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Definitions

• This invention relates to novel compounds which are thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor ⁇ , to methods of preparing such compounds and to methods for using such compounds such as in the regulation of metabolism.
• thyroid hormone agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
• Thyroid hormones affect the metabolism of virtually every cell of the body. At normal 20 levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, 25 bone loss in post enopausal women, and anxiety.
• LDL serum low density lipoprotein
• Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of 30 thyroid-stimulating hormone (TSH), thyroxine (3,5,3',5'-tetraiodo-L-thyronine, or T 4 ) and triiodothyronine (3,5,3'-triiodo-L-thyronine, or T 3 ).
• TSH thyroid-stimulating hormone
• thyroxine 3,5,3',5'-tetraiodo-L-thyronine, or T 4
• triiodothyronine 3,5,3'-triiodo-L-thyronine, or T 3 .
• replacement therapy particularly in older individuals is limited by certain of the deleterious effects of thyroid hormones.
• thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated.
• These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation.
• Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
• Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes.
• Thyroid hormone receptor agonists that interact selectively with the ⁇ -form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
• TRs Thyroid hormone receptors
• the various receptor forms appear to be products of two different genes, ⁇ and ⁇ . Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene.
• the TRoti, TR ⁇ i and TR ⁇ 2 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TR ⁇ i isoform is the most prevalent form in most tissues, especially in the liver and muscle.
• the TR 2 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor.
• TR ⁇ -selective agonist might not influence the cardiac rhythm and rate, but would elicit many other actions of the hormones. It is believed that the ⁇ -form of the receptor is the major drive of heart rate for the following reasons: (i) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TR ⁇ -forms, and high circulating levels of T 4 and T 3 ; (ii) there was a tachycardia in the only described patient with a double deletion of the TR ⁇ gene (Takeda et al, J. Clin. Endrocrinol & Metab.
• a TR ⁇ -selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart.
• Such a compound may be used for: (i) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (ii) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (iii) obesity; (iv) hypercholesterolemia due to elevations of plasma LDL levels; (v) depression; (vi) osteoporosis in combination with a bone resorption inhibitor.
• Ri is selected from C 6 -i5 aryl; C5-15 heteroaryl; C ⁇ - 20 alkyl; C 2 - 2 o alkenyl; C 2 - 2 o alkynyl; C 3 -i5 cycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl, being optionally substituted with 1, 2 or 3 groups R a which groups may be the same or different, said aryl and heteroaryl being optionally substituted with 1, 2 or 3 groups of R which groups may be the same or different;
• R 2 is selected from hydrogen; halogen; -NO 2 ; -CN; C 6 - ⁇ o aryl; C5-10 heteroaryl; C ⁇ -10 alkyl; C 3 - 8 cycloalkyl; C2-10 alkenyl; C2-10 alkynyl, said alkyl, cycloalkyl, alkenyl, alkynyl optionally substituted with 1, 2 or 3 groups R a which groups may be the same or different, said aryl, heteroaryl optionally substituted with 1, 2 or 3 groups of R b which groups may be the same or different;
• Ri can be linked through the available atoms to position R 2 , thus forming an aza containing C 5 -C 8 heterocyclic ring, saturated or partially unsaturated, and optionally substituted with 1, 2 or 3 groups of R c which groups may be the same or different;
• R 3 and t are independently selected from: halogen; C ⁇ - alkyl; C 3 - 4 cycloalkyl; C 2 - 4 alkenyl; and C 2 - alkynyl, said alkyl, cycloalkyl, alkenyl, alkynyl, or a bioisosteric equivalent thereof and optionally substituted with 1, 2 or 3 groups R d which groups may be the same or different;
• n 1 or 2;
• R5 is independently selected from: carboxylic acid (-CO 2 H); phosphonic acid (-PO(OH) 2 ); phospha ic acid (-PO(OH)NH 2 ); sulphonic acid (-SO 2 OH); hydroxamic acid (-CONHOH); oxamic acid (-NHCOCO2H); malonamic acid (-NHCOCH 2 CO 2 H); acylsulphonamide (-CONHSO2R'); and a carboxylic acid amide (-CONR'R") where the amine portion of the amide is derived either from a L or D ⁇ -amino acid, or from a mixture of L and D ⁇ -aminoacid stereoisomers such that the general structure -CONR'R" can be represented by: o R*
• R* is any of the side chains found in the naturally occuring ⁇ -amino acids, including those examples wherein R' and R* are connected to form 4 to 8-membered rings (such as when R' and R* comprise consecutive -(CH 2 )- groups to form proline or homoproline);
• R a is selected from: hydrogen; halogen; -CN; -CO 2 H; -CHO; -NO 2 ; C 6 - ⁇ o aryl; C5-10 heteroaryl; C1-4 alkoxy; C 2 . 4 alkenoxy; C 2 - alkynoxy; C 6 . ⁇ o aryloxy; C5-10 heteroaryloxy; C1-4 alkylthio; C2-4 alkenylthio; C 2 -4 alkynylthio; C ⁇ -io arylthio; C5-10 heteroarylthio; -N(C W alkyl) 2 ; -NH(d- 6 alkyl); -N(C 2 . 6 alkenyl) 2 ; -NH(C 2 .
• R b is selected from: hydrogen; halogen; -CN; -CO 2 H; -CHO; -NO 2 ; -OH; C w alkyl; C 2 -4 alkenyl; C 2 - 4 alkynyl; C1.4 alkoxy; C 2 - alkenoxy; C 2 .
• R c is selected from: hydrogen; C alkyl; C2-4 alkenyl; C 2 -4 alkynyl or a bioisosteric equivalent;
• R d is selected from: hydrogen; halogen, or a bioisosteric equivalent
• a method for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T 3 regulated gene wherein a compound of formula I is admimstered in a therapeutically effective amount.
• the compound of formula I is preferably an agonist that is preferably selective for the thyroid hormone receptor-beta.
• diseases associated with metabolism dysfunction or are dependent upon the expression of a T 3 regulated gene are set out hereinafter and include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure.
• the present invention relates to compounds useful as thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor ⁇ , and have the general formula I as described above.
• Ri is selected from d-i. aryl, C5-9 heteroaryl, C 3 - ⁇ o alkyl, C 3 . ⁇ o alkenyl or C 3 - ⁇ 0 alkynyl or C 3 - ⁇ o cycloalkyl;
• R2 is selected from hydrogen, halogen or C1-2 alkyl;
• R 3 and t is selected from chlorine;
• R 5 is -CO 2 H;
• R a is hydrogen, halogen, -CO 2 H, C 6 aryl, -N(C ⁇ - 4 alkyl) 2 ;
• R b is hydrogen, halogen, -CO 2 H, C1-4 alkoxy, -N(C ⁇ - 4 alkyl) 2 ;
• n is 1 or 2; and the Q variable kept as described in Claim 1.
• Compounds of the invention include, but are not limited to, the following:
• Another embodiment of the present invention is a method for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T 3 regulated gene is provided, wherein a compound of formula I is administered in a therapeutically effective amount.
• the compound of formula I is preferably an agonist that is preferably selective for the thyroid hormone receptor-beta.
• diseases associated with metabolism dysfunction or are dependent upon the expression of a T 3 regulated gene are set out hereinafter and include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure.
• Yet another embodiment of the present invention is a method for preventing, inhibiting or treating skin disorders or diseases involving dermal atrophy such as glucocorticoid induced dermal atrophy, including restoration of dermal atrophy induced by topical glucocorticoids, the prevention of dermal atrophy induced by topical glucocorticoids (such as the simultaneous treatment with topical glucocorticoid or a pharmacological product including both glucocorticoid and a compound of the invention), the restoration/prevention of dermal atrophy induced by systemic treatment with glucocorticoids, restoration/prevention of atrophy in the respiratory system induced by local treatment with glucocorticoids, UV-induced dermal atrophy, or dermal atrophy induced by aging (wrinkles, etc.), wound healing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier's disease,
• Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
• exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the for the treatment of a disease or disorder which is dependent on the expression of a T 3 regulated gene or is associated with metabolic dysfunction. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the for the treatment of obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiac arrhythmia, congestive heart failure, or skin disorders.
• Said skin disease or disorder could be dermal atrophy such as glucocorticoid induced dermal atrophy, including restoration of dermal atrophy induced by topical glucocorticoids, the prevention of dermal atrophy induced by topical glucocorticoids (such as the simultaneous treatment with topical glucocorticoid or a pharmacological product including both glucocorticoid and a compound of the invention), the restoration/prevention of dermal atrophy induced by systemic treatment with glucocorticoids, restoration/prevention of atrophy in the respiratory system induced by local treatment with glucocorticoids, UV-induced dermal atrophy, or dermal atrophy induced by aging (wrinkles, etc.), wound healing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichty
• thyroid receptor ligand as used herein is intended to cover any chemical substance which binds to a thyroid receptor.
• the ligand may act as an antagonist, an agonist, a partial antagonist or a partial agonist.
• alkyl refers to acyclic straight or branched chain radical, containing 1 to 20 carbons, preferable 1 to 10 carbons in the normal chain, i.e. methyl, ethyl, propyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl.
• Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkane, cycloalkene, aryl or heteroaryl ring, preferable 5 or 6 membered rings, saturated or unsaturated, as exemplified below: — (CH 2 ) W ⁇ _ (CH 2 )— and — (CH 2 ) ⁇ - o ⁇ - ⁇ -j-(CH 2 ) y —
• alkyl portions can be attached at any variable point of attachement to the 5 or 6 membered ring.
• Alkyl also includes a straight or branched alkyl chain which is terminated at one, two or three points of substitution by a cycloalkane, cycloalkene, aryl or heteroaryl ring, preferable 5 or 6 membered rings, saturated or unsaturated, as exemplified below:
• substituted alkyl this refers to a straight or branched alkyl group, including a chain interrupted or terminated by a ring, as defined above, substituted with 1-3 groups of R a , which groups may be the same or different at any available point, including above defined rings, as defined with respect to each variable.
• alkenyl as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons and at least one carbon to carbon double bond. Preferably one to two carbon-to-carbon double bonds is present, and up to 5 carbon-to-carbon bonds may be present. Preferable 2 to 10 carbons are present in the normal chain radical, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, decenyl, dodecenyl and the like.
• the straight or branched portion of the alkenyl group may be interrupted or terminated by a ring and optionally substituted by 1 to 3 R a which groups may be the same or different when a substituted alkenyl group is provided.
• alkynyl refers to straight or branched chain radicals of 2 to 20 carbons with at least one carbon-to-carbon triple bond.
• one carbon-to-carbon triple bond is present, and up to 5 carbon-to-carbon triple bonds may be present.
• 2 to 10 carbons are present in the normal chain, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, decynyl, dodecynyl and the like.
• the straight or branched portion of the alkynyl group may be interrupted or terminated by a ring and optionally substituted by 1 to 3 groups of R a which groups may be the same or different when a substituted alkynyl group is provided.
• cycloalkyl as employed herein alone or as part of another group refers to saturated cyclic hydrocarbon groups or partially unsaturated cyclic hydrocarbon groups, independently containing 1 to 2 carbon to carbon double bonds or carbon to carbon triple bonds.
• the cyclic hydrocarbon contain 3 to 15 carbons, including rings that are fused. It should also be understood that the present invention also involve cycloalkyl rings where 1 to 2 carbons in the ring are replaced by either -O-, -S- or -N-, thus forming a saturated or partially saturated heterocycle.
• heterocyclic rings are piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine, oxazolidine, thiazolidine, tetrahydrofurane, tetrahydrothiophene and the like.
• Preferred heterocyclic rings are 5- or 6-membered, which may be optionally substituted by 1 to 3 groups of R a which groups may be the same or different through available carbons as in the case of "alkyl".
• Preferred cycloalkyl groups include 3 to 7 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, which may be optionally substituted by 1 to 3 groups of R a which groups may be the same or different through available carbons as in the case of "alkyl".
• aryl as employed herein alone or as part of another group refers to monocyclic, bicyclic and tricyclic aromatic groups, consisting of 6 to 15 carbons in the ring portion, including partially saturated rings as indanyl and tetrahydronaphthyl.
• the preferred aryl groups are phenyl and naphthyl, which may be substituted with 1 to 3 groups selected from R b which groups may be the same or different.
• halogen refers to fluorine, chlorine, bromine and iodine.
• R 2 is selected from alkyl, and is substituted with 1-3 groups of R b which groups may be the same or different, the preferred substitution include fluorine, thus forming substituents such as -CF 3 and -CHF 2 .
• alkoxy refers to those groups of the designated carbon length in either a straight or branched configuration attached through an oxygen linkage and if two or more carbons in length, they may incude a double or a triple bond.
• alkoxy groups are methoxy, ethoxy, propoxy, allyloxy, propargyloxy, butoxy, isobutoxy, tertiary butoxy, and the like.
• thio refers to a carbon-sulphur-carbon bond and may also include higher oxidation states of sulphur, such as sulfoxides -SO- and sulphones -SO 2 -.
• heteroaryl or as used herein alone or as a part of another group refers to a group containing 5 to 15 atoms, where the aromatic ring includes 1, 2, 3 or 4 heteroatoms, as nitrogen, oxygen or sulfur. Such rings may be fused to another aryl or heteroaryl ring, and includes possible N-oxides.
• the heteroaryl group may optionally be substituted by the available carbons with 1 to 3 substituents of R b which groups may be the same or different.
• Ri and R a is selected from heterocycles it refers to mainly to 5 to 9 membered rings, including fused rings thereof.
• phosphonic acid and "phosphamic acid” refers to a phosphorus containing group of the structures:
• R'" and R" are independently selected from hydrogen, C M alkyl, C 2 . alkenyl, or C 2 . alkynyl.
• bioisosteric equivalent refers to compounds or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical and biological properties. Examples of such equivalents are: (i) fluorine vs. hydrogen, (ii) oxo vs. thia, (iii) hydroxyl vs. amide, (iv) carbonyl vs. oxime, (v) carboxylate vs. tetrazole.
• the compounds of formula I can be present as salts, in particular "pharmaceutically acceptable salts".
• a compound having at least one acid group can form salts with bases.
• Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or trilower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine.
• metal salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts
• salts with ammonia or an organic amine such as morpholine,
• Corresponding internal salts may furthermore be formed.
• Preferred salts of the compounds of formula I include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
• the compounds of formula I having at least one basic center (for example -NH- in piperidine) can also form acid addition salts.
• acetic acid such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C ⁇ -C 4 ) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid
• Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
• Preferred salts of the compounds of formula I which include an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
• Preferred salts of the compounds of formula I which include a basic groups include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
• An acid center (for example -COOH) part in formula I can form "prodrug ester forms" known in the art such as pivaloyloxymethyl or dioxolenylmethyl.
• prodrug esters are described in standard references such as Chapter 31, written by Camille G. Wermuth et al., in "The Practice of Medicinal Chemistry", ed. C. G. Wermuth, Academic Press, 1996 (and the references contained therein).
• Certain compounds of the invention can be "stereoisomers", which have one or more asymmetric centers and can exist in the form of racemates, single enantiomers, as individual diastereomers, with all possible isomers, and mixtures thereof, all of which are within the scope of the invention.
• the compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. With respect to the reaction scheme below, although the various Ri, R 2 , R 3 , Rt, Rs,R a , R b , R c , R d and n moieties sometimes are specifically defined, unless otherwise indicated, it is to be understood that Ri, R 2 , R 3 , Rt, Rs, R ⁇ R b , R c , R d may be any of the groups encompassed thereby and n may be 0, 1, 2, or 3.
• Scheme 1 outlines a synthetic route which leads to the preparation of the intermediate aniline derivative 6, including several other key intermediates, used in the invention.
• Alternative synthetic routes to these compounds can be visualized by any person skilled in the art and the present synthetic route is not limiting for the invention.
• the synthetic route starts as depicted below, when a mixture of the appropriate phenol 2 and arylfluoride 1 is heated at reflux in a solvent as dimethyl- formamide, and in the presence of copper bronze and a base such as potassium carbonate.
• Other combinations of phenols, aryl halides, bases and solvents can be appropriate and are well known for those skilled in the art.
• the reaction mixture is purified by standard extraction procedures and recrystallization, to give biaryl ether 3 as an end product.
• the intermediate nitro product 6 is reduced by hydrogenation at 1-2 atmospheres of hydrogen in the presence of a catalyst such as platinum(II) oxide in an inert solvent such as ethylacetate at room temperature.
• a catalyst such as platinum(II) oxide
• an inert solvent such as ethylacetate
• Standard work-up and purification yields the desired aniline product 7.
• Other combinations of catalysts, solvent and hydrogen pressure, alternatively transfer hydrogenation, may be employed and are evident for those skilled in the art. But, with more active catalysts such as palladium on graphite, with increased pressures of hydrogen and/or higher temperatures, there is an increased risk of dehalogenation during catalytic hydrogenation.
• R 2 -substituted phenoxy amides of formula I can be obtained from intermediate 7 in Scheme 2.
• it can be regioselectively ⁇ rt/zo-brominated by for example 2,4,4,6-tetrabromo-2,5-cyclohexadienone to give 10.
• Numerous other methodologies for bromination of aromatics to give the corresponding aryl bromide are well known to those skilled in the art.
• Amides can also be prepared by parallel solution phase synthesis to give the end products 9 and 12.
• a coupling reagent such as 3-ethyl-l-[3-(dimethylamino)propyl]carbodiimide hydrochloride, a base such as 1-hydroxybenzotriazole hydrate and an inert solvent as dichloromethane is loaded in separate vessels.
• the amine 7 or 10 is added, the reaction mixture heated and the methyl ester function removed as described above to give the amide end-products (Examples 33, 37-47, 49, 52, 54, 57-61, 66-72).
• benzotriazole-1-yl- oxy-tris- pyrrolidino phosphonium hexafluorophosphate is added to the reaction vessel after 18 hours (Example 48, 50-51, 53, 62-65, 73-74).
• Scheme 3 shows how a R 2 -substituent can be present prior the formation of the biaryl ether.
• Standard coupling procedures as described above, might involve any substitution at the R 2 -position.
• intermediate 15 is coupled with intermediate 16 to give biaryether 17.
• amide 8 can be substituted at the R 2 -position by aromatic electrophilic substitution, using any one of the methods described in for example "Advanced Organic Chemistry", 4th edition, Jerry March, Wiley-Interscience publication, 1992, p 521-568, including references cited therein.
• 8 is regioselectively ortbo-chlorinated by tert-butyl hypochorite. Standard hydrolysis, as described above, gives the end product 19.
• a library of sulphonamides can also be prepared by parallel solution phase synthesis (Examples 34, 55-56, 75-80).
• the appropriate sulfonyl chloride, a base such as pyridine and an inert solvent as dichloromethane is loaded in separate vessels.
• the amine 7 is added, the reaction mixture heated and the methyl ester function removed as described above to give the sulphonamide end-products 20.
• Examples of compounds of formula I in which R5 is an amide produced by coupling to an amino acid are shown in Scheme 7.
• the following procedure involve the coupling of an acetic acid derivative such as 9 or 12, with protected amino acids, to afford after any necessary protecting removal the corresponding amides 22.
• a mixture of compound 9, a coupling reagent such as 3-ethyl-l-[3-(dimethylamino)- propyljcarbodiimide hydrochloride, and a base such as 1-hydroxybenzotriazole hydrate in dimethylformamide is stirred at room temperature.
• the appropriate protected amino acid and triethylamine is added.
• reaction mixture yields after work-up and purification by either chromatography or recrystallization the corresponding coupled material, which after the removal of protecting groups, gives the desired final amide products 22 (Example 9-14).
• R' groups in the examples should not be seen as limiting, but may also be any of the side chains found in the naturally occuring alpha-amino acids and their analogs. Numerous other related methodologies exist for the coupling of amino acids with aromatic, as well as non-aromatic, carboxylic acids in solution or solid phase and are known to those skilled in the art.
• Reaction of diaryl ether 3 with an acrylate ester such as ethyl acrylate, using palladium acetate, triphenyl phosphine and triethylamine in a solvent such as acetonitrile with heating at elevated temperatures gives a cinnamate ester product 23.
• the double bond can be reduced to the saturated analogue 26, alternatively ortb ⁇ -brominated by the methods descibed previously.
• alkenyl carboxylic acid 25 and propionic acid 27 is obtained (Example 22-28).
• a coupling reagent such as
• All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
• the compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof.
• the process for separation can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, for example, by chromatographic means or by fractional crystallization.
• the compounds of the invention are agonists, that preferably may be selective for the thyroid hormone receptor-beta, and as such are useful in the treatment of obesity, hypercholesterolemia and atherosclerosis by lowering of serum LDL levels, alone or in combination with a lipid modulating drug such as an HMG-CoA reductase inhibitor, fibrate, thiazolidinedione, or MTP inhibitor, amelioration of depression alone or in combination with an antidepressant, and stimulation of bone formation to treat osteoporosis in combination with any known bone resorption inhibitor such as alendronate sodium.
• a lipid modulating drug such as an HMG-CoA reductase inhibitor, fibrate, thiazolidinedione, or MTP inhibitor
• the compounds of the invention may be useful as replacement therapy in elderly patients with hypothyroidism or subclinical hypothyroidism who are at risk for cardiovascular complications, in the treatment of the elderly to provide a sense of well-being, and in the treatment of non-toxic goiter; in the management of papillary or follicular thyroid cancer (alone or with T ); in the treatment of skin disorders such as psoriasis, glaucoma, cardiovascular disease such as in the prevention or treatment of atherosclerosis, and congestive heart failure.
• the compounds of the invention may be employed alone or in combination with an appetite suppressant such as sibutramine, and/or in combination with anti-obesity agents such as orlistat, and/or in combination with a b3 agonist, for treating obesity.
• an appetite suppressant such as sibutramine
• anti-obesity agents such as orlistat
• a b3 agonist for treating obesity.
• the compounds of the invention may also be used to treat skin disorders or diseases involving dermal atrophy such as glucocorticoid induced dermal atrophy, including restoration of dermal atrophy induced by topical glucocorticoids, the prevention of dermal atrophy induced by topical glucocorticoids (such as the simultaneous treatment with topical glucocorticoid or a pharmacological product including both glucocorticoid and a compound of the invention), the restoration/prevention of dermal atrophy induced by systemic treatment with glucocorticoids, restoration/prevention of atrophy in the respiratory system induced by local treatment with glucocorticoids, UV-induced dermal atrophy, or dermal atrophy induced by aging (wrinkles, etc.), wound healing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier's disease, eczema, a
• the compounds of the invention may be used alone or optionally in combination with a retinoid such as tretinoin or a vitamin D analog, employing amounts as disclosed in the PDR.
• a retinoid such as tretinoin or a vitamin D analog
• hypolipidemic agent which may be optionally employed in combination with the compounds of formula I of the invention may include thiazolidinediones, MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibric acid derivatives, ACAT inhibitors, cholesterol absorption inhibitors, ileal NaVbile acid cotransporter inhibitors, bile acid sequestrants, and/or nicotinic acid and derivatives thereof.
• MTP inhibitors employed herein include MTP inhibitors disclosed in U.S. Patent No. 5,595,872, U.S. Patent No. 5,739,135, U.S. Patent No. 5,712,279, U.S. Patent No. 5,760,246, U.S. Patent No. 5,827,875, U.S. Patent No. 5,885,983 and U.S. Application Serial No. 09/175,180 filed October 20, 1998, now U.S. Patent No. 5,962,440. Preferred are each of the preferred MTP inhibitors disclosed in each of the above patents and applications.
• MTP inhibitors to be employed in accordance with the present invention include preferred MTP inhibitors as set out in U.S. Patent Nos. 5,739,135 and 5,712,279, and U.S. Patent No. 5,760,246.
• the most preferred MTP inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• the hypolipidemic agent may be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
• HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S.
• keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No.0,142,146 A2, as well as other known HMG CoA reductase inhibitors.
• phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
• the squalene synthetase inhibitors suitable for use herein include, but are not limited to, a-phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates as well as other squalene synthetase inhibitors as disclosed in U.S. Patent No. 4,871,721 and 4,924,024 and in Biller, S.A., Neuenschwander, K., Ponpipom, M.M., and Poulter, CD., Current Pharmaceutical Design, 2, 1-40 (1996).
• squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the famesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc, 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R.W. et al, J.A.C.S., 1987, 109, 5544 and cyclopropanes reported by Capson, T.L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
• hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No.
• bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (Secholex®, policexide®), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin
• the other hypolipidemic agent may be an ACAT inhibitor such as disclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB 100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev.
• the hypolipidemic agent may be a cholesterol absorption inhibitor preferably
• the hypolipidemic agent may be an ileal Na + /bile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).
• Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin.
• the compounds of formula I of the invention will be employed in a weight ratio to the hypolypidemic agent, the antidepressant, and/or bone resorption inhibitor and/or appetite suppressant (where present), within the range from about 500: 1 to about 0.005:1, preferably from about 300:1 to about 0.01:1.
• the antidiabetic agent which may be optionally employed in combination with compounds of formula I of the invention may include biguanides, sulfonyl ureas, glucosidase inhibitors, thiazolidinediones and/or aP2 inhibitors and/or PPAR a agonists, PPAR g agonists or PPAR a/ g dual agonists, and/or SGLT2 inhibitors, or meglitinide.
• the antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof.
• the compounds of structure I will be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1.
• the antidiabetic agent may also preferably be a sulfonylurea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Patent No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the b-cells, with glyburide and glipizide being preferred.
• the compounds of structure I will be employed in a weight ratio to the sulfonyl urea in the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.
• the oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No. 4,904,769) or miglitol (disclosed in U.S. Patent No. 4,639,436), which may be administered in a separate oral dosage form.
• acarbose disclosed in U.S. Patent No. 4,904,769
• miglitol disclosed in U.S. Patent No. 4,639,436
• the compounds of structure I will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
• the compounds of structure I may be employed in combination with a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Lambert's Rezulin®, disclosed in U.S. Patent No. 4,572,912), rosightazone (SEIB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Patent No. 5,594,016), Glaxo-Welcome's GI-262570, englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer).
• a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers which has an insulin sensitivity effect in NIDDM patients
• insulin sensitizers which has an insulin sensitivity effect in NIDDM patients
• the compounds of structure I will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
• the sulfonylurea and thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with the compounds of structure I.
• the compounds of structure I may also be employed in combination with a non-oral antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-l(l-36) amide, GLP-l(7-36) amide, GLP-l(7-37) (as disclosed in U.S. Patent No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), which may be administered via injection, intranasal, or by transdermal or buccal devices.
• GLP-1 glucagon-like peptide-1
• metformin the sulfonylureas, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and the glucosidase inhibitors acarbose or miglitol or insulin may be employed in formulations as described above and in amounts and dosing as indicated in the Physician's Desk Reference.
• metformin or salt thereof may be employed in amounts within the range from about 500 to about 2000 mg per day which may be administered in single or divided doses one to four times daily.
• the thiazolidinedione anti-diabetic agent may be employed in amounts within the range from about 0.01 to about 2000 mg/day which may be administered in single or divided doses one to four times per day.
• insulin may be employed in formulations, amounts and dosing as indicated by the Physician's Desk Reference.
• GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Patent Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.
• the antidiabetic agent may also be a PPAR a/ g dual agonist such as disclosed by Murakami et al, "A Novel Insulin Sensitizer Acts As a Coligand for Peroxisome
• PPAR alpha Proliferation - Activated Receptor Alpha
• PPAR gamma Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats", Diabetes 47, 1841-1847 (1998).
• the antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S. application Serial No. 09/391,053, filed September 7, 1999, and U.S. provisional application No. 60/127,745, filed April 5, 1999 (attorney file LA27*), employing dosages as set out herein.
• the antidiabetic agent may be an SGLT2 inhibitor such as disclosed in U.S. provisional application 60/158,773 filed October 12, 1999 (Attorney file LA0049*).
• the compounds of formula I will be employed in a weight ratio to the PPAR a agonist, PPAR g agonist, PPAR g/a dual agonists, SGLT2 inhibitor and/or aP2 inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
• the dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
• hypolipidemic agent and antidiabetic agent will be as disclosed in the various patents and applications discussed above and in the PDR.
• the MTP inhibitor for oral administration, a satisfactory result may be obtained employing the MTP inhibitor in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg, one to four times daily.
• a preferred oral dosage form such as tablets or capsules, will contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg, one to four times daily.
• the MTP inhibitor will be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg kg and preferably from about 0.005 mg/kg to about 8 mg/kg, one to four times daily.
• an HMG CoA reductase inhibitor for example, pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin in dosages employed as indicated in the Physician's Desk Reference, such as in an amount within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
• the squalene synthetase inhibitor may be employed in dosages in an amount within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
• a preferred oral dosage form such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
• a preferred oral dosage form such as tablets or capsules will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
• the compounds of formula I and the hypolipidemic agent, antidepressant or bone resorption inhibitor may be employed together in the same oral dosage form or in separate oral dosage forms taken at the same time.
• compositions described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
• the preferred hypolipidemic agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.
• the compounds of the invention can be administered orally or parenterally such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.
• the active substance can be utilized in a composition such as tablet, capsule, ointment, hydrophilic ointment, cream, lotion, solution or suspension or in other type carrier materials such as transdermal devices, iontophoretic devices, rectal suppositories, inhalant devices and the like.
• the composition or carrier will contain about 5 to about 500 mg per unit of dosage of a compound of formula I. They may be compounded conventional matter with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice.
• Methyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) acetate was coupled with crotonyl chloride (35 mg), using the method described in Example 1 (h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1 :2), 60 mg (47 %) ofmethyl(3,5-dichloro-4-[3-bromo-4-(3-methylcrotonoyIamido)phenoxy]phenyl) acetate was obtained.
• ester (19 mg) was hydrolysed using the method described in Example l(i), to give 15 mg (82 %) of 3,5-dichloro-4-(3-bromo-4-[3-methylcrotonylamido]- phenoxy)phenylacetic acid.
• Methyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) acetate (110 mg) was coupled with acetyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether), 110 mg (100 %) of methyl [3,5-dichloro-4-(4-acetamido-3-bromophenoxy)phenyl] acetate was obtained.
• Methyl[3,5-dichloro-4-(4-acetamido-3-bromophenoxy)phenyl] acetate (100 mg) was coupled with r ⁇ -tributylphenyltin (140 mg, 0.38 mmol), using the same procedure as described in Example 3(a). This gave 70 mg (70 %) of methyl(3,5-dichloro-4-[4-acetamido- 3-phenylphenoxy]phenyl) acetate.
• ester 50 mg was hydrolysed using the method described in Example l(i), to give 45 mg (95 %) of 3,5-dichloro-4-(4-acetamido- 3-phenyl ⁇ henoxy)phenylacetic acid, m/z 430.
• N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine The ester was hydrolyzed using the method described in Example l(i) and purified as above, to give 25 mg (31%) of N-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetyl]glycine, m/z 439.
• Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (60 mg) was reacted with trifluoroacetic acid anhydride (42 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1 :9), 70 mg (93 %) ofmethyl(3,5-dichloro-4-[3-bromo-4-trifluoroacetamidophenoxy]phenyl) acetate was obtained, which was hydrolysed using the method described in Example l(i)..This gave 50 mg (73 %) of 3,5-dichloro-4-(3-bromo-4-trifluoroacetamido- phenoxy)phenylacetic acid.
• Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (60 mg) was coupled with -fluorobenzoyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1 :9), 80 mg (100 %) of methyl(3,5-dichloro-4-[3-bromo-4- -fluorobenzamido- phenoxyjphenyl) acetate was obtained, which was hydrolysed using the method described in Example l(i). This gave 50 mg (65 %) of 3 J 5-dichloro-4-(3-bromo-4- ⁇ -fluorobenzamidophenoxy)phenylacetic acid.
• reaction mixture was concentrated and purified on column (silica gel, ethyl acetate/petrolium ether, 5:95), to give 0.70 g of 3,5-dichloro-4-(4-nitro-3-trifluoro- methylphenoxy)trimetylsilylacetylenebenzene.
• Example 23 3,5-Dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylcinnamic acid
• Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) cinnamate (70 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h).
• Example 25 3,5-Dichloro-4-(3-bromo- 4- .-fluorobenzamidopheno ⁇ y)phenylpropionic acid
• Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate 70 mg was coupled with -fluorobenzoyl chloride (35 mg), using the method described in Example 1(h).
• 80 mg of ethyl(3,5-dichloro-4-[3- bromo-4-p-fluorobenzamidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example l(i). This gave 60 mg of 3,5-dichloro- 4-(3-bromo-4-p-fluorobenzamidophenoxy)phenylpropionic acid.
• Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) propionate (80 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 90 mg of ethyl(3,5-dichloro-4-[3-bromo-4-(2-chloropropionamido)phenoxy]- phenyl) propionate was obtained, which was hydrolysed using the method described in Example l(i). This gave 30 mg of 3,5-dichloro-4-(3-bromo-4-[2-chloropropionamido]phenoxy)phenylpropionic acid.
• Ethyl(3,5-dichloro-4-[4-aminophenoxy]phenyl) propionate (80 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After recrystallization (ethyl acetate/petrolium ether), 80 mg of ethyl(3,5-dichloro-4-[4-isobutyr- amidophenoxy] ⁇ henyl) propionate was obtained, which was hydrolysed using the method described in Example l(i). This gave 50 mg of 3,5-dichloro-4-(4-isobutyramidophenoxy)- phenylpropionic acid, m/z 382.
• Example 28 3,5-DicMoro-4-(4-[2-chloropropionamido]phenoxy)phenylcinnamic acid
• Stannic chloride 50 mg was added to a stirred mixture of ethyl(3,5-dichloro-4- [4-aminophenoxy]phenyl) cinnamate (0.10 g), triethylamine (40 mg), dichloromethane (5 mL) and 2-chloropropionyl chloride (50 mg). The reaction mixture was heated at reflux for 16 hours.
• Method A The appropriate carboxylic acids (3 equivalents) were placed in separate reaction vessels. To each reaction vessel was added a solution consisting of 1 -hydroxybenzo- triazole hydrate (1.7 equivalents),
• Method B In analogy with Method A, but after 18 hours benzotriazole-1-yl-oxy- tris-pyrrolidino phosphonium hexafluorophosphate (1.1 equivalents) in dichloromethane (0.5 mL) was added to each vessel.
• Method C The appropriate sulfonyl chloride (3.0 equivalents) were placed in separate reaction vessels. To each reaction vessel was added pyridine (1 mL) in dichloromethane (0.5 mL). A solution of Example 1(f) or the methyl ester of Example 2 in dichloromethane (1 mL) was added to each reaction vessel, the vessels were sealed and stirred under Argon at 40°C for 18 hours.
• Method D The appropriate isocyanate (1.5 equivalents) in dichloromethane (1.0 mL) were placed in separate reaction vessels. A solution of Example 1(f) in dichloromethane (1 mL) was added to each reaction vessel, the vessels were sealed and stirred under Argon at 40°C for 18 hours
• reaction mixture was allowed to cool down to room temperature and poured into an aqueous solution of hydrochloric acid (IN).
• the aqueous layer was extracted with ethyl acetate, and the combined organic layers was washed with water, dried over MgSO 4 , filtered, and concentrated at reduced pressure.
• the residue was purified on column (silica gel, gradient: from n-heptane/ethyl acetate 1:9 to n-heptane/ethyl acetate 3:7) to give 16 mg ofmethyl ⁇ 3,5-dichloro-4-[3-((E)-2-carboxyvinyl)- 4-isobutyramidophenoxy]phenyl ⁇ acetate, m/z 494.
• the aqueous layer was extracted with ethyl acetate, and the combined organic layers was washed with water, dried over MgSO 4 , filtered, and concentrated at reduced pressure to give 3.2 mg (35 %) of 3,5-dichloro-4-[3-((E)-2-carboxyvinyl)-4-isobutyr- amidophenoxy]phenylacetic acid, m z 452.
• the compounds of Examples 1-81 exhibit binding affinities to the thyroid receptor beta in the range of IC 50 of 0.2 to 10000 nM.

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