MXPA01006482A

MXPA01006482A - Novel thyroid receptor ligands and method ii

Info

Publication number: MXPA01006482A
Application number: MXPA/A/2001/006482A
Authority: MX
Inventors: Jon Hangeland; Minsheng Zhang; Yolanda Caringal; Denis Ryono; Yilin Li; Johan Malm; Ye Liu; Neeraj Garg; Chris Litten; Collazo Ana Maria Garcia; Konrad Koehler
Original assignee: Bristolmyers Squibb Company; Karo Bio Ab
Priority date: 1998-12-24
Filing date: 2001-06-22
Publication date: 2001-12-13

Abstract

New thyroid receptor ligands are provided which have general formula (I) in which:n is an integer from 0 to 4;R1 is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons;R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at least one of R2 and R3 being other than hydrogen;R4 is a carboxylic acid amide (CONR'R'') or an acylsulphonamide (CONHSO2R') derivative, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof;or when n is equal to or greater than one, R4 may be a heteroaromatic moiety which may be substituted or unsubstituted, or an amine (NR'R''). R5 is hydrogen or an acyl (such as acetyl or benzoyl) or other group capable of bioconversion to generate the free phenol structure (wherein R5=H). In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T3 regulated gene, wherein a compound as described above is administered in a therapeutically effective amount. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T3 regulated gene include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma, congestive heart failure and skin disorders.

Description

LIGANDOS OF NOVEDOUS THYROID RECEPTORS AND METHOD II FIELD OF THE INVENTION This invention relates to novel compounds that are thyroid receptor ligands, and are preferably selective for the receptor. of thyroid hormone, to the methods of preparation of these compounds and to the methods of using such compounds as in the regulation of metabolism.

BACKGROUND OF THE INVENTION Although the extensive function of thyroid hormones in the regulation of metabolism in humans is well recognized, the discovery and development of new specific drugs to improve the treatment of hyperthyroidism and hypothyroidism has been slow. This fact has also limited the development of thyroid hormone agonists and antagonists for the treatment of other important clinical indications such as hypercholesterolemia, obesity and cardiac arrhythmias. Thyroid hormones affect the metabolism of almost every cell in the body. In normal concentrations, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence concentrations of Low density lipoprotein (LDL) in serum. Thus, in hypothyroidism there is an increase in weight, high concentrations of LDL cholesterol and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, reduced serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in post-menopausal women and anxiety. Currently, thyroid hormones are used primarily as replacement therapy for patients with hypothyroidism. The treatment with L-thyroxine returns the metabolic functions to their normal state and can easily be controlled with normal serum measurements of the concentrations of the thyroid stimulating hormone (TSH), thyroxine (3, 5, 3 ', 5'- tetraiodine-L-thyronine or T4) and triiodothyronine (3,5,3'-triiodo-L-thyronine or T3). However, replacement therapy, particularly in older adults, is limited by certain detrimental effects of thyroid hormones. In addition, some effects of thyroid hormones may be useful therapeutically in disorders that do not belong to the thyroid if it is possible to minimize or eliminate the adverse effects. These potentially useful influences include weight reduction, reduction of LDL concentrations in serum, reduction of depression and stimulation for bone formation. Previous attempts to use thyroid hormones and pharmacologically treat these disorders have been limited by manifestations of hypertension and, in particular, by cardiovascular toxicity. The development of selective and selective thyroid hormone receptor agonists can lead to specific treatments for these common disorders while avoiding cardiovascular toxicities and other natural thyroid hormones. Tissue-selective thyroid hormone agonists can be obtained by selective tissue uptake or expulsion, topical or local delivery, choice of cells through other ligands attached to the agonist, and choice of receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the β-form of the thyroid hormone receptor offer an especially attractive method of avoiding cardiotoxicity. The thyroid hormone (TR) receptors are, like other nuclear receptors, individual polypeptide chains. The different receptor forms appear to be pdducts of two different genes a and ß. Other The differences in the isoform are due to the fact that the differential processing of RNA originates at least two isoforms for each gene. The isoforms TRcti, TRßx and TRß2 bind to the thyroid hormone and act as transcription factors regulated by the ligand. In adults, isofo :: ma TRßi is the most prevalent form in most tissues, especially in the liver and muscle. The TRa2 isoform is prevalent in the pituitary gland and other parts of the central nervous system, does not bind to thyroid hormones, and acts in many contexts as a transcriptional repressor. The TROTI isoform is also widely distributed, although its levels are usually lower than those of the TRβ isoform. This isoform may be especially important for development. Although multiple mutations have been found in the TRβ gene and have given rise to the syndrome of generalized resistance to thyroid hormone, no mutations have been found that give rise to the damaged function of TRa. An increasing amount of data suggests that many or most of the effects of thyroid hormones on the heart, and in particular, on heart rate and frequency, are mediated by the a form of the TRoii isoform, while most of the Hormone actions such as in liver, muscle and other tissues are mediated further through the ß forms of the receptor. A) Yes thus, a selective TRβ agonist may not elucidate influences on the rhythm and heart rate of the hormones but elucidate many other actions of the hormones. It is considered that the a-form of the receptor is the largest driver of the heart rate for the following reasons: 1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRß forms, and high levels circulating T and T3 2) there was a tachycardia in the only patient described with a double lesion of the TRβ gene (Takeda et al., J. Clin Endocrinol. &Metab. 1992, vol 74, p.49) 2) a TRa double knockout gene (but not the ß gene) in the mouse had a slower pulse than the control mouse, and 4) the western blot analysis of the human myocardial TR shows the presence of TRai, TR 2 and If these indications are correct, then it would be possible to use a selective TRβ agonist to mimic a number of actions of the thyroid hormone, while having a lesser effect on the heart. Such compound can be used for: (1) replacement therapy in elderly individuals with hypothyroidism who are at risk of complications cardiovascular; (2) replacement therapy in elderly individuals with subclinical hypothyroidism who are at risk of cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL concentrations; (5) depression; and (6) osteoporosis in combination with an inhibitor of bone resorption.

DESCRIPTION OF THE INVENTION According to the present invention, the compounds that are thyroid receptor ligands are provided, and have the general formula I: wherein: n is an integer from 0 to 4 Ri is halogen, trifluoromethyl or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to carbons, at least one of R2 or R3 being different from hydrogen R3 is a heteroaromatic portion that may be substituted or unsubstituted and is linked to (CH2) n by a nitrogen atom or a carbon atom; an amine (NR'R "), including those in which the amine is derived from an alpha amino acid of natural (L) or non-natural stereochemistry (D), an acyl sulfonamide (CONHS02R ') or a carboxylic acid amide (CONR'R) ") in which the amine portion of the carboxylic amide can come from an achiral alpha amino acid or L or D as it can be when the general structure -CONR'R" can be represented by: and R ', R ", R"', and R "" are the same or different and are independently selected from hydrogen, alkyl, aryl and heteroaryl, substituted or unsubstituted and R * may be hydrogen, alkyl, aryl and heteroaryl, substituted or unsubstituted, and may also be any of the side chains found in the alpha amino acids that occur in nature and their analogs, including those examples where R 'and R * are connected to form rings of 4 to 8 members (as it may be when R 'and R * comprises - (CH2) -consecitive groups to form proline or homoproline); and with the proviso that when n is equal to zero (n = 0), then R 4 can only be a carboxylic acid amide or an acylsulfonamide. R5 is hydrogen or an acyl group (such as cetyl or benzoyl) or another group capable of bioconversion to generate the free phenol structure (wherein R5 = H) including all the stereoisomers thereof, the esters of the prodrugs thereof and the acceptable salts for pharmaceutical use of these. Furthermore, according to the present invention, there is provided a method for the prevention, inhibition or treatment of a disease associated with metabolic dysfunction or that is pending the expression of a gene regulated by T3, wherein a compound of the Formula I in an effective amount for therapeutic use. The compound of formula I is preferably an agonist which is preferably selective for the β-receptor for thyroid hormone. Examples of these diseases associated with metabolic dysfunction or that are pending the expression of a gene regulated by T3 are set forth below and include: obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure.

DETAILED DESCRIPTION OF THE INVENTION The following definitions apply to terms as used throughout this specification, unless otherwise limited in specific cases. The term "thyroid receptor ligand" as used herein is intended to cover any portion that binds to a thyroid receptor. The ligand can act as an agonist, an antagonist, a partial agonist or a partial antagonist. The term "aliphatic hydrocarbon (s)" when used herein refers to linear or branched chain acyclic groups that include alkyl, alkenyl or alkynyl groups. The term "aromatic hydrocarbon (s)" when used herein refers to groups that include allyl groups as defined herein. The term "heteroaryl" or "heteroaromatic portion" when used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring that includes 1, 2, 3 or 4 heteroatoms, one of which must be a nitrogen atom; the other heteroatoms when present may be nitrogen, oxygen or sulfur, and such rings may be fused to another aryl or heteroaryl ring, and include the N-oxides possible. The heteroaryl group may optionally include from 1 to 4 substituents such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, cyano, nitro, amino and / or carboxyl, and includes the following: ? ? D s > c > C > and similar. Unless otherwise indicated, the term "lower alkyl," "alkyl," or "ale" as used herein solely as or part of another group includes straight and branched chain hydrocarbons, containing from 1 to 12 atoms carbon (in the case of alkyl or ale), in the normal chain, preferably 1 to 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl or isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, which may optionally be substituted with 1 to 4 substituents which may include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl , hydroxy, cyano, nitro, amino and / or carboxyl.

The term "aryl" when used in the present sol or as part of another group refers to monocyclic and bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including l-naphthyl) and 2-naphthyl) and may be optionally substituted through the available carbon atoms with 1, 2 or 3 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino , nitro, cyano and carboxylic acids. Unless indicated otherwise, the term "lower alkenyl" or "alkenyl" when used herein by themselves or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, Preference of 2 to 5 carbons, in the normal chain, including 1 to 6 double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenium, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl and the like, which may be substituted as in the case of "alkyl". Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" when used in the present by itself or as part of another group, refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons in the normal chain, which include a triple bond in the normal chain, such as it can be 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decinyl, 3-undecinyl, 4-dodecinyl and the like, which may be substituted as in the case of "alkyl". Unless otherwise indicated, the term "cycloalkyl" when used herein alone or as part of another group includes saturated cyclic hydrocarbon groups or partially unsaturated cyclic hydrocarbon groups (containing 1 or 2 double bonds), which contain a ring and a total of 3 to 7 carbons, preferably of 3 to 5 carbons, forming the ring, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl and cyclohexenyl, which may be substituted as in the case of "alkyl" " The term "halogen" or "halo" when used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine as well as to CF3, with chlorine or bromine being preferred.

The compounds of formula I can be present as salts, in particular, as salts acable for pharmaceutical use. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids such as mineral acids, for example, sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids such as 1 to 4 carbon alkanocarboxylic 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 acids, such as hydroxycarboxylic acids, for example, acids ascorbic, glycolic, lactic, malic, tartaric or citric, such as amino acids (for example, aspartic or glutamic acid or lysine or arginine) or benzoic acid, or with organic sulfonic acids such as alkyl (C? -C4) acids or arylsulfonic which are unsubstituted or substituted, for example by halogen, for example, methyl- or p-toluenesulfonic acid. The corresponding acid addition salts can also be formed having, if desired, a basic core additionally present.

The compounds of the formula I having at least one acid group (e.g., COOH) can also form salts with bases. The salts with suitable 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, mono alkylamine, di or tri lower, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, or a mono, di or trihydroxy alkylamine, for example mono, di or triethanolamine. The corresponding internal salts can also be formed. Salts which are unsuitable for pharmaceutical uses but which can be used, for example, for the isolation or purification of the free compounds I or their salts acable for pharmaceutical use, are also included. Preferred salts of the compounds I included in a basic group include monohydrochloride, acid sulfate, methanesulfonate, phosphate or nitrate. Preferred salts of the compounds of the formula I which include an acid group include sodium, potassium and magnesium salts and the organic amines acable for pharmaceutical use.

Preferred are the compounds of the invention of the formula I wherein Ri is isopropyl R and R3 are independently halogen as bromine or chlorine, or R2 and R3 are each methyl or one is methyl and the other is ethyl c one of R2 or R3 is halogen as bromine or chlorine, and the other is alkyl as methyl, or hydrogen, and n is 0, 1 or 2 R4 is derived from the carboxylic acid of the type: amides, acylsulfonamides or an amide formed from an amino acid residue, and Rs is hydrogen The most preferred compounds have the structures: and other preferred compounds of the invention have the structures: for example wherein Ri = isopropyl, methyl, ethyl, tert-butyl, cyclopentyl, cyclohexyl; R2 and R3 can be independently selected from Br, Cl and Me; R * can be hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; * defines the stereochemistry D or L; and R 'and [sic] is selected from hydrogen, lower alkyl, especially ethyl and methyl, or where the group COOR' represents the ester forms of the prodrug known in the art as pivaloyloxymethyl or dioxolenylmethyl. These prodrug esters are described in the normal references such as Chapter 31, written by Camille G. Wermuth et al., "The Practice of Medicinal Chemistry", ed. C. G. Wermuth. Academic Press, 1996 (and the references contained in this). The compounds of the formula I can be prepared by the exemplary processes described in the following reaction schemes. The reagents and exemplary procedures of these reactions appear hereinafter and in the working examples. The compounds of the formula I of the invention can be prepared using the sequence of the steps outlined in Schemes 1 to 5 set out below. Scheme 1 represents a synthesis of the compounds of the formula I in which R 4 = an amino acid, aniline derivative or heterocyclic ring containing aza, which through its nitrogen atom are connected to the aromatic ring by an intervening group (CH2) n. In Scheme 1, the amino acid, the aniline derivative or the aza-containing heterocyclic ring, dissolved in a convenient solvent, is treated with 1-3 molar equivalents of a suitable base, such as potassium carbonate, cesium carbonate, potassium hydroxide or sodium hydride. The resulting anion is then alkylated with the substituted iodide. It is possible to employ other combinations of alkylating agents or bases and are known to those skilled in the art. Mix Reaction is stirred at room temperature or heated until the raw materials are consumed. After standard treatment and purification, the methyl ester function is removed by treatment with 3-6 molar equivalents of a strong acid such as boron tribromide [sic] at 0 ° C to 25 ° C in an inert solvent such as dichloromethane. The reaction mixture produces after the normal treatment and purification, the final products 6. Various alternative methods for the conversion of the intermediates such as 3 and 4 to products 6 are well known to those skilled in the art. Scheme 1 also outlines the preparation of the intermediate iodide, the sequence similar to that used in: "Novel Thyroid Receptor Ligands and Methods, Li, Yi-Lin, Liu, Ye, Hedfors, Asa, Malm, Johan, Mellin, Charlotte, Zhang, Minsheng, Sun. Int. PCT., 40 pp. CODEN: PIXXD2, WO 990353 Al 990107". An iodonium salt derived from aniso! 2 and copper bronze in an inert solvent such as dichloromethane are mixed at room temperature. A mixture of the appropriate phenol ester 1 and a base such as triethylamine in an inert solvent such as dichloromethane was added to the mixture, generally using two molar equivalents each time of phenol and base, and three molar equivalents of the iodonium salt 2. After stirring overnight at room temperature, the reaction mixture is purified by chromatography on silica gel to obtain the 3-biaryl ether products. Other methods exist in the literature for the synthesis of di aryl ethers, for example, two references apply directly to the synthesis of thyroid hormone analogues: D. A. Evans et al., Tet. Letters, volume 38, 6965-6968 (1997). The carboxylic acid ester can be hydrolyzed with a mixture of aqueous sodium hydroxide and methanol. The methyl ether function can be eliminated by treating the free acid product of the above process with 4-6 molar equivalents of a strong acid such as boron tribromide at 0 ° C in an inert solvent such as dichloromethane. Other combinations of protecting groups for the carboxylic acid present in one and phenolic hydroxyl in the iodonium salt 2 can be employed, and their use is known to those skilled in the art (references describing the strategy of protecting groups include, for example, "Protecting Groups in Organic Chemistry", JFW McOmie, Plenum Press, London, New York, 1973, and "Protective Groups in Organic Synthesis", TW Greene, Wiley, New York, 1984). The intermediate ester product 3 is reduced by treatment with a suitable reducing agent as diisobutyl aluminum hydride in an inert solvent such as tetrahydrofuran at 0 ° C. If R2 and R3 are alkyl, then it is possible to employ lithium aluminum hydride without the risk of reducing the halogen substituents in these positions. The normal treatment and purification produces the desired alcohol product 4. Other reducing agents can be employed and are known to those skilled in the art. Intermediate 4 in Scheme 1 is finally converted to the intermediate iodide 5 by treatment of alcohol 4 with two molar equivalents of sodium iodide, phosphorous pentoxide and phosphorous acid, and heated at 120 ° C for 15 minutes. Various methodologies for converting simple hydroxyl groups to the corresponding alkyl iodides are well known to those skilled in the art.

Esquena 1 (= Am¡no «cid, anilint, hefcrocy ltc ring Scheme 2 represents a synthesis of the compounds of the formula I in which R 4 is a tetrazole ring. Phenylacetonitrile 7 is easily prepared from benzylic iodide by standard means such as reaction with sodium cyanide in a solvent mixture such as water / ethanol. The reaction of phenylacetonitrile 7 with azide and ammonium chloride in dimethylformamide at elevated temperatures provides the tetrazole derivatives 8 (Example 1 and, 2), after normal treatment and purification procedures. In Example 2 this step was followed by a normal demethylation procedure, as in the above, to remove the protecting group. Examples of substituted tetrazoles that can be prepared by additional chemistry are also represented in Scheme 2. The tetrazole derivative 8 can, for example, be treated with a suitable base such as sodium acid carbonate in acetone, followed by N-alkylation with methyl iodide to produce the derivatives 9 and 10, after the normal treatment and purification procedures. Other alkylating agents and bases may be employed and are known to those skilled in the art.

Scheme 2 Examples of compounds of formula I in which R 4 is an amide produced by the coupling of an amino acid are shown in Scheme 3. The following processes involve the coupling of benzoic or acetic acid derivative 11 (n = 0 or 1), with its phenolic hydroxyl group protected by a methyl, left unprotected or bound to a resin, with some protected amino acids to produce the corresponding amides 10 3, 5-dihalo-4- (4-hydroxy-3-isopropyl-phenoxy) carboxylic acids. The carboxylic acids 11 are easily obtained, for example, by hydrolysis of the corresponding esters 3. In a process, a mixture of 11 with R = Me, a coupling reagent such as 3-ethyl-1- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDCI), and a base such as hydrate 1- Hydroxybenzotriazole (HBT) in dichloromethane is stirred at room temperature. The appropriate protected amino acid and N-methylmorpholine are added. The reaction mixture produces, after treatment and purification by chromatography or recrystallization, the corresponding coupled material, which after the normal demethylation and hydrolysis procedures, produces the final, desired amide products (Example 87). Some examples of the coupled products, using different protecting groups for the carboxylic acid group were also prepared and isolated (Examples 29, 57, 71-72, 75, 77, 80-82, 84). Of other Thus, the amide end products containing free carboxylic acid groups can be reesterified by the normal procedures, for example, by heating them in a mixture of refluxing methanol and thionyl chloride, to obtain the corresponding alkyl acid ester derivatives (Example 82) . In another more successful modification of the same procedure as the previous one, 11 is kept unprotected (R = H) from the beginning of the sequence to obtain, after basic hydrolysis or treatment with a Lewis acid such as BBr3, and treatment and purification procedures normal, other examples of carboxylic acid amides (Example 3-24, 25-28, 56, 73-74, 76, 78-79, 83, 85-86, 203, 207-208). An amide library can also be prepared by solid phase synthesis (Examples 30-55). In this process a methyl ester of intermediate 11 is loaded onto a resin such as Merrifield resin by standard procedures well known to those skilled in the art. The resulting resin is then treated with sodium hydroxide in methanol to provide the free carboxylic acid form bound to the resin of 11. Each resin pin is then filled with a solution of the corresponding amino acid ester, PyBOP (benzotriazole-1-hexafluorophosphate). il-oxy-tris- pyrrolidino phosphonium). The HBT and N, N-diisopropylethylamine (Huning's base, DIEA) and an inert solvent such as dichloromethane and stir at room temperature for days. Other combinations of base and coupling reagents can be used in this case with good results. After the treatment of each of the individual sticks with a suitable base such as aqueous potassium hydroxide and the washing of the resin, the amides are disassembled from the resin by treatment of a mixture of trifluoroacetic acid, dimethylsulfite and water. Some other related methods exist for the coupling of the amino acids with aromatic carboxylic acids, as well as non-aromatics in solution or solid phase and are known to those skilled in the art. The amino acid product 12 can be reduced by treatment with a suitable reagent such as sodium borohydride in a polar solvent such as ethanol at room temperature. If R2 and R3 are alkyl, then lithium aluminum hydride can be employed without the risk of reducing the halogen substituents in these positions. The normal treatment and purification produces the desired alcohol product. Other reducing agents can be employed and are known to those skilled in the art.

Scheme 3 R = Me, H or resin R? = Isopropyl, R = C-Amino acid O Scheme 4 represents the sinteis of the compounds of the formula I in which R 4 is an acylsulfonamide. Similar procedures are employed as for the coupling of the above amino acids. In one method, 13 is left unprotected (R = H), mixed with a base such as DIEA and the appropriate sulfonamide in dichloromethane. Dimethylformamide is added to the mixture if the sulfonamide does not dissolve completely. The treatment of the mixture with a base and combinations of coupling reagents such as HOBt and PyBOP, provide after heating and subsequent treatment with moderate acid during the treatment and purification by HPLC, the desired acyl sulfonamides (Examples 58-70). In an exemplified procedure, a mixture of 13 with R = Me, a coupling reagent such as 3-hydrochloride ethyl-1- [3- (dimethylamino) propyl] carbodiimide (EDCI), and a base such as dimethylaminopyridine (DMAP) and the appropriate sulfonamide in dichloromethane are stirred at room temperature. The reaction mixture produces, after treatment and purification by chromatography or recrystallization, the corresponding coupled material which, after normal demethylation processes, still produces other acylsulfonamides. Other combinations of protecting groups and processes may be employed. For example, by applying the chemistry similar to the previous one, but with R = Si (CH3) 2t-Bu, it produces other examples of acyl sulfonamides after removing the protective silyl group with ammonium fluoride (Examples 88-91).

Scheme 4 Example 58-70, n = 0 Example 88-91, n = l The procedures described in Scheme 5 further exemplify the methods for the synthesis of the compounds of the formula I. Some structurally diverse amides, primary as well as secondary, were prepared as outlined in Scheme 5. Many alternative methods for coupling the above amino acids can be employed and are also known to those skilled in the art.

For example, in a process, secondary diacytic acid amides are obtained by treatment of dimethyliminodiacetate and EDCI in dimethylformamide or dichloromethane, followed by normal treatment procedures and final basic hydrolysis of the ester function (Example 206). In another procedure, aromatic amides were obtained by a similar procedure as in Example 3-24 above (Example 192-202). A library containing 100 different primary and secondary amides was also prepared in an automated mode, using the normal methods of the literature (Example 92-191).

Scheme 5 R = Me, H R, = isopropyl, R ^ = CNR'R "O Example 2-191, n = l, RJ = RJ = BG Example 192-202 n-0, R2 = R3 = C1 With respect to the above reaction schemes, although the different portions Ri, R2, R3, R4 and n are specifically defined, unless otherwise indicated, it should be understood that Ri, R2, R3 and R4 can be any of the Groups comprised by these and n can be 0, 1, 2, 3 or 4. The compounds of the invention are agonists which are preferably selective for the thyroid hormone beta receptor, and as such are useful in the treatment of obesity, hypercholesterolemia and atherosclerosis by reducing LDL concentrations in serum, alone or in combination with lipid-modulating drugs such as the HMG-CoA reductase inhibitor, fibred, thiazolidinedione or MTP inhibitor, improving depression alone or in combination with an antidepressant, and the stimulation of bone formation to treat osteoporosis in combination with any bone resorption inhibitor known as alendronate sodium. In addition, the compounds of the invention may be useful as replacement therapy in elderly patients with hypothyroidism or subclinical hypothyroidism who are at risk of cardiovascular complications, in the treatment of elderly patients to provide a sense of well-being, and in the non-toxic goiter treatment; in the management of papillary or follicular thyroid cancer (alone or with T4); in the treatment of skin disorders such as psoriasis, glaucoma, cardiovascular disease such as the prevention or treatment of atherosclerosis, and congestive heart failure. The compounds of the invention can also be used to treat skin disorders or diseases involving dermal atrophy such as glucocorticoid-induced dermal atrophy, including the restoration of dermal atrophy induced by topical glucocorticoids, the prevention of dermal atrophy induced by topical glucocorticoids (as may be the simultaneous treatment with topical glucocorticoids or a pharmacological product including glucocorticoid and a compound of the invention), the restoration / prevention of induced skin atrophy 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, stretch marks, cellulitis, skin Rough, actinic skin damage, lichen planus, ichthyosis, acne, psoriasis, Dernier's disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring. In the treatment of skin disorders or diseases as already described, the compounds of the invention can be used in combination with a retincide or a vitamin D analog. The compounds of the invention can be administered orally or parenterally as it can be subcutaneously or intravenously, as well as by nasal, rectal or sublingual application to different mammalian species known to be subject to these conditions, for example, 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, most preferably, about 0.5 to about 25 mg / kg (or from about 1 to about about 2500 mg, preferably from about 5 to about 2000 mg) in a scheme in single doses or daily doses divided by 2 to 4. The active substance can be used in a composition as a tablet, capsule, ointment, hydrophilic ointment, cream, lotion , solution or suspension or in other types of carriers of materials such as transdermal devices, iontophoretic devices, rectal suppositories, inhaling devices and the like. The composition or carrier will contain about 5 to about 500 mg per dosage unit of a compound of formula I. These may be compounds in a traditional manner with a carrier or carrier, excipient, binder, preservative, stabilizer, flavoring, acceptable for use physiological, also accepted by pharmaceutical practice. The following working examples represent the preferred embodiments of the present invention. Suitable processes for the preparation of raw materials can be found in: Li, Yi-Lin; Liu, Ye; Hedfors, Asa; Malm, Johan; Mellin, Charlotta; Zhang, Minsheng PCT Int. Appl., 40 pp CODEN: PIXXD2 WO 9900353 Al 990107. "The XH NMR spectrum was all consistent with the assigned structures.

Example 1 3, 5-dimethyl-4- (4-hydroxy-3-isopropylphen ^? I) benzyltetrazole To a stirring solution of 3,5-dimethyl-4- (4-hydroxy-3-isopropylphenoxy) phenylacetonitrile (154 mg) in 6.3 ml of dimethylformamide, ammonium chloride (297 mg, 5.21 mmol) and sodium azide (339 mg). mg, 5.21 mmol) was added to reflux. After 4.5 hours, the reaction mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, chloro ormo / methanol / acetic acid 96: 4: 1) to obtain 68 mg (37%) of the title compound.

Example 2 3, 5-di-clcro-4- (4-hydroxy-3-isopropylphenoxy) benzyltetrazole (a) To a stirred solution of 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) phenylacetonitrile (160 mg) in 3.0 ml of dimethylformamide, ammonium chloride (500 mg) and azide were added at reflux. of sodium (600 mg). After 2 hours, the reaction mixture was concentrated, treated with 6 M hydrochloric acid and extracted several times with ethyl acetate. The combined organic phases were dried over magnesia sulfate filtered and concentrated. The residue was purified by column chromatography (silica gel, 96: 4: 1 chloroform / methanol / acetic acid) to obtain 60 mg (34%) of 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) Benzyltetrazole (b) A reaction mixture of 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) benzyltetrazole (60 mg), BF3.Me2S (0.5 ral) and CH2C12 (6 ml) was stirred at room temperature for the night. The yield after purification was quantitative.

Examples 3-24 General procedure A mixture of 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (222 mg), 3-ethyl-1- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDCI), (95 mg), 1-hydroxybenzotriazole hydrate (HBT), in dichloromethane (5 ml) was stirred under argon at room temperature for 2 hours. In a separate flask, stirred for 1 hour under nitrogen the appropriate amino acid, triethylamine (100 mg) and 5 ml of dichloromethane. The two mixtures were combined and the reaction mixture was stirred at 40 ° C overnight. When the initial carboxylic acid was consumed, the organic phase was removed in vacuo and the residue was dissolved in methanol (20 ml) and 1 N NaOH (10 ml). The reaction mixture was stirred at 40 C [sic] for 24 hours and evaporated. The residue was subjected to semipreparative HPLC, using gradient elution as outlined below. The amine "R" and the stereochemistry of the amino acids are indicated in the following table. The retention time of 1HPLC [sic] in minutes and gradient method. Reversed phase HPLC analyzes were performed on Zorbax-C8-5u-4.6x5C mm analytical columns, flow rate 3 ml / min, detection at 220 nm and 10-minute gradient elution by solvent A (10% CH3CN + 10 mmol HOOH) and B (CH3CN + 10 mmol HOOH). The gradient elution was performed as follows: 0-1 minute 90% A, 1-7 minutes at 100% B, 7-9 minutes 100% B and 9-10 minutes return to 10% A. The purification of the Examples are performed using a Zorbax-C8-5u-21.5x50 mm semipreparative column, flow rate 25 ml / min, detection at 220 nm, using the same gradient as for the column analytics. 2MS the results obtained in a PESciEx-API150EX using electrospray, positive and negative ion modes.

Example 25 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] methionine (a) A solution of 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (222 mg), 3-ethyl-1- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDCI) (106 mg), 1-hydroxybenzotriazole hydrate (HBT), (101 mg) in dimethylformamide (5.5 ml) was stirred at room temperature for 0.5 hour followed by addition of a solution of D-methionine methyl ester hydrochloride (298 mg ) and triethylamine (111 mg) in dimethylformamide (2.2 ml). After stirring for one hour, the mixture was separated by partition between water and chloroform. The organic phase was dried, filtered and concentrated. The residue was subjected to column chromatography (silica gel), gradient elution with 20% to 40% ethyl acetate in petroleum ether) to obtain 256 mg (87%) of D-methyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] methionate. LC-MS (electrospray): m / z 590 (M + H). (b) D-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetylmethionate (88 mg) was hydrolyzed by treatment with a 1M aqueous sodium hydroxide solution (1 ml) in methanol (2.25 ml) to obtain 81 mg (94%) of the title compound after column chromatography (silica gel, gradient elution with chloroform, ethanol and acetic acid). LC-MS (electrospray): m / z 574 (M + H) Example 26 L-N- [3,5-dibromo- - (4-hydroxy-3-isopropylphenoxy) phenylacetyl] methionine (a) 3,5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (222 mg) was coupled with D-methionine hydrochloride (298 mg) using the method described in Example 25 (a) ) to obtain 236 mg (80%) of L-methyl- N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] methionine after column chromatography (Silica gel, gradient elution with 20% to 40% ethyl acetate in petroleum ether ) LC-MS (electrospray): m / z 590 (M + H). b) D-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] -methionate (24 mg) was hydrogenated using a method described in Example 25 (b) to obtain 20 mg (87%) of the title compound after column chromatography (silica gel, gradient elution with chloroform, methanol and acetic acid). LC-MS (electrospray): m / z 574 (M-H) [sic].ts.

Example 27 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] a-methylalanine (a) 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (22 mg) was coupled with Da-methylalanine hydrochloride (238 mg) using the method described in Example 25 (a) get 269 mg (92%) of Dt-butyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] a-methylalanine after column chromatography (silica gel, gradient elution with 20% up to 40% ethyl acetate in ether of oil). LC-MS (electrospray): m / z 586 (M + H). (b) Dt-butyl-N- [3, 5-dibromo-4- (4-hydroxy-^ - isopropylphenoxy) phenylacetyl] a-methylalanine (88 mg) was treated with boron tribromide (1 M in dichloromethane, 2.3 ml ) at 0 ° C. The mixture was stirred overnight at room temperature before water / ice was added. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was dried, filtered and concentrated to obtain 46 mg (58%) of the title compound after column chromatography (silica gel, gradient elution with chloroform, methanol and acetic acid). LC-MS (electrospray): m / z 528 (M-H).

Example 28 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] asparagine 3, 5-Dibromo-4- (4-hydroxy-3-isopro-ylphenoxy) phenylacetic acid (444 mg) was mixed with 10 ml of thionyl chloride and heated to reflux for 3 hours. The reaction mixture was co-evaporated with toluene to obtain the crude 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic chloride. N, 0-bis (trimethylsilyl) acetamide (670 mg) was added at 0 ° C under an atmosphere of nitrogen, to a mixture of D-asparagine (225 mg) and 10 ml of acetonitrile. The reaction mixture was further stirred at room temperature and a solution of 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid chloride in 10 ml of acetonitrile was added. After stirring for 16 hours, the reaction mixture was poured into water and the filtered solid. The solid was dissolved in methanol and the organic phase was removed in vacuo. The residue was purified by HPLC to obtain 76 mg (14%) of D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] asparagine. LC-MS (electrospray): m / z 557 (M-H) [sic].

Example 29 L-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] alanine 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-methylalanine hydrochloride (126 mg) using the method described in Example 25 (a) to obtain 140 mg (60%) of the title compound. LC-MS (electrospray): m / z 530 (M + l).

General procedure for the preparation of the amino acid library by solid phase synthesis (Examples 30-55) Loading of the resin with 3,5-dibromo-4- (4-hydroxy-3-isopropyl phenoxy) benzoic acid A mixture of methyl 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoate (7.6 g, 17.1 mmol,) Merrifield resin (5 g, 1.2 mmol / g) and sodium hydride (432 mg, 18 mmol) in 100 ml of dimethylformamide was stirred in a 250 ml round flask at 50 ° C for 40 hours after cooling, the mixture was filtered and the resin was washed with water (3 x 10 ml), dimethylformamide (3 x 10 ml), ethyl acetate (3 x 10 ml) and dichloromethane (3 x 10 ml). The resulting resin was dried in vacuo overnight to obtain 8.54 g of resin, charged with e! methyl ester The resin was added with methanol (100 ml) and an aqueous solution of sodium hydroxide (100 ml, 1 M). The suspension was stirred at 80 ° C for one day, cooled to room temperature and filtered. The resin was washed with water (3 x 10 ml), tetrahydrofuran (3 x 10 ml), ethyl acetate (3 x 10 -ml) and dichloromethane (3 x 10 ml). After drying in vacuo, 5.94 g of charge resin was obtained with the title compound.

Determination of the load capacity of the resin: The resin (100 mg) was treated with a mixture of trifluoroacetic acid, dimethyl sulfite and water (85: 15: 5). The mixture was stirred at room temperature for two days. The resin was removed by filtration and the organic phase was collected and concentrated in vacuo. The resulting residue was subjected to chromatography on silica gel (methanol / chloroform / acetic acid 10: 90: 1). The pure fractions were combined and concentrated yielding 17.5 mg (51% acid 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid as a white solid. The loading rate was estimated as 0.04 mmol, (17.5 mg) per ICO mg of the loaded resin.

Copulation of 3, 5-dibromo-4- (4-hydroxy-3-isopropyl phenoxy) benzoic acid in different amino acids The DIVERSOMER® 8-100 synthesizer was used for the synthesis and the Savant Speed Vac® concentration system. To each of the eight PINs was added 100 (± 5) mg of the loaded resin (17.5 mg / 100 mg, 0.04 mmol / 100 mg). The resin loaded PINs were placed in a support block. Eight small bottles (12 ml) were placed on the reservoir shelf, equipped with a magnetic stir bar and filled with a mixture consisting of the corresponding amino acid ester (0.4 mmol), PyBOP (104 mg, 0.2 mmol), HBT (27 mg, 0.2 mmol), DIEA (52 mg, 0.4 mmol) and dichloromethane (5 ml). The support block was assembled in the tank shelf. The reaction was carried out at room temperature with stirring for two days. The tank shelf was disassembled from the support block. Each resin in the PINs was dosed with 2 ml each of dimethylformamide, water, ethyl acetate and dichloromethane. The washing procedure was repeated twice and finally the resin in the PINs was dried by a flow of compressed air. Eight new small bottles (12 ml) were placed in the shelf of reservoirs and each small bottle was equipped with a magnetic stir bar. The support block was assembled into the reservoir shelf, a methanolic solution of potassium hydroxide (5 ml, 2M) was introduced in increments of 1 ml across the side of each PIN. The apparatus was left in a smoke hood with agitation for two days. The synthesizer was disassembled and the resins were washed with water (4 x 2 ml), methanol (4 x 2 ml) and dichloromethane (4 x 2 ml). The resin in the PIN was dried by air flow compressed. The support block was again assembled. of the storage shelf. A standard solution of 50 ml of trifluoroacetic acid / dimethyl sulfite / water (85: 15: 5; v / v) was prepared. The solution (5 ml) was added to each of the eight PINs in 1 ml increments. The apparatus was left to rest in a smoke hood with agitation for two days. The tank shelf and support block were disassembled. Each PIN was washed with 1 ml of the previous solution. The contents of the eight small reservoir flasks were concentrated to dryness. Each small flask was separated by partition between aqueous hydrochloric acid (1 ml, 1M) and ethyl acetate (2 ml). The contents of the eight small reservoir bottles were carefully transferred to eight drying cartridges (Chem elute CE1003, VARIAN), equipped with test tubes underneath. The cartridges were allowed to drain by gravity, rinsed with ethyl acetate (3 x 1.5 ml) after 5 minutes and finally forced to drain under reduced pressure. The organic layer was collected and concentrated to obtain the following products in the yields mentioned below.

Example 30 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] valine 12.2 mg (57.7%) Example 31 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] leucine 20.1 mg (92.5%) Example 32 L-S-benzyl, N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] cysteine 14.9 mg (60%) Example 33 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] tyrosine 5.9 mg (24.8%) Example 34 L-N-d- (2,2,5,7,8-pentamethylchroman-6-sulfonyl) N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] arginine 10.7 mg (31%) Example 35 L-N- \ 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] aminobutyric acid . 6 mg (75.5%) Example 36 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] valine 19.7 ng (93%) Example 37 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] leucine 14.8 mg (68%) Example 38 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] proline 8.6 mg (41%) Example 39 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] cysteine 2.88 mg (13.5%) Example 40 N- [3, -dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] glycine 15.8 mg (81%) Example 41 L-N-a- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine 23.5 mg (105%) Example 42 D-N-a- [3,5-dibromo-4- (4-hydroxy-3-isoprcphenylphenoxy) benzoyl] lysine 24.9 mg (112%) Example 43 N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] aminoisobutyric acid 6.72 mg (32.6%) Example 44 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopro-phenoxy) benzoyl] phenylglycine 7.1 mg (31%) Example 45 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] phenylglycine 15.1 mg (67%) EXAMPLE 46 N- [3,5-dibromo-4- (4-hydroxy-3-isoprcphenylphenoxy) benzoyl] sarcosine 6.7 mg (33.4%) Example 47 DL-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -a-methyphenylalanine 7.4 mg (31.4%) Example 48 L-N- [3,5-dibromo- (4-hydroxy-3-isopropylphenoxy) benzoyl] isoleucine 16.1 mg (70%) Example 49 D-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -methionine 11.7 mg (52%) Example 50 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] methionine 13.2 mg (58.6%) Example 51 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] • phenylalanine 9.7 mg (41.9%) Example 52 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -phenylolanine 12.2 mg (52.9%) Example 53 L-N- [2, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -cyclohexane 10.1 rrg (43.7%) Example 54 L-N-e- (benzyloxycarbonyl), N-a- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine 10 mg (36%) Example 55 D-N-e- (benzyloxycarbonyl), N-a- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine 24.4 mg (88%) Example 56 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] alanine 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-methyl alanine hydrochloride (126 mg) using the method described in Example 25 (a) and subsequently hydrolyzed using the method described in Example 25 (b). The crude mixture was partitioned by semipreparative HPLC to obtain 40 mg (21%) of L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] alanine. LC-MS (electrospray): m / z 516 (M + H).

Example 57 L-Dimethyl-N- [3,5-dibromo-4- (4-hydroxy-3-isoprc-phenylphenoxy) phenylacetyl] glutamate 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-hydrochloride dimethyl-glutamate (190 mg) using the method described in Example 25 (a). The crude mixture was purified by semi-preparative HPLC to obtain 150 mg (55%) of the title compound. LC-MS (electrospray): m / z 601 (M + l).

Example 58 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-5-hydroxy-1-naphthalenesulfonamide To a stirring mixture of 5-hydroxy-1-naphthalenesulfonamide (0.175 mmol) in dichloromethane (0.2 ml) was added a solution of 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (0.035 mmol). ), DIEA (0.175 mmol) and dichloromethane (0.2 ml). Dimethylformamide was added to the solution if the sulfonamide did not completely dissolve in dichloromethane. After 15 minutes, PyBOP (0.042 mmol) and HOBt (0.001 mmol) in dichloromethane (0.3 ml) were added. The reaction mixture was heated at 50 ° C for 20 hours. After cooling to room temperature, dichloromethane (1 ml) and a solution of citric acid (5%, 1 ml) were added and stirred vigorously for 30 minutes. The organic phase was dried, concentrated and the residue was finally subjected to emulsifying HPLC (silica column: 250 x 20 mm, ethyl acetate / n-heptane (both with 0.5% acetic acid). Gradient: first two minutes 15% ethyl acetate, then for 13 minutes to 100% ethyl acetate, then an additional 5 minutes 100% ethyl acetate to obtain 12 mg (54%) of the title compound.

Example 59 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4-toluenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with toluenesulfonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue afforded 14 mg (69%) of the title compound.

Example 60 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4-nitro-benzenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 4-nitrophenylsulfonamide (0.175 mmol) using the method described in Example 58. HPLC purification of the residue produced 8 mg (37%) of the title compound.

Example 61 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoylsulfamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with sulfonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 13 mg (73%) of the title compound.

Example 62 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-5-dimethylamino-1-naphthalenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 5-dimethylamino-1-naphthalene sulfonamide (0.175 mmol) using the method described in Example 58. The purification in HPLC of the residue afforded 8 mg (34%) of the title compound.

Example 63 3, 5-d: '. Bromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4-aminobenzenesulfonamide 3, 5-dibromo-4- (4-methoxy-3-isopropylphenoxy) Benzoic acid (0.035 mmol) was coupled with 4-aminobenzenesulfonamide (0.175 mmol) using e1. method described in Example 58. HPLC purification of the residue afforded 7 mg (34%) of the title compound.

Example 64 [3,5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-2-sulfonamide] methyl benzoate 3, 5-dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with methyl 2-sulfonamide benzoate (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 12 mg (55%) of the title compound.

Example 65 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-2-aminobenzenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 2-aminobenzenesulfonamide (0.175 mmol) using the method described in Example 58. The HPLC purification of the residue gave 11 mg (54%) of the title compound.

Example 66 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-2-toluenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 2-toluenesulfonamide (0.175 mmol) using the method described in Example 58. HPLC purification of the residue gave 15 mg (74%) of the title compound.

Example 67 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4- (2-aminoethyl) benzenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 4- (2-aminoethyl) benzenesulfonamide (0.175 mmol) using the method described in Example 58. The purification HPLC on the residue gave 10 mg (47%) of the title compound.

Example 68 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4- (2-aminomethyl) benzenesulfonamide 3, 5-dibromo-4- (4-methoxy-3-isopropylphenoxy) Benzoic acid (0.035 mmol) was coupled with 4- (2-aminoethyl) benzenesulfonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 16 mg (76%) of the title compound. - Example 69 3, 5-? Ibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-3-nitrobenzenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 3-nitrobenzenesulfonamide (0.175 mmol) using the method described in Example 58. HPLC purification of the residao gave 7 mg (33%) of the title compound.

Example 70 3, 5-dibromo-4- (-hydroxy-3-isopropylphenoxy) benzoyl-4-chlorobenzenesulfonamide 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (0.035 mmol) was coupled with 4-chlorobenzenesulfonamide (0.175 mmol) using the method described in Example 58. HPLC purification of the residue gave 13 mg (62%) of the title compound.

Example 71 L-dimethyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutama ^ o 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-dimethyl glutamate hydrochloride (190 mg) using the method described in Example 25 (a). The crude mixture was purified by semi-preparative HPLC to obtain 150 mg (55%) of the title compound. LC-MS (electrospray): m / z 601 (M + H).

Example 72 L- (O-: er-butyl) methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamate 3,5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L- (O -tertbutyl) methyl glutamate hydrochloride (228 mg) using the method described in Example 25 (a). The crude mixture was purified by semi-preparative HPLC to obtain 70 mg (24%) of the title compound. LC-MS (electrospray): m / z 643 (M + H).

Example 73 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamic acid 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-dimethyl glutamate hydrochloride (190 mg) using the method described in Example 25 (a) and subsequently was hydrolyzed using the method described in Example 25 (b). The crude mixture was purified by semi-preparative HPLC to obtain 62 mg (31%) of the title compound. LC-MS (electrospray): m / z 574 (M + H).

Example 74 L-N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] aspartic acid (a) A solution of 3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (50 mg), 3-ethyl-1- [3- (dimethylamino) propyl] carbodiimide hydrochloride (EDCI) (30 mg), 1-hydroxybenzotriazole hydrate (HBT), (28 mg) in dimethyl formamide (1 ml) was stirred at room temperature for 0.5 hours followed by addition of a solution of L-di-t hydrochloride. -butyl aspartate (52 mg) and tri.ethylamine (32 mg) in dimethyl formamide (1 ml).

After stirring for three days, the mixture was partitioned between water and e + ethyl acetate. The organic phase was washed with brine and then dried, filtered and concentrated. The residue was subjected to chromatography on silica gel eluted with ethyl acetate / light petroleum ether (1: 4). The pure fractions were combined and concentrated to obtain L-di-t-butyl N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylcycline] aspartate (68 mg, 83%). (b) The above ester (48 mg) was hydrolyzed using the method described in Example 25 (b) to obtain the acid LN- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] aspartic acid (27 mg, 70%).

Example 75 D-di-tert-butyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamate 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with D-di-tert-butyl-glutamate hydrochloride (266 mg) using the method described in Example 25 (to). The crude mixture was purified by semi-preparative HPLC to obtain 170 mg (70%) of the title compound. LC-MS (electrospray): m / z 685 (M + H).

Example 76 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamic acid 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with D-di-tert-butyl-glutamate hydrochloride (190 mg) using the method described in Example 25 (a) and subsequently hydrolyzed using the method described in Example 25 (b). The crude mixture was purified by semi-preparative HPLC to obtain 60 mg (23%) of the title compound. LC-MS (elec rospray): m / z 574 (M + H).

Example 77 L-O-tert-butyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamine 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with LO-tert-butyl glutamine hydrochloride (230 mg) using the method described in Example 25 (a) . The crude mixture was purified by semi-preparative HPLC to obtain 100 mg (44%) of the title compound. LC-MS (electrospray): m / z 629 (M + H).

Example 78 L-N- 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamine The 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-tert-butyl glutamine hydrochloride (230 mg) using the method described in Example 25 (a ) and subsequently hydrolyzed using the method described in Example 25 (b). The crude mixture was purified by semi-preparative HPLC to obtain 40 mg (15%) of the title compound. LC-MS (electrospray): m / z 574 (M + H).

Example 79 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamine 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with D-glutamine glutamine hydrochloride (163 mg) using the method described in Example 25 (a) and subsequently hydrolyzed using the method described in Example 25 (b). The crude mixture was purified by semi-preparative HPLC to obtain 30 mg (12%) of the title compound. LC-MS (electrospray): m / z 574 (M + H).

EXAMPLE 80 L-O-Benzyl-N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] aspartic acid 3, 5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with L-O-benzyl aspartic acid (266 mg) using the method described in Example 25 (a). The crude mixture was purified by semi-preparative HPLC to obtain 140 mg (38%) of the title compound. LC-MS (electrospray): m / z 650 (M + H).

Example 81 L-O-tert-butyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] asparagine 3,5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (200 mg) was coupled with LO-tert-butyl asparagine hydrochloride (170 mg) using the method described in Example 25 (a) . The crude mixture was purified by semi-preparative HPLC to obtain 40 mg (16%) of the title compound. LC-MS (electrospray): m / z 558 (M + H).

Example 82 L-O-methyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) phenylacetic acid (134 mg) was coupled with L-homoserine (36 mg) using the method described in Example 25 (a). The crude residue was dissolved in MeOH and heated to reflux with S0C12 for two hours. After evaporation of the solvent, the residue was subjected to column chromatography (silica gel, CHCl3 / MeOH 97: 3). The pure fractions were combined and concentrated to obtain 100 mg (64%) of the title compound.

Example 83 L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine L-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine (100 mg) was hydrolyzed using the method described in Example 25 (b). The crude product was purified by HPLC to obtain 30 mg (30%) of L-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine.

Example 84 D-met.yl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine 3, 5-Dibromo-4- (4-methoxy-3-isopropylphenoxy) phenylacetic acid (140 mg) was coupled with L-homoserine (36 mg) and re-esterified using the method described in Example 82. This produced 100 mg (64%) of D-methyl-N- [3,5-dibromo-4- (-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine.

Example 85 D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine L-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine (100 mg) was hydrolyzed using the method described in Example 25 (b). The crude product was purified by HPLC to obtain 30 mg (30%) of D-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine.

Example 86 N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] glycine (a) A stirring mixture of 3,5-diclcro-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid (9.56 g, 28.02 mmol), methyl glycine ester hydrochloride (5.28 g, 42.05 mmol), hydrochloride 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (6.45 g, 33.64 mmol), 1-hydroxybenzotriazole (4.54 g, 33.60 mmol), CH2C12 (260 mL) and DMF (20 mL) was cooled with a water bath. ice water. N-Methylmorpholine (5.7 g, • 6.2 ml, 56.35 mmol) was added under N2 and the reaction mixture was left at room temperature. After 18 hours, CH2C12 was removed in vacuo and the residue was partitioned between EtOAc. (300 ml) and H20 (150 ml). The organic phase was washed successively with IN HCl (2 x 150 ml), saturated aqueous NaHCO 3 (2 x 150 ml) and brine (2 x 150 ml). The organic phase was dried (Na 2 SO 4), filtered and concentrated in vacuo to obtain 11.5 g of the crude product as an orange solid. The crude product was purified by chromatography (silica gel, 40% EtOAc in hexane) to obtain 9.76 g (84% yield) of slightly yellowish solid. 1ti NMR (500 MHz, CDC13): d 7.82 (s, 2H), 6.78 (d, ÍH, J = 2.7 Hz), 6.63 (d, ÍH, J = 8.8 Kz), 6.61 (t, ÍH, J = 4.9 Hz), 6.38 (dd, ÍH, J = 8.8, 3.3 Hz), 4.65 (s, ÍH), 4.24 (d, -2H, J = 5 Hz), 3.82 (s, 3H), 3.16 (heptet, ÍH, 6.6 Hz), 1.22 (d, 6H, J = 6.6 Hz); 13H NMR: d 170.18, 165.65, 150.66, 148.36, 136.26, 131.63, 130.57, 128.10, 115.76, 113.94, 112.28, 52.69, 41.87, 27.34, 22.38; MS-ESI "[M-H]" = 410, 412, 414 (100: 64: 10). (b) To a solution of methyl N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] glycinate (7.30 g, 17.71 mmol) in THF (106 ml) was added a solution of aqueous lithium hydroxide IN (53 ml, 53 mmol). After two lores, the mixture was acidified with IN HCl and extracted with EtOAc (200 ml). The organic phase was washed with brine (2 x 75 ml), dried (Na 2 SO), filtered and concentrated in vacuo. The concentrate was triturated with CH2C12 (100 ml) and the white solid material obtained was dried in vacuo to obtain 6.85 g of the title product (yield 975). H NMR (500 MHz, CD3OD): d 7.82 (s, 2H), 6.78 (d, ÍH, J = 2.7 Hz), 6.63 (d, ÍH, J = 8.8 Hz), 6.61 (t, ÍH, J = 4.9 Hz), 6.38 (dd, ÍH, J = 8.8, 3.3 Hz), 4.65 (s, ÍH), 4.24 (d, 2H, J = 5 Hz), 3.16 (heptet, ÍH, 6.6 Hz), 1.22 (d, 6H, J = 6.6 Hz); 13C NMR: d 172.88, 167.20, 151.81, 151.34, 151.13, 137.67, 133.40, 131.39, 129.63, 116.41, 114.19, 113.28, 42.27, 28.19, 22.85; MS-ESI "[M-H]" = 396, 398, 400 (200: 64: 10).

EXAMPLE 87 N- [3, -Dicarloro-4- (4-hydroxy-3-isopropyiphenoxy) benzoyl] sarcosine (a) To a solution of 3,5-dichloro-4- (4-methoxy-3-isopropyiphenoxy) benzoic acid (60 mg, 0.169 mmol), in CH2C12 (10 mL) cooled with an ice-bath H20 was added sarcosine hydrochloride methyl ester (35.4 mg, 0.253 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (38.9 mg, 0.203 mmol) and l-hydroxy-7-azaber zotriazole (27.6 mg, 0.203 mmol) ) and N-methylmorpholine (34.2 mg, 37 uL, 0.338 mmol). The mixture was allowed to warm to room temperature and was left stirring overnight (ca, 18 hours). The mixture was taken up in EtOAc (50 ml) and H20 (20 ml). The organic layer was separated and then washed successively with IN HCl (2 x 25 ml), saturated aqueous NaHCO 3 solution (2 x 25 ml) and brine (2 x 25 ml). The organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography (25 g of silica gel, 30% EtOAc in hexane) to obtain 41 mg of the purified material (55% yield). The satisfactory proton and LC-MS were obtained. (b) To a solution of the previous product (30 mg, 0.068 mmol) in anhydrous CH2C12 (3 ml) cooled with a bath of h: Lelo-H2? boron tribromide (0.7 ml, 1.0 M in CH2Cl2, 0.7 mmol) was added. After two hours, the mixture was poured into ice-H20 (25 ml). After 15 minutes of stirring, the product was extracted with EtOAc (50 ml). The organic extract was washed with brine (2 x 25 ml), dried (MgSO 4), filtered and concentrated in vacuo. The crude product, a mixture of free acid and methyl ester, was dissolved in THF (2 ml) and an aqueous solution of 1 N lithium hydroxide (1 ml) was added. After one hour, the mixture was acidified with IN HCl and then extracted with EtOAc (25 mL). The EtOAc extract was washed with brine (2 x 25 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to obtain 35 mg of the crude product. The crude product was purified by preparative HPLC to obtain 12.3 mg of a slightly yellowish solid as purified material (yield 44%). Satisfactory proton and mass spectrum results were obtained.

Example 88 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl-5-dimethylamino-1-naphthalenesulfonamide To a solution of 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetic acid (50 mg, 0.09 mmol), dimethylaminopyridine (4 mg, 0.018 mmol) and 5-dimethylamino-1-naphthalenesulfonamide (45 mg, 0.18 mmol) in 50% dichloromethane in dimethyl formamide (0.2 ml) was added a solution of 1- (3-dimethylaminopropyl) hydrochloride - 3-ethylcarbodiimide (28 mg, 0.13 mmol) and diisopropylethyl amine (17 mg, 0.13 mmol) in 50% methylene chloride in dimethylformamide (0.2 ml). The reaction mixture was vortexed and allowed to stand at room temperature for 6 hours. A solution of ammonium fluoride (0.5 M in methanol, 0.4 ml) was added. After 16 hours, the reaction mixture was evaporated to dryness, redissolved in a solvent mixture containing 90% methanol, 10% water and 0.1% trifluoroacetic acid (2 ml) and purified by preparative HPLC ( YMC S5 ODS 30 X 250 mm: 50-100% solvent B in 30 minutes: solvent A-90% water, 10% methanol, 0.1 trifluoroacetic acid, solvent B-10% water, 90% methanol, 0.1% trifluoroacetic acid: speed flow rate 25 ml per minute: detection at 220 nm). In yield it was 10.1 mg (16%).

Examples 89-91 These compounds were prepared and purified in the same way as above. For a table of Examples 88-91 containing the coupled sulfonamide, the Retention times and mass spectra, see the following Scheme.

XYMC ODS 4.6 x 50 mm: 50-100% solvent B in 8 minutes: solvent A-90% water, 10% methanol, 0.2% phosphoric acid; solvent B-10% water, 90% methanol, 0.2% phosphoric acid: flow rate 2.5 ml per minute: detection 220 nm.

Examples 91-191 The procedures for the synthesis of the library compounds indicated in the following Table are described in Lawrence, R. M .; Biller, S. A .; Fryszman, O. M.; Poss, M.A. Synthesis 1997, 553. 1HPLC retention time in minutes and gradient method. Real-phase reversed-phase HPLC analyzes on YMC S5 ODS 4.6 x 50 ml analytical columns, detection at 220 nm, and gradient elutions of 4 minutes by: method a, 0% B, 100% A up to 100% B , 0% A; or method b, 20% B, 80% A up to 100% B, 0% A, where solvent A is 90% water, 10% methanol, 0.2% phosphoric acid and solvent B is 10% water, 90% methanol , 0.2% phosphoric acid. 2MS results obtained in Micromass Platform II using electrospray, in the positive and negative ion modes. 3 Method A. The examples were prepared by synthesis procedure A in the reference before mentioned. In these examples a second basic nitrogen is present in the amine coupler. However, only one nitrogen can give the product of normal acylation. The examples of method B were prepared by procedure C in the aforementioned reference.

Examples 192-203 General procedure 3,5-Dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid was coupled with the appropriate amino acid, using the general procedure outlined for Examples 3-24. The residue was subjected to semipreparative HPLC using the same elution in gradient as mentioned for Examples 3-24. The amine part "R" and the stereochemistry of the amino acids are indicated in the following Table. The retention times, yields and the masses of the individual products are also provided in the following.

EXAMPLE 204 2- [3,5-Dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzyl] -4-thiazole acetic acid (a) A reaction mixture of 3,5-dibromo-4- (4-methoxy-3-isopropylphenoxy) phenyl acetamide (150 mg) and the LAVESON reagent (100 mg) in dioxane (3 ml) was stirred at room temperature. environment for 15 hours. The resulting suspension was filtered and poured onto ice water and stirred. The aqueous phase was extracted with EtOAc (3 x 7 ml) and the combined organic phases were washed with water. The organic phase was dried over Na 2 SO 3, concentrated and produced 153 mg of crude 3,5-dibromo-4- (4-methoxy-3-isopropylphenoxy) phenylthioamide. The crudc product was used directly in the next step. (b) To a suspension of 3,5-dibromo-4- (4-methoxy-3-isopropylphenoxy) phenyl thioamide (80 mg) in EtOAc (2 ml), ethyl chloroacetoacetonate (0.03 ml) was added. The mixture was stirred in a closed tube at 75 ° C for two hours. The reaction mixture was concentrated in EtOAc and water was added. The aqueous phase was extracted with EtOAc (3 x 5 ml) and the combined organic phases were washed with NaHCO 3 (saturated solution). The organic phase was dried over Na 2 SO 4, concentrated and purified by chromatography (silica gel, 15% EtOAc / p-ether). This produced 80 mg (86%) of ethyl-2- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzyl] -4-thiazole acetate. (c) BF3, Et2 (0.06 ml) was added slowly to a solution of ethyl ester (60 mg) in CHC12 (4 ml). The reaction mixture was stirred at room temperature for two days. Water was added. The aqueous phase was extracted with EtOAc (3 x 5 ml) and the combined organic phases were washed with an aqueous solution of HCl (1 N). The organic phase was dried over Na 2 SO 4, concentrated and purified by semipreparative HPLC. This produced 20 mg (37%) of the title compound.

EXAMPLE 205 2- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzyl] -4-methylthiazole A) 3,5-dibromo-4- (4-methoxy-3-isopropylphenoxy) phenyl thioamido (70 mg) in EtOH (2 ml) reacted with ethylchloroacetoacetonate (0.014 ml) using the method described in Example 204 ( b) The crude product was purified by chromatography (silica gel, 15% EtOAc / p-ether). 60 mg (78%) of 2- [3,5-dibromo-4- (4-methoxy-3-isopropylphenoxy) benzyl] -4-methylthiazole was obtained. (b) The above methoxy compound (50 mg) was demethylated with BF3Et2 (0.06 ml), using the method already described. The crude mixture was purified by semi-preparative HPLC to give 20 mg (41% of the title compound).

EXAMPLE 206 3,5-Dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenyl-formylimino-diacetic acid (a) To a solution of 3,5-dichloro-4- (4-methoxy-3-isopropylphenoxy) benzoic acid (60 mg, 0.169 mmol) in CH2Cl2 (10 ml) cooled in an ice-bath H20 was added dimethyliminodiacetate (35.4 mg, 0.253 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (38.9 mg, 0.203 mmol) and l-hydroxy-7-azabenzotriazole (27.6 mg, 0.203 mmol). The mixture was allowed to warm to room temperature and was allowed to stir overnight (approximately 18 hours). The mixture was taken up in EtOAc (50 ml) and H20 (20 ml). The organic layer was separated and then washed successively with HCl and IN (2 x 25 ml), saturated aqueous solution of NaHCO 3 (2 x 25 ml) and brine (2 x 25 ml). The organic extract was dried (Na 2 SO 4), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel 25 g, 15% EtOAc in hexane) to obtain 31 mg of the purified material (35% yield). Satisfactory proton and LC-MS data were obtained. (b) To a solution of the above ethyl ester (25 mg, 0.047 mmol) in anhydrous CH2Cl2 (3 mL) cooled in an ice-bath H20 was added boron tribromide (0.7 mL, 1.0 M in CH2C12, 0.7 mmol). After two hours, the mixture was poured into ice-H20 (25 ml). After 15 minutes of stirring, the product was extracted with EtOAc (50 mL). The organic extract was washed with brine (2 x 25 ml, dried (MgSO 4), filtered and concentrated in vacuo The crude product, a mixture of free acid and methyl ester, was dissolved in THF (2 ml) and a solution was added aqueous lithium hydroxide solution 1 N (1 ml). hour, the mixture was acidified with IN HCl and then extracted with EtOAc (25 ml). The EtOAc extract was washed with brine (2 x 15 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to obtain 27.7 mg of the crude product. The crude product was purified by preparative HPLC to obtain 9.2 mg (38%) of the title compound as a light yellow solid. Satisfactory proton and mass spectrum data were obtained.

Example 207 N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -beta-alanine (a) 3, 5-dibromo-4- (4-hydroxy-3-isopropoylphenoxy) benzoic acid (50 mg, 0.116 mmol), beta-alanine hydrochloride methyl ester (70 mg, 0.42 mmol) ,. and hydroxybenzotriazole (78 mg, 0.57 mmol) were dissolved in dichloromethane (0.6 ml), N, N-dimethylformamide (0.2 ml) and triethyl amine (0.12 ml, 0.58 mmol). The solution was cooled to 0 ° C and acid chloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (110 mg, 0.58 mmol) was added. The reaction was warmed to room temperature and stirred for 12 hours. The reaction was diluted with dichloromethane (100 ml) and washed with water (2 x 150 ml). The organic layer was washed once with brine (100 ml), dried over sodium sulfate and concentrated in vacuo. The methyl ester (50 mg, 90% yield) was purified by chromatography (silica gel, 7: 3 hexane / ethyl acetate). (b) The crude ester was dissolved in 1.0 ml of methanol and 0.4 ml of IN sodium hydroxide. The hydrolysis was completed in two hours. The methanol was removed and the aqueous layer was acidified with aqueous hydrochloric acid (1 N). The aqueous layer was extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine (2 x 75 ml) and dried over sodium sulfate. The organic layer was concentrated in vacuo. The title compound (51 mg, 98%) was obtained without further purification. 1 H-NMR, 13 C-NMR and mass spectrum satisfactory for the title compound were obtained.

Example 208 N- [3, -Dicarloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -beta-alanine (a) The ester was prepared by adding the reactants to the reaction in a manner described in Example 207. The starting acid (122 mg, 0.356 mmol), B-alanine methyl ester hydrochloride and hydroxybenzotriazole (240 mg, 1.76 mmol) were dissolved in triethyl amine (0.6 ml, 2.5 mmol), dichloromethane 1.2 ml and 0.8 ml of dimethylamide. The acid chloride of 1- (3-dimet-1-laminopropyl) -3-ethylcarbodiimide (110 mg, 0.58 mmol) was added in the manner already described.The ester (75 mg, 50%) was isolated without further purification. The ester was dissolved in 3.0 ml of methanol and 1.6 ml of IN sodium hydroxide using the procedure described for the title acid.The title acid (72 mg, 98% yield) was obtained from the reaction. The acid was purified by preparative HPLC using YMC ODS 20 x 100 mm column which yielded 53.6 mg (yield 74%) of the purified acid.

Example 209 L-N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] serine 3, 5-Dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid (122 mg) was coupled with L-serine methyl ester hydrochloride using the method described in Example 207 (a) and subsequently hydrolysed using the method described in Example 207 (b). The crude mixture was purified as in the above. Satisfactory data were obtained from the - "? - NMR, 13 C-NMR and the mass spectrum for the title compound.

Example 210 D-N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] serine 3, 5-Dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoic acid (122 mg) was coupled with D-serine methyl ester hydrochloride using the method described in Example 207 (a) and subsequently hydrolyzed using the method described in Example 207 (b). The crude mixture was divided as above. Satisfactory data were obtained for 1 H-NMR, 13 C-NMR and the mass spectrum for the title compound.

Examples 211-228 The compounds listed in the following table are all examples of other compounds, which can be easily prepared by the synthetic procedure described in Example 86.

Examples 229-231 N- [3,5-dichloro-4- (4-hydroxy-3-bromophenoxy) benzoyl] glycine N- [3,5-dichloro-4- (4-hydroxy-3-methylphenoxy) benzoyl] glycine N- [3,5-dichloro-4- (-hydroxy-3-ethylphenoxy) benzoyl] glycine These compounds were all prepared by a method similar to that used in Example 86. For the t.:es compounds satisfactory yields of Hl-N F, 13C-NMR and the mass spectrum were obtained.

Claims

1. A compound that has the formula: wherein: is an integer from 0 to 4 Ri is halogen, trifluoromethyl or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons , at least one of R2 or R3 being different from hydrogen R4 is a heteroaromatic portion which may be substituted or unsubstituted and is linked to (CH) n by a nitrogen atom or a carbon atom; an amine (NR'R "), including those in which the amine is derived from an alpha amino acid of natural (L) or non-natural stereochemistry (D), an acyl sulfonamide (CONHS02R ') or a carboxylic acid amide (CONR'R) ") with the proviso that when n is equal to zero (n = 0), then R 4 can only be one carboxylic acid amide or one acyl sulfonamide R 5 is hydrogen or an acyl group (such as cetyl or benzoyl) or another group capable of bioconversion to generate the free phenol structure (wherein R5 = H) included all of these stereoisomers, the esters of the prodrugs thereof and the pharmaceutically acceptable salts thereof.

2. The compound as defined in claim 1, wherein R4 is a carboxylic acid amide (CONR'R ") in which the amine portion of the carboxylic amide can be obtained from an achiral alpha amino acid or L or D as it can be when the General structure -CONR'R "can be represented by: and R ', R ", R"', and R "" are the same or different and are independently selected from hydrogen, alkyl, aryl and heteroaryl, substituted or unsubstituted and R * may be hydrogen, alkyl, aryl and heteroaryl, substituted or unsubstituted, and can also be any of the side chains found in the alpha amino acids that occur in nature.

2. The compound as defined in claim 2, wherein R 'and R * are connected to form a ring of 4 to 8 members.

4. The compound as defined in claim 2, wherein R 'and R * comprise consecutive - (CH2) - groups to form proslina or homoproline.

5. The compound as defined in claim 1 wherein n is 0 or 1 or 2.

6. The compound as defined in claim 1, wherein R2 and R3 are each independently halogen.

7. The compound as defined in claim 1 wherein R2 and R3 are each independently an alkyl group.

8. The compound as defined in claim 1, wherein R2 or R3 is halogen and the other is an alkyl group.

9. The compound as defined in claim 1, wherein R2 or R3 is halogen and the other is hydrogen.

10. The compound as defined in claim 1, wherein R2 or R3 is alkyl and the other is hydrogen.

11. The compound as defined in claim 1 wherein R2 or R3 are independently Cl, Br, methyl or ethyl.

12. The compound as defined in claim 1, wherein Ri is isopropyl.

13. The compound as defined in claim 1, wherein R 4 is heteroaromatic hydrocarbon, carboxylic acid amide or an acylsulfonamide.

14. The compound as defined in claim 1, wherein R5 is hydrogen.

15. The compound as defined in claim 1, which is: 3,5-dimethyl-4- (4-hydroxy-3-isopropylphenoxy) benzyltetrazole 3,5-di.chloro-4- (4-hydroxy-3-isopropylphenoxy) ) Benzyltetrazole 2- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzyl] -4-thiazole acetic acid 2- [3, -dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzyl] -4-methylthi ^ zol

16. The compound as defined in claim 1, which is: 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-5-hydroxy-1-naphthalenesulfonamide 3, 5-dibromo-4- (4 -hydroxy-3-isopropylphenoxy) benzoyl-4-toluenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4-nitrobencenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) ) benzoylsulfamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-5-dimethylamino-1-naphthalenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4- aminotencenesulfonamide [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-2-sulfonamide] methyl benzoate 3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-2-aminobenzenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-iso? Ropilphenoxy) benzoyl-2-toluenesulfonamide 3, 5-dibromo- - (4-hydroxy-3-isopropylphenoxy) benzoi-1- (2-aminoethyl) benzenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4- (2-aminopae, 'yl) benzenesulfonamide 3, 5-dibromo- - (4-hydroxy-3-isopropylphenoxy) benzoyl-3 -nirrobenzenesulfonamide 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl-4-chlorobenzenesulfonamide and the compounds shown below

17. The compound as defined in claim 1 which is in the following Table R = N * H 'V compounds indicated in the following table

18. The compound as defined in claim 1, which is: DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] valine DN- [3,5-dibromo-4- (4 -hydroxy-3-isoprooylphenoxy) benzoyl] leucine LS-beicil, N- [3, 5-dibromo-4- (4-hydroxy-3- isopropylphenoxy) benzoyl] cysteine DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] tyrosine LNd- (2,2,5,7,8-pentamethylchroman-6-sulfonyl) N- [ 3,5-dibromo-4- (4-hydroxy-3-isoprc-phenyl-phenoxy) benzoyl] arginine LN- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] aminobutyric acid LN- [3, 5] -dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] valine LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] leucine LN- [3,5-dibromo-4] - (4-hydroxy-3-isopropylphenoxy) benzoyl] proline LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] cysteine N- [3,5-dibromo-4- (4- hydroxy-3-isopropylphenoxy) benzoyl] glycine LNa- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine DNa- | 3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] aminoisobutyric acid LN- [3, 5 -dibromo-4- (4-hydroxy-3-) isopropylphenoxy) benzoyl] phenylglycine DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] phenylglycine N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] sarcosine DL-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -a-methylphenylalanine LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl) ] -isoleucine DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -methionine LN- [2 > , 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] • methionine LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] -phenylalanine DN- [3, 5 -dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] • phenylalanine LN- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] • cyclohexylalanine LNe- (benzyloxycarbonyl), -a - [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] lysine DNe- (benzyloxycarbonyl), -a- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl) ] lysine DN- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] homoserine N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] glycine N- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] sarcosine Acid 3, 5 -dichloro-4- (4-hydroxy-3-isopropylphenoxy) phenylformylimino diacetic N- [3, -dibromo-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] beta-alanine N- [3, 5-dichloro- 4- (4-hydroxy-3-isopropylphenoxy) benzoyl] beta-alanine DN- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] methionine LN- [3,5-dichloro-4-] (4-hydroxy-3-isopropylphenoxy) benzoyl] serine DN- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) benzoyl] serine N- [3, -dichloro-4- (4-hydroxy) 3-bromophenoxy) benzoyl] glycine N- [3,5-dichloro-4- (4-hydroxy-3-methylphenoxy) benzoyl] glycine N- [3, -dichloro-4- (4-hydroxy-3-ethylphenoxy) benzoyl] glycine

19. The compound as defined in claim 1, which is: DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] methionine LN- [3, 5-dibromo-4- (4 -hydroxy-3- isopropylphenoxy) phenylacetyl] methionine DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] a-methylalanine DN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] asparagine L-methyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] alanine LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] alanine L-dimethyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamate L-dimethyl-N- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamate [sic] L- (o-tert-butyl) methyl-N- [3, 5-dibromo-4- (4-hydroxy-3 -isopropylphenoxy) phenylacetyl] glutamate LN- [3, 5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamic acid LN- [3,5-dichloro-4- (4-hydroxy-3-isopropylphenoxy) acid ) phenylacetyl] aspartic D-di-tert-butyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamate DN- [3, 5-dibromo-4- (4- hydroxy-3-isopropylphenoxy) phenylacetyl] glutamic LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] glutamine DN- [3,5-dibromo-4- (4-hydroxy-3-i = opropylphenoxy) phenylacetyl] glutamine Lo-benzyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) acid) phenylacetyl] aspartic Lo-tert-butyl-N- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] asparagine L-methyl-N- [3, 5-dibromo-4- (4- hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine LN- [3,5-dibromo-4- (4-hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine D-met il-N- [3, 5-dibromo-4- (4 -hydroxy-3-isopropylphenoxy) phenylacetyl] homoserine and the compounds shown in the following table: 25

20. The compounds as defined in claim 1 having the structures: or a salt or ester (s) acceptable for pharmaceutical use thereof.

21. The compounds as defined in claim 1 having the structures: or the salt or ester (s) acceptable for pharmaceutical use thereof.

22. The compounds as defined in claim 1 having the structures wherein Ri = isopropyl, methyl, ethyl; R2 and R3 can be independently selected from Br, Cl and Me; n = 0 or 1; R * can be hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; * denotes the stereochemistry D or L when R * is not hydrogen; R5 is hydrogen; and R 'is selected from hydrogen, lower alkyl, especially ethyl and methyl.

23. A method of preventing, inhibiting or treating a disease associated with dysfunction of metabolism, or which depends on the expression of a gene regulated by T3, which consists of administering to a patient in need of treatment an effective amount for therapeutic use of a compound as defined in claim 1.

24. The method as defined in the claim 23, where the disease associated with metabolic dysfunction or that depends on the expression of a gene regulated by T3 is obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiac arrhythmia, congestive heart failure or skin disorders.

25. The use of a compound according to claim 1 in the preparation of a medicament for the treatment of a disease or disorder that depends on the expression of a gene regulated by T3.

26. The use of a compound according to claim 1 in which the disease or disorder is selected from hypothyroidism, hypercholesterolemia, obesity, skin disorders, glaucoma, cardiovascular disease, congestive heart failure and other endocrine disorders related to thyroid hormone.

27. A pharmaceutical composition containing an effective amount of a compound according to claim 1 or a pharmaceutically effective salt thereof, together with an acceptable carrier for pharmaceutical use.

28. The method according to claim 24, wherein the skin disorder or disease is skin atrophy, post-surgical contusion caused by superficial laser resurfacing, keloids, striae, cellulitis, rough skin, actinic skin damage, lichen flat, ichthyosis, acne, psoriasis, Dernier's disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring.

29. A method for treating skin disorders or diseases by using a compound of claim 1 in combination with a retinoid or a vitamin D analog. SUMMARY OF THE INVENTION New thyroid receptor ligands having the general formula (I) are provided in which: n is an integer from 0 to 4; Ri is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons; R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at least one of R2 or R3 being different from hydrogen; R4 is a carboxylic acid amide (CONR'R ") or an acyl sulfonamide derivative (CONHS02R ') or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof; or when n is equal to or greater than 1, R 4 may be a heteroaromatic portion that may be substituted or unsubstituted, or an amine (NR'R "). R 5 is hydrogen or an acyl (such as acetyl or benzoyl) or other group capable of bioconversion to generate the free phenol structure (where R5 = H) In addition, a method is provided for the prevention, inhibition or treatment of a disease associated with metabolic dysfunction or that depends on the expression of a gene regulated by T3 , where a compound such as those already described is administered in an effective amount for therapeutic use, examples of these diseases associated with dysfunction of the metabolism or that are dependent on the expression of a gene regulated by 7; they include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, as well as glauccra, congestive heart failure and skin disorders.