyl-2,4,6-trimethyl- biphenyl, and cesium carbonate (1 g, 3.06 mmol) were stiπed in 10 ml acetonitrile for 3h, filtered, concentrated, and purified by normal phase chromatography to afford the title product. MS m/z 451 (M+ 1 ).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(2I,4',6'-trimethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid
The title compound was prepared in the manner analogous to Example 1 using 5A. mp 141 °C; 400 MHz 1H NMR (DMSO- ) δ 12.81 (br(s), IH), 7.04 (d, 2H, J = 8.4 Hz), 6.77 (m, 3H), 6.69 (s, 2H), 6.36 (s, IH), 4.43 (s, 2H), 3.82 (s, 2H), 3.58 (s, 3H), 2.03 (s, 3H), 1.82 (s, 3H), 1.67 (s, 6H). MS m/z 437 (M+l).
Example 6
Synthesis of r4-(4'-Chloro-3'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2- methyl-phenoxyl-acetic acid (compound 6)
Figure imgf000062_0001
Step 1. Preparation of (4'-Chloro-3,-trifluoromethyl-biphenyl-4-yl)-methanol (compound 6A)
Figure imgf000063_0001
6A
The title compound was prepared in the manner analogous to Example 3A using 4- bromo-l-chloro-2-trifluoromethyl-benzene. MS m/z 288 (M+l).
Step 2. Preparation of 4-Chloro-4'-chloromethyl-3-trifluoromethyl-biphenyl (compound 6B)
Figure imgf000063_0002
6B
The title compound was prepared in the manner analogous to Example 3B using 6A. MS m/z 305 (M).
Step 3. Preparation of [4-(4'-Chloro-3"-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (compound 6C)
Figure imgf000063_0003
6C The title compound was prepared in the manner analogous to Example IF using 2C and 6B. MS /z 481 (M+l).
Step 4. Preparation of [4-(4'-Chloro-3'-trifluoromethyl-biphenyl-4- yImethylsulfanyl)-2-methyl-phenoxy]-acetic acid (compound 6)
The title compound was prepared in the manner analogous to Example 1 using 6C. 400 MHz 1H NMR DMSO-d6) δ 7.97 (s, IH), 7.92 (d, IH, 7= 10.5 Hz), 7.74 (d, IH, 7 = 10.5 Hz), 7.64 (d, 2H, 7 = 8.9 Hz), 7.34 (d, 2H, 7= 8.9 Hz), 7.14 (s, IH), 7.08 (d,
IH, 7 = 11.0 Hz), 6.70 (d, IH, 7 = 11.0 Hz), 4.62 (s, 2H), 4.12 (s, 2H), 2.08 (s, 3H); MS m/z 465 (M-l).
Example 7
Synthesis of r4-(2',4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2- i methyl-phenoxyl-aeetic acid (compound 7)
Figure imgf000064_0001
Step 1. Preparation of [4-(2',4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5- methoxy-2-methyl-phenoxy]-acetic acid methyl ester (compound 7A)
Figure imgf000064_0002
7A The title compound was prepared in the manner analogous to Example 5A using ID and l-bromo-2,4-dichloro-benzene. MS m/z 479 (M+2).
Step 2. Preparation of [4-(2',4'-Dichloro-biphenyl-4-ylmethyIsulfanyI)-5- methoxy-2-methyl-phenoxy]-acetic acid (compound 7)
The title compound was prepared in the manner analogous to Example 1 using 7A. 400 MHz Η NMR (DMSO- 6) δ 12.95 (br(s), IH), 7.67 (dd, IH, 7 = 2 Hz, 7=8.4 Hz), 7.43 (d, IH, 7=2.4 Hz), 7.37 (s, IH), 7.28 (s, 4H), 7.02 (s, IH), 6.52 (s, IH), 4.70 (s, 2H), 4.02 (s, 2H), 3.72 (s, 3H), 2.01 (s, 3H); MS m/z 465 (M-tJ2).
Example 8
Synthesis of f4-(3'.4'-Dichloro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2- methyl-phenoxyl-acetic acid (compound 8)
Figure imgf000065_0001
8
Step 1. Preparation of [4-(3',4'-DichIoro-biphenyI-4-ylmeth!ylsulfanyl)-5- methoxy-2-methyl-phenoxy]-acetic acid methyl ester (compound 8A)
Figure imgf000065_0002
8A The title compound was prepared in the manner analogous to Example 5A using ID and 4-bromo-l,2-dichloro-benzene. MS m/z 479 (M+2).
Step 2. Preparation of [4-(3',4'-Dichloro-biphenyI-4-ylmetlrylsulfany_)-5- methoxy-2-methyl-phenoxy]-acetic acid (compound 8)
The title compound was prepared in the manner analogous to Example 1 using 8A. mp 161-162°C; 400 MHz 1H NMR (DMSO- ) δ 7.87 (d, IH, 7 = 2 Hz), 7.57-7.66 (m, 4H), 7.29 (d, 2H, 7 = 8.4 Hz), 7.01 (s, IH), 6.52 (s, IH), 4.69 (s, 2H), 4.02 (s, 2H), 3.72 (s, 3H), 2.03 (s, 3H); MS m/z 494 (M+l).
Example 9
Synthesis of r5-Methoxy-2-methv]-4-(3'-trifluoromethvI-biphenyl-4- ylmethylsulfanvP-phenoxyl-acetic acid (compound 9)
Figure imgf000066_0001
Step 1. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 9A)
Figure imgf000066_0002
9A The title compound was prepared in the manner analogous to Example 5A using ID and l-bromo-3-trifluoromethyl-benzene. MS m/z 477 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4- ylmethylsu!fanyl)-phenoxy]-acetic acid (compound 9)
The title compound was prepared in the manner analogous to Example 1 using 9A. mp 138-139 °C; 400 MHz 1H NMR (DMSO- ) δ 12.95 (br(s), IH), 7.91 (m, 2H), 7.63 (m, 4H), 7.32 (d, 2H, 7= 8.4 Hz), 7.02 (s, IH), 6.52 (s, IH), 4.69 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 2.06 (s, 3H); MS m/z 463 (M+l).
Example 10
Synthesis of r4-(4l-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-m'ethoxy-2-methyl- phenoxyl-acetic acid (compound 10)
Figure imgf000067_0001
10
Step 1. Preparation of (4'-Fluoro-biphenyl-4-yl)-methanol (compound 10A)
Figure imgf000067_0002
10A
The title compound was prepared in the manner analogous to Example 3A using 1- bromo-4-fluorobenzene. MS m/z 185 (M-H2O).
Step 2. Preparation of 4-Chloromethyl-4'-fluoro-biphenyl (compound 10B)
Figure imgf000068_0001
Example 10B
The title compound was prepared in the manner analogous to Example 3B using 10A. MS m/z 222 (M+2).
Step 3. Preparation of [4-(4'-Fluoro-biphenyl-4-ylmethylsu fanyl)-5-methoxy-2- methyl-phenoxy]-acetic acid methyl ester (compound IOC)
Figure imgf000068_0002
IOC
The title compound was prepared in the manner analogous to Example IF using 10B and ID. MS m/z 427 (M+l).
Step 4. Preparation of [4-(4'-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2- methyl-phenoxy]-acetic acid
The title compound was prepared in the manner analogous to example 1 using IOC. 400 MHz 1H NMR (DMSO- ) δ 12.93 (br(s), IH), 7.62 (m, 2H), 7.49 (d, 2H, 7 = 8.4 Hz), 7.27 (d, 2H, 7= 8.4 Hz), 7.22 (m, 2H), 7.02 (s, IH), 6.52 (s, IH), 4.69 (s, 2H), 4.01 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z 41 1 (M-l ).
Example 11
Synthesis of r5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-4- yl ethylsulfanvD-phenoxyl-acetic acid (compound 11)
Figure imgf000069_0001
11
Step 1. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluorometnoxy-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 11 A)
Figure imgf000069_0002
11A
The title compound was prepared in the manner analogous to Example 5A using ID and ]-bromo-3-trifluoromethoxy-benzene. MS m/z 493 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluorqjmethoxy-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 11)
The title compound was prepared in the manner analogous to Example 1 using 11A. mp 137 °C; 400 MHz Η NMR (DMSO- 6) δ 12.95 (br(s), 1HJ, 7.66 (d, IH, 7 = 8.8 Hz), 7.56 (m, 4H), 7.30 (m, 3H), 7.02 (s, IH), 6.52 (s, IH), 4.69 (s, 2H), 4.02 (s, 2H), 3.73 (s, 3H), 2.01 (s, 3H). MS m/z 493 (M+l).
Example 12
Synthesis of r7-(4'-TrifluoromethvI-biphenyl-4-ylmethylsulfanyl)-indan-4-vIoxy1- acetic acid (compound 12)
Figure imgf000070_0001
12
Step 1. Preparation of Indan-4-ol (compound 12A)
Figure imgf000070_0002
12A
A mixture of 4-hydroxy-indan-l-one (5.0 g, 33.7 mmol), sodium) cyanoborohydride (6.4 g, 101.1 mmol), and zinc iodide (32.3 g, 101.1 mmol) in dichloroethane, was heated at reflux for two hours. The reaction mixture was then filtered through 50 g
SiO2 while still warm, eluting further with dichloroethane. The filtrate was collected and concentrated under vacuum. The residue was added to diethyl ether and the resulting white precipitate was filtered off. The filtrate was collected and concentrated in vacuo to give 4.2 g of the title compound with purity high enough for subsequent use. 400 MHz 1H NMR (DMSO- 6) δ 9.06 (s, 1 H), 6.86 (t, 1 H, 7 = 7.8
Hz), 6.59 (d, IH, 7 = 7.8 Hz), 6.48 (d, IH, 7 = 7.8 Hz), 2.75 (t, 2H, 7 = 7.3 Hz), 2.67 (t, 2H, 7= 7.3 Hz), 1.92 (m, 2H).
Step 2. Preparation of 7-Thiocyanato-indan-4-ol (compound 12B)
Figure imgf000070_0003
12B
The title compound was prepared in the manner analogous to Example IB using 12A. MS m/z 192 (M+l). Step 3. Preparation of (7-Mercapto-indan-4-yloxy)-acetic acid methyl ester (compound 12C)
Figure imgf000071_0001
12C
7-Thiocyanato-indan-4-ol. (Example 12B) ( 1.47g, 7.7 mmol), cesium carbonate (3.77g, 11.6 mmol) and methyl bromoacetate (1.24g, 8.08 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was treated under the conditions of Example ID to afford the title product. MS m/z 239 (M+l).
Step 4. Preparation of [7-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- indan-4-yloxy]-acetic acid methyl ester (compound 12D)
Figure imgf000071_0002
12D
The title compound was prepared in the manner analogous to Example IF using 12C and 3B. MS m z 473 (M+l).
Step 5. Preparation of [7-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- indan-4-yloxy]-acetic acid (compound 12) The title compound was prepared in the manner analogous to Example 1 using 12D. mp 158-159 °C; 400 MHz 1H NMR (OMSO-d6) δ 12.94 (br(s), IH), 7.82 (d, 2H, 7 = 8 Hz), 7.74 (d, 2H, 7 = 8.8 Hz), 7.60 (d, 2H, 7 = 6.4 Hz), 7.31 (d, 2H, 7=8 Hz), 7.08 (d, IH, 7=8.8 Hz), 6.58 (d, IH, 7=8.4 Hz), 4.61 (s, 2H), 4.06 (s, 2H), 2.72 (m, 4H), 1.90 (q, 2H); MS m/z 457 (M-l).
Example 13
Synthesis of [4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy1-acetic acid (compound 13)
Figure imgf000072_0001
13
Step 1. Preparation of [4-(4-Benzyloxy-benzyIsulfanyl)-2-riiethyl-phenoxy]- acetic acid methyl ester (compound 13A)
Figure imgf000072_0002
13A
The title compound was prepared in the manner analogous to Example IF using 1- chloromethyl-4-benzyloxy-benzene and 2C. MS m/z 409 (M+l).
Step 2. Preparation of [4-(4-Benzyloxy-benzylsulfanyl)-2-methyl-phenoxy]- acetic acid (compound 13) The title compound was prepared in the manner analogous to Example 1 and 13A. mp 120 - 121 °C; 400 MHz 1H NMR (DMSO- ) δ 7.39 - 7.25 (m, 5H), 7.15 - 7.03 (m, 4H), 6.85 (d, 2H, 7 = 8.5 Hz), 6.68 (d, IH, 7 = 8.4 Hz), 5.00 (s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 395 (M+l).
Example 14
Synthesis of f5-Methoxy-2-methyl-4-r4-(4-trifluoromethyl-benzyloxy)- benzylsulfanyll-phenoxyl-acetic acid (compound 14)
Figure imgf000073_0001
14
Step 1. Preparation of [4-(4-Trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 14A)
Figure imgf000073_0002
14A
4-Hydroxymethyl-phenol (lg, 8.06 mmol), l-Chloromethyl-4-trifluoromethyl-be nzene (1.57g, 8.06 mmol), and cesium carbonate (5.26g, 16.12!mmol) were refluxed in acetonitrile for 20h, cooled, filtered, and concentrated to give the title compound. MS m/z 265 (M-H2O+l). Step 2. Preparation of 4-Chloromethyl-(4-trifluoromethyl-benzyloxy-benzene) (compound 14B)
Figure imgf000074_0001
14B
The title compound was prepared in the manner analogous to Example 3B using 14A. MS z 265 (M-Cl+l).
Step 3. Preparation of {5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl- benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 14C)
Figure imgf000074_0002
14C
The title compound was prepared in the manner analogous to Example IF using 14B and ID. MS m/z 507 (M+l).
Step 4. Preparation of {5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl- benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid (compound 14)
The title compound was prepared in the manner analogous to Example 1 using 14C. mp 145 °C; 400 MHz 1H NMR (DMSO-rf6) δ 12.94 (br(s), IH), 7.70 (d, 2H, 7 = 8
Hz), 7.76 (d, 2H, 7= 8 Hz), 7.14 (d, 2H, 7 = 8.8 Hz), 6.97 (s, IH), 6.87 (m, 2H), 6.50 (s, IH), 5.14 (s, 2H), 4.68 (s, 2H), 3.91 (s, 2H), 3.71 (s, 3H), 2.00 (s, 3H); MS m/z 491 (M-l). Exa ple 15
Synthesis of {2-Methyl-4-r4-(4-trifluoromethyl-benzyloxy)-benzylsulfanvn- phenoxyl-acetic acid (compound 15)
Figure imgf000075_0001
15
Step 1. Preparation of {2-Methyl-4-[4-(4-trifluoromethyl-benzyloxy)- benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 15A)
Figure imgf000075_0002
15A
The title compound was prepared in the manner analogous to Example IF using 2C and l4B. MS m/z 411 (M+l).
Step 2. Preparation of {2-MethyI-4-[4-(4-trifluoromethyl-benzyloxy)- benzylsulfanyl]-phenoxy}-acetic acid (compound 15)
The title compound was prepared in the manner analogous to Example 1 using 15A. mp 133 °C; 400 MHz 1H NMR (OMSO-d6) 67.70 (d, 2H, 7 = 8 Hz), 7.76 (d, 2H, 7 = 8 Hz), 7.14 (d, 2H, 7 = 8.8 Hz), 7.09 (m, IH), 7.04 (dd, IH, 7=2.4 Hz, J'=8.4 Hz), 6.87 (m, 2H), 6.68 (d, IH, 7=8.4 Hz), 5.14 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H); MS m/z 461 (M-l).
Example 16
Synthesis of r5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3- ylmethylsulfanvD-phenoxyl-acetic acid (compound 16)
Figure imgf000076_0001
16
Step 1. Preparation of (S'-Trifluoromethoxy-biphenyl-S-y -methanol (compound 1 A)
Figure imgf000076_0002
16A
The title compound was prepared in the manner analogous to Example 3A using 3- hydroxymethylphenylboronic acid and 1 -bromo-3-trifluoromethoxy-benzene. MS m/z 251 (M-l).
Step 2. Preparation of 3-Chloromethyl-3'-trifluorometh xV-biphenyl
(compound 16B)
Figure imgf000076_0003
16B The title compound was prepared in the manner analogous to Example 3B using 16A. MS m/z 251 (M-l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 16C)
Figure imgf000077_0001
16C
The title compound was prepared in the manner analogous to Example IF using 16B and ID. MS m/z 491 (M-l).
Step 4. Preparation of [5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3- ylmethylsulfanyI)-phenoxy]-acetic acid (compound 16)
The title compound was prepared in the manner analogous to Example 1 using 16C. mp 92-94 °C; 400 MHz ]H NMR (DMSO- ) δ 12.96 (br(s), IH), 7.55-7.24 (m, 8H), 7.01 (s, IH), 6.52 (s, IH), 4.68 (s, 2H), 4.03 (s, 2H), 3.72 (s, 3H), 1.99 (s, 3H); MS m/z 479 (M+l).
Example 17 Synthesis of r4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxyl-acetic acid (compound 17)
Figure imgf000077_0002
17 Step 1. Preparation of (9H-Fluoren-2-yl)-methanol (compound 17A)
Figure imgf000078_0001
17A
9H-Fluorene-2-carbaldehyde (500 mg, 2.6 mmol) was dissolved in 10 ml methanol. Sodium borohydride (200 mg, 5.2 mmol) was added and allowed to stir at ambient temperature for 1 h. Water (10 ml) was added and the crude product was extracted into ethyl acetate (50 ml), washed with brine (50 ml), dried over anhydrous sodium sulfate, decanted and concentrated to afford the title product in good purity. MS m/z 195 (M+l).
Step 2. Preparation of 2-Chloromethyl-9H-fluorene (compound 17B)
Figure imgf000078_0002
17B
The title compound was prepared in the manner analogous to Example 3B using 17A. MS m z l79 (M-Cl+l).
Step 3. Preparation of [4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]- acetic acid methyl ester (compound 17C)
Figure imgf000078_0003
17C The title compound was prepared in the manner analogous to Example IF using 17B and 2C. MS m/z 422 (M+l).
Step 4. Preparation of [4-(9H-Fluoren-2-ylmethylsulfanyl-2-methyl-phenoxy]- acetic acid (compound 17)
The title compound was prepared in the manner analogous to Example 1 using 17C. 400 MHz 1H NMR (DMSO- ) δ 12.93 (br(s), IH), 7.80 (d, IH, 7 = 7.6 Hz), 7.23 (d, IH, 7 = 8 Hz), 7.5 (d, IH, 7 = 7.6 Hz), 7.43 (s, IH), 7.31 (t, 1H,|7=6.4 Hz), 7.24 (m,
2H), 7.15 (m, IH), 7.08 (dd, IH, 7=2.4 Hz, 7 =8.4 Hz), 6.7 (d, IH, 7=8.8 Hz), 4.62 (s, 2H), 4.13 (s, 2H), 3.82 (s, 2H), 2.09 (s, 3H). MS m/z 375 (M-l). Anal. Calc'd for C23H20O3S-0.3 H2O C, 72.34; H, 5.44; found: C, 72.46; H, 5.20.
Example 18
Synthesis of {(5-Methoxy-2-methyl-4-r4-(5-trifluoromethyl-pyridin-2-yl)- henzylsulfanvH-phenoxyl-acetic acid (compound 18)
Figure imgf000079_0001
18 Preparation of [4-(5-Trifluoromethyl-pyridin-2-yl)-phenylJ-jmethanol
(compound 18A)
Figure imgf000079_0002
18A The title compound was prepared from 2-Chloro-5-trifluoromethyl-pyridine and 4- (hydroxymethyl)boronic acid PdCl2(dppb) catalyst in the manner analogous to Example 3A. 400 MHz ]H NMR (DMSO-d6) δ 8.98 (s, IH), 8.2 (dd, IH, 7 = 2.4 Hz, 7' = 8.4 Hz), 8.09 (m, 3H), 7.42 (d, 2H, 7 = 8.54 Hz), 5.23j(t, IH), 4.54 (d, 2H, 7 = 6 Hz); MS m/z 254 (M+l).
Preparation of 2-(4-ChloromethyI-phenyl)-5-trifluoromethyl-pyridine (compound 18B)
Figure imgf000080_0001
18B
The title compound was prepared in the manner analogous to Example 3B using 18A. MS m/z 272 (M+l).
Preparation of {5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 18C)
Figure imgf000080_0002
18C
The title compound was prepared in the manner analogous to Example IF using ID and 18B. MS m/z 478 (M+l). Prepa ration of {5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyI]-phenoxy}-acetic acid (compound 18)
The title compound was prepared from the product of Example 18C in the manner analogous to Example 1. mp 225 °C (dec); 400 MHz 1H NMR (DMSO-d6) δ 8.97 (s,
IH), 8.2 (dd, IH, 7 = 2.4 Hz, T = 8.4 Hz), 8.13 (m, IH), 8.01 (d, 2H, 7 = 8.4 Hz), 7.34 (s, 2H, 7= 8.4 Hz), 6.95 (s, IH), 6.42 (s, IH), 4.23 (s, 2H), 4.01 (s, 2H), 3.69 (s, 3H), 1.96 (s, 3H) MS m z 464 (M+ 1 ).
Example 19
Synthesis of f5-Methoxy-2-methyl-4-r6-(4-trifluoromethyl-phenyl)-pyridin-3- γlmethylsulfanyll-phenoxyl-acetic acid (compound 19) .
Figure imgf000081_0001
19
Step 1. Preparation of [4-(6-Chloro-pyridin-3-ylmethylsulfanyI)-5-methoxy-2- methyl-phenoxy]-acetic acid methyl ester (compound 19A)
Figure imgf000081_0002
19A
The title cυπipυuiid was piepaied from 2-Chloro-5-chloromcthyl-pyridine and ID in a
! manner analogous to Example IF. MS m/z 370 (M+2). Step 2. Preparation of {5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)- pyridin-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 19B)
Figure imgf000082_0001
19B
The title compound was prepared from the product of Example 19A and 1 -bromo-4- trifluoromethyl-benzene in a manner analogous to Example 3A. MS m/z 478 (M+l).
Step 3. Preparation of {5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)- pyridin-3-ylmethylsulfanyI]-phenoxy}-acetic acid (compound 19)
The title compound was prepared from the product of Example 19B in the manner analogous to Example 1. mp 203 °C (dec); 400 MHz 1H NMR (DMSO-d6) δ 8.34 (d,
IH, 7 = 1.6 Hz), 8.21 (d, 2H, 7 = 8 Hz), 7.92 (d, IH, 7 = 8.4 Hz), 7.77 (d, 2H, 7 = 8.4 Hz), 7.65 (dd IH, 7= 2.4 Hz, J = 8.4 Hz), 6.93 (s, IH), 6.39 (s, IH), 4.15 (s, 2H), 4.00 (s, 2H), 3.66 (s, 3H), 1.95 (s, 3H). MS m/z 464 (M+l).
Example 20
Synthesis of r5-Chloro-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanvD-phenoxyl-acetic acid (compound 20)
Figure imgf000083_0001
20
Step 1. Preparation of 5-Chloro-2-methyl-4-thiocyanato-phenol (compound
20A)
OH
C'XX CHa
20A
The title compound was prepared in a manner analogous to Example IB from 5- chloro-2-methyl-phenol. 400 MHz 1H NMR (DMSO- ) δ 10.60 (s, IH), 7.54 (s, IH), 6.98 (s, IH), 2.07 (s, 3H).
Step 2. Preparation of (5-Chloro-2-methyl-4-thiocyanatό-ι)henoxy)-acetic acid methyl ester(compound 20B)
Figure imgf000083_0002
20B
The title compound was prepared from the product of Example 20A in a manner analogous to Example IC. 400 MHz 1H NMR (DMSO- ) δ 7.62 (s, IH), 7.40 (s, IH), 4.94 (s, 2H), 3.65 (s, 3H), 2.15 (s, 3H). Step 3. Preparation of (5-Chloro-4-mercapto-2-methyl-phenoxy)-acetic acid methyl ester (compound 20C)
HS CH3
20C
The title compound was prepared from (5-chloro-2-methyl-4-thiocyanato-phenoxy)- acetic acid methyl ester in a manner analogous to Example ID. 400 MHz 1H NMR (DMSO- ) δ 7.27 (s, IH), 6.97 (s, IH), 5.31 (s, IH), 4.79 (s, 2H), 3.64 (s, 3H), 2.07 (s, 3H).
Step 4. Preparation of [5-Chloro-2-methyl-4-(4'-trifluorpπτ|ethyl-biphenyl-4- y!methylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 20D)
Figure imgf000084_0001
20D
The title compound was prepared in the manner analogous to Example IF using 3B and 20C. 400 MHz 1H NMR (DMSO- 6) δ 7.82 (d, 2H, 7 = 8.3 Hz), 7.74 (d, 2H, 7 = 8.3 Hz), 7.62 (d, 2H, 7 = 8.3 Hz), 7.39 (d, 2H, 7 = 8.3 Hz), 7.27 (s, IH), 7.00 (s, IH),
4.82 (s, 2H), 4.20 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H); MS m/z 480 (M+).
Step 5. Preparation of [5-Chloro-2-methyI-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 20)
Figure imgf000085_0001
20
The title compound was prepared in the manner analogous to Example 1 using 20D. mp 161-162 °C; 400 MHz ]H NMR (DMSO- ) δ 7.83 (d, 2H.ll/ = 8.3 Hz), 7.74 (d, 2H, 7 = 8.3 Hz), 7.62 (d, 2H, 7 = 8.3 Hz), 7.51 (d, 2H, 7 = 8.3 Hz), 7.26 (s, IH), 6.95 (s, IH), 4.69 (s, 2H), 4.20 (s, 2H), 2.08 (s, 3H); MS m/z 467 (M+l).
Example 21
Synthesis of r3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanvI)- phenoxyl-acetic acid (compound 21)
Figure imgf000085_0002
Step 1. Preparation of 3-Methoxy-4-thiocyanato-phenol (compound 21A)
CH,
NCS XT
21A The title compound was prepared in a manner analogous to Example IB from 3- methoxy-phenol. 400 MHz 1H NMR (DMSO-d6) δ 10.21 (s, IH), 7.34 (d, IH, 7 = 8.3 Hz), 6.53 (s, IH), 6.43 (d, IH, 7 = 8.3 Hz), 3.81 (s, 3H).
Step 2. Preparation of (3-Methoxy-4-thiocyanato-phenoxyj)-acetic acid methyl ester (compound 21B)
Figure imgf000086_0001
21B
The title compound was prepared from the product of Example 21A in a manner analogous to Example IC. MS m/z 227 (M-CN).
Step 4. Preparation of (4-Mercapto-3-methoxy-phenoxy)-acetic acid methyl ester (compound 21 C)
Figure imgf000086_0002
21C
The title compound was prepared from (3-Methoxy-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example ID. 400 MHz Η NMR (DMSO- ) δ 7.13 (d, IH, 7 = 8.5 Hz), 6.56 (s, IH), 6.39 (d, IH, 7 = 8.5 Hz), 4.72 (s, 2H), 4.51 (s, IH), 3.75 (s, 3H), 3.64 (s, 3H).
Step 5. Preparation of [3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 21D)
Figure imgf000087_0001
21D
The title compound was prepared in the manner analogous to Example IF using 3B and 21C. 400 MHz 1H NMR (DMSO- ) δ 7.81 (d, 2H, 7 = 8.3 Hz), 7.53 (d, 2H, 7 = 8.3 Hz), 7.59 (d, 2H, 7 = 8.3 Hz), 7.32 (d, 2H, 7 = 8.3 Hz), 7.11 (d, IH, 7 = 8.5 Hz), 6.56 (s, IH), 6.37 (d, IH, 7= 8.5 Hz), 4.73 (s, 2H), 4.04 (s, 2H), 3.76 (s, 3H) , 3.63 (s, 3H); MS m/z 463 (M+l).
Step 6. Preparation of [3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 21)
Figure imgf000087_0002
21
The title compound was prepared in the manner analogous to Example 1 using 21D. 400 MHz Η NMR (DMSO- ) δ 7.83 (d, 2H, 7 = 8.3 Hz), 7.76 (d, 2H, 7 = 8.3 Hz), 7.61 (d, 2H, 7= 8.3 Hz), 7.34 (d, 2H, 7 = 8.3 Hz), 7.13 (d, IH, 7 = 8.5 Hz), 6.56 (s, IH), 6.39 (d, IH, 7 = 8.5 Hz), 4.63 (s, 2H), 4.06 (s, 2H), 3.77 (s 3H); MS m/z 449 (M+l ). Anal. Calc'd for C23H]9F3O S, C, 61.60; H, 4.27; found: C, 61.35; H, 4.25. Example 22
Synthesis of {2-Methyl-4-r2-(4/-trifluoromethvI-biphenvI-4-yl)-ethylsulfanvn- phenoxyl-acetic acid (compound 22)
Figure imgf000088_0001
22
Step 1. Preparation of 2-(4'-TrifIuoromethyl-biphenyl-4-yl)-ethanol (compound
22A)
Figure imgf000088_0002
22A
A mixture of 2-(4-bromo-phenyl)-ethanol (2.3 ml, 3.3 g, 16.4 mmol), 4- trifluoromethylphenylboronic acid (5.0 g, 26.3 mmol), 1.0 M aqueous sodium carbonate solution (44.0 ml), and tetrakis(triphenylphosphine)palladium (0.98 g, 0.85 mmol) in 180 ml of ethanol and 180 ml of toluene was heated at reflux for 4 h. The cooled reaction mixture was diluted with 500 ml of ethyl acetate and filtered through a bed of Celite filter-aid. The filtrate was washed with 5% aqueous sodium carbonate solution (2x750 ml) and brine (3x750 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography. MS m/z 266 (M).
Step 2. Preparation of 4-(2-Bromo-ethyl)-4'-trifluoromethyl}biphenyl (compound 22B)
Figure imgf000089_0001
22B
A solution of 2-(4'-trifluoromethyl-biphenyl-4-yl)-ethanol (2.8 g, 10.3 mmol) and carbon tetrabromide (3.8 g, 11.5 mmol) in 50 ml of dichloromethane was cooled in ice, and triphenylphosphine (2.9 g, 11.1 mmol) was added in portions over 10 minutes. The mixture was stiπed at room temperature for 18 h, and the solvent was evaporated. The residue was stiπed in 75 ml of ether, and the mixture was filtered. The insoluble material was washed on the funnel with fresh ethe'r (3x75 ml). The combined ether filtrates were concentrated, and the crude product was purified by normal phase chromatography. MS m/z 328 (M-l).
Step 3. Preparation of {2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)- ethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 22C)
Figure imgf000090_0001
22C
A solution 4-(2-bromo-ethyl)-4'-trifluoromethyl-biphenyl (0.66 g, 2.0 mmol) and (4- mercapto-2-methyl -phenoxy )-acetic acid methyl ester (0.42 g, 2.0 mmol) in 10 ml of acetonitrile was treated with cesium carbonate (1.3 g, 4.0 mmol), and the mixture was stiπed at room temperature for 18 h. The reaction mixture was added to 200 ml of brine and extracted with ethyl acetate (4x75 ml). The combined extracts were washed with brine (2x200 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography. MS m z 461
(M+l).
Step 4. Preparation of {2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)- ethylsulfanyl]-phenoxy}-acetic acid (compound 22)
A solution of {2-methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]- phenoxy} -acetic acid methyl ester (0.78 g, 1.7 mmol) in 10 ml of tetrahydrofuran and 2.0 ml of water was treated with lithium hydroxide monohydrate (0.21 g, 5.0 mmol), and the mixture was stiπed at room temperature for 2 h. The reaction mixture was diluted with 5.0 ml of water and made strongly acidic by the addition of 4.0 N hydrochloric acid. The mixture was extracted with ethyl acetate (4x30 ml), and the combined extracts were washed with brine (2x50 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was recrystallized from ethyl acetate/hexane. mp 132-134 °C; IR (thin film) cm"1: 1741, 1709, 1490, 1326, 1239, 1 110; 400 MHz 1H NMR (OMSO-d6) δ 7.82 (d, 2H, 7 = 8.0 Hz), 7.74 (d, 2H, 7 = 8.0 Hz), 7.61 (d, 2H, 7= 8.3 Hz), 7.31 (d, 2H, 7= 8.3 Hz), 7.15 (m, 2H), 6.75 (d, 1H, 7 = 8.3 Hz), 4.64 (s, 2H), 3.11 (t, 2H, 7 = 7.6 Hz), 2.82 (t, 2H, 7 = 7.6 Hz), 2.12 (s, 3H); MS m/z 447 (M+l). Anal. Calc'd for C2 H2ιF3O3S: C, 64.56; H, 4.74; found: C, 64.45; H, 4.58.
Example 23
Synthesis of (5-Methoxy-2-methyl-4-r2-(4/-trifluoromethyl-biphenyl-4-yl)- ethylsulfanvn-phenoxyl-acetic acid (compound 23)
Figure imgf000091_0001
Step 1. Preparation of {5-Methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biphenyl- 4.yl)-ethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 23A)
Figure imgf000091_0002
23A
The title compound was prepared in the manner analogous to Example 22C using 4- (2-bromo-ethyl)-4'-trifluoromethyl-biphenyl and ID. MS m/z 491 (M+l). Step 2. Preparation of {5-Methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biphenyl- 4-yI)-ethylsuIfanyI]-phenoxy}-acetic acid (compound 23)
The title compound was prepared in the manner analogous to Example 1 using {5- methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]-phenoxy}- acetic acid methyl ester, mp 169-171 °C; IR (thin film) cm-1: 1718, 1500, 1330, 1162, 1109, 1052; 400 MHz 1H NMR (DMSO- ) δ 7.82 (d, 2H, 7 = 8.3 Hz), 7.74 (d, 2H, 7 = 8.6 Hz), 7.61 (d, 2H, 7 = 8.3 Hz), 7.31 (d, 2H, 7 = 8.3 Hz), 7.06 (s, IH), 6.53 (s, IH), 4.69 (s, 2H), 3.73 (s, 3H), 3.02 (t, 2H, 7 = 7.5 Hz), 2.78 (t, 2H, 7 = 7.5 Hz), 2.06
(s, 3H); MS m/z 477 (M+l). Anal. Calc'd for C25H23F3O4S: C, 63.02; H, 4.87; found: C, 62.77; H, 4.62.
Example 24
Synthesis of (2-Methv]-4-r2-(4,-trifluoromethyl-biphenyl-4-JvI)-vinyll-phenoxyl- acetic acid (compound 24)
Figure imgf000092_0001
Step 1. Preparation of (4-Bromo-2-methyI-phenoxy)-acetic acid methyl ester (compound 24A)
Figure imgf000093_0001
A solution of o-tolyloxy-acetic acid methyl ester (Belleney J., et al., J. Heterocyclic Chem., 1984; 21:1431; 3.7 g, 20.5 mmol) in 70 ml of acetonitrile was treated in portions over 10 minutes with N-bromosuccinimide (3.8 g, 21.3 mmol). The mixture was stirred at room temperature for 18 h, and the solvent was evaporated. The residue was stirred in 75 ml of carbon tetrachloride, and the mixture was filtered. The insoluble material was washed on the funnel with fresh carbon trachloride (2x50 ml). The combined filtrates were concentrated, and the crude product was purified by normal phase chromatography. MS m/z 258 (M-l).
Step 2. Preparation of 4-Trifluoromethyl-4'-vinyl-biphenyl (compound 24B)
Figure imgf000093_0002
24B
The title compound was prepared in the manner analogous to Example 3A using 1- bromo-4-vinyl-benzene and 4-trifluoromethylphenylboronic acid. MS m/z 248 (M). Step 3. Preparation of {2-Methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-vinyl]- phenoxyj-acetic acid methyl ester and {2-methyl-4-[2-(4'-trifluoromethyl- biphenyl-4-yl)-vinyl]-phenoxy}-acetic acid (compound 24)
A mixture of 4-trifluoromethyl-4'-vinyl-biphenyl (1.9 g, 7.7 mmol), (4-Bromo-2- methyl-phenoxy)-acetic acid methyl ester (2.0 g, 7.7 mmol), anhydrous sodium acetate (1.2 g, 14.6 mmol), N,N-dimethylglycine (0.23 g, 2.2 mmol), and palladium acetate (0.025 g, 0.11 mmol) in 10 ml of l-methyl-pyπolidin-2-one was heated at 130 °C for 10 h. The reaction mixture was partitioned between 250 ml of brine and 300 ml of ethyl acetate. The total mixture was filtered through a bed of Celite filter-aid.
The organic layer was washed with 5% aqueous sodium carbonate solution (3x250 ml) and brine (2x250 ml), then dried over anhydrous sodium sulfate and concentrated. The residue was purified by normal phase chromatography to give {2-methyl-4-[2- (4'-trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy} -acetic acid methyl ester; MS m/z 427 (M+l).
During the above sodium carbonate washings, a precipitate formed and was removed by filtration. The solid was stiπed for 18 h in a solution of 150 ml of water, 50 ml of methanol, and 50 ml of 4.0 N hydrochloric acid. The acidified product was filtered and recrystallized from aqueous acetonitrile to give {2-methyl-4-[2-(4'- trifluoromethyl-biphenyl-4-yl)-vinyl]-phenoxy} -acetic acid, m 243-245 °C; IR (thin film) cm"1: 1746, 1717, 1502, 1323, 1125, 1069; 400 MHz 1H NMR (DMSO- ) δ 7.88 (d, 2H, 7 = 8.0 Hz), 7.76 (d, 2H, 7 = 8.3 Hz), 7.71 (d, 2H, 7 = 8.5 Hz), 7.64 (d, 2H, 7 = 8.5 Hz), 7.43 (d, IH, 7 = 1.7 Hz), 7.32 (dd, IH, 7 = 2.1 , 8.5 Hz), 7.21 (d, IH, 7 = 16.5 Hz), 7.10 (d, IH, 7 = 16.4 Hz), 6.79 (d, IH, 7 = 8.5 Hz), 4.68 (s, 2H), 2.18 (s, 3H); MS m/z 413 (M+l). Anal. Calc'd for C24H]9F3O3: C, 69.90; H, 4.64; found: C,
69.77; H, 4.57. Example 25
Synthesis of {2-MethvI-4-r2-(4,-trifluoromethyl-biphenyl-4-yl)-ethvn-phenoxy)- acetic acid (compound 25)
Figure imgf000095_0001
25
A solution of { 2-methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)j-vinyl]-phenoxy } - acetic acid (0.98 g, 2.4 mmol) in 100 ml of tetrahydrofuran was |hydrogenated over 0.16 g of 20% palladium on carbon catalyst. The catalyst was removed by filtration, and the filtrate was evaporated. The crude product was recrystallized from aqueous acetonitrile. mp 174-176 °C; TR (thin film) cm"1: 1747, 1711, 1500, 1318, 1160, 1123; 400 MHz Η NMR (DMSO- ) δ. 7.83 (d, 2H, 7 = 8.1 Hz), 7.74 (d, 2H, 7 = 8.3 Hz),
7.60 (d, 2H, 7 = 6.5 Hz), 7.32 (d, 2H, 7 = 8.3 Hz), 7.01 (d, IH, 7 = 2.0 Hz), 6.94 (dd, IH, 7 = 2.0, 8.3 Hz), 6.66 (d, IH, 7= 8.3 Hz), 4.59 (s, 2H), 2.83 (m, 2H), 2.76 (m, 2H), 2.11 (s, 3H); MS m/z 413 (M-l). Anal. Calc'd for C24H2]F3O3: C, 69.56; H, 5.11; found: C, 69.28; H, 4.96.
Example 26
Synthesis of {7-r4-(5-TrifluoromethvI-pyridin-2-yl)-benzylsulfanyl1-indan-4- yloxy)-acetic acid (compound 26)
Figure imgf000096_0001
26
Step 1. Preparation of {7-[4-(5-TrifluoromethyI-pyridin-2-yl)-benzylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 26A)
Figure imgf000096_0002
26A
The title compound was prepared in the manner analogous to Example IF using 18B and 12C. MS m/z 474 (M+l).
Step 2. Preparation of {7-[4-(5-Trifluoromethyl-pyridin-2-yl)-benζylsulfanyl]- indan-4-yloxy}-acetic acid (compound 26)
Figure imgf000096_0003
26 The title compound was prepared from the product of Example 26A in the manner analogous to Example 1. mp 220 °C (dec); 400 MHz 1H NMR (DMSO- ) δ 12.94 (s, IH), 8.97 (s, IH), 8.2 (dd, IH, 7= 2 Hz, 7' = 8.8 Hz), 8.13 (d, IH, 7 = 8.4 Hz), 8.01 (d, 2H, 7 = 8.4 Hz), 7.34 (d, 2H, 7 = 8.8 Hz), 7.07 (d, IH, 7 = 8.4 Hz), 6.57 (d, IH, 7 = 8 Hz), 4.61 (s, 2H), 4.07 (s, 2H), 2.72 (m, 4H), 1.89 (ml, 2H). MS m/z 460
(M+l).
Example 27
Synthesis of {5-Methyl-7-r4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanvn- indan-4-yloxyl-acetic acid (compound 27)
Figure imgf000097_0001
27
Step 1. Preparation of {5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 27 )
Figure imgf000097_0002
27A The title compound was prepared from the products of Example 18B and (7- mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester (prepared in a similar manner as described for Example 12C) in a manner analogous to Example IF. MS m/z 488 (M+l).
Step 2. Preparation of {5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-indan-4-y!oxy}-acetic acid (compound 27)
Figure imgf000098_0001
27
The title compound was prepared from the product of Example! 27A in the manner analogous to Example 1. mp 186 °C ; 400 MHz 1H NMR (DMSO-^) δ 12.94 (s, IH), 8.97 (s, IH), 8.24 (dd, IH, 7 = 2 Hz, 7' = 8.8 Hz), 8.14 (d, IH, 7 = 8.4 Hz), 8.01 (d, 2H, 7= 8.4 Hz), 7.34 (d, 2H, 7 = 8.8 Hz), 6.99 (s, IH), 4.41 (s, 2H), 4.13 (s, 2H),
2.83 (t, 2H, 7 = 7.2 Hz), 2.62 (t, 2H, 7 = 7.2 Hz), 2.13 (s, 3H), 1.87 (m, 2H). MS m/z 474 (M+l).
Example 28
Synthesis of r5-Methyl-7-(4'-trifluoromethyI-biphenvI-4-ylmethylsulfanyl)- indan-4-yloxyl-acetic acid (compound 28)
Figure imgf000099_0001
28
Step 1. Preparation of [5-Methyl-7-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 28A)
Figure imgf000099_0002
28A
The title compound was prepared from the product of Example 3B and (7-Mercapto-
5-methyl-indan-4-yloxy)-acetic acid methyl ester in a manner analogous to Example IF. MS m/z 487 (M+l).
Step 2. Preparation of [5-Methyl-7-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-indan-4-yloxy]-acetic acid (compound 28)
Figure imgf000099_0003
28 The title compound was prepared from the product of Example 28A in the manner analogous to Example 1. mp 177 °C; 400 MHz 1H NMR (DMSO--f6) δ 12.82 (s, IH), 7.82 (d, 2H, 7 = 8 Hz), 7.75 (d, 7 = 8 Hz), 7.61 (d, 2H, 7 = 8 Hz), 7.35 (d, 2H, 7 = 8 Hz), 6.99 (s, IH), 4.41 (s, 2H), 4.12 (s, 2H), 2.83 (t, 2H, 7= 7.2 Hz), 2.62 (t, 2H, 7 = 7.2 Hz), 2.13 (s, 3H), 1.89 (m, 2H). MS m/z 473 (M+l).
Example 29
Synthesis of (4-{4-r2-(3-Fluoro-phen vI)-vinvP-benzylsulfanyl )-5-methoχy-2- methyl-phenoxy)-acetic acid (compound 29)
Figure imgf000100_0001
29
Step 1. Preparation of {4-[2-(3-Fluoro-phenyl)-vinyl]-phenyl}-methanol
(compound 29 A)
Figure imgf000100_0002
29A
(4-Bromo-phenyl)-methanol (lg, 5.35 mmol), 3-fluorostyrene (718 mg, 5.89 mmol), palladium acetate (60 mg, 0.3 mmol), and triphenylphosphine (140 mg, 0.6 mmol) were heated in triethylamine at 90 °C in a sealed tube for 18h. The reaction was concentrated and purified by normal phase chromatography to afford the title compound. MS m/z 227 (M-l).
Step 2. Preparation of {4-[2-(3-FIuoro-phenyI)-vinyl]-phenyI}-chloromethane (compound 29B)
Figure imgf000101_0001
29B
The title compound was prepared from the product of Example 29A in a manner analogous to Example 3B. MS m/z 245 (M-l).
Step 3. Preparation of (4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benζylsulfanyI}-5- methoxy-2-methyl-phenoxy)-acetic acid methyl ester (compound 29C)
Figure imgf000101_0002
29C
The title compound was prepared from the product of Example 29B and the product of Example ID in a manner analogous to Example IF. MS m/z 453 (M+l).
Step 4. Preparation of (4-{4-[2-(3-Fluoro-phenyl)-vinyl]-b[enzyIsulfanyl}-5- methoxy-2-methyl-phenoxy)-acetic acid (compound 29)
Figure imgf000102_0001
29
The title compound was prepared from the product of Example 29C in the manner analogous to Example 1. mp 154 °C (dec); 400 MHz 1H NMR (DMSO-d6) δ 12.94 (s, IH), 7.46-7.34 (m, 5H), 7.27-7.15 (m, 4H), 7.06-6.99 (m, 2H), 6.52 (s, IH), 4.69 (s, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 2.00 (s, 3H), MS m/z 439 (M l).
Example 30
Synthesis of {2-MethvI-4-r4-(5-trifluoromethv1-pyridin-2-yl)-benzylsulfanvn- phenoxyl-acetic acid (compound 30)
Figure imgf000102_0002
30
Step 1. Preparation of {2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 30A)
Figure imgf000103_0001
30A
The title compound was prepared from the product of Example 2C and the product of Example 18B in a manner analogous to Example IF. MS m/z 448 (M+l).
Preparation of {2-Methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benζylsulfanyl]- phenoxy}-acetic acid
Figure imgf000103_0002
30
The title compound was prepared from the product of Example |30 A in the manner analogous to Example 1. 400 MHz 1H NMR (DMSO- ) δ 8.97 (s, IH), 8.2 (dd, IH, 7 = 2 Hz, 7' = 8.8 Hz), 8.13 (d, IH, 7 = 8.4 Hz), 8.01 (d, 2H, 7 =' 8.4 Hz), 7.36 (d, 2H, 7 = 8.4 Hz), 7.07 (s, IH), 7.01 (dd, IH, 7 = 8.4 Hz, T = 2.4 Hz), 6.57 (d, IH, 7 = 8.8 Hz), 4.09 (s, 2H), 4.06 (s, 2H), 2.04 (s, 3H). MS m/z 434 (M+l).
Example 31
Synthesis of {4-r4-(2.4-Difluoro-benzγloxy)-benzylsuIfanvn-2-methyl-phenoxyl- acetic acid (compound 31)
Figure imgf000104_0001
31
Step 1. Preparation of [4-(2,4-Difluoro-benzyloxy)-phenyl]-methanol (compound 31A)
Figure imgf000104_0002
31A
The title compound was prepared in the manner analogous to Example 14A using 1- bromomethyl-2,4-difluoro-benzene and 4-hydroxymethyl-phendl. MS m/z 233 (M- OH).
Step 2. Preparation of l-(4-Chloromethyl-phenoxymethyl)-2,4-difluoro-benzene (compound 31B)
Figure imgf000104_0003
31B
The title compound was prepared in the manner analogous to Example 3B using
31A. MS m/z 233 (M-Cl). Step 3. Preparation of {4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxyj-acetic acid methyl ester (compound 31C)
Figure imgf000105_0001
31C
The title compound was prepared in the manner analogous to Example IF using 31B and 2C. MS /z 445 (M+l).
Step 4. Preparation of {4-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid
Figure imgf000105_0002
31
To a solution of the product from Example 31 C (1.5 g, 3.3 mmol) in a mixture of 20 mL of tetrahydrofuran and 4 mL of water was added lithium hydroxide monohydrate (0.42 g, 9.9 mmol). The reaction mixture was stiπed at room temperature for 18 hrs and then evaporated to afford a residue, which was suspended in 50 mL of water. The mixture was acidified with IN hydrochloric acid to pH 2. The precipitated solid was collected be filtration, washed with water, and then dried to provide the title compound without any further purification, mp 139-141 °C; ^ (KB^ cm"1: 3081, 2917, 1735, 1604, 1508, 1233; 400 MHz 1H NMR DMSO-d6): δ 7.51-7.59 (m, IH), 7.02-7.31 (m, 6H), 6.85-6.92 (m, 2H), 6.68 (d, IH, 7 = 8.6 Hz), 5.01 (s, 2H), 4.60 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 429 (M-l). Anal, Calc'd for C23H20F2O4S: C, 64.17; H, 4.68; found: C, 64.11; H, 4.59.
Example 32
Synthesis of l4-r4-(2.4-Dichloro-benzvIoxy)-benzylsulfanvn-2-methyl-phenoχy)- acetic acid (compound 32)
Figure imgf000106_0001
32
Step 1. Preparation of [4-(2,4-Dichloro-benzyloxy)-phenyIl-methanol (compound 32A)
Figure imgf000106_0002
32A
The title compound was prepared in the manner analogous to Example 14A using 2,4-dichloro-l-chloromethyl-benzene and 4-hydroxymethyl-phenol. MS m/z 265 (M-
OH).
Step 2. Preparation of 2,4-Dichloro-l-(4-chIoromethyl-phenoxymethyl)-benzene (compound 32B)
Figure imgf000107_0001
32B
The title compound was prepared in the manner analogous to Example 3B using 32A. MS m/z 265 (M-Cl).
Step 3. Preparation of {4-[4-(2,4-Dichloro-benζyloxy)-benζylsulfanyl]-2-methyl- phenoxyj-acetic acid methyl ester (compound 32C)
Figure imgf000107_0002
32C
The title compound was prepared in the manner analogous to Example IF using 32B and 2C. MS m/z 477 (M+l).
Step 4. Preparation of {4-[4-(2,4-Dichloro-benζyloxy)-benζylsulfanyl]-2-methyl phenox }-acetic acid (compound 32)
Figure imgf000107_0003
32 The title compound was prepared in the manner analogous to Example 1 using 32C. mp 143-145 °C; TR (KBr) cm"1: 3062, 2936, 1724, 1492, 1227, 1192; 400 MHz 1H NMR (DMSO- ): δ 12.97 (br(s), IH), 7.64 (d, IH, 7 = 2.0 Hz), 7.54 (d, IH, 7 = 8.3 Hz), 7.42 (dd, IH, 7 = 8.3, 2.0 Hz), 7.01-7.20 (m, 4H), 6.84-6.92 (m, 2H), 6.69 (d, IH, 7 = 8.5 Hz), 5.05 (s, 2H), 4.62 (s, 2H), 4.01 (s, 2H), 2.08 (s, 3H); MS m/z 461
(M-l). Anal. Calc'd for C23H2oCl2O4S: C, 59.62; H, 4.35; found: C, 59.33; H, 4.28.
Example 33
Synthesis of {4-r4-(4-Methoxy-benζyloxy)-benζylsulfanyl |-Zτmethyl-phenoxy)- acetic acid (compound 33)
Figure imgf000108_0001
33
Step 1. Preparation of [4-(4-Methoxy-benzyloxy)-phenyl]-methanol (compound
33A)
Figure imgf000108_0002
33A
The title compound was prepared in the manner analogous to Example 14A using 1 - chloromethyl-4-methoxy-benzene and 4-hydroxymethyl-phenol. MS m/z 221 (M- OH). Step 2. Preparation of 4-Methoxy-l-(4-chloromethyl-phenoxymethyl)-benzene (compound 33B)
Figure imgf000109_0001
33B
The title compound was prepared in the manner analogous to Example 3B using 33A. MS m/z 227 (M-Cl).
Step 3. Preparation of {4-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid methyl ester (compound 33C)
Figure imgf000109_0002
33C
The title compound was prepared in the manner analogous to Example IF using 33B and 2C. MS m/z 439 (M+l).
Step 4. Preparation of {4-[4-(4-Methoxy-benζyloxy)-benζylsulfanyl]-2-methyl- phenoxy}-acetic acid (compound 33)
Figure imgf000110_0001
33
The title compound was prepared in the manner analogous to Example 1 using 33C. mp 150-152 °C; HPLC: area % = 96.69, r.t. = 2.93 min., γ= 214 nm, mobile phase = acetonitrile/water with 0.10% TFA; TR (KBr) cm"1: 2929, 1728, 1707, 1513, 1491, 1225; 400 MHz 1H NMR (DMSO- ): δ 12.98 (br(s), IH), 7.27-7.34 (m, 2H), 7.02- 7.16 (m, 4H), 6.81-6.91 (m, 4H), 6.69 (d, IH, 7 = 8.6 Hz), 4.91 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 3.69 (s, 3H), 2.08 (s, 3H); MS m/z 423 (M-l). Anal. Calc'd for C2 H2 O5S: C, 67.90; H, 5.70; found: C, 67.48; H, 5.59.
Example 34
Synthesis of {4-r4-(4-tert-Butyl-benζyloxy)-benζylsulfanvπ-2-methyl-phenoxy)- acetic acid (compound 34)
Figure imgf000110_0002
34
Step 1. Preparation of [4-(4-tert-Butyl-benzyloxy)-phenyl]-jmethanol (compound 34A)
Figure imgf000111_0001
34A
The title compound was prepared in the manner analogous to Example 14A using 1 - bromornethyl-4-tert-butyl-benzene and 4-hydroxymethyl-phenol. MS m/z 253 (M- OH).
Step 2. Preparation of 4-tert-Butyl-l-(4-chloromethyl-phenoxymethyl)-benzene (compound 34B)
Figure imgf000111_0002
34B
The title compound was prepared in the manner analogous to Example 3B using 34A. MS m/z 253 (M-Cl).
Step 3. Preparation of {4-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid methyl ester (compound 34C)
Figure imgf000111_0003
34C The title compound was prepared in the manner analogous to Example IF using 34B and 2C. MS m/z 465 (M+l).
Step 4. Preparation of {4-[4*(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxyj-acetic acid (compound 34)
Figure imgf000112_0001
34
The title compound was prepared in the manner analogous to Example 1 using 34C. mp 135-137 °C; TR (KBr) cm"1: 2961, 2908, 1751, 1495, 1233, 1194; 400 MHz 1H NMR (DMSO-rfe): δ 13.00 (br(s), IH), 7.27-7.38 (m, 4H), 7.02-7.17 (m, 4H), 6.82- 6.88 (m, 2H), 6.69 (d, IH, 7 = 8.5 Hz), 4.96 (s, 2H), 4.61 (s, 2H), 3.99 (s, 2H), 2.08 (s, 3H), 1.22 (s, 9H); MS m/z 451 (M+l). Anal. Calc'd for C27jl3oO4S: C, 71.97; H,
6.71; found: C, 71.66; H, 6.52.
Example 35
Synthesis of 12-Methyl-4-r4-(4-trifluoromethoxy-benζyloxy)-benζylsulfanvn- phenoxyl-acetic acid (compound 35)
Figure imgf000113_0001
35
Step 1. Preparation of [4-(4-Acetoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (compound 35A)
Figure imgf000113_0002
35A
The title compound was prepared in the manner analogous to Example IF using acetic acid 4-chloromethyl-phenyl ester and 2C. MS m/z 361 (M+l).
Step 2. Preparation of [4-(4-Hydroxy-benzylsuIfanyl)-2-methyl-phenoxy]-acetic acid (compound 35B)
Figure imgf000113_0003
35B
The title compound was prepared in the manner analogous to Example 1 using 35A. MS m/z 303 (M-l). Step 3. Preparation of [4-(4-Hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (compound 35C)
Figure imgf000114_0001
35C
To a solution of the product from Example 35B (0.43 g, 1.4 mmol) in 14 mL of 2,2- dimethoxy propane was added 1.4 mL of concentrated hydrochloric acid. The reaction mixture was stiπed at room temperature for 18 hours. The mixture was concentrated and purified by flash chromatography to provide the title compound. MS m/z 317 (M-l).
Step 4. Preparation of {2-Methyl-4-[4-(4-trifluoromethoxy-benzyloxy)- benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 35D)
Figure imgf000114_0002
35D
The title compound was prepared in the manner analogous to Example IF using 1- bromomethyl-4-trifluoromethoxy-benzene and 35C. MS m/z 493 (M+l).
Step 5. Preparation of {2-Methyl-4-[4-(4-trifiuoromethoxy-benzyloxy)- benzy!sulfanyI]-phenoxy}-acetic acid (compound 35)
Figure imgf000115_0001
35
The title compound was prepared in the manner analogous to Example 1 using 35D. mp 141-142 °C; 400 MHz 1H NMR (DMSO-d6): δ 12.96 (br(s), IH), 7.46-7.57 ( , 2H), 7.28-7.38 (m, 2H), 7.00-7.20 (m, 4H), 6.82-6.91 (m, 2H), 6.69 (d, IH, 7= 8.6 Hz), 5.05 (s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 477 (M-l). Anal. Calc'd for C24H2JF3O5S: C, 60.25; H, 4.42; found: C, 59.92; H, 4.07.
Example 36
Synthesis of |6-Methyl-8-r4-(5-trifluoromethyl-pyridine-2-yl)-benζvIsulfanvn- chroman-5-yloxy)-acetic acid (compound 36)
Figure imgf000115_0002
36
Step l. {6-Methyl-8-[4-(5-trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]- chroman-5-yloxy}-acetic acid methyl ester (compound 36A)
Figure imgf000116_0001
36A
The title compound was prepared in the manner analogous to Example IF using (8- mercapto-6-methyl-chroman-5-yloxy)-acetic acid methyl ester and 18B. MS m/z 504 (M+l).
Step 2. {6-Methyl-8-t4-(5-trifluoromethyl-pyridine-2-yl)-benζylsulfanyl]- chroman-5-yloxy}-acetic acid methyl ester (compound 36)
Figure imgf000116_0002
36
The title compound was prepared in the manner analogous to Example 1 using 36A. mp 156-157 °C; IR CKB^ cm"1. 2928, 1731, 1710, 1603, 1329, 11 13, 1082; 400
MHz Η NMR (DMSO-dβ): δ 12.84 (br(s), IH), 8.97 (s, IH), 8.22 (dd, IH, 7 = 8.4, 2.0 Hz), 8.12 (d, IH, 7 = 8.4 Hz), 8.04 (d, 2H, 7 = 8.2 Hz), 7.42 i (d, 2H, 7 = 8.2 Hz),
6.88 (s, IH), 4.29 (s, 2H), 4.05-4.14 (m, 4H), 2.64 (t, 2H, 7 = 6.3 Hz), 2.04 (s, 3H), 1.81 (pentet, 2H) ; MS m/z 490 (M+l). Anal. Calc'd for C25H2iF3NO4S: C, 61.34; H, 4.53; N, 2.86; found: C, 60.96; H, 4.48; N, 2.79. Example 37
Synthesis of {5-Chloro-2-methyl-4-r4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyll-phenoxyl-acetic acid (compound 37)
Figure imgf000117_0001
37
Step 1. Preparation of {5-Chloro-2-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyI]-phenoxy}-acetic acid methyl ester (compound 37 A)
Figure imgf000117_0002
37A
Compound 37A was prepared in the manner analogous to Example IF using the products from Example 18B and Example 20C. MS m/z 482 (M+).
Step 2. Preparation of {5-chloro-2-methyl-4-[4-(5-trifluorom|ethyl-pyridin-2-yl)- benζylsulfanyl]-phenoxy}-acetic acid (compound 37)
The title compound was prepared in the manner analogous to Example 1 using 37A. TR cm'':1708, 1122; 400 MHz 1H NMR (DMSO-d6) δ 8.97 (s, IH), 8.22 (d, IH, 7 = 8.3 Hz), 8.12 (d, IH, 7 = 8.3 Hz), 8.04 (d, 2H, 7 = 8.3 Hz), 7.43 (d, 2H, 7 = 8.3 Hz), 7.25 (s, IH), 6.94 (s, IH), 4.70 (s, 2H), 4.21 (s, 2H), 2.06 (s, 3H). Anal. Calc'd for C22HI7ClF3NO3S: C, 56.47, H, 3.66, N 2.99; found: C, 56.48, H, 3.28, N 3.04. Example 38
Synthesis of r5-hvdroxy-2-methvI-4-(4'-trifluoromethyI-biphenyl-4- yl ethvIsuIfanvD-phenoxyl-acetic acid (compound 38)
Figure imgf000118_0001
38
A solution of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid, prepared according to Example 4,(1.0 g, 2.2 mmol) in 75 mL DCM at 0 °C, was treated with dropwise addition of BBr3 (5.5 mL of a 1.0 M solution in DCM). After 30 minutes, the reaction was carefully quenched with 50% NrLjOH. The reaction was then acidified to pH 1 with cone HCl, and extracted with EtOAC. The organic layer was dried (Na2SO ) and concentrated in vacuo. The crude reaction mixture was then taken up in MeOH, followed by addition of 50 μL H2SO4, and then refluxing for 3 hours. The reaction was then diluted with EtOAc, washed 1 x 50 mL water, dried (Na2SO ), and the reaction concentrated in vacuo. The resulting ester was purified by recrystallization from EtOAC/Hexanes. The ester was then saponified in the same manner as described for Example 1, to give the title compound in 37% overall yield. DR cm"1 :3408, 1752, 1323; 400 MHz 1H
NMR (DMSO-d6) δ 9.56 (s, IH), 7.82 (d, 2H, 7 = 8.4 Hz), 7.74 (d, 2H, 7 = 8.4 Hz), 7.31 (d, 2H, 7 = 8.4 Hz), 6.92 (s, IH), 6.30 (s, IH), 4.55 (s, 2H), 4.00 (s, 2H), 1.95 (s, 3H). Anal. Calc'd for C23H]9F3NO4S -0.1 H2O C, 61.35; H, 4.30; found: C, 61.08; H, 3.92.
Example 39
Synthesis of r5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethvI-biphenyl-4- ylmethylsulfanvD-phenoxyl-acetic acid (compound 39)
Figure imgf000119_0001
39
Step 1. Preparation of (3-Methyl-4'-trifluoromethyl-biphenyI-4-yl)-methanol (compound 39 A)
Figure imgf000119_0002
39A
The title compound was prepared in the manner analogous to Example 3A using (4- bromo-2-methyl-phenyl)-methanol and 4-(trifluoromethyl)benzeneboronic acid. MS /z 249 (M-OH).
Step 2. Preparation of 4-chloromethyl-3-methyI-4'-trifluoi|omethyl-biphenyl
(compound 39B)
Figure imgf000119_0003
39B The title compound was prepared in the manner analogous to Example 3B using 39A. 400 MHz Η NMR (DMSO- 6) δ 7.84 (d, 2H, 7 = 8.3 Hz), 7.76 (d, 2H, 7 = 8.3 Hz), 7.57 (s, IH), 7.48 (m, 2H), 4.80 (s, 2H), 2.41 (s, 3H).
Step 3. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl- biphenyl-4-y!methylsuIfanyl)-phenoxy]-acetic acid methyl ester (compound 39C)
Figure imgf000120_0001
39C
The title compound was prepared in the manner analogous to Example IF using ID and 39B. MS m/z 491 (M+l).
Step 4. Preparation of [5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl- biphenyl-4-ylmethylsulfanyI)-phenoxy]-acetic acid (compound 39)
The title compound was prepared in the manner analogous to Example 1 using 39C. IR cm"1:1740, 1322; 400 MHz 1H NMR (DMSO- ) δ 7.81 (d, 2H, 7 = 8.1 Hz), 7.73 (d, 2H, 7= 8.1 Hz), 7.51 (s, IH), 7.39 (d, IH, 7= 7.8 Hz), 7.16 (d, IH, 7 = 7.8 Hz), 7.04 (s, IH), 6.53 (s, IH), 4.71 (s, 2H), 4.00 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H), 2.02 (s, 3H); MS m/z 477 (M+l). Anal. Calc'd for C25H23F3O S-0.1 H2O; C, 62.78; H, 4.89; found: C, 62.57; H, 4.82.
Example 40
Synthesis of l7-r4-(4-trifluoromethyl-benzyl)-benzvIsulfanvn-indan-4-yloxy)- acetic acid (compound 40)
Figure imgf000121_0001
40
Step 1. Preparation of 4-(4-trifluoromethyl-benzyl)-benzoic acid methyl ester (compound 40A)
Figure imgf000121_0002
40A
A solution of l-bromo-4-trifluoromethyl-benzene (10.0 g, 44.4 mmol) in THF at -78 °C was treated with dropwise addition of n-butyl lithium (33.3 mL of a 1.6 M solution in hexanes). After 20 minutes, 4-formyl-benzoic acid methyl ester in 50 mL THF was added. The reaction was allowed to come to room temperature and after 1 H, quenched with sat. NH CI. The reaction was then concentrated in vacuo, taken up in EtOAc, and washed with 2 M HCl (1 x 100 mL), brine (1 x 100 mL), dried (Na2SO4) and the solvent removed in vacuo to give the alcohol intermediate.
Purification by flash column chromatography (gradient elution: 5% EtOAc hexane to 40% EtOAc/hexane) gave 6.2 g of the alcohol intermediate. 4.0 g (12.9 mmol) of the intermediate was then hydrogenated in EtOAc using 0.5g of 10 % Pd(OH)2/C as catalyst. Filtration through Celite® , and concentration in vacuo gave the title compound (3.60 g, 95%). MS m/z 295 (M+l).
Step 2. Preparation of [4-(4-trifiuoromethyl-benζyl)-phenyl]-methanol (compound 40B)
Figure imgf000121_0003
40B A solution of 40A (3.6 g, 12.2 mmol) in 75 mL THF at room temperature was treated portionwise with lithium aluminum hydride (0.97 g, 25.6 mmol). After 1 hour, the reaction mixture was carefully quenched with sat. NFLCl. The reaction mixture was then extracted with EtOAc, and the organic layer washed with 2 M HCl (1 x 50 mL), brine (1 x 50 mL), dried (Na2SO4) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 40% EtOAc/hexane) gave the title compound (2.8 g, 86%). MS m/z 265 (M-l).
Step 3. Preparation of Chloro- [4-(4-trifluoromethyI-benzyI)-phenyl]-methane (compound 40C)
Figure imgf000122_0001
40C
The title compound was prepared in a similar manner as described for 3B using 40B and thionyl chloride. 400 MHz 1H NMR (DMSO- 6) 7.59 (d, 2H, 7 = 8.4 Hz), 7.40 (d, 2H, 7 = 8.4 Hz), 7.31 (d, 2H, 7 = 8.4 Hz), 7.20 (d, 2H, 7=8.4 Hz), 4.67 (s, 2H), 3.99 (s, 2H).
Step 4. Preparation of{7-[4-(4-Trifluoromethyl-benzyl)-benzylsulfanyl]-indan- 4-yloxy}-acetic acid methyl ester (compound 40D)
Figure imgf000122_0002
40D The title compound was prepared in the manner analogous to Example IF using the products from Example 12C and Example 40C. MS m/z 487 (M+l).
Step 5. Preparation of {7-[4-(4-trifluoromethyl-benζyl)-benζylsuIfanyl]-indan- 4-yloxy}-acetic acid (compound 40)
The title compound was prepared in the manner analogous to example 1 using 40D. IR cm"1: 1745, 1704, 1325; 400 MHz 1H NMR (DMSO-d6) 67.58 (d, 2H, 7 = 8.1 Hz), 7.37 (d, 2H, 7 = 8.1 Hz), 7.09 (s, 2H), 7.05 (d, 2H, 7=8.3 Hz), 6.55 (d, IH, 7 = 8.3 Hz), 4.60 (s, 2H), 3.94 (s, 4H), 2.71 (t, 2H, 7 = 8.3 Hz), 2.58 (t, 2H, 7 = 8.3 Hz), 1.81 (m, 2H); MS m/z 473 (M+l). Anal. Calc'd for C26H23F3O3S-0.1 H2O, C, 65.84; H,
4.93; found: C, 65.58; H, 4.96.
Example 41
Synthesis of {4-r5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyll-5-methoxy-2- methyl-phenoxyj-acetic acid (compound 41)
Figure imgf000123_0001
41
Step 1. Preparation of {4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5- methoxy-2-methyl-phenoxy}-acetic acid methyl ester (compound 41A)
Figure imgf000124_0001
41A
The title compound was prepared in the manner analogous to Example IF using ID and 3-chloromethyl-5-(4-chloro-phenyl)-isoxazole. MS m z 434 (M+l).
Step 2. Preparation of {4-[5-(4-Chloro-phenyI)-isoxaζol-3-ylmethylsulfanyI]-5- methoxy-2-methyl-phenoxy}-acetic acid (compound 41)
The title compound was prepared in the manner analogous to Example 1 using 41A.
IR cm"1: 1747, 1432; 400 MHz Η NMR (DMSO- 6) δ 7.81 (d, 2H, 7 = 8.8 Hz), 7.53 (d, 2H, 7 = 8.8 Hz), 7.05 (s, IH), 6.92 (s, IH), 6.52 (s, IH), 4.69 (s, 2H), 4.01 (s, 2H), 3.71 (s, 3H), 2.00 (s, 3H); MS m/z 420 (M+l). Anal. Calc'd for C2oHι8ClNO5S, C 57.21; H, 4.32 N, 3.34; found: C, 56.84; H, 4.62, N, 2.96.
Example 42
Synthesis of |2-Methyl-4-r5-(4-trifluoromethyl-phenvI)-isoxaζol-3- ylmethylsulfanvπ-phenoxyl-acetic acid (compound 42)
Figure imgf000124_0002
42 Step 1. Preparation of 5-(4-TrifluoromethyI-phenyl)-isoxazole-3-carboxylic acid ethyl ester (compound 42A)
Figure imgf000125_0001
Sodium hydride (1.6 g, 63.7 mmol, 95%) was added to a solution of l-(4- trifluoromethyl-phenyl)-ethanone (10.0 g, 53.1 mmol) and oxalic acid diethyl ester (8.7 L, 63.7 mmol) in 75 mL dry DMF at 0 °C. The reaction was allowed to come to room temperature and then heated to 45 °C for 45 minutes. The reaction was then cooled, concentrated in vacuo, and the residue taken up in EtOAc. The organic layer was then washed with 2 M HCl (1 x 100 mL), dried (Na2SO ) and the solvent removed in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 55% EtOAc/hexane) gave the intermediate 2,4-dioxo-4-(4- trifluoromethyl-phenyl)-butyric acid ethyl ester (12.2 g, 80%) which was then taken up in EtOH and refluxed in the presence of hydroxyl amine hydrochloride (10.2 g, 132.3 mmol) for 3H. The reaction was then cooled, diluted with EtOAc, washed with dilute NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. Recrystallization from EtOAc/hexane gave 5.2 g of the title compound. MS m/z 286 (M+l).
Step 2. Preparation of [5-(4-Trifluoromethyl-phenyl)-isoxajzol-3-yl]-methanol (compound 42B)
Figure imgf000126_0001
The title compound was prepared in a manner analogous to Example 40B using 42A. MS m/z 244 (M+l).
Step 3. Preparation of 3-chloromethyl-5-(4-trifluoromethyl-phenyl)-isoxaζole (compound 42C)
Figure imgf000126_0002
The title compound was prepared in a manner analogous to Example 3B using 42B. MS m/z 262 (M+l).
Step 4. Preparation of {2-methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxazoI-3- ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 42
Figure imgf000127_0001
42D
The title compound was prepared in a manner analogous to Example IF using 42C and 2C. MS m/z 438 (M+l).
Step 5. Preparation of {2-Methyl-4-[5-(4-trifluoromethyl-phenyl)-isoxaζoI-3- ylmethylsulfanyl]-phenoxy}-acetic acid (compound 42)
The title compound was prepared in a manner analogous to Example 1 using 42D. IR cm"1:1746, 1326; 400 MHz ]H NMR (DMSO-d6) δ 12.97 (br(s), IH), 8.02 (d, 2H, 7 = 8.0 Hz), 7.83 (d, 2H, 7= 8.0 Hz), 7.20 (s, IH), 7.15 (s, 2H), 6.71 (d, IH, 7= 8.5 Hz), 4.63 (s, 2H), 4.14 (s, 2H), 2.08 (s, 3H); MS m/z 424 (M+l). Anal. Calc'd for C2oHι6F3NO4S C, 56.73; H, 3.81; N, 3.31 found: C, 56.59; H, 3.58; N, 3.22.
Example 43
Synthesis of {5-Methoxy-2-methyl-4-r5-(4-trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfanyll-phenoxyl-acetic acid (compound 43)
Figure imgf000128_0001
43
Step 1. Preparation of {5-Methoxy-2-methyl-4-[5-(4-trifluoromethyI-phenyl)- isoxazol-3-yImethylsulfanyI]-phenoxy}-acetic acid methyl ester (compound 43A)
Figure imgf000128_0002
The title compound was prepared in a manner analogous to Example IF using 42C and ID. MS m/z 468 (M+l).
Step 2. Preparation of {5-Methoxy-2-methyI-4-[5-(4-trifluoromethyl-phenyl)- isoxaζol-3-ylmethylsuIfanyl]-phenoxy}-acetic acid (compound 43)
The title compound was prepared in a manner analogous to Example 1 using 43A. IR cm"1:1745, 1322; 400 MHz 1H NMR (OMSO-d6) δ 12.96 (br(s), IH), 8.01 (d, 2H,
7= 8.3 Hz), 7.83 (d, 2H, 7= 8.3 Hz), 7.07 (s, 2H), 6.52 (s, IH), 4.70 (s, 2H), 4.03 (s, 2H), 3.71 (s, 3H), 1.99 (s, 3H); MS m/z 454 (M+l). Anal. Calc'd for C2ιHι8F3NO5S- 0.1H2O C, 54.46; H, 3.92; N, 3.01 found: C, 54.54; H, 3.74; N.,2.93.
Example 44
Synthesis of {7-r5-(4-TrifluoromethvI-phenvI)-isoxaζol-3-yImethylsulfanyl1- indan-4-yloxy}-acetic acid (compound 44)
Figure imgf000129_0001
44
Step 1. Preparation of {7-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfany]]-indan-4-yloxy}-acetic acid methyl ester (compound 44A)
Figure imgf000129_0002
44A
The title compound was prepared in a manner analogous to Example IF using 42C and 12C. MS m/z 464 (M+l). Step 2. Preparation of {7-[5-(4-TrifluoromethyI-phenyI)-isoxazoI-3- ylmethylsulfanyl]-indan-4-yloxy}-acetic acid (compound 44)
The title compound was prepared in a manner analogous to Example 1 using 44A. 400 MHz 1H NMR (DMSO-d6) δ 12.94 (br(s), IH), 8.01 (d, 2H, 7 = 8.4 Hz), 7.83 (d,
2H, 7= 8.4 Hz), 7.09 (s, 2H), 6.58 (d, IH, 7= 8.6 Hz), 4.62 (s, 2H), 4.08 (s, 2H), 2.77 (m, 4H), 1.89 (m, 2H); MS m/z 450 (M+l). Anal. Calc'd for C22H]8F3NO4S C, 58.79; H, 4.04; N, 3.12 found: C, 58.59; H, 3.80; N, 3.01.
Example 45
Synthesis of l2-Methv -4-r3-(4-trifluoromethyl-phenyl)-isόxazol-5- ylmethylsulfanvπ-phenoxyl-aeetic acid (compound 45)
Figure imgf000130_0001
45
Step 1. Preparation of 5-chloromethyl-3-(4-trifluoromethyl-phenyl)-isoxazole (compound 45A)
Figure imgf000130_0002
A solution of 4-trifluoromethyl-benzaldehyde oxi e (8.9 g, 47.1 mmol) in 100 L DCM was added to a rapidly stirred solution of propargyl chloride (47.1 mmol), triethyl amine (4.71 mmol) and 91 mL of commercial bleach (6.5% by weight) all in 50 mL DCM at 0 °C. After 1 hour the layers were separated and the organic layer dried (Na2SO ), and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 5% EtOAc/hexane to 25% EtOAc/hexane) gave the title compound (2.9 g, 23%) MS m z 262 (M+l).
Step 2. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxaζol-5- ylmethyIsuIfanyl]-phenoxy}-acetic acid methyl ester (compound 45B)
Figure imgf000131_0001
45B
The title compound was prepared in a manner analogous to Example IF using 45A and 2C. MS m/z 438 (M+l).
Step 3. Preparation of {2-Methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxaζol-5- y!methylsuIfanyI]-phenoxy}-acetic acid (compound 45)
The title compound was prepared in a manner analogous to Example 1 using 45B. TR cm"1: 1747; 400 MHz ]H NMR (DMSO- ) δ 12.97 (br(s), IH), 7.99 (d, 2H, 7 = 8.0 Hz), 7.81 (d, 2H, 7= 8.0 Hz), 7.21 (s, IH), 7.16 (d, IH, 7= 8.5 Hz), 6.86 (s, IH), 6.74 (d, IH, 7 = 8.5 Hz), 4.63 (s, 2H), 4.30 (s, 2H), 2.09 (s, 3H); MS m/z 424 (M+l). Example 46
Synthesis of (5-Methoxy-2-methyl-4-r3-(4-trifluoromethyl-phenyl)-isoxazol-5- ylmethylsulfanyll-phenoxy)-acetic acid (compound 46)
Figure imgf000132_0001
46
Step 1. Preparation of {5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)- isoxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 46A)
Figure imgf000132_0002
The title compound was prepared in a manner analogous to Example IF using 45A and ID. MS m/z 468 (M+l).
Step 2. Preparation of {5-Methoxy-2-methyl-4-[3-(4-trifIupromethyl-phenyl)- isoxaζol-5-ylmethylsulfanyI]-phenoxy}-acetic acid (compound 46) The title compound was prepared in a manner analogous to Example 1 using 46A. IR cm"1:1752, 1711; 400 MHz 1H NMR (DMSO-dβ) δ 12.96 (br(s), IH), 7.98 (d, 2H, J = 8.1 Hz), 7.81 (d, 2H, 7= 8.1 Hz), 7.09 (s, IH), 6.80 (s, IH), 6.54 (s, IH), 4.71 (s, 2H), 4.18 (s, 2H), 3.79 (s, 3H), 2.00 (s, 3H); MS m/z 454 (M+l)
Example 47
Synthesis of r2-Methyl-4-(4-phenoxy-benzylsulfanvI)-phenoxy1-acetic acid (compound 47)
Figure imgf000133_0001
Step 1. Preparation of [2-Methyl-4-(4-phenoxy-benzylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 47A)
Figure imgf000133_0002
47A
The title compound was prepared in the manner analogous to Example IF with 1- chloromethyl-4-phenoxy-benzene and 2C. MS m/z 321 (M-methylacetate).
Step 2. Preparation of [2-Methyl-4-(4-phenoxy-benζylsuIt[anyl)-phenoxy]-acetic acid (compound 47)
The title compound was prepared in the manner analogous to Example 1 using 47A. 400 MHz 1H NMR (DMSO- ) δ 12.95 (br(s), IH), 7.33 ( , 2H), 7.22 (m, 2H), 7.07 (m, 3H), 6.93 (m, 2H), 6.87 (m, 2H), 6.71 (d, IH, 7=8.3 Hz), 4.62 (s, 2H), 4.04 (s, 2H), 2.09 (s, 3H). MS m/z 379 (M-l).
Example 48
Synthesis of r7-(4'-Trifluoromethyl-biphenvI-3-ylmethyIsulfanyl)-indan-4-yloxy1- acetic acid (compound 48)
Figure imgf000134_0001
48
Step 1. Preparation of (4'-Trifluoromethyl-biphenyl-3-yI)-methanol (compound
48A)
Figure imgf000134_0002
48A
The title compound was prepared in the manner analogous to Example 3A with 1- bromo-4-trifluoromethyl-benzene and 3-(hydroxymethyl)phenyl boronic acid. MS m/z 251 (M-l). Step 2. Preparation of 3-Chloromethyl-4'-trifluoromethyl-biphenyl (compound 48B)
Figure imgf000135_0001
48B
The title compound was prepared in the manner analogous to Example 3B using 48A. MS m/z 236 (M+l -Cl).
Step 3. Preparation of [7-(4'-Trifluoromethyl-biphenyl-3-ylmethylsulfanyl)- indan-4-yloxy]-acetic acid methyl ester (compound 48C)
Figure imgf000135_0002
48C
The title compound was prepared in the manner analogous to Example IF using 12C and 48B. MS m/z 473 (M+l).
Step 4. Preparation of [7-(4'-Trifluoromethyl-biphenyI-3-ylmethylsulfanyl)- indan-4-yloxy]-acetic acid (compound 48)
The title compound was prepared in the manner analogous to Example 1 using 48C. 400 MHz 1H NMR (DMSO- ) δ 12.96 (br(s), IH), 7.75 (d, 2H, 7= 8.3 Hz), 7.67 (d, 2H, 7= 8.1 Hz), 7.52 (m, IH), 7.37 (t, IH, 7=7.6 Hz), 7.29 (m, 2H), 7.13 (d, IH, 7=8.5 Hz), 6.61 (d, IH, 7=8.5 Hz), 4.63 (s, 2H), 4.05 (s, 2H), 2.71 (t, 2H), 2.58 (t,
2H), 1.81 (m, 2H). MS m/z 459 (M+l). Example 49
Synthesis of r5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenvI-3- ylmethylsulfanvD-phenoxyl-acetic acid (compound 49)
Figure imgf000136_0001
49
Step 1. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyI-3- ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 49A)
Figure imgf000136_0002
49A
The title compound was prepared in the manner analogous to Example IF using 48B and ID. MS m/z 477 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluor!omethyl-biphenyl-3- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 49)
The title compound was prepared in the manner analogous to Example 1 using 49A. 400 MHZ 1H NMR (DMSO- 6) δ 12.96 (br(s), IH), 7.73 (d, 2H, 7=9 Hz), 7.71 (d,
2H, 7=9 Hz), 7.50 (m, IH), 7.42 (m, IH), 7.36 (t, IH, 7=7.8 Hz), 7.28 (m, IH), 6.99 (s, IH), 6.53 (s, IH), 4.70 (s, 2H), 4.03 (s, 2H), 3.73 (s, 3H), 1.99 (s, 3H). MS m/z 463 (M+l).
Example 50
Synthesis of r5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethanesulfonvD-phenoxyl-acetic acid (compound 50)
Figure imgf000137_0001
50
Step 1. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethanesulfonyl)-phenoxy]-acetic acid methyl ester (compound 50A)
Figure imgf000137_0002
50A
Example 4 (200 mg) was dissolved in 5 ml dichloromethane. Excess m- chloroperbenzoic acid (300 mg) was added and the reaction was allowed to stir 3h. The solvent was removed under vacuum and the crude product was purified by
MPLC. MS m/z 509 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethanesulfonyI)-phenoxy]-acetic acid (compound 50) The title compound was prepared in the manner analogous to Example 1 using 50A. 400 MHz 1H NMR (DMSO-d6) δ 13.13 (br(s), IH), 7.85 (d, 2H, 7=8.1 Hz), 7.77 (d, 2H, 7=8.3 Hz), 7.66 (d, 2H, 7=8.6 Hz), 7.3 (m, 3H), 6.76 (s, IH), 4.89 (s, 2H), 4.67 (s, 2H), 3.96 (s, 3H), 2.04 (s, 3H). MS m/z 495 (M+l).
Example 51
Synthesis of r5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethanesulfinvD-phenoxyl-acetic acid (compound 51)
Figure imgf000138_0001
51
Step 1. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyI-biphenyl-4- ylmethanesulfinyl)-phenoxy]-acetic acid methyl ester (compound 51A)
Figure imgf000138_0002
51A
Example 4 (0.5g, 1.0 mmol) was dissolved in 25 ml dichlorolmethane followed by the addition of 2-benζenesulfonyl-3-phenyl-oxaζiridine (0.274, li.04 mmol). The reaction was stiπed lh. 10 ml water was added, the layers were separated, and dichloromethane solution was dried over anhydrous sodium sulfate, decanted, and concentrated. The product was recrystallized from ethyl acetate to give the title product. MS m/z 493 (M+l).
Step 2. Preparation of [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethanesu]finyl)-phenoxy]-acetic acid (compound 51)
The title compound was prepared in the manner analogous to Example 1 using 51A. 400 MHz ]H NMR (DMS -d6) δ 7.83 (d, 2H, 7=8.78 Hz), 7.76 (d, 2H, 7=8.30 Hz), 7.59 (d, 2H, 7=8.30 Hz), 7.11 (d, 2H, 7=8.30 Hz), 7.02 (s, IH), 6.64 (s, IH), 4.79 (s, 2H), 4.20 (d, IH, 7=12.7 Hz), 3.91 (d, IH, 7=12.4 Hz), 3.76 (s, 3H), 2.03 (s, 3H). MS m/z 479 (M+l).
Example 52
Synthesis of r2-Propyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxyl-acetic acid (compound 52)
Figure imgf000139_0001
52
Step 1. Preparation of [2-Propyl-4-(4,-trifluoromethyl-biphenyl-4- y!methylsulfanyl)-phenoxy]-acetic acid methyl ester (compoμnd 52A)
Figure imgf000140_0001
52A
The title compound was prepared in the manner analogous to Example IF using 48B and (4-Mercapto-2-propyl-phenoxy)-acetic acid methyl ester, prepared from 2- propylphenol in a manner analagous to Example 2. MS m z 475 (M+l).
Step 2. Preparation of [2-Propyl-4-(4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid (compound 52)
The title compound was prepared in the manner analogous to Example 1 using 52A. 400 MHz 1H NMR (DMSO- 6) δ 7.81 (d, 2H, 7=8.5 Hz), 7.74 ;(d, 2H, 7=8.5 Hz),
7.60 (d, 2H, 7=8.1 Hz), 7.33 (d, 2H, 7=8.3 Hz), 7.10 (m, IH), 7.02 (m, IH), 6.71 (d, IH, 7=8.5 Hz), 4.60 (s, 2H), 4.11 (s, 2H), 1.43 (m, 2H), 0.77 (m, 3H). MS m/z 459 (M-l).
Example 53
Synthesis of {7-r3-(5-Trifluoromethv1-pyridin-2-yl)-benζylsuIfanyl1-indan-4- yloxyl-acetic acid (compound 53)
Figure imgf000141_0001
53
Step 1. Preparation of [3-(5-Trifluoromethyl-pyridin-2-yl)-phenyl]-methanol (compound 53A)
Figure imgf000141_0002
53A
The title compound was prepared in the manner analogous to Example 3A using 3- (hydroxymethyl)phenyl boronic acid and 2-chloro-5-trifluoromethyl-pyridine. MS m/z 253 (M+l).
Step 2. Preparation of 2-(3-Chloromethyl-phenyl)-5-trifluoromethyl-pyridine (compound 53B)
Figure imgf000141_0003
53B
The title compound was prepared in the manner analogous to Example 3B using 53A. MS m/z 237 (M+l-Cl).
Step 3. Preparation of {7-[3-(5-Trifluoromethyl-pyridin-2!-yl)-benζylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 53C)
Figure imgf000142_0001
53C
The title compound was prepared in the manner analogous to Example IF using 12C and 53B. MS m/z 474 (M+l).
Step 4. Preparation of {7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benζyIsulfanyl]- indan-4-yloxy}-acetic acid (compound 53)
The title compound was prepared in the manner analogous to Example 1 using 53C.
400 MHz 1H NMR (OMSO-d6) δ 8.98 (m, IH), 8.23 (dd, IH, 7=1.7 Hz, 7' =8.5 Hz), 7.99 (m, 2H), 7.87 (s, IH), 7.39 (t, IH, 7=7.6 Hz), 7.33 (m, IH), 7.11 (d, IH, 7=8.5 Hz), 6.58 (d, IH, 7=8.5 Hz), 4.61 (s, 2H), 4.08 (s, 2H), 2.70 (t, 2H, 7=7.3 Hz), 2.63 (t, 2H, 7=7.6 Hz), 1.84 (m, 2H). MS m/z 460 (M+l).
Example 54
Synthesis of (5-Methoxy-2-methyl-4-(2-π -(4-trifluoromethyl-benzyl)-lH-indol-3- γπ-ethylsulfanvI)-phenoxy)-acetic acid (compound 54)
Figure imgf000142_0002
54 Step 1. Preparation of {4-[2-(lH-Indol-3-yl)-ethylsulfanyIl-5-methoxy-2-methyl- phenoxy}-acetic acid methyl ester (compound 54A)
Figure imgf000143_0001
54A
The compound ID (1.622 g, 6.7 mmol) and 3-(2-bromo-ethyl)-lH-indole (1.50g, 6.69 mmol) was dissolved in 5 ml DMF. Potassium carbonate (1.1 lg, 8.03 mmol) was added followed by stirring at room temperature for 3h. The reaction was filtered, concentrated and purified by MPLC to give the title compound. MS m/z 225 (M+l).
Step 2. Preparation of (5-Methoxy-2-methyl-4-{2-[l-(4-trifluoromethyI-benζyl)- lH-indol-3-yl]-ethy!sulfanyl}-phenoxy)-acetic acid methyl ester (compound 54B)
Figure imgf000143_0002
The compound 54A (0.300g, 0.778 mmol) was dissolved in 5 ml DMF. NaH was added and stiπed for 1/2 h. 4-trifluoromethylbenzyl bromide (0.223 g, 0.934 mmol) was added and the reaction was stiπed for 1.5h. 10 ml 2N HCl was added to pH<4.
The DMF solution was partitioned between 30ml water and 30 ml ethyl acetate. The organic solution was washed 2x30ml water 1x30ml brine, dried over sodium sulfate, decanted, concentrated and purified by MPLC to give the title product. MS m/z 544 (M+l). Step 3. Preparation of (5-Methoxy-2-methyl-4-{2-[l-(4-trifluoromethyl-benzyl)- lH-indoI-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid (compound 54)
The title compound was prepared in the manner analogous to Example 1 using 54B. 400 MHz 1H NMR (DMSO- ) δ 13.0 (br(s), 1H)7.60 (d, IH, 7=8.1 Hz), 7.42 (d, IH, 7=7.96 Hz), 7.31 (m, 4H), 7.04 (m, 2H), 6.96 (m, IH), 6.53 (s, IH), 5.43 (s, 2H), 4.70 (s, 2H), 3.72 (s, 3H), 3.03 (t, 2H, 7=8.8 Hz), 2.86 (t, 2H, 7=7.6 Hz), 2.04 (s, 3H). MS /z 530 (M+l).
Example 55
Synthesis of r7-(4,-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)-indan-4-yloχv1- acetic acid (compound 55)
Figure imgf000144_0001
Step 1. Preparation of [7-(4*-Trifluoromethyl-biphenyl-2-ylmethylsulfanyl)- indan-4-yloxy]-acetic acid methyl ester (compound 55A)
Figure imgf000144_0002
The title compound was prepared in the manner analogous to Example IF using 12C. and 2-chloromethyl-4'-trifluoromethyl-biphenyl, which was prepared in a manner analogous to Examples 3A and 3B. MS m/z 473 (M+l).
Step 2. Preparation of [7-(4'-Trifluoromethyl-biphenyl-2-ylmethylsuIfanyI)- indan-4-yloxy]-acetic acid (compound 55)
The title compound was prepared in the manner analogous to Example 1 using 55A. 400 MHZ 1H NMR (DMSO-dβ) δ 12.97 (br(s), IH), 7.68 (d, 2H, 7=8.5 Hz), 7.32 (m, 5H), 7.11 (m, IH), 6.77 (d, IH, 7=8.5 Hz), 6.47 (d, IH, 7=8.3 Hz), 4.62 (s, 2H), 3.87
(s, 2H), 2.70 (m, 2H), 1.76 (m, 2H). MS m/z 459 (M+l).
Example 56
Synthesis of {5-Methoxy-2-methvI-4-r2-(4-trifluoromethyl-benζyloxy)- henzylsulfanyll-phenoxyl-acetic acid (compound 56)
Figure imgf000145_0001
56
Step 1. Preparation of {5-Methoxy-2-methyl-4-[2-(4-trifluoromethyI- benzyloxy)-benzylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 56A)
Figure imgf000146_0001
56A
The title compound was prepared in the manner analogous to Example IF using 81A and ID. MS m/z 507 (M+l).
Step 2. Preparation of 5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benζyloxy)- benzylsulfanyl]-phenoxy}-acetic acid (compound 56)
The title compound was prepared in the manner analogous to Example 1 using 56A. 400 MHz Η NMR (DMSO-J6) δ 12.95 (br(s), IH), 7.67 (m, 411), 7.12 (m, 2H), 6.96 (m, 2H), 6.80 (m, IH), 6.49 (s, IH), 5.19 (s, 2H), 4.68 (s, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 1.96 (s, 3H). MS m/z 493 (M+l).
Example 57
Synthesis of {4-r4-(4-Fluoro-benζyloxy)-benζylsulfanyll-2-methyl-phenoxy}- acetic acid (compound 57)
Figure imgf000146_0002
57 Step 1. Preparation of [4-(4-Fluoro-benzyIoxy)-phenyl]-methanol (compound
57A)
Figure imgf000147_0001
57A
The title compound was prepared in the manner analogous to Example 14A using 1- bromomethyl-4-fluoro-benzene and 4-hydroxymethyl-phenol. MS m/z 215 (M-OH).
Step 2. Preparation of l-(4-Chloromethyl-phenoxymethyl)-4-difluoro-benζene
(compound 57B)
Figure imgf000147_0002
57B
The title compound was prepared in the manner analogous to Example 3B using 57A. MS /z 215 (M-Cl).
Step 3. Preparation of {4-[4-(4-Fluoro-benζyIoxy)-benζylsulfanyl]-2-methyl- phenoxyj-acetic acid methyl ester (compound 57C)
Figure imgf000147_0003
57C The title compound was prepared in the manner analogous to Example IF using 57B and 2C. MS m/z 427 (M+l).
Step 4. Preparation of {4-[4-(4-FIuoro-benζyloxy)-benζylsulfanyl]-2-methyl- phenoxyj-acetic acid (compound 57)
The title compound was prepared in the manner analogous to Example 1 using the product from Example 57C. mp 154-155 °C; IR (KBr) cm"1: 3050, 2925, 1727, 1495, 1228, 1156; 400 MHz 1H NMR (DMSO- ): δ 13.00 (br(s), IH), 7.37-7.48 (m, 2H)
6.99-7.22 (m, 6H), 6.80-6.90 (m, 2H), 6.69 (d, IH, J = 8.5 Hz), 4.98 (s, 2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 411 (M-l). Anal. Calc'd for C23H2IFO4S: C, 66.97; H, 5.13; found: C, 66.64; H, 4.88.
Example 58
Synthesis of f4-r4-(4-Chloro-benζyloxy)-benζylsulfanvπ-2-methyl-phenoxy)- acetic acid (compound 58)
Figure imgf000148_0001
58
Step 1. Preparation of {4-[4-(4-Chloro-benzyIoxy)-benzylsulfanyl]-2-methyl- phenoxy -acetic acid methyl ester (compound 58A)
Figure imgf000149_0001
58A
The title compound was prepared in the manner analogous to Example IF using 1- bromomethyl-4-chloro-benzene and the product from Example 35C. MS m/z 443
(M+l).
Step.2. Preparation of {4-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid (compound 58)
The title compound was prepared in the manner analogous to Example 1 using 58A. mp 164 °C; IR (KBr) cm"1: 3062, 1727, 1612, 1493, 1226, 1193; 400 MHz 1H NMR (DMSO-dβ): δ 12.99 (br(s), IH), 7.36-7.44 (m, 4H), 7.01-7.17 (rή, 4H), 6.81-6.89 ( , 2H), 6.69 (d, IH, J = 8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); MS m/z 427 (M-l). Anal. Calc'd for C23H2ιClO4S: C, 64.40; H, 4.93; found: C,
64.43; H, 4.81.
Example 59
Synthesis of 4-r4-(2.5-Dichloro-benζyloxy)-benζylsulfanvn-2-methyl-phenoxyl- acetic acid (compound 59)
Figure imgf000150_0001
59
Step 1. Preparation of {4-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid methyl ester (compound 59 A)
Figure imgf000150_0002
59A
The title compound was prepared in the manner analogous to Example IF using 2- bromomethyl-l,4-dichloro-benzene and the product prepared from Example 35C. m/z 265 (M-21 1).
Step 2. Preparation of {4-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-2-methyl- phenoxyj-acetic acid (compound 59)
The title compound was prepared in the manner analogous to Example 1 using 59A. mp 101-103 °C; IR (KBr) cm'1: 3077, 1715, 1608, 1496, 1437[ 1234; 400 MHz 1H NMR (DMSO- ): δ 7.37-7.63 (m, 3H), 6.99-7.20 (m, 4H), 6.85-6.94 (m, 2H), 6.63 (d, IH, J = 8.5 Hz), 5.05 (s, 2H), 4.45 (s, 2H), 3.99 (s, 2H), 2.07 (s, 3H); HPLC: area
% = 97.61, r.t. = 5.56 min., λ = 214 nm, mobile phase = acetonitrile/water with 0.10% TFA; MS m/z 461 (M-l). Anal. Calc'd for C23H 0C12O4S: C, 59.62; H, 4.35; found: C, 58.04; H, 4.26. Example 60
Synthesis of {2-Methyl-4-r4-(pyridine-2-ylmethoxy)-benzylsulfanyll-phenoχy}- acetic acid (compound 60)
Figure imgf000151_0001
60
Step 1. Preparation of {2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsuIfanyl]- phenoxy }-acetic acid methyl ester (compound 60A)
Figure imgf000151_0002
The title compound was prepared in the manner analogous to Example IF using 2- bromomethyl-pyridine hydrochloride and the product prepared from Example 35C. MS m/z 410 (M+l).
Step 2. Preparation of {2-Methyl-4-[4-(pyridine-2-ylmethoxy)-benzylsulfanyl]- phenoxy }-acetic acid (compound 60)
The title compound was prepared in the manner analogous to Example 1 using 60A. mp 150 °C; rR (KBr) cm"': 2917, 1723, 1605, 1511, 1490, 1217; 400 MHz 1H NMR (DMSO-dβ): δ 12.95 (brs, IH), 8.49-8.55 (s, IH), 7.73-7.81 (m, IH), 7.40-7.48 (m, 1H), 7.24-7.33 (m, IH), 7.00-7.19 (m, 4H), 6.83-6.93 (m, 2H), 6.69 (d, IH, J = 8.5 Hz), 5.08 (s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); HPLC: area % = 96.24, r.t. = 1.95 min., γ= 214 nm, mobile phase = acetonitrile/water with 0.10% TFA; MS m/z 396 (M+l). Anal. Calc'd for C22H21NO4S: C, 66.82; H, 5.35; N, 3.54; found: C, 66.12; H, 5.09; N, 3.44.
Example 61
Synthesis of {5-ChIoro-2-methyl-4-r4-(4-trifluoromethyl-benζyloxy)- benzylsulfanvn-phenoxyl-acetic acid (compound 61)
Figure imgf000152_0001
61
Step 1. Preparation of {5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)- benzyl-sulfanyI]-phenoxy}-acetic acid methyl ester (compound 61A)
Figure imgf000152_0002
61A
The title compound was prepared in the manner analogous tojExample IF using 14B and 20C. MS m/z 265 (M-245). Step 2. Preparation of {5-Chloro-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)- benzyl-sulfanyl]-phenoxy}-acetic acid (compound 61)
The title compound was prepared in the manner analogous to Example 1 using 61A. mp 142-143 °C; IR (KBr) cm"1: 3074, 1747, 1321, 1234, 1175, 1124; 400 MHz 1H NMR (DMSO-i6): δ 13.01 (br(s), IH), 7.67-7.73 (m, 2H), 7.57-7.64 (m, 2H), 7.16- 7.25 (m, 4H), 6.87-6.95 (m, 4H), 5.15 (s, 2H), 4.69 (s, 2H), 4.07 (s, 2H), 2.07 (s, 3H); MS m/z 495 (M-l). Anal. Calc'd for C24H20C1F3O4S: C, 58.01; H, 4.06; found: C, 57.73; H, 4.06.
Example 62
Synthesis of {7-r4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl"l-indan-4-yloxy)- acetic acid (compound 62)
Figure imgf000153_0001
62
Step 1. Preparation of {7-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 62A)
Figure imgf000153_0002
62A The title compound was prepared in the manner analogous to Example IF using 12C and 4-chloromethyl-(2,4-dichloro-benzyloxy-benzene) prepared from 4- hydroxymethyl-phenol and l-chloromethyl-2,4-dichloro-benzene in the manner analagous to Examples 14A and 14B. MS m/z 503 (M+l).
Step 2. Preparation of {7-[4-(2,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid (compound 62)
The title compound was prepared in the manner analogous to Example 1 using 62A. mp 149-150 °C; IR (KBr) cm"1: 3089, 1734, 1512, 1473, 1295, 1234; 400 MHz 1H
NMR (DMSO- ): δ 13.11 (br(s), IH), 7.40-7.71 (m, 3H), 6.88-7.19 (m, 5H), 6.58 (d, IH, J = 8.5 Hz), 5.07 (s, 2H), 4.61 (s, 2H), 3.96 (s, 2H), 2.77 (t, 2H, t, J = 7.4 Hz), 2.69 (t, 2H, J = 7.4 Hz), 1.91 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53; found: C, 60.95; H, 4.41.
Example 63
Synthesis of (7-r4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyn-indan-4- yloxy 1-acetic acid (compound 63)
Figure imgf000154_0001
63
Step 1. Preparation of {7-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 63A)
Figure imgf000155_0001
63A
The title compound was prepared in the manner analogous to Example IF using 14B and l2C. MS m/z 265 (M-237).
Step 2. Preparation of {7-[4-(4-Trifluoromethyl-benζyloxy)-benζylsulfanyl]- indan-4-y!oxy}-acetic acid (compound 63)
The title compound was prepared in the manner analogous tojExample 1 using 63A. mp 145 °C; IR (KBr) cm"1: 2968, 1740, 1510, 1325, 1248, 1110; 400 MHz 1H NMR (DMSO--4): δ 12.99 (br(s), IH), 7.66-7.75 (m, 2H), 7.55-7.65 (m, 2H); 7.01-7.15 (m, 3H) 6.83-6.90 (m, 2H), 6.56 (d, IH, J = 8.5 Hz), 5.14 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, t, J = 7.6 Hz), 2.65 (t, 2H, J = 7.4 Hz), 1.87 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75; found: C, 63.95; H,
4.65.
Example 64
Synthesis of (5-Methyl-7-r4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl1- indan-4-yloxy)-acetic acid (compound 64)
Figure imgf000155_0002
64 Step 1. Preparation of {5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 64A)
Figure imgf000156_0001
64A
The title compound was prepared in the manner analogous to Example IF using 14B and (7-mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester, which was prepared in a similar manner as described for Example 12C. MS m/z 265 (M-251 ).
Step 2. Preparation of {5-Methyl-7-[4-(4-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 64)
The title compound was prepared in the manner analogous to Example 1 using 64A. mp 165-167 °C; IR (KBr) cm'1 : 3039, 1707, 1510, 1329, 1163, 1112; 400 MHz 1H NMR (DMSO-dβ): δ 12.81 (br(s), IH), 7.66-7.74 (m, 2H), 7.56-7.64 (m, 2H); 7.11- 7.19 (m, 2H), 6.94 (s, IH), 6.85-6.91 (m, 2H), 5.15 (s, 2H), 4.40 (s, 2H), 3.99 (s, 2H), 2.81 (t, 2H, J = 7.4 Hz), 2.59 (t, 2H, J = 7.4 Hz), 2.13 (s, 3H), !1.86 (pentet, 2H); MS m/z 501 (M-l). Anal. Calc'd for C27H25F3O4S: C, 64.53; H, 5.01; found: C, 64.33; H,
4.82. Example 65
Synthesis of (7-r4-(4-Fluoromethyl-benzyloxy)-benzylsulfanvπ-indan-4-yloxyl- acetic acid (compound 65)
Figure imgf000157_0001
65
Step 1. Preparation of {7-[4-(4-Fluoromethyl-benzyloxy)-benzylsulfanyl]-indan- 4-yloxy}-acetic acid methyl ester (compound 65A)
Figure imgf000157_0002
65A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-chloromethyl-(4-fluoro-benzyloxy-benzene), prepared from 4-hydroxymethyl- phenol and 1 -bromomethyl-4-fluoro-benzene in a manner analagous to Examples 14A and 14B. MS m/z 453 (M+l).
Step 2. Preparation of {7-[4-(4-Fluoromethyl-benζyloxy)-benζylsulfanyl]-indan-
4-yloxy}-acetic acid (compound 65)
The title compound was prepared in the manner analogous to Example 1 using 65A. mp 153-155 °C; IR (KBr) cm"1: 3117, 3028, 1731, 1512, 147J, 1231; 400 MHz 1H NMR (DMSO- 6): δ 12.94 (br(s), IH), 7.39-7.47 (m, 2H), 7.01-7.20 (m, 5H); 6.82- 6.89 (m, 2H) 6.56 (d, IH, J = 8.4 Hz), 4.99 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 7.5 Hz), 1.89 (pentet, 2H); MS m/z 437 (M-l). Anal. Calc'd forC25H23FO4S: C, 68.48; H, 5.29; found: C, 68.24; H, 5.15.
Example 66
Synthesis of {7-r4-(2.4-Difluoro-benζyloxy)-benζylsulfanvI1-indan-4-yloxy)-acetic acid (compound 66)
Figure imgf000158_0001
66
Step 1. Preparation of {7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 66A)
Figure imgf000158_0002
66A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-chloromethyl-(2,4-difluoro-benzyloxy-benzene) prepared from 4- hydroxymethyl-phenol and l-bromomethyl-2,4-difluoro-benzene in the manner analagous to Examples 14A and 14B. MS m/z 471 (M+l). Step 2. Preparation of {7-[4-(2,4-Difluoro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid (compound 66)
The title compound was prepared in the manner analogous to Example 1 using 66A. mp 158-160 °C; IR (KBr) cm"1: 3065, 3043, 1751, 1510, 1433, 1239; 400 MHz Η
NMR (DMSO- ): δ 12.94 (br(s), IH), 7.51-7.61 (m, IH), 7.21-7.30 (m, IH); 7.01- 7.16 (m, 4H) 6.83-6.92 (m, 2H), 6.57 (d, IH, J = 8.5 Hz), 5.01! (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.76 (t, 2H, J = 7.4 Hz), 2.68 (t, 2H, J = 7.4 Hz), 1.90 (pentet, 2H); MS m/z 455 (M-l). Anal. Calc'd for C25H22F2O4S: C, 65.78; H, 4.86; found: C, 65.58; H, 4.83.
Example 67
Synthesis of {7-r4-(4-tert-ButvI-benzyloxy)-benzylsulfanvn-indan-4-yloxy)-acetic acid (compound 67)
Figure imgf000159_0001
67
Step 1. Preparation of {7-[4-(4-tert-Butyl-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 67A)
Figure imgf000160_0001
67A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-chloromethyl-(4-tert-butyl-benzyloxy-benzene) prepared from 4- hydroxymethyl-phenol and l-bromomethyl-4-tert-butyl-benzene in the manner analagous to Examples 14A and 14B. m/z 491 (M+l).
Step 2. Preparation of {7-[4-(4-tert-Butyl-benζyloxy)-benζylsulfanyl]-indan-4- yloxyj-acetic acid (compound 67)
The title compound was prepared in the manner analogous to Example 1 using 67A. mp 152-153 °C; IR (KBr) cm"1: 3134, 3032, 1745, 1708, 1473, 1228; 400 MHz 1H NMR (DMSO- : δ 12.94 (br(s), IH), 7.25-7.39 (m, 4H), 7.01-7.14 (m, 3H) 6.80-
6.89 (m, 2H), 6.57 (d, IH, J = 8.5 Hz), 4.97 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 7.5 Hz), 1.89 (pentet, 2H), 1.22 (s, 9H); MS m/z 475 (M-l). Anal. Calc'd for C29H32O4S: C, 73.08; H, 6.77; found: C, 72.97; H, 6.84.
Example 68
Synthesis oπ7-r4-(4-Methoxy-benζyloxy)-benζylsulfanyll-indan-4-yloxyl-acetic acid (compound 68)
Figure imgf000161_0001
Step 1. Preparation of {7-[4-(4-Methoxy-benzyIoxy)-benzylsulfanyl]-indan-4- yloxyj-acetic acid methyl ester (compound 68A)
Figure imgf000161_0002
68A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-chloromethyl-(4-methoxy-benzyloxy-benzene) prepared from 4- hydroxymethyl-phenol and 1 -bromomethyl-4-methoxy-benzene in the manner analagous to Examples 14A and 14B. MS m/z 465 (M+l).
Step 2. Preparation of {7-[4-(4-Methoxy-benζyloxy)-benζylsulfanyl]-indan-4- yloxy}-acetic acid (compound 68)
The title compound was prepared in the manner analogous to Example 1 using 68A. p 183-185 °C; IR (KBr) cm"1: 3015, 2588, 1742, 1716, 1514, 1243; 400 MHz 1H NMR (DMSO--i6): δ 12.97 (br(s), IH), 7.26-7.34 (m, 2H), 7.06-7.13 (m, 2H) 7.04 (d,
IH, J = 8.5 Hz), 6.80-6.92 (m, 4H), 6.56 (d, IH, J = 8.5 Hz), 4.92 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 3.69 (s, 3H), 2.75 (t, 2H, J = 7.3 Hz), 2.67 (t, 2H, J = 7.3 Hz), 1.89 (pentet, 2H); MS m/z 449 (M-l). Anal. Calc'd for C26H26O5S: C, 69.31; H, 5.82; found: C, 69.00; H, 5.74. Example 69
Synthesis of r7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxyl-acetic acid (compound 69)
Figure imgf000162_0001
69
Step 1. Preparation of [7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 69A)
Figure imgf000162_0002
69A
The title compound was prepared in the manner analogous to Example IF using 12C and 1 -benzyloxy-4-chloromethyl-benzene prepared from 4-hydroxymethyl-phenol and 4-bromomethyl-benzene in the manner analagous to Examples 14A and 14B. MS m/z 435 (M+l).
Step 2. Preparation of [7-(4-Benzyloxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid (compound 69)
The title compound was prepared in the manner analogous to Example 1 using 69A. mp 145-147 °C; IR (KBr) cm"1: 3066, 2584, 1742, 151 1, 1234; 400 MHz 1H NMR (DMSO- ): δ 12.94 (br(s), IH), 7.21-7.44 (m, 5H), 6.99-7.15 (m, 3H) 6.80-6.90 (m, 2H), 6.56 (d, IH, J = 8.3 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.93 j[s, 2H), 2.75 (t, 2H, J = 7.3 Hz), 2.67 (t, 2H, J = 7.3 Hz), 1.89 (pentet, 2H); MS m/z 419 (M-l). Anal. Calc'd for C25H24O4S: C, 71.40; H, 5.75; found: C, 71.46; H, 5.75.
Example 70
Synthesis of {7-r4-(4-ChIoro-benzvIoxy)-benzylsulfanvn-indan-4-yloxy}-acetic acid (compound 70)
Figure imgf000163_0001
70
Step 1. Preparation of {7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 70A)
Figure imgf000163_0002
70A
The title compound was prepared in the manner analogous to Example IF using 12C and 1 -(4-chloro-benzyloxy)-4-chloromethyl benzene prepared from 1 -bromomethyl-
4-chloro-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 469 (M+l). Step 4. Preparation of {7-[4-(4-Chloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid (compound 70)
The title compound was prepared in the manner analogous to Example 1 using 70A. mp 170-172 °C; IR (KBr) cm"1: 3054, 25.77, 1731, 1710, 1471, 1234; 400 MHz 1H NMR (DMSO-dβ): δ 12.95 (br(s), IH), 7.39 (s, 4H), 6.99-7.25 (m, 3H), 6.79-6.97 (m, 2H), 6.56 (d, IH, J = 8.4 Hz), 5.01 (s, 2H), 4.60 (s, 2H), 3.93 (s, 2H), 2.74 (t, 2H, J = 7.4 Hz), 2.66 (t, 2H, J = 7.4 Hz), 1.88 (pentet, 2H); MS m/z 453 (M-l). Anal. Calc'd for C25H23ClO4S: C, 66.00; H, 5.10; found: C, 65.95; H.i4.97.
Example 71
Synthesis of (7-r4-(2.5-Dichloro-benzyloxy)-benzylsulfanvIl-indan-4-yloxy)- acetic acid (compound 71)
Figure imgf000164_0001
71
Step 1. Preparation of {7-[4-(2,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 71A)
Figure imgf000164_0002
71A The title compound was prepared in the manner analogous to Example IF using 12C and l,4-Dichloro-2-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1,4- dichloro-2-chloromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 265 (M-237).
Step 2. Preparation of {7-[4-(2,5-Dichloro-benζyloxy)-benζylsuIfanyl]-indan-4- yloxy}-acetic acid (compound 71)
The title compound was prepared in the manner analogous to Example 1 using 71 A. mp 158-160 °C; IR (KBr) cm"1: 3070, 2573, 1747, 1716, 1236, 1106; 400 MHz 1H NMR (DMSO- e): δ 12.95 (br(s), IH), 7.57-7.62 (m, IH) 7.47-7.53 (m, IH), 7.38- 7.45 (m, IH), 7.08-7.16 (m, 2H), 7.04 (d, IH, J = 8.5 Hz), 6.85-6.92 (m, 2H), 6.56 (d, IH, J = 8.5 Hz), 5.06 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J = 7.3 Hz), 2.67 (t, 2H, J = 7.3 Hz), 1.89 (pentet, 2H); MS m/z 487 (M- 1 ). Anal. Calc'd for
C25H22Cl2O4S: C, 61.35; H, 4.53; found: C, 61.24; H, 4.43.
Example 72
Synthesis of {7-r4-(3.4-Dichloro-benζyloxy)-benζylsulfanvn-indan-4-yloxy>- acetic acid (compound 72)
Figure imgf000165_0001
72 Step 1. Preparation of {7-[4-(3,4-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid methyl ester (compound 72A)
Figure imgf000166_0001
72A
The title compound was prepared in the manner analogous to Example IF using 12C and l,2-Dichloro-4-(4-chloromethyl-phenoxymethyl)-benzene prepared from 1- bromomethyl-3,4-dichloro-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 503 (M+l).
Step 2. Preparation of {7-[4-(3,4-Dichloro-benζyloxy)-benζylsulfanyl]-indan-4- yloxyj-acetic acid (compound 72)
The title compound was prepared in the manner analogous to Example 1 using 72A. mp 168 °C; IR (KBr) cm"1: 3084, 3039, 1744, 1708, 1244, 1226; 400 MHz 1H NMR (DMSO-dβ): δ 12.95 (br(s), IH), 7.57-7.67 (m, 2H) 7.37 (dd, IH, J = 8.3, 2.0 Hz), 7.01-7.14 (m, 3H), 6.82-6.89 (m, 2H), 6.56 (d, IH, J = 8.4 Hz), 5.04 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J = 7.4 Hz), 2.66 (t, 2H, J = 7.4 Hz), 1.88 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53; found: C,
61.13; H, 4.38.
Example 73 Synthesis of {7-r4-(4-Chloro-3-trifluoromethyl-benzyloxy)-benzylsulfanvn- indan-4-yloxyl-acetic acid (compound 73)
Figure imgf000167_0001
73"
Step 1. Preparation of {7-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 73A)
Figure imgf000167_0002
73A
The title compound was prepared in the manner analogous to Example IF using 12C and 1 -Chloro-4-(4-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene prepared from 1 -bromomethyl-4-chloro-3-trifluoromethyl-benzene and 4-hydroxymethyl- phenol in the manner analagous to Examples 14A and 14B. MS m/z 299 (M-237).
Step 2. Preparation of {7-[4-(4-Chloro-3-trifluoromethyl-benζyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 73)
The title compound was prepared in the manner analogous to Example 1 using 73A. p 151-152 °C; IR (KBr) cm"1: 3076, 3050, 1748, 1426, 1244, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), IH), 7.87 (s, IH), 7.68-7.72 (m, 2H) 7.00-7.15 (m, 3H), 6.82-6.92 (m, 2H), 6.56 (d, IH, J = 8.5 Hz), 5.12 (s, 2H), 4.61 (s, 2H), 3.94 (s,
2H), 2.74 (t, 2H, J = 7.5 Hz), 2.66 (t, 2H, J = 7.5 Hz), 1.87 (pentet, 2H); MS m/z 521 (M-l). Anal. Calc'd for C26H22ClF3O4S: C, 59.71; H, 4.24; found: C, 59.54; H, 4.11. Example 74
Synthesis of {7-r4-(4-Fluoro-3-trifluoromethyl-benzyloxγ)-benzylsulfanvn-indan-
4-yloxyl-acetic acid (compound 74)
Figure imgf000168_0001
Step 1. Preparation of {7-[4-(4-Fluoro-3-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 74A)
Figure imgf000168_0002
74A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-(4-Chloromethyl-phenoxymethyl)-l -fluoro-2-trifluoromethyl-benzene prepared from 1 -bromomethyl-4-fluoro-3-trifluoromethyl-benzene and 4-hydroxymethyl- phenol in the manner analagous to Examples 14A and 14B. MS m/z 283 (M-237).
Step 2. Preparation of {7-[4-(4-Fluoro-3-trifluoromethyl-benζyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 74)
The title compound was prepared in the manner analogous to Example 1 using 74A. mp 116-117 °C; IR (KBr) cm"1: 3028, 1741, 1704, 1511, 1235, 1110; 400 MHz 1H NMR (DMSO- ): δ 12.96 (br(s), IH), 7.74-7.85 (m, 2H) 7.45-7.54 (m, IH), 7.08- 7.15 (m, 2H), 7.04 (d, IH, J = 8.5 Hz), 6.84-6.91 (m, 2H), 6.56 (d, IH, J = 8.5 Hz), 5.09 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J = 7.5 Hz), 2.66 (t, 2H, J = 7.5 Hz), 1.88 (pentet, 2H); MS m/z 505 (M-l). Anal. Calc'd for C26H22F4O4S: C, 61.65; H, 4.38; found: C, 61.50; H, 4.07.
Example 75 Synthesis oπ7-r4-(4-Trifiuoromethoxy-benζyloxy)-benζylsulfanvn-indan-4- yloxyl-acetic acid (compound 75)
Figure imgf000169_0001
Step 1. Preparation of [7-(4-Acetoxy-benzylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 75A)
Figure imgf000169_0002
75A
The title compound was prepared in the manner analogous to Example 35A using acetic acid 4-chloromethyl-phenyl ester and 12C. MS m/z 387 (M+l).
Step 2. Preparation of [7-(4-Hydroxy-benζylsulfanyl)-indan-4-yloxy]-acetic acid
(compound 75B)
Figure imgf000170_0001
75B
The title compound was prepared in the manner analogous to Example 35B using 75A. MS m/z 391 (M-l).
Step 3. Preparation of [7-(4-Hydroxy-benζylsulfanyl)-indan-4-yloxy]-acetic acid methyl ester (compound 75C)
Figure imgf000170_0002
75C
The title compound was prepared in the manner analogous to Example 35C using the product from Example 75B. MS m/z 237 (M-l 07).
Step 4. Preparation of {7-[4-(4-Trifluoromethoxy-benζyloxy)-benζylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 75D)
Figure imgf000170_0003
75D
The title compound was prepared in the manner analogous to Example IF using 1- bromomethyl-4-trifluoromethoxy-benzene and 75C. MS m/z 519 (M+l). Step 5. Preparation of {7-[4-(4-Trifluoromethoxy-benzyloxy)-benzylsulfanylJ- indan-4-yloxy}-acetic acid (compound 75)
The title compound was prepared in the manner analogous to Example 1 using 75D. mp 140-142 °C; IR (KBr) cm"1: 3072, 3043, 1724, 1511, 1226, 1156; 400 MHz Η
NMR (DMSO-<26): δ 12.95 (br(s), IH), 7.47-7.57 (m, 2H), 7.29-7.39 (m, 2H), 7.00- 7.16 (m, 3H), 6.81-6.91 (m, 2H), 6.56 (d, IH, J = 8.5 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.94 (s, 2H), 2.75 (t, 2H, J = 7.4 Hz), 2.67 (t, 2H, J = 7.4 Hz), 1.88 (pentet, 2H) MS m/z 503 (M-l). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60; found: C, 61.53; H, 4.36.
Example 76 Synthesis of f7-r4-(4-Fluoro-2-triflooromethyl-benzyloxy)-benzvIsulfanvπ-indan- 4-yloxyl-acetic acid (compound 76)
Figure imgf000171_0001
76
Step 1. Preparation of {7-[4-(4-Fluoro-2-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 76A)
Figure imgf000171_0002
76A The title compound was prepared in the manner analogous to Example IF using 1- bromomethyl-4-fluoro-2-trifluoromethyl-benzene and the product prepared from Example 75C. MS m z 283
5 Step 2. Preparation of {7-[4-(4-Fluoro-2-trifluoromethyl-benζyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 76)
The title compound was prepared in the manner analogous to Example 1 using 76A. mp 125-127 °C; TR (KBr) cm"1: 3132, 3032, 1742, 1708, 1244v 1110; 400 MHz 1H 10 NMR (DMSO- o): δ 12.95 (br(s), IH), 7.71-7.81 ( , IH), 7.65 (dd, IH, J = 9.3, 2.6
Hz), 7.51-7.61 (m, IH), 7.01-7.19 (m, 3H), 6.81-6.91 (m, 2H), 6.57 (d, IH, J = 8.5 Hz), 5.11 (s, 2H), 4.61 (s, 2H), 3.95 (s, 2H), 2.75 (t, 2H, J = 7.4 Hz), 2.66 (t, 2H, J = 7.4 Hz), 1.89 (pentet, 2H); MS m/z 502 (M-l). Anal. Calc'd for C26H22F4O4S: C, 61.65; H, 4.38; found: C, 61.28; H, 4.12.
15
Example 77
Synthesis of {7-r4-(3,5-Dichloro-benzyloxy)-benzylsulfanvn-indan-4-yloxyl- acetic acid (compound 77)
Figure imgf000172_0001
77
Step 1. Preparation of {7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyI]-indan-4- yloxy}-acetic acid methyl ester (compound 77A)
25
Figure imgf000173_0001
77A
The product from Example 75C (0.42 g, 1 mmoles), (3,5-dichlorophenyl)-methanol (0.24 g, 1.3 mmoles), triphenyl phosphine (0.38 g, 1.5 mmoles), and 0.23 mL of diethyl azodicarboxylate (0.25 g, 1.5 mmoles) were dissolved in 9 mL of tetrahydrofuran. The reaction mixture was stiπed at room temperature under nitrogen for 18 hrs. The reaction mixture was evaporated to give a residue, which was flash chromatographed (silica gel, 20% ethyl acetate in hexane) to afford the title compound in good purity. MS m/z 265
Step 2. Preparation of {7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4- yloxy}-acetic acid (compound 77)
The title compound was prepared in the manner analogous to Example 1 using 77A. mp 134-135 °C; IR (KBr) cm"1: 3070, 1747, 1708, 1572, 14321 1244; 400 MHz 1H NMR (DMSO- ): δ 12.95 (br(s), IH), 7.51-7.53 (m, IH), 7.42-7.45 (m, 2H), 7.07- 7.13 (m, 2H), 7.04 (d, IH, J = 8.6 Hz), 6.83-6.90 (m, 2H), 6.56 (d, IH, J = 8.6 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J = 7.5 Hz), 2.66 (t, 2H, 7.5 Hz), 1.88 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H,
4.53; found: C, 61.01; H, 436. Example 78
Synthesis of {7-r4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyll- indan-4-yloxyl-acetic acid (compound 78)
Figure imgf000174_0001
78
Step 1. Preparation of [4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-phenyI]- methanol (compound 78A)
Figure imgf000174_0002
78A
The title compound was prepared in the manner analogous to Example 14A using 1- bromomethyl-4-trifluoromethyl-benzene and 5-hydroxymethyl-2-methoxy-phenol. MS m/z 295 (M-OH).
Step 2. Preparation of 4-Chloromethyl-l-methoxy-2-(4-trifluoromethyl- benzyloxy)-benzene (compound 78B)
Figure imgf000175_0001
78B.
The title compound was prepared in the manner analogous to Example 3B using 78A. MS m/z 295 (M-Cl).
Step 3. Preparation of {7-[4-Methoxy-3-(4-trifluoromethyl-benζyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 78C)
Figure imgf000175_0002
78C
The title compound was prepared in the manner analogous to Example IF using 78B and 12C. MS m/z 373 (M-l 59).
Step 4. Preparation of {7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 78)
The title compound was prepared in the manner analogous to Example 1 using 78C. mp 150-151 °C; IR (KBr) cm"1: 3046, 1722, 1515, 1328, 1232, 1106; 400 MHz 1H
NMR (DMSO-rfe): δ 12.95 (br(s), IH), 7.71 (d, 2H, J = 8.1 Hz), 7.58 (d, 2H, J = 8.1 Hz), 7.03 (d, IH, J = 8.5 Hz), 6.70-6.86 (m, 3H), 6.57 (d, IH, J = 8.5 Hz), 5.01 (s, 2H), 4.61 (s, 2H), 3.89 (s, 2H), 3.69 (s, 3H), 2.75 (t, 2H, J = 7.3 Hz), 2.62 (t, 2H, J = 7.3 Hz), 1.87 (pentet, 2H); MS m/z 517 (M-l). Anal. Calc'd for C27H25F3O5S: C, 62.54; H, 4.86; found: C, 62.54; H, 4.71.
Example 79
Synthesis of f7-r3-(4-Trifluoromethyl-benζyloxy)-benζylsulfanyl1-indan-4- yloxyl-acetic acid (compound 79)
Figure imgf000176_0001
79
Step 1. Preparation of [3-(4-trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 79 A)
Figure imgf000176_0002
79A
The title compound was prepared in the manner analogous to Example 14A using 1- bromomethyl-4-trifluoromethyl-benzene and 3-hydroxymethyl-phenol. MS m/z 265 (M-OH).
Step 2. Preparation of l-(4-trifluoromethyl-benζyloxy)-3-chloromethyl-benζene (Compound 79B)
Figure imgf000177_0001
79B
The title compound was prepared in the manner analogous to Example 3B using 79A. MS m/z 265 (M-Cl).
Step 3. Preparation of {7-[3-(4-Trifluoromethyl-benζyloxy)-benζylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 79C)
Figure imgf000177_0002
79C
The title compound was prepared in the manner analogous to Example IF using 79B and l2C. MS m/z 503 (M+l).
Step 4. Preparation of {7-[3-(4-Trifluoromethyl-benζyloxy)-benζylsulfanyl]- indan-4-yloxy}-acetic acid (compound 79)
The title compound was prepared in the manner analogous to Example 1 using 79C. mp 145-146 °C; TR (KBr) cm"1: 3076, 3028, 1705, 1318, 1232, 1109; 400 MHz 1H
NMR (OMSO-dβ): δ 12.94 (br(s), IH), 7.71 (d, 2H, J = 8.2 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.10-7.19 (m, IH), 7.05 (d, IH, J = 8.5 Hz), 6.75-6.86 (ni, 4H), 6.58 (d, IH, J = 8.5 Hz), 5.08 (s, 2H), 4.61 (s, 2H), 3.95 (s, 2H), 2.75 (t, 2H, J = 7.5 Hz), 2.64 (t, 2H, J = 7.5 Hz), 1.88 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75; found: C, 63.78; H, 4.53.
Example 80
Synthesis of {7-r3-(4-Chloro-3-trifluoromethyl-benζyloxy)-benζylsulfanvn- indan-4-yloxy)-acetic acid (compound 80)
Figure imgf000178_0001
Step 1. Preparation of [3-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]- methanol (compound 80A)
Figure imgf000178_0002
80A
The title compound was prepared in the manner analogous to xample 14A using 4- bromomethyl-l-chloro-2-trifluoromethyl -benzene and 3-hydro'xymethyl-phenol. MS m/z 299 (M-OH).
Step 2. Preparation of l-Chloro-4-(3-chloromethyl-phenoxymethyl)-2- trifluoromethyl-benzene (compound 80B)
Figure imgf000179_0001
80B
The title compound was prepared in the manner analogous to Example 3B using 80A. MS m/z 299 (M-Cl).
Step 3. Preparation of {7-[3-(4-ChIoro-3-trifluoromefhyl-benζyloxy)- benzylsulfanyI]-indan-4-yloxy}-acetic acid methyl ester (compound 80C)
Figure imgf000179_0002
80C
The title compound was prepared in the manner analogous to Example IF using 80B and l2C. MS m/z 537 (M+l).
Step 4. Preparation of {7-[3-(4-Chloro-3-trifluoromethyl-benζyloxy)- benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 80)
The title compound was prepared in the manner analogous to Example 1 using 80C. mp 121-122 °C; IR (KBr) cm"1: 3027, 2584, 1742, 1255, 1129, 1109; 400 MHz 1H NMR (DMSO-rf6): δ 12.95 (br(s), IH), 7.87 (s, IH), 7.64-7.75 (m, 2H), 7.09-7.19
(m, IH), 7.01-7.09 (m, IH), 6.73-6.88 (m, 3H), 6.56 (d, IH, J = 8.5 Hz), 5.06 (s, 2H), 4.60 (s, 2H), 3.95 (s, 2H), 2.74 (t, 2H, J = 7.4 Hz), 2.63 (t, 2H, J = 7.4 Hz), 1.87 (pentet, 2H); MS m/z 523 (M+l). Anal. Calc'd for C26H22ClF3O S: C, 59.71; H, 4.24; found: C, 59.45; H, 4.08. Example 81
Synthesis of (7-r2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanvπ-indan-4- yloxyl-acetic acid (compound 81)
Figure imgf000180_0001
81
Step 1. Preparation of [2-(4-Trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 81A)
Figure imgf000180_0002
The title compound was prepared in the manner analogous to Example 14A using 1 - bromomethyl-4-trifluoromethyl-benzene and 2-hydroxymethy] -phenol. MS m z 265 (M-OH).
Step 2. Preparation of l-(4-trifluoromethyl-benζyloxy)-2-chloromethyl-benζene (compound 81B)
Figure imgf000181_0001
The title compound was prepared in the manner analogous to Example 3B using 81A. MS m/z 265 (M-Cl).
Step 3. Preparation of {7-[2-(4-Trifluoromethyl-benζyloxy)-benζylsulfany.]- indan-4-yloxy} -acetic acid methyl ester (compound 81 C)
Figure imgf000181_0002
81C
The title compound was prepared in the manner analogous to Example IF using 81B and 12C. MS m/z 503 (M+l).
Step 4. Preparation of {7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]- indan-4-yloxy}-acetic acid (compound 81)
The title compound was prepared in the manner analogous to Example 1 using 81C. mp 150-152 °C; TR (KBr) cm"1: 3074, 3042, 1701, 1324, 1124, 1099; 400 MHz 1H
NMR (DMSO-^e): δ 7.58-7.75 (m, 2H), 6.92-7.20 (m, 4H), 6.80 (t, IH, J = 7.5 Hz), 6.51 (d, IH, J = 8.5 Hz), 5.16 (s, 2H), 4.57 (s, 2H), 3.99 (s, 2H), 2.70 (t, 2H, J = 7.5 Hz), 2.62 (t, 2H, J = 7.5 Hz), 1.80 (pentet, 2H); MS m/z 487 (M-l). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75; found: C, 63.54; H, 4.52.
Example 82
Synthesis of {7-r3,5-Dichloro-4-(4-trifluoromethyl-benζyloxy)-benζylsulfonyll- indan-4-yloxy)-acetic acid lithium salt (compound 82)
Figure imgf000182_0001
82
Step 1. Preparation of [3,5-Dichloro-(4-trifluoromethyl-benzyloxy)-phenyl]- methanol (compound 82A)
Figure imgf000182_0002
82A
The title compound was prepared in the manner analogous to Example 14A using 1- bromomethyl-4-trifluoromethyl-benzene and 2,6-dichloro-4-hydroxymethyl-phenol. MS /z l91 (M-159).
Step 2. Preparation of l,3-Dichloro-5-chloromethyl-2-(4-trifluoromethyl- benζyloxy)-benζene (compound 82B)
Figure imgf000183_0001
The title compound was prepared in the manner analogous to Example 3B using 82A. MS m/z 333 (M-Cl).
Step 3. Preparation of {7-[3^-Dichloro-4-(4-trifluoromethyl-benzyloxy)- benzylsulfonyl]-indan-4-yloxy}-acetic acid methyl ester (compound 82C)
Figure imgf000183_0002
82C
The title compound was prepared in the manner analogous to Example IF using 82B and l2C. MS m/z 571 (M+l).
Step 4. Preparation of The Lithium Salt of {7-[3,5-Dichloro-4-(4- trifluoromethyl-benζyloxy)-benζylsulfonyl]-indan-4-yloxy}-acetic acid (compound 82)
The title compound, in unprotonated form, was prepared in the manner analogous to
Example 1 using 82C. mp 235 °C dec; IR (KBr) cm"1: 3414, 1622, 1591, 1472, 1326, 1265; 400 MHz 1H NMR (DMSO-cfc): δ 7.66-7.77 (m, 4H), 7.26 (s, 2H), 6.99 (d, IH, J = 8.5 Hz), 6.45 (d, IH, J = 8.5 Hz), 5.03 (s, 2H), 4.02 (s, 2H), 3.92 (s, 2H), 2.73 (t, 2H, J = 7.3 Hz), 2.65 (t, 2H, J = 7.3 Hz), 1.88 (pentet, 2H); MS m/z 555 (M- 1). Anal. Calc'd for C26H2oCl2F3O4S: Li: 0.50 H2O: C, 54.56; H, 3.70; Li, 1.21; H2O, 1.57; found: C, 54.63; H, 3.68; Li, 1.46; H20, 1.61.
Example 83
Synthesis of {8-r4-(4-Trifluoromethyl-benzv1oxy)-benzvIsulfanyl1-chroman-5- yloxyl-acetic acid (compound 83)
Figure imgf000184_0001
83
Step 1. Preparation of {8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]- chroman-5-yloxy}-acetic acid methyl ester (compound 83A)
Figure imgf000184_0002
83A
The title compound was prepared in the manner analogous to Example IF using (8- mercapto-chroman-5-yloxy)-acetic acid methyl ester and 14B. MS m/z 519 (M+l).
Step 2. Preparation of {8-[4-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]- chroman-5-yloxy}-acetic acid (compound 83) The title compound was prepared in the manner analogous to Example 1 using 83A. mp 143-144 °C; HPLC: area % = 96.02, r.t. = 3.770 min, γ= 214 nm, mobile phase = acetonitrile / water w/0.10% TFA; IR (KBr) cm"1: 3042, 2581, 1739, 1714, 1325, 1116; 400 MHz 1H NMR (OMSO-d6): δ 12.95 (br(s), IH), 7.66-7.74 (m, 2H), 7.56- 7.63 (m, 2H); 7.10-7.17 (m, 2H), 6.92 (d, IH, J = 8.7 Hz), 6.83-6.89 (m, 2H), 6.26 (d, IH, J = 8.5 Hz), 5.13 (s, 2H), 4.58 (s, 2H), 4.08 (t, 2H, J = 4.8 Hz), 3.90 (s, 2H), 2.55 (t, 2H, J = 6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M-l). Anal. Calc'd for 6H23F3O5S: C, 61.90; H, 4.60; found: C, 61.41; H, 4.50.
Example 84
Synthesis of (8-r3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanvn-chroman-5- yloxyl-acetic acid (compound 84)
Figure imgf000185_0001
84
Step 1. Preparation of {8-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]- chroman-5-yloxy}-acetic acid methyl ester (compound 84A)
Figure imgf000186_0001
84A
The title compound was prepared in the manner analogous to Example IF using (8- mercapto-chroman-5-yloxy)-acetic acid methyl ester and 79B. MS m/z 519 (M+l).
Step 2. Preparation of {8-[3-(4-Trifluoromethyl-benζyloxy)-benζylsulfanyl]- chroman-5-yloxy}-acetic acid (compound 84)
The title compound was prepared in the manner analogous to Example 1 using 84A. mp 113-115 °C; HPLC: area % = 97.30, r.t. = 3.140 min, γ = 214 nm, mobile phase = acetonitrile/ water w/0.10% TFA; IR (KBr) cm"1: 2952, 2577, 1742, 1582, 1323, 1120; 400 MHz 1H NMR (OMSO-d6): δ 7.67-7.74 (m, 2H), 7.56-7.63 (m, 2H); 7.13 (t, IH, J = 7.8 Hz), 6.76-6.93 (m, 4H), 6.22 (d, IH, J = 8.7 Hz), 5.08 (s, 2H), 4.45 (s, 2H), 4.08 (t, 2H, J = 4.8 Hz), 3.91 (s, 2H), 2.54 (t, 2H, J = 6.6 Hz), 1.82 (pentet, 2H);
MS m/z 505 (M+l). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60; found: C, 61.49; H, 4.44.
Example 85
Synthesis of {8-r4-(2,5-DichIoro-benζyloxy)-benζylsulfanyl1-chroman-5-yloxy>- acetic acid (compound 85)
Figure imgf000187_0001
85
Step 1. Preparation of {8-[4-(2,5-Dichloro-benzyloxy)-benzyIsulfanyl]-chroman- 5-yloxy}-acetic acid methyl ester (compound 85A)
Figure imgf000187_0002
85A
The title compound was prepared in the manner analogous to Example IF using (8- mercapto-chroman-5-yloxy)-acetic acid methyl ester and 1 ,4-Dichloro-2-(4- chloromethyl-phenoxymethyl)-benzene prepared in the manneri analagous to Example 71A. m/z 519 (M+l).
Step 2. Preparation of {8-[4-(2,5-Dichloro-benζyloxy)-benζylsulfanyl]-chroman-
5-yloxy}-acetic acid (compound 85)
The title compound was prepared in the manner analogous to Example 1 using 85A. mp 98-100 °C; IR (KBr) cm"1: 3038, 2854, 1729, 1508, 1240, 1124; 400 MHz 1H NMR (DMSO-dβ): δ 12.95 (br(s), IH), 7.57-7.62 (m, IH), 7.39-7.53 (m, 2H); 7.12-
7.20 (m, 2H), 6.84-6.96 (m, 3H), 6.26 (d, IH, J = 8.6 Hz), 5.05 (s, 2H), 4.58 (s, 2H), 4.09 (t, 2H, J = 4.9 Hz), 3.92 (s, 2H), 2.55 (t, 2H, J = 6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M-l). Anal. Calc'd for C25H22Cl2O5S: C, 59.41; H, 4.39; found: C, 59.20; H, 4.20.
Example 86
Synthesis of (8-r4-(5-TrifluoromethvI-pyridine-2-yl)-benζylsulfanvn-chroman-5- yloxyl-acetic acid (compound 86)
Figure imgf000188_0001
86
Step 1. {8-[4-(5-Trifluoromethyl-pyridine-2-yl)-benzylsulfanyl]-chroman-5- yloxy}-acetic acid methyl ester (compound 86A)
Figure imgf000188_0002
86A
The title compound was prepared in the manner analogous to Example IF using (8- mercapto-chroman-5-yloxy)-acetic acid methyl ester and 18B. MS m/z 490 (M+l).
Step 2. {8-[4-(5-TrifIuoromethyl-pyridine-2-yl)-benζylsulfanyI]-chroman-5- yloxy}-acetic acid (compound 86) The title compound was prepared in the manner analogous to Example 1 using 86A. mp 178-179 °C; rR (KBr) cm"': 3034, 2577, 1707, 1604, 1332, 1111; 400 MHz 1H NMR (DMSO- ): δ 12.95 (br(s), IH), 8.97 (s, IH), 7.99-8.24 (m, 4H), 7.33-7.40 (m, 2H), 6.95 (d, 2H, J = 8.5 Hz), 6.26 (d, 2H, J = 8.6 Hz), 4.57 (s, 2H), 4.11 (t, 2H, J = 4.9 Hz), 4.04 (s, 2H), 2.56 (t, 2H, J = 6.5 Hz), 1.84 (pentet, 2H); MS m/z 476 (M+l). Anal. Calc'd for C24H2oF3NO4S: C, 60.63; H, 4.24; N, 2.95; found: C, 60.31; H, 4.24; N, 3.02.
Example 87
Synthesis of {7-r5-(2-Chloro-phenyI)-isoxazoI-3-ylmethylsulfanyn-indan-4- yloxyl-acetic acid (compound 87)
Figure imgf000189_0001
87
Step 1. Preparation of {7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 87 A)
Figure imgf000189_0002
87A The title compound was prepared in the manner analogous to Example IF using commercially available 3-chloromethyl-5-(2-chloro-phenyl)-isoxazole and 12C. MS m/z 430 (M+l).
Step 2. Preparation of {7-[5-(2-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]- indan-4-yloxy}-acetic acid (compound 87)
The title compound was prepared in the manner analogous to Example 1 using 87A. mp 161-162 °C; IR (KBr) cm'1: 3177, 3065, 1706, 1475, 1432, 1233; 400 MHz 1H NMR (DMSO-ie): δ 13.00 (bs, IH), 7.78-7.85 (m, IH), 7.58-7.64 (m, IH), 7.42-7.53
(m, 2H), 7.15 (d, IH, J = 8.6 Hz), 6.84 (s, IH), 6.60 ( d, IH, J = 8.6 Hz), 4.62 (s, 2H), 4.09 (s, 2H), 2.72-2.82 (m, 4H), 1.91 (pentet, 2H); MS m/z 416 (M+l). Anal. Calc'd for C2ιHι8ClNO4S: C, 60.65; H, 4.36; N, 3.37; found: C, 60.56; H, 4.28; N, 3.16.
Example 88
Synthesis of |7-r3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-ylmethvIsulfanvn- indan-4-yloxy)-acetic acid (compound 88)
Figure imgf000190_0001
88
Step 1. Preparation of {7-[3-(2,6-DichIoro-phenyl)-5-methyl-isoxazol-4- ylmethylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 88A)
Figure imgf000191_0001
88A
The title compound was prepared in the manner analogous to Example IF using commercially available 4-bromomethyl-3-(2,6-dichloro-phenyl)-5-methyl-isoxazole and l2C. MS m/z 478 (M+l).
Step 2. Preparation of {7-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxaζol-4- ylmethylsulfanyI]-indan-4-yloxy}-acetic acid (compound 88)
The title compound was prepared in the manner analogous to Example 1 using 88A. mp 151-152 °C; IR (KBr) cm"1: 3084, 1743, 1430, 1277, 1245, 1106; 400 MHz 1H NMR (OMSO-d6): δ 12.97 (br(s), IH), 7.47-7.70 (m, 3H), 6.90 (d, IH, J = 8.5 Hz), 6.52 (d, IH, J = 8.5 Hz), 4.63 (s, 2H), 3.58 (s, 2H), 2.75 (t, 2H, J = 7.6 Hz), 2.65 (t, 2H, J = 7.6 Hz), 2.07 (s, 3H), 1.89 (pentet, 2H) MS m/z 464 (M+ 1 ). Anal. Calc'd for
C22HI9Cl2NO4S: C, 56.90; H, 4.12; N, 3.02; found: C, 56.51; H, 3.96; N, 2.95.
Example 89
Synthesis of l7-r3-(4-Trifluoromethyl-phenvI)-isoxaζol-5-ylmethylsulfanvn- indan-4-yloxyl-acetic acid (compound 89)
Figure imgf000192_0001
89
Step 1. Preparation of {7-[3-(4-Trifluoromethyl-phenyl)-isbxazol-5- ylmethylsulfanyl]-indan-4-yIoxy}-acetic acid methyl ester (compound 89 A)
Figure imgf000192_0002
89A
The title compound was prepared in the manner analogous to Example IF using 42C and l2C. MS m/z 464 (M+l).
Step 2. Preparation of {7-[3-(4-Trifluoromethyl-phenyl)-isoxaζoI-5- ylmethylsulfanyl]-indan-4-yloxy}-acetic acid (compound 89)
The title compound was prepared in the manner analogous to Example 1 using 89A. mp 166-168 °C; HPLC: area % = 96.95, r.t. = 3.140 min, γ= 214 nm, mobile phase = acetonitrile / water w/0.10% TFA. IR (KBr) cm"1: 3140, 3085, 1742, 1322, 1255, 1109; 400 MHz 1H NMR (DMSO- 6): δ 12.96 (br(s), IH), 7.99 (d, 2H, J = 8.3 Hz), 7.81 (d, 2H, J = 8.3 Hz), 7.14 (d, IH, J = 8.4 Hz), 6.81 (s, IH), 6.61 ( d, IH, J = 8.4 Hz), 4.63 (s, 2H), 4.23 (s, 2H), 2.76 (t, 4H, J = 7.5 Hz), 1.91 (pentet, 2H); MS m/z 450 (M+l). Anal. Calc'd for C22H,8F3NO S: C, 58.79; H, 4.04; N, 3.12; found: C, 58.38; H, 3.92; N, 2.95.
Example 90
Synthesis of {7-r2-(4 -Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyll-indan-4- yloxyl-acetic acid (compound 90)
Figure imgf000193_0001
90
Step 1. Preparation of {7-[2-(4'-Trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 90A)
Figure imgf000193_0002
90A
The title compound was prepared in the manner analogous to Example IF using 12C and 4-(2-bromo-ethyl)-4'-trifluoromethyl-biphenyl (compound 22B). MS m/z 487 (M+l). Step 2. Preparation of {7-[2-(4'-Trifluoromethyl-biphenyl-4-yI)-ethylsulfanyl]- indan-4-yloxy}-acetic acid (compound 90)
The title compound was prepared in the manner analogous to Example 1 using 90A. mp 170-172 °C; IR (thin film) cm"1: 1724, 1471, 1327, 1239, 1175, 1110; 400 MHz 1H NMR (DMSO- e) δ 12.96 (br s, IH), 7.82 (d, 2H, J = 8.3 Hz), 7.74 (d, 2H, J = 8.3 Hz), 7.61 (d, 2H, J = 8.3 Hz), 7.31 (d, 2H, J = 8.3 Hz), 7.12 (d, 2H, J = 8.5 Hz), 6.62 (d, IH, J = 8.5 Hz), 4.63 (s, 2H), 3.08 (t, 2H, J = 7.6 Hz), 2.80 (m, 6H), 1.96 (m, 2H); MS m/z 411 (M-l). Anal. Calc'd for C26H23F3O3S: C, 66.09; H, 4.91; found: C,
65.95; H, 4.63.
Example 91 Synthesis of {7-r2-(4/-Trifluoromethyl-biphenyl-4-yl)-ethvn-indan-4-yloxyl- acetic acid (compound 91)
Figure imgf000194_0001
91
Step 1. Preparation of (Indan-4-yloxy)-acetic acid methyl ester (compound 91A) e
Figure imgf000195_0001
91A
Compound 91A was prepared from indan-4-ol and bromo-acetic acid methyl ester in the manner analogous to Example IC. 400 MHz 1H NMR (DMSO- 6) δ 7.00 (t, IH,
J = 7.8 Hz), 6.79 (d, IH, J = 7.3 Hz), 6.56 (d, IH, J = 8.1 Hz), 4.74 (s, 2H), 3.63 (s, 3H), 2.77 (m, 4H), 1.95 (m, 2H).
Step 2. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-acetic acid (compound 91B)
Figure imgf000195_0002
91B
A mixture of (4-bromo-phenyl)-acetic acid (10.2 g, 47.4 mmol), 4- trifluoromethylphenylboronic acid (10.0 g, 52.7 mmol), and 50% water-wet 5% palladium on charcoal catalyst (4.6 g) in 50 ml of water and 8.0 ml of 2-propanol was treated dropwise over 30 minutes with a solution of sodium carbonate (6.8 g, 64.2 mmol) in 18 ml of water. The mixture was heated at 65-70°C for 3 h, then cooled to 40°C and treated with 13.0 ml of a solution of 2-propanol/water/2.0 N aqueous sodium hydroxide solution (70/15/1). The reaction mixture was filtered through a bed of Celite filter-aid, and the filter cake was washed 5x with the above 2- propanol/water/2.0 N aqueous sodium hydroxide solution. The combined filtrates were diluted with 125 ml of water, and the solution was digested on the steam bath with charcoal and filtered. The filtrate was diluted with an additional 150 ml of water and made strongly acidic by the addition of 4.0 N hydrochloriq acid. The precipitated product was filtered and suspended in 350 ml of water plus 5θ ml of methanol. The new mixture was stiπed for several hours and filtered again. The crude product was recrystallized from aqueous acetonitrile. A sample recrystallized a second time from aqueous acetonitrile had mp 158-160°C; MS m/z 280 (M).
Step 3. Preparation of (4'-Trifluoromethyl-biphenyl-4-yl)-acetvI chloride (compound 91 C)
Figure imgf000196_0001
91C
A suspension 91B (2.0 g, 7.1 mmol) and 5 drops of N, N-dimethylformamide in 30 ml of dichloromethane was cooled in ice and treated dropwise with a solution of oxalyl chloride (0.70 ml, 1.0 g, 8.0 mmol) in 10 ml of dichloromethane. The ice bath was removed, and the mixture was stirred at room temperature for 3 h. The solution was filtered, and the filtrate was evaporated. The residue quickly crystallized to yield the acid chloride intermediate, which was used immediately in the next step.
Step 4. Preparation of {7-[2-(4'-Trifluoromethyl-biphenyl-4-yl)-acetyI]-indan-4- yloxy}-acetic acid methyl ester (compound 91D)
Figure imgf000197_0001
91D
A solution of 91C (2.1 g, 7.0 mmol) in 25 ml of 1,2-dichloro-ethane was cooled in ice and treated with anhydrous ferric chloride (1.2 g, 7.4 mmol). The mixture was stiπed, and a solution of 91A (1.5 g, 7.3 mmol) in 10 ml of 1 ,2-dichloro-ethane was added dropwise. The mixture was stiπed at room temperature for 18 h. The reaction mixture was added to 300 g of ice and of brine and extracted with ethyl acetate (4x100 ml). The combined extracts were washed with 5% aqueous sodium bicarbonate solution (4x250 ml) and brine (1x250 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography. A sample recrystallized from ethyl acetate/hexane had mp 141-143 °C; MS m/z 467 (M-l).
Step 5. Preparation of {7-[2-(4'-Trifluoromethyl-biphenyl-4-yl)-ethyl]-indan-4- yloxy}-acetic acid methyl ester (compound 91E)
Figure imgf000197_0002
91E A solution of 91D (1.0 g, 2.1 mmol) in 10.0 ml of trifluoroacetic acid was treated dropwise with triethylsilane (1.5 ml, 1.1 g, 9.4 mmol). The mixture was stirred at room temperature for 3 h and then added to 200 g of ice and water. The precipitated solid was extracted out with ethyl acetate (4x100 ml). The combined extracts were washed with brine (1x250 ml), 5% aqueous sodium bicarbonate solution (4x250 ml), and brine again, then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography.400 MHz Η NMR (DMSO- δ 7.82 (d, 2H, J = 8.3 Hz), 7.75 (d, 2H, J = 8.3 Hz), 7.61 (d, 2H, J = 8.3 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.90 (d, IH, J = 8.3 Hz), 6.53 (d, IH, J = 8.3 Hz), 4.71 (s, 2H), 3.63 (s, 2H), 2.77 (m, 8H), 1.94 (m, 2H).
Step 6. Preparation of {7-[2-(4 -TrifluoromethyI-biphenyl-4-yl)-ethyl]-indan-4- yloxy}-acetic acid (compound 91)
The title compound was prepared in the manner analogous to Example 1 using 91E. mp 188-190 °C; IR (thin film) cm"1: 1745, 1322, 1252, 1170, 1112, 1071; 400 MHz 1H NMR (DMSO- ) δ 12.89 (br s, IH), 7.83 (d, 2H, J = 8.1 Hz), 7.74 (d, 2H, J = 8.5 Hz), 7.61 (d, 2H, J = 8.1 Hz), 7.30 (d, 2H, J = 8.3 Hz), 6.90 (d,| IH, J = 8.3 Hz), 6.51 (d, IH, J = 8.3 Hz), 4.58 (s, 2H), 2.75(m, 8H), 2.45 (m, 2H); MS m/z 439 (M-l). Anal. Calc'd for C26H23F3O3: C, 70.90; H, 5.26; found: C, 70.92; H, 5.01.
Example 92
Synthesis of {5-MethvI-7-r4-(5-trifluoromethyl-pyridin-2-yl)-benζylsulfanvπ-2, 3-dihvdro-benzofuran-4-vloxv)-acetic acid (compound 92)
Figure imgf000199_0001
92
Step 1. Preparation of {5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-2, 3-dihydro-benzofuran-4-yloxy}-acetic acid methyl ester (compound 92A)
Figure imgf000199_0002
92A
The title compound was prepared in the manner analogous to Example IF using 18B and 7-mercapto-5-methy-2, 3-dihydro-benzofuran-4-yloxy)-acetic acid methyl ester (prepared in a similar manner as described for Example 12C). mp 94-95 °C; MS m/z
490 (M+l).
Step 2. Preparation of (5-Methyl-7-[4-(5-trifluoromethyl-pyridin-2-yl)- benzylsulfanyl]-2, 3-dihydro-benzofuran-4-yloxy)-acetic acid (compound 92)
The title compound was prepared in the manner analogous to Example 1 using 92A. mp 155-157 °C; IR (thin film) cm"1: 1732, 1587, 1416, 1331, 1211, 1129; 400 MHz 1H NMR (DMSO- ) δ 12.89 (br s, IH), 8.97 (m, IH), 8.21 (dd, IH, J = 2.0, 8.5 Hz), 8.12 (d, IH, J = 8.3 Hz), 8.02 (d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.5 Hz), 6.83 (s, IH), 4.56 (s, 2H), 4.48 (t, 2H, J = 8.7 Hz), 4.08 (s, 2H), 3.24 (t, 2H, J = 8.7 Hz), 2.02 (s, 3H); MS m/z 474 (M-l). Anal. Calc'd forC24H20F3NO4S: C, 60.63; H, 4.24; N, 2.95; found: C, 60.54; H, 4.19; N, 2.94.
Example 93
Synthesis of r8-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-chroman-5- yloxyl-acetic acid (compound 93)
Figure imgf000200_0001
93
Step 1. Preparation of [8-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- chroman-5-yloxy]-acetic acid methyl ester (compound 93A)
Figure imgf000200_0002
93A
The title compound was prepared in the manner analogous to Example IF using 18B and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester, mp 122-124 °C; MS m/z 489 (M+l).
Step 2. Preparation of [8-(4'-Trifluoromethyl-biphenyl-4-ylmethylsulfanyI)- chroman-5-yloxy]-acetic acid (compound 93) The title compound was prepared in the manner analogous to Example 1 using 93A. mp 170-172 °C; IR (thin film) cm"1: 1717, 1584, 1473, 1330, 1231, 1118; 400 MHz 1H NMR (DMSO-d6) δ 12.94 (br s, IH), 7.82_(d, 2H, J = 8.1 Hz), 7.74 (d, 2H, J = 8.5 Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.28
(d, 2H, J = 8.8 Hz), 4.58 (s, 2H), 4.11 (t, 2H, J = 5.0 Hz), 4.03 (s, 2H), 2.56 (t, 2H, J = 6.5 Hz), 1.84 (m, 2H); MS m/z 473 (M-l). Anal. Calc'd for C25H2,F3O4S: C, 63.28; H, 4.46; found: C, 63.28; H, 4.26.
Example 94
Synthesis of f8-r5-(4-TrifluoromethvI-phenyl)-isoxaζoI-3-ylmethylsulfanvn- chroman-5-yloxy)-acetic acid (compound 94)
Figure imgf000201_0001
Step 1. Preparation of {8-[5-(4-Trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfanyl]-chroman-5-yloxy}-acetic acid methyl ester (compound 94A)
Figure imgf000202_0001
The title compound was prepared in the manner analogous to Example IF using 42C and (8-mercapto-chroman-5-yloxy)-acetic acid methyl ester, mp 112-113 °C; MS m/z 480 (M+l).
Step 2. Preparation of {8-[5-(4-Trifluoromethyl-phenyl)-isoxaζol-3- ylmethylsulfanyl]-chroman-5-yloxy}-acetic acid (compound 94)
The title compound was prepared in the manner analogous to Example 1 using 94A.
The crude product was recrystallized from ethyl acetate/hexane to yield the final product, mp 171-173 °C; IR (thin film) cm"1: 1722, 1432, 1322, 1232, 1103, 1065; 400 MHz 1H NMR (DMSO-cf6) δ 12.94 (br s, IH), 8.01 (d, 2H, J = 8.1 Hz), 7.84 (d, 2H, J = 8.3 Hz), 7.09 (s, IH), 7.03 (d, IH, J = 8.5 Hz), 6.29 (d, IH, J = 8.5 Hz), 4.59 (s, 2H), 4.08 (t, 2H, J = 5.0 Hz), 4.04 (s, 2H), 2.55 (t, 2H, J = 6.5 Hz), 1.83 (m, 2H);
MS m/z 464 (M-l). Anal. Calc'd forC22H18F3NO5S: C, 56.77; H, 3.90; N, 3.01; found: C, 56.80; H, 3.58; N, 3.07.
Example 95
Synthesis of {8-r5-(4-ChIoro-phenylVisoxazol-3-ylmethylsulfanyl1-chrornan-5- yloxyl-acetic acid (compound 95)
Figure imgf000203_0001
Step 1. Preparation of {8-[5-(4-Chloro-phenyI)-isoxazol-3-ylmethylsulfanyI]- chroman-5-yloxy}-acetic acid methyl ester (compound 95A)
Figure imgf000203_0002
The title compound was prepared in the manner analogous to Example IF using 3- chloromethyl-5-(4-chloro-phenyl)-isoxazole and (8-mercapto-chroman-5-yloxy)- acetic acid methyl ester, mp 131-133 °C; MS m/z 446 (M+l).
Step 2. Preparation of {8-[5-(4-Chloro-phenyl)-isoxaζol-3-ylmethylsulfanyI]- chroman-5-y!oxy}-acetic acid (compound 95) The title compound was prepared in the manner analogous to Example 1 using 95A. mp 181-183 °C; IR (thin film) cm"1: 1723, 1612, 1479, 1428, 1231, 1134; 400 MHz 1H NMR (DMSO-d6) δ 12.95 (br s, IH), 7.82 (m, 2H), 7.54 (m, 2H), 7.02 (d, IH, J = 8.8 Hz), 6.94 (s, IH), 6.29 (d, IH, J = 8.5 Hz), 4.59 (s, 2H), 4.08 (t, 2H, J = 5.0 Hz), 4.01 (s, 2H), 2.55 (t, 2H, J = 6.6 Hz), 1.83 (m, 2H); MS m/z 430 (M-l). Anal. Calc'd forC2,H]8CINO5S: C, 58.40; H, 4.20; N, 3.24; found: C, 58.30; H, 3.91; N, 3.28.
Example 96
Synthesis of {4-r5-(4-Chloro-phenyl)-isoxaζol-3-ylmethylsulfanvn-2-methvI- phenoxyl-acetic acid (compound 96)
Figure imgf000204_0001
Step 1. Preparation of {4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-2- methyl-phenoxy}-acetic acid methyl ester (compound 96A)
Figure imgf000205_0001
The title compound was prepared in the manner analogous to Example IF using 3- chloromethyl-5-(4-chloro-phenyl)-isoxazole and 2C. mp 79-80 °C; MS m/z 404 (M+l).
Step 2. Preparation of {4-[5-(4-Chloro-phenyl)-isoxaζol-3-ylmethylsulfanyl]-2- methyl-phenoxyj-acetic acid (compound 96)
The title compound was prepared in the manner analogous to Example 1 using 96A. mp 152-153 °C; IR (thin film) cm"1: 1724, 1495, 1433, 1309, 1225, 1196; 400 MHz "H NMR (DMSO-de) δ 12.96 (br s, IH), 7.82 ( , 2H), 7.54 (m, 2H), 7.19 (d, IH, J = 1.5 Hz), 7.12 (dd, IH, J = 2.1, 8.4 Hz), 6.97 (s, IH), 6.72 (d, IH, J = 8.5 Hz), 4.63 (s, 2H), 4.11 (s, 2H), 2.09 (s, 3H); MS m/z 388 (M-l). Anal. Calc'd forCι96ClNO4S: C, 58.54; H, 4.14; N, 3.59; found: C, 58.53; H, 4.08;
N, 3.50.
Example 97
Synthesis of l7-r5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsuIfanvn-indan-4- yloxyl-acetic acid (compound 97)
Figure imgf000206_0001
Step 1. Preparation of {7-[5-(4-Chloro-phenyl)-isoxazoI-3-ylmethylsulfanyl]- inda -4-yloxy}-acetic acid methyl ester (compound 97 A)
Figure imgf000206_0002
The title compound was prepared in the manner analogous to Example IF using 3- cchhlloorroonmethyl-5-(4-chloro-phenyl)-isoxazole and 12C. mp 112- 114 °C; MS m/z 430
(M+l).
Step 2. Preparation of {7-[5-(4-Chloro-phenyI)-isoxaζoI-3-ylmethyIsulfanyl]- indan-4-yIoxy}-acetic acid (compound 97) .
The title compound was prepared in the manner analogous to Example 1 using 97A. mp 157-159 °C; IR (thin film) cm"1: 1731, 1612, 1465, 1433, 1231, 1110; 400 MHz !H NMR (DMSO-ύfe) δ 7.81 (m, 2H), 7.54 (m, 2H), 7.10 (d, IH, J = 8.3 Hz), 6.95 (s, IH), 6.59 (d, IH, J = 8.5 Hz), 4.62 (s, 2H), 4.06 (s, 2H), 2.77 (m, 4H), 1.92 (m, 2H); MS m/z 414 (M-l). Anal. Calc'd forC218ClNO4S: C, 60.65;IH, 4.36; N, 3.37; found: C, 60.62; H, 4.10; N, 3.31.
Example 98
Synthesis of (7-r3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyll-indan-4- yloxyl-acetic acid (compound 98)
Figure imgf000207_0001
Step 1. Preparation of {7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]- indan-4-yloxy}-acetic acid methyl ester (compound 98A)
Figure imgf000207_0002
The title compound was prepared in the manner analogous to Example IF using 5- chloromethyl-3-(4-chloro-phenyl)-isoxazole and 12C. mp 92-94 °C; MS m/z 430 (M+l).
Step 2. Preparation of {7-[3-(4-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]- indan-4-yloxy}-acetic acid
The title compound was prepared in the manner analogous to Example 1 using 98A. mp 158-160 °C; IR (thin film) cm"1: 1741, 1574, 1476, 1429, 1252, 1110; 400 MHz
1H NMR (DMSO-<26) δ 7.78 (m, 2H), 7.51 (m, 2H), 7.13 (d, IH, J = 8.6 Hz), 6.72 (s, IH), 6.60 (d, IH, J = 8.5 Hz), 4.62 (s, 2H), 4.20 (s, 2H), 2.76 (m, 4H), 1.91 (m, 2H); MS m/z 414 (M-l). Anal. Calc'd forC21H18ClNO4S: C, 60.65; H, 4.36; N, 3.37; found: C, 60.55; H, 4.17; N, 3.34.
Example 99
Synthesis of {5-Chloro-2-methyl-4-f5-(4-trifluoromethyl-phenyl)-isoxazol-3- ylmethylsulfanyll-phenoxyl-acetic acid (compound 99)
Figure imgf000208_0001
Step 1. Preparation of {5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)- isoxazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid methyl ester (compound 99A)
The title compound was prepared in the manner analogous to Example IF using 3- chloromethyl-5-(4-chloro-phenyl)-isoxazole and 20C. mp 120-121 °C; MS m/z 472 (M+l).
Step 2. Preparation of {5-Chloro-2-methyl-4-[5-(4-trifluoromethyl-phenyl)- isoxaζol-3-ylmethylsulfanyI]-phenoxy}-acetic acid (compound 99)
The title compound was prepared in the manner analogous to Example 1 using 99A. mp 180-182 °C; IR (thin film) cm"1: 1743, 1484, 1325, 1236, 1 165, 1111 ; 400 MHz ]H NMR (DMSO- δ 13.03 (br s, IH), 8.03 (d, 2H, J = 8.1 Hz), 7.84 (d, 2H, J = 8.3
Hz), 7.33 (s, IH), 7.14 (s, IH), 6.96 (s, IH), 4.71 (s, 2H), 4.23 (s, 2H), 2.07 (s, 3H); MS m/z 456 (M-l). Anal. Calc'd for C20H15C1F3NO4S: C, 52.47; H, 3.30; N, 3.06; found: C, 52.39; H, 3.02; N, 2.86. Example 100
Synthesis of 2-r2-butyl-4-(f 4-r4- (trifluoromethyl)phenvnphenyllmethylthio)phenoxylacetic acid (compound 100)
Figure imgf000210_0001
Step 1. Preparation of 2-((lE)buta-l,3-dienyl)-l-methoxybenzene (compound 100A)
Figure imgf000210_0002
100A
Methyltriphenylphosphonium bromide (42.9 g, 0.12 mol) was suspended in 400 ml of anhydrous THF under nitrogen and cooled to - 78 °C. Sodium hydride (60% in mineral oil, 6.0 g, 0.15 mol) was added portionwise. The reaction mixture was allowed to warm up slowly to room temperature and stiπed at the same temperature for 1 h, then 2-methoxycinnamaldehyde (16.2 g, 0.10 mol) in 200 ml of THF was added dropwise at room temperature, and stiπed at the same temperature for 3 h. Water (200 ml) and diethyl ether (800 ml) were added. The organic layer was separated, dried over sodium sulfate, concentrated, and purified using normal phase chromatography to afford the title product. 400 MHz 1H NMR (CDC13) δ 7.48-6.56 (m, 7H), 5.32 (d, IH), 5.16 (d, IH), 3.84 (s, 3H). Step 2. Preparation of 2-butyl-l-methoxybenzene (compound 100B)
Figure imgf000211_0001
100B
A mixture of the product from example 100A (12.8 g, 0.08 mol) and palladium/carbon (10%, 50% water, 12 g) in 400 ml of ethyl acetate was hydrogenated at 50 psi, at room temperature overnight, then filtered through Celite®, and concentrated to give 100B. 400 MHz 1H NMR (CDC13) δ 7.16 (m, 2H), 6.85 (m, 2H), 3.81 (s, 3H), 2.61 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.92 (t, 3H).
Step 3. Preparation of 2-butylphenol (compound 100C)
Figure imgf000211_0002
100C
To a stiπed solution of the product from example 100B (13.1 g, 0.08 mol) in 400 ml of dichloromethane at - 78 °C was added dropwise a solution of boron tribromide (100.2 g, 0.4 mol) in 200 ml of dichloromethane. After the completion of addition of boron tribromide, the reaction mixture was maintained at - 78 °C for 1 h, then allowed to reach room temperature and stiπed at the same temperature overnight.
The mixture was cooled to 0 °C, and carefully quenched with 100 ml of water. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated to give lOOC. 400 MHz 1H NMR (CDC13) δ 7.10 (m, 2H), 6.86 (m, IH), 6.78 (d, IH), 4.61 (brs, IH), 2.61 (m, 2H), 1.60 (m, 2H), 1.40 (m, 2H), 0.96 (t, 3H). Step 4. Preparation of (3-butyl-4-hydroxyphenyl)thiocarbonitrile (compound 100D)
Figure imgf000212_0001
100D
The title compound was prepared in the manner analogous to Example IB with the product from example 100C (2.38 g, 0.016 mol), sodium thiocyanate (5.14 g, 0.063 mol), sodium bromide (1.63 g, 0.016 mol), and bromine (2.8 g, 0.017 mol) in methanol. 400 MHz 1H NMR (CDC13) δ 7.30 (m, 2H), 6.81 (d, IH), 5.49 (brs, IH), 2.60 (m, 2H), 1.59 (m, 2H), 1.38 (m, 2H), 0.95 (t, 3H).
Step 5. Preparation of methyl 2-(2-butyl-4-cyanothiophenoxy)acetate (compound 100E)
Figure imgf000212_0002
100E
The title compound was prepared in the manner analogous to Example IC with the product from example 100D (2.80 g, 0.014 mol), methyl bromoacetate (2.28 g, 0.015 mol), and cesium carbonate (6.60 g, 0.020 mol) in 100 ml of acetonitrile. 400 MHz 1H NMR (CDC13) δ 7.38 (m, 2H), 6.72 (d, IH), 4.66 (s, 2H), 3J80 (s, 3H), 2.67 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.98 (t, 3H).
Step 6. Preparation of methyl 2-(2-butyl-4-sulfanylphenoxy)acetate (compound 100F)
Figure imgf000213_0001
100 F
The title compound was prepared in the manner analogous to Example ID with the product from example 100E (2.79 g, 10.0 mmol), dithiothreitol (3.08 g, 20.0 mmol), and 0.2 M potassium dihydrogenphosphate (15 ml) in 60 ml of methanol. 400 MHz Η NMR (CDC13) δ 7.11 (m, 2H), 6.60 (d, IH), 4.61 (s, 2H), 3.81 (s, 3H), 3.36 (s, IH), 2.63 (m, 2H), 1.57 (m, 2H), 1.38 (m, 2H), 0.98 (t, 3H).
Step 7. Preparation of methyl 2-[2-butyl-4-({4-[4- (trifluoromethyI)phenyl]phenyl}methylthio)phenoxy]acetate (compound 100G)
Figure imgf000213_0002
100G The title compound was prepared in the manner analogous to Example IF using 100F and l-(bromomethyl)-4-[4-(trifluoromethyl)phenyl]benzene prepared from and phosphorous tribromide and (4'-trifluoromethyl-biphenyl-4-yl)-methanol in a manner analagous to Example 3B. 400 MHz 1H NMR (CDC13) δ 7.68 (m, 4H), 7.51 (d, 2H), 7.29 (d, 2H), 7.15 (m, 2H), 6.60 (d, IH), 4.62 (s, 2H), 4.04 (s, 2H), 3.79 (s, 3H), 2.60 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 0.88 (t, 3H).
Step 8. Preparation of 2-[2-butyl-4-({4-[4- (trifluoromethyl)phenyl]phenyl}methylthio)phenoxy]acetic acid (compound 100)
The title compound was prepared in the manner analogous to Example 1 with the product from example 100G. mp 155-157 °C; 400 MHz 1H NMR (DMSO-rf6) δ 7.88 (d, 2H), 7.80 (d, 2H), 7.65 (d, 2H), 7.38 (d, 2H), 7.17 (dd, IH), 7.09 (d, IH), 6.79 (d, IH), 4.65 (s, 2H), 4.17 (s, 2H), 2.50 (m, 2H), 1.43 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H). MS m/z 473 (M-l). Anal. Calc'd for C26H25O3SF3: C, 65.81 ; H, 5.31 ; Found:
C, 65.95; H, 5.36.
Example 101
Preparation of {6-methyl-8-r4-(4-trifluoromethyl-benzyloxy)-benzyl-sulfanyll- chroman-5-yloxy)-acetic acid (compound 101)
Figure imgf000214_0001
101 Step 1. {6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman- 5-yloxy}-acetic acid methyl ester (compound 101A)
Figure imgf000215_0001
101A
The title compound was prepared in the manner analogous to Example IF using (8- mercaρto-6-methyl-chroman-5-yloxy)-acetic acid methyl ester and the product from Example 14B. MS m/z 533 (M+l).
Step 2. {6-methyl-8-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-chroman-
5-yloxy}-acetic acid (compound 101)
2N KOH solution (5 ml) was added to a stiπed slurry of the product from Example 101A (0.4g, 0.75 mmol) in 2-3 ml of methanol, and the mixture was heated briefly on a steambath until nearly clear, then stiπed at room temp. After 3 hours the mixture was diluted with 15-20 ml of ice-water and acidified with H3PO4. After 15 minutes the precipitate was filtered off, rinsed 3x with water, and dried to afford the title product, 0.2g, 51 %. 400 MHz 1H NMR (DMSO- ) δ 7.70 (d, 2H, J = 8 Hz), 7.59 (d, 2H, J = 8 Hz), 7.18 (d, 2H, /= 8.5 Hz), 6.88 (d, 2H, J = 8.5 Hz), 6.83 (s, IH), 5.14 (s, 2H), 4.21 (s, 2H), 4.06 (t, 2H, J = 4.9Hz), 3.95 (s, 2H), 2.63 (t, 2H, J = 6.3Hz), 2.03 (s, 3H), 1.79 (quint, 2H); MS m/z 517 (M-l).
Example 102
Preparation of {4-r5-(4-trifluoromethyl-phenyl)-isoxaζol-3-ylmethylsulfanvπ- 5.6.7.8-tetrahydro-naphthalen-l-vIoxy)-acetic acid (compound 102)
Figure imgf000216_0001
102"
Step l. {4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyI]-5,6,7,8- tetrahydro-naphthalen-l-yloxy}-acetic acid methyl ester (compound 102A)
Figure imgf000216_0002
102A
The title compound was prepared in the manner analogous to Example 1 F using (4- mercapto-5,6,7,8-tetrahydro-naphthalen-l-yloxy)-acetic acid methyl ester and the product from Example 42C; recrystallization from methanol afforded the title compound. MS m/z 478 (M+l).
Step 2. {4-[5-(4-trifluoromethyl-phenyl)-isoxaζol-3-ylmethylsulfanyl]-5,6,7,8- tetrahydro-naphthalen-l-yloxy}-acetic acid (compound 102)
The title compound was prepared in the manner analogous to Example 1 using the product from Example 102A. mp 167-170°C; 400 MHz ]H NMR DMSO-d6) δ 8.01 (d, 2H, J= 8 Hz), 7.83 (d, 2H, J= 8.3 Hz), 7.14 (d, 2H, J= 8.5 Hz), 7.07 (s, IH), 6.58
(d, 2H, J= 8.8 Hz), 4.56 (s, 2H), 4.07 (s, 2H), 2.64 (m, 2H), 2.53 (m, 2H), 1.60 (m, 4H,); MS m/z 464 (M+l).
The compounds of the present invention can also be prepared using combinatorial chemistry methods. In particular, compounds of Examples 103-134 were prepared using combinatorial chemistry analagous to that previously described in Examples 1- 102. The combinatorial chemistry methods useful in the present invention include those where an activated alcohol is contacted with a thiol followed by saponification of the resulting ester to afford the desired products. Such methods can be illustrated by previously described Scheme 1 where compound D is an exemplary thiol, compound Y is an exemplary activated alcohol, and compound F is an exemplary desired product.
Examples 103-134
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
The preparation of Examples 103-134 is further described below.
Preparation of Thiols used in Combinatorial Methods Thiol WW Preparation of 2,5-Dimethyl-4-thiocyanato-phenol (compound WWA)
Figure imgf000220_0001
WWA
The title compound was prepared in a manner analogous to compound IB.
400 MHz 1H NMR (DMSO-d6) δ 10.0 (s, IH), 7.35 (s, IH), 6.73 (s, IH), 2.3 (s, 3H),
2.04 (s, 3H); MS m/z 180 (m+l).
Preparation of (2,5-Dimethyl-4-thiocyanato-phenoxy)-acetic acid methyl ester
(compound WWB)
Figure imgf000220_0002
WWB
The title compound was prepared from compound WWA in a manner analogous to compound IC. 400 MHz 1H NMR (DMSO-J6) δ 7.07 (s, IH), 6.50 (s, IH), 4.56 (s, 2H), 3.76 (s, 3H), (s, IH), 2.26 (s, 3H), 2.17 (s, 3H); MS m/z 252 (m+l).
Preparation of (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid methyl ester (compound WW)
Figure imgf000220_0003
WW The title compound was prepared from compound WWB in a manner analogous to compound ID. 400 MHz 1H NMR (DMSO- 6) δ 7.07 (s, IH), 6.50 (s, IH), 4.56 (s, 2H), 3.76 (s, 3H), 3.07 (s, IH), 2.26 (s, 3H), 2.17 (s, 3H); MS m/z 227 (M+l).
Thiol XX Preparation of 2,6-Dimethyl-4-thiocyanato-phenoI (compound XXA)
Figure imgf000221_0001
Compound XXA was prepared from 2,6-dimethylphenol in a similar manner as described for compound IB. 400 MHz 1H NMR (DMSO- ) δ 8.96 (s, IH), 7.22 (s, 2H), 2.13 (s, 6H).
Preparation of (2,6-Dimethyl-4-thiocyanato-phenoxy)-acetic acid methyl ester (compound XXB)
Figure imgf000221_0002
XXB
Compound XXB was prepared from compound XXA in a similar manner as described for compound IC to give 2.5 g (46%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-J6) δ 7.11 (s, 2H), 4.41 (s, 2H), 3.63 (s, 3H), 2.14 (s, 6H). Preparation of (4-Mercapto-2,6-dimethyl-phenoxy)-acetic acid methyl ester (compound XX)
Figure imgf000222_0001
XX
Compound XX was prepared from compound XXB in a similar manner as described for compound ID to give, after purification by flash column chromatography (gradient elution: 100% hexanes to 30% EtOAc/hexanes), 1.8 g (82%) of the title compound. 400 MHz ]H NMR DMSO-d6) δ 6.90 (s, 2H), 5.51 (s, IH), 4.39 (s, 2H),
3.66 (s, 3H), 2.10 (s, 6H); MS m/z 225 (M-l).
Thiol YY Preparation of 4-Thiocyanato-5,6,7,8-tetrahydro-naphthalen-l-ol (compound YYA)
.OH
NCS J
YYA
5,6,7,8-Tetrahydro-naphthalen-l-ol (lg, 6.8 mmol) was dissolved in 25 ml acetonitrile. Sodium thiocyanate (1.76 g, 22 mmol) and sodium bromide (0.7 g, 6.8 mmol) were added and stiπed for 5 minutes at. ambient temperature. Bromine (1.2 g, 7.48 mmol) was added drop wise over 5 minutes. The orange solution was allowed to stir two hours. Brine was added and the crude product was extracted twice into ethyl acetate. The combined organic extracts were washed once with brine, dried over anhydrous sodium sulfate, decanted and concentrated. Normal phase chromatography afforded the title product, 1.28 g, 92%. 400 MHz 1H NMR (DMSO- δ) δ 11.1 (s, IH), 7.40 (d, IH, J = 8.8 Hz), 6.61 (d, IH, 8.8 Hz), 2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+l)
Preparation of (4-Thiocyanato-5,6,7,8-tetrahydro-naphthalen-l-yloxy)-acetic acid methyl ester (compound YYB)
Figure imgf000223_0001
YYB
The title compound was prepared in the manner analogous to example IC utilizing compound YYA. 400 MHz 1H NMR (DMSO-rfe) δ 7.4 (d, IH, J = 8.8 Hz), 6.80 (d, IH, 8.8 Hz), 4.84 (s, 2H), 3.64 (s, 3H), 2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+l).
Preparation of (4-Mercapto-5,6,7,8-tetrahydro-naphthalen-l-yloxy)-acetic acid methyl ester (compound YY)
Figure imgf000223_0002
YY
The title compound was prepared in the manner analogous to example ID utilizing compound YYB. 400 MHz 1H NMR (DMSO-i6) δ 7.08 (d, IH, J = 8.8 Hz), 6.55 (d, IH, 8.8 Hz), 4.71 (s, IH), 4.70 (s, 2H), 3.63 (s, 3H), 2.45 (m, 2H), 2.44 (m, 2H), 1.65 (m, 4H). MS m/z 253 (M+l). Thiol ZZ Preparation of 4-Thiocyanato-phenol (compound ZZA)
Figure imgf000224_0001
ZZA
The title compound was prepared in the manner analogous to Example IB using phenol. MS m/z 152 (M+l)
Preparation of [(4-Thiocyanato-phenoxy)-acetic acid methyl ester (compound
Figure imgf000224_0002
ZZB
The title compound was prepared in the manner analogous to Example IC using ZZA. MS m/z 224 (M+l)
Preparation of (4-Mercapto-phenoxy)-acetic acid methyl es^er (compound ZZ)
Figure imgf000224_0003
TIL The title compound was prepared in the manner analogous to Example ID using
ZZB. MS m/z 197 (M-l)
Preparation of Examples 103-134
Alcohol Preparation: The appropriate alcohols in the salt form (0.65mmόl) were dissolved in 3.0mL of low water MeOH. MP-CO3 (3.21 mmol/g, 3.70 equivalents to alcohol, 2.41 mmol) was then added to each vial containing the alcohol and shaken at ambient temperature for 3h. The samples were then filtered into tared vials and concentrated.
Alcohol Activation:
Each alcohol sample was then diluted to 0.15M with DCM and l.OmL of each delivered to a reaction tube. PS-morpholine (4.0 mmol/g, 2 equivalents to alcohol, 0.3mmol) and 25 μL methanesulfonyl chloride was then added to each reaction tube. The reaction tubes were shaken at ambient temperature for 16h. The samples were then filtered into collection tubes, the resin rinsed with two l.OmL aliquots of DCM, and concentrated.
Alkylation: Examples 103- 134 were synthesized in the following fashion using either the thiol products 2C, ID, WW, XX, YY or ZZ and the appropriate activated alcohol or alkyl halide. Each thiol was diluted to 0.15M with CH3CN and each activated alcohol diluted to 0.15M with CH3CN. 1.OmL aliquots of each thiol (0.15 mmol) and 1.OmL aliquots of each activated alcohol (1.0 equivalents, 0.15mmol) were then delivered to a reaction tube and lOO g Cs2CO3 (2 equivalents, 0.3mmol) was added. The reaction tubes were shaken at 60°C for 2.5h. The reacion mixtures were filtered into collection tubes, the resin rinsed with two 1.OmL aliquots of CH3CN, and concentrated.
Saponification:
Examples 103-134 were synthesized in the following fashion using the products from the alkylation step discussed above. Each alkylation product was diluted with 3.0mL of 0.5M LiOH in 4: 1 methoxyethanol:H2O, shaken at 60°C for 4h and cooled to ambient temperature. To each reaction, was then added l.OmL IN HCl and l.OmL brine. Each reaction was extracted twice with 2.0mL EtOAc, and the organic layers concentrated to afford the desired products.
BIOLOGICAL ASSAYS
The compounds of the present invention have demonstrated PPAR modulating activity in the standard assays commonly employed by those skilled in the art. Accordingly, such compounds and formulations comprising such compounds are useful for supressing appetite, modulating leptin, and treating, preventing or controlling hypercholesterolemia, dyslipidemia, obesity, eating disorders, hyperglycemia, atherosclerosis, hypertriglyceridemia, hyperinsulinemia and diabetes.
A. Selectivity Measurements
1. Test A. Transient transfections assay using the HepG2 hepatoma cell line.
HepG2 cells were transiently transfected with an expression plasmids encoding hPPARα, hPPARβ or mPPARγ chimeric receptors and a reporter containing the yeast upstream activating sequence (UAS) upstream of the viral El B promoter controlling a luciferase reporter gene^ In addition, the plasmid pRSNβ-gal was used to control for transfection efficiency. HepG2 cells were grown in DMEM supplemented with 10%FBS and lμM non-essential amino acid. On the first day, cells were split into 100mm dishes at 2.5x106 /dish and incubated overnight at 37C°/5% CO2. On the second day the cells were transiently transfected with plasmid
DΝA encoding a chimeric receptor, the luciferase reporter gene; and β-gal. For each 100 mm dish, 15μg of lucifease reporter (PG5Elb) DΝA, 15μg of Gal4-PPAR chimeric receptor DΝA, and 1.5μg of β-gal plasmid DΝA were mixed with 1.4ml of opti-MEM in the tube. 28μl of LipoFectamine-2000 reagent was added to 1.4ml of. opti-MEM in the tube, and incubate for 5 min.at RT. The diluted Lipofectamine-2000 reagent was combined with the DNA mixture, and incubate for 20 min at RT. After fresh medium was added to each 100mm dish of cells, 2.8ml of Lipofectamine2000- DNA mixture was added dropwise to the 100mm dish containing 14ml of medium, and incubate 37°C overnight. On day three cells were trypsinized off thelOO mm dishes and re-plated on 96 well plates. Cells were plated at 2.5x 04 cells per well in
150μl of media and 50μl of compound diluted by media was added. The test compound added were in the range from 50μM to 50pM. After addition of compounds, the plates were incubated at 37C° for 24 hours. Subsequently cells were washed with once with lOOμl of PBS, lysed, and processed for measuring luciferase and β-gal activity using Dual-Light luciferase kit from Tropix ®, according to the manufacturer's recommendations, on an EG&G Bethold MicroLumat LB96P luminometer. EC50 values were obtained using the GraphPad Prism™ program. Surprisingly, the compounds of the present invention exhibit activity for both PPARα and PPARβ. Compounds of the present invention exhibited a range of Hep G2-hBeta EC50' s ("EC50β") and Hep G2-hAlpha EC50' s ("EC50α") from greater than zero to about 20μM. Specifically, as shown in Table 1, the Hep G2-hBeta ECso's and Hep G2-hAlpha ECso's for. the compounds of the present invention fall within the following 6 groups:
I) >0-300 nM
H) >300-500 nM
ΠD >500-1000 nM rv) >1000-2000 nM
V) >2000-5000 nM
VI) >5000 nM Table 1
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
B. Effect of PPAR modulators on lipid and human apoprotein Al concentrations in the hApoAl transgenic mouse
Mice, transgenic for human apoAl , were purchased from Jackson laboratories. All animals were allowed normal chow (Ralstoή-Purina) and water ad libitum in temperature controlled rooms, under a 12-h light, 12-h dark cycle beginning with lights on at 6 AM. During the treatment phase of the study the mice were dosed daily between 6 and 9 AM by oral gavage using a suspension vehicle of
1.5% carboxymethylcellulose plus 0.2 percent Tween-20 (CMC/T een) containing the specified compounds. Control animals received vehicle alone. Vehicle volume represented 0.25 percent of body weight. Under anesthesia, tail blood was obtained weekly in the morning at the indicated days of study. At termination, tissue samples (liver, intestine, fat, and muscle) were taken to study effects on genes effecting lipid metabolism. Each of the compounds of the present invention that were tested effected a significant increase in HDL over the values observed for the control animals. Furthermore, these compounds resulted in triglyceride levels which were lower than observed in controls. Compounds of the present invention tested in the hApoAl transgenic mouse model showed a range of HDL-c , elevation and
! triglyceride lowering when dosed at 30 mg/kg/day. For instance, Example 4 raised
HDL-c 97% and lowered triglycerides 65 % relative to the control population, Example 6 raised HDL-c 24% and lowered triglycerides 59 % relative to the control population, and Example 3 raised HDL-c 9% and lowered triglycerides 70% relative to the control population.
C. Effect of Compounds of the Invention on Insulin Resistant or Diabetic
Cynomolgus Monkeys
Cyno olgus monkeys that were either insulin resistant or diabetic (type π) were treated for eight weeks with [5-Methoxy-2-methyl-4-(4'-trifluoromethyl- biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid in a rising dose fashion (0.1 to 1 mg/kg). Plasma was sampled bi-weekly and analyzed for glycemics and leptin. Body weight was also measured at various time points across the study. The diabetic monkey mean body weight data is presented in Table 2 and the insulin resistant monkey mean body weight data is presented in Table 3.
Table 2 Diabetic Monkey Mean Body Weight
-7wk - -4wk - Mean Baseline 2wk 5wk •■ 7wk '8wk
Diab Ctl Mean 8.10 8.05 8.08 8.17 8.18, 8.17 8.19 Diab Ctl StDev 3.77 3.77 3.77 3.74 3.7θ' 3.70 3.64 Diab Ctl SEM 1.89 1.88 1.89 1.87 1.85 1.85 1.82
Diab Txt Mean 8.84 8.91 8.87 8.75 8.37 8.08 7.80
Diab Txt StDev 3.73 3.68 3.70 3.61 3.52 3.34 3.20
Diab Txt SEM 1.32 1.30 1.31 1.28 1.24 1.18 1.13
IR = insulin resistant, Diab = diabetic, Ctl = control, Txt = experimental,! StDev = standard deviation, SEM = standard error of the mean Table 3 Insulin Resistant Monkey Mean Body Weight
-7wk -4wk Mean Baseline 2wk 4wk 6wk 8wk
BR. Ctl Mean 6.18 6.15 6.17 6.04 6.00 5.94 5.91 TR Ctl StDev 3.48 3.43 3.46 3.22 3.19 3.16 3.17 TR Ctl SEM 1.74 1.72 1.73 1.61 1.60 1.58 1.59
IR Txt Mean 5.25 5.32 5.29 5.26 5.04 4.91 4.7]
TR Txt StDev 3.17 3.22 3.19 3.42 3.40 3.34 3.20
IR Txt SEM 0.95 0.97 0.96 1.03 1.03 1.01 0.96
IR = insulin resistant, Diab = diabetic, Ctl = control, Txt = treated, StDev = standard deviation, SEM = standard error of the mean
Plasma leptin values, presented as baseline values vs. 8-week treatment, were determined by ELISA and are presented in Table 4. The effect of [5-Methoxy-2- methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid on plasma leptin values, in. diabetic and insulin.resistant obese cynornolgus monkeys is demonstrated by the lesser increase in plasma leptin values seen in, the treated animals.
The amount of exogenous insulin the diabetic monkeys received to maintain proper glucose levels, the exogenous insulin requirement, is also presented in Table 4 as baseline values vs. 8-week treatment. By definition, insulin resistant monkeys are not yet diabetic and do not receive exogenous insulin. A reduction in exogenous insulin requirements is a measure of improved insulin sensitivity and glucose control.
Table 4 Leptin and Exogenous Insulin
Figure imgf000234_0001
FORMULATIONS The compounds of the present invention can be administered alone or in combination with one or more therapeutic agents. These include, for example, other agents for the treatment, control, or prevention of hypercholesteremia, dyslipidemia, obesity, hyperglycemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, and hypeτinsulιnemia;-The. compounds of the. present invention can be dministered alone or iri~cdmbiήafion with one" or more therapeutic agents for the sύpression of appetite and modulation of leptin.
The compounds are, thus: well, suited to formulation for convenient administration to mammals for the prevention and treatment of such disorders.
The.following examples further illustrate typical formulations provided by the invention. Formulation 1
Figure imgf000235_0001
The above ingredients are mixed and dissolved in the saline for IV administration to a patient.
Formulation 2
Figure imgf000235_0002
The ingredients are blended to uniformity and pressed into a tablet that is well suited for oral administration to a patient.
Formulation 3
Figure imgf000235_0003
The ingredients are combined and milled to afford material suitable for filling hard gelatin capsules administered to a patient.
Formulation 4
Figure imgf000235_0004
The ingredients are combined via melting and then poured into molds containing 2.5 g total weight.
While, embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation, and it is understood that various changes may. be made without departing from the spirit and scope of the invention.

Claims

What is claimed. is:
A compound of formula (I):
Figure imgf000237_0001
I and pharmaceutically acceptable salts thereof, wherein:
X° and X1 are independently absent, O, S, -CH2-, -CH2-CH2-, -CH=CH- CH≡CH- , -S(O)2-, or-S(O)
Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl;
-- is absent; or when present, — is a saturated or unsaturated hydrocarbon, chain which is substituted or unsubstituted, wherein said chain has from
1 to 4 atoms so' that ^~-- , Ar', X', (CH2)r and Al together form a five to eight membered ring;
R1 and R2 are selected from hydrogen, lower, alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3^ halogen, nitro, cyano, -OH, -SH, -CF^ -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2R5, or-NR6R7, or together with the atoms to which they are attached form a five to eight member ring;
R3 and R4 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)mCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)mOR5, -(CH2)mNR6R7, -COR5, -CO2H, -CO2R5, or-NR6R7; provided that at least one of Ri- j is H, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2) CF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, S(O)paryl, - (CH2)raOR5, -(CH2)mNR6R7, orNR6R7;
R5 is hydrogen, alkyl, alkenyl, alkynyl, or aryl; R6 and R7 are each independently hydrogen, alkyl, alkenyl, alkynyl, -COalkyl,
-COaryl, cycloalkyl, -CO2alkyl, -CO2aryl, or-R and R7 together with the atoms to which they are attached form a 4 to 7 membered ring having 1 to 3 heteroatoms; m is 0 to 5; , p is O, l, or 2; ... q is 0 to 6; and r is 0 to 6.
2. The compound of claim 1, wherein X° is S; , X1 is absent;
Ar1 and r2 are each independently unsubstituted or substituted aryl;
Figure imgf000238_0001
3. The compound of cl aim .1; wherei n '
- -X 's Sj'rr. -" ": - X1 is'abseiήt; Ar is phenyl;
Ar2 is substituted phenyl;
V
v-- is absent; R1 is hydrogen; R2 is lower alkoxy; R3 is lower alkyl; R4 is hydrogen; q is 1 ; and r is O.
A compound having Formula H:
Figure imgf000239_0001
II
and pharmaceutically acceptable salts thereof, wherein: (
X° and X1 are independently absent, O, S, -CH2- -CH2-CH2-, -CH=CH-,
CH≡CH- , -S(O)2-, or -S(O)-;
Ar1 and Ar2 are each independently unsubstituted or substituted aryl or heteroaryl, provided that Ar1 is not thiazolyl or oxazolyl;
Figure imgf000240_0001
Figure imgf000240_0002
is absent; or when present, ^-- is a saturated or unsaturated hydrocarbon chain which is substituted or unsubstituted, wherein said chain has from /' v"1 \ \
1 to 4 atoms so that ~ , Ar , X , (CH2)r, and Ar , together form a four to eight member ring;
Figure imgf000240_0003
p is 0 to 2; q is 0 to 6; and ris O to ό.
The compound of claim 18, wherein
Figure imgf000240_0004
-~ is absent; R3 is hydrogen, lower alkyl, lower alkoxy;
R4 is hydrogen, lower alkyl, lower alkoxy; m is 0 to 5; p is 0, i,;pr:2; q is l; r is 1 ; and
(T
S- is -CH2-CH2-CH2-CH2-, -CH2-CH2-CHr, -CH2-CH2-O-CH2-, -CH2-O,CH2-CH2- , -CH2-HC=CH-CH2-, -CH2-HC=CH-, -CH2CH2-N R4-CH2-, -COCH=CH-O-, -O-
CH=CH-CO-, -CH=CH-NR4-, -NR4-CH=CH-, -CH=CH-CH2-, -CH2-CH2-NR4-, - NR4-CH2-CH2-, -O-CH2-CH2-, -CH2-CH2-O-, -CH2-CH2-CH2-NR4-, -NR4-CH2-CH2- CH2-, -O-CH2-CH2-CH2-, -CH2-CH2-CH2-O-.
6.
,
Figure imgf000241_0001
7. A compound selected from:
[4-(Biphenyi-4-ylmethylsulfanyl)-5-methoxy-2-'methyT-phenoxy]-acetic acid; [5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfaηyl)- pherioxy]-acetic,acid
[4-(2',4'-Dichϊoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl- phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)- phenoxyl-acetic acid; [4-(4'-Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2-methyl-phenoxy]- acetic acid;
[7-(4'-Triflubromethyl-biphenyl-4-ylmethylsulfanyl)1-indan-4-yloxy]-acetic acid; {5-Methoxy-2-methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]- phenoxy} -acetic acid;
[5-Methoxy-2-methyl-4-(3'-trifluoromethoxy-biphenyl-3-ylmethylsulfanyl)- phenoxy]-acetic acid; { { 5-Methoxy-2'-methyl-4-[4-(5-trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]- phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3- ylmethylsulfanyl]-phenoxy } -acetic acid;
[3-Methoxy-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]- acetic acid;
{5-Methoxy-2-methyl-4-[2-(4'-trifluoromethyl-biphenyl-4-yl)-ethylsulfanyl]- phenoxy} -acetic acid;
(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl- phenoxy)-acetic acid; [5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl-biphenyl-4- ylmethylsulfanyl)-phenoxy]-acetic acid;
{4-[5-(4-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-m,ethoxy-2-methyl- phenoxy} -acetic acid;*
{5-Methoxy-2-methyl-4-[5-(4-trifluoromethyl-ρhenyl)-isoxazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid;
{5-Methoxy-2-methyl-4-[3-(4-trifluoromethyl-phenyl)-isoxazol-5- ylmethylsulfanyl]-phenoxy }-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-3l-ylmethylsulfanyl)- phenoxy]-acetic acid; {7-[4- 4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid;
{5-Methyl-7-*[4-(5-trifIuorόrhethyl-pyridin-2-yl)-benzylsulfanyl]-2, 3-dihydro- benzofuran-4-yloxy } -acetic'acid; and pharmaceutically acceptable salts thereof.
8. A pharmaceutical composition comprising a compound of Claim 1 admixed with a carrier, diluent, or excipient.
5 9. A method of treating, preventing or controlling non-insulin dependent diabetes mellitus in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Claim 1.
1
10. A method of treating, preventing or controlling obesity jn a mammal o comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Claim 1.
11. A method of modulating leptin levels in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of a 5 compound of Claim 1.
12. A method of treating, preventing or controlling dyslipidemia in a mammal comprising administering to the mammalin need thereof a therapeutically effective amount ;of: a compound of Claim 1., ■ , . .
-13. A method of treating, preventing or -controlling.hypercholesteremia in a mammal comprising administering to the mammal in need thereof a;: -.. therapeutically effective amount of. a compound of Claim 1.. , 14. A method of making a compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising, reacting:
with:
Figure imgf000243_0001
wherein: X° is OH or SH; X1 is absent, O, or S;
Ar'and Ar2 are each independently a unsubstituted or substituted aryl or heteroaryl; '
-- is absent or a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydocarbon-heteroatom chain having from 0 to 3 atoms wherein a four to eight member ring is formed fused to Ar1 and
'1 ,
\
Ar2 wherein if ^-- is absent and either " — " is a bond. then Ar1 is directly bonded to Ar2; R! and R2 are selected from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- -(CH2)pCE3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl, . .' S(O)paryϊ, -(CH2)mOR8, -(CH2)mNR9R10, -COR8, -CO2H, -CO2R8, or - NR R10, or joined together to form a five to eight member ring; R3 and R4 are selected, from hydrogen, lower alkyl, lower alkoxy, haloalkyl,- O-(CH2)pCF3, halogen, nitro, cyano, -OH, -SH, -CF3, -S(O)palkyl,
S(O)paryl, -(CH2)mOR8, -(CH2)mNR9R10, -COR8, -CO2H, -CO2R8, or-
NR9R10; - . ! . . .
R5 and R6 are independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, or joined together to form a 3 to 7 member cycloalkyl or cycloalkenyl; R7 and R8 are independently hydrogen; alkyl, alkenyl, alkyriyl, or aryl;
R9 and R10 are each independently hydrogen, alkyl, alkenyl, alkynyl, - COalkyl, -COaryl, cycloalkyl, -CO2alkyl, -CO2aryl, -SO2alkyl, - S02aryl, or joined together to form a.4 to 7 member ring having 1 to 3 heteroatoms; R11 is a lower alkyl;
X is a halogen; . m is 0 tp 5;. : ; p is 0 to ;- .. . q is 0 to 6; and r is θ to' 6. - ■ •
15. A process for preparing the compound of formula 1-4 which is:
Figure imgf000245_0001
comprising:
(a) conversion of phenol }A to the thiocyante IB;
Thiocyanation
Figure imgf000245_0003
Figure imgf000245_0002
IA : IB
(b) alkylation of phenol moiety of thiocyanate 1 B to acetoxyester
Figure imgf000245_0004
IB IC
(c) reduction of the thiocyanate moiety in lG'toforrh thiol ID;
Figure imgf000246_0001
IC ID
(d) alkylation of thiol ID with chloride 3C to form 4a;
Figure imgf000246_0002
ID 3C 4a ; and
(e) saponification of the ester moiety in 4a to form 1-4; wherein
R1 is hydrogen or together with R2 forms a 5 membered carbocyclic ring;
R2 is methoxy or together with R1 forms a 5 membered carbocyclic ring;
R3 is hydrogen or methyl;
R4 is hydrogen,
"X1 is absent or O; and r is 0 or 1.
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NANTEUIL DE G ET AL: "5-IMIDAZOL-1-YL-1H-BENZIMIDAZOLES INHIBITEURS DE L'INTERLEUKINE-1: UNE NOUVELLE VOIE POUR LE TRAITEMENT DE L'ARTHROSE" L'ACTUALITE CHIMIQUE, SOCIETE CHIMIQUE DE FRANCE, PARIS, FR, July 2000 (2000-07), pages 48-54, XP001147539 ISSN: 0151-9093 *

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