MXPA00002133A - Cyano containing oxamic acids and derivatives as thyroid receptor ligands - Google Patents

Abstract

The present invention provides novel compounds of the Formula and prodrugs thereof, geometric and optical isomers thereof, and pharmaceutically acceptable salts of such compounds, prodrugs and isomers, wherein R1 - R8 and X are as described herein. Pharmaceutical compositions containing such compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and methods, pharmaceutical compositions and kits for treating obesity, hyperlipidemia, thyroid disease, hypothyroidism and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis are also provided.

Description

OXAMINE ACIDS CONTAINING CYANUM AND DERIVED FROM THEM AS LIGANDS OF THYROID RECEPTORS FIELD OF THE INVENTION The present invention relates to new thyroid receptor ligands and, more particularly, relates to novel cyano-containing oxamic acids, and their derivatives, which are useful in the treatment of obesity, hyperlipidemia, thyroid disease, hypothyroidism and related disorders and diseases. such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis. Methods, pharmaceutical compositions and kits for treating such diseases and disorders are also provided.

BACKGROUND OF THE INVENTION It is generally accepted that thyroid hormones, specifically biologically active iodothyronines, are critical for normal development and for the maintenance of metabolic ostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and intensify the responses (policies of fat cells to other hormones.) Thyroid hormones also affect cardiac function both directly and indirectly, e.g., by increasing basal metabolism.

For example, tachycardia, increased blood volume per beat, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure in patients with hyperthyroidism are observed. Thyroid disorders are generally treated with hormone replacement therapy by administration, or thyroid hormones of natural origin or thyromimetic analogs thereof that mimic the effects of thyroid hormones. Next, two thyroid hormones of natural origin are shown, namely thyroxine or SdS'.d'-tetraiodinated-L-thyronine (commonly referred to as "T4") and 3,5,3'-triiodo-L-thyronine ( commonly called "T3"): HO- / TV-CW * V -CH COOH Td T3 is the most biologically active of the two and, as will be appreciated from the structural formulas given above, differs from T4 in the absence of the iodine at the 5 'position. T3 can be produced directly from the thyroid gland, or, in peripheral tissues, by removal of iodine from the 5 'position by deiodinated enzymes. Thyromimetic analogs are often designed to be structurally similar to T3. In addition, metabolites of T3 of natural origin are known.

As indicated above, thyroid hormones affect cardiac function, for example, causing an increase in heart rate and, consequently, an increase in oxygen consumption. Although the increase in oxygen consumption may result in certain desired metabolic effects, nevertheless, extra work on the heart takes place, which in some situations, may give rise to harmful side effects. Therefore, as is known in the art, as described by A.H. Underwood et al. in an article published in Nature, vol. 324: pp. 425-429 (1986), attempts have been made to synthesize analogs of thyroid hormones that function by lowering serum lipids and cholesterol without generating the adverse cardiac effects mentioned above. U.S. Pat. No. 4,766,121; 4,826,876; 4,910,305 and 5,061,798 disclose certain mimetics of thyroid hormones, namely 3,5-dibromo-3 '- [6-oxo-3 (1 H) -pyridazinylmethyl] -thrones. U.S. Pat. No. 5,284,971 discloses certain thyromimetic agents that lower cholesterol, namely, 4- (3-cyclohexyl) -4-hydroxy-or-methoxy-phenylsulfonyl) -3,5-dibromo-phenylacetic compounds. U.S. Pat. No. 5,401,772; 5,654,468 and . 569,674 disclose certain lipid-lowering agents, namely, heteroacetic acid derivatives, which compete with radiolabeled T3 in binding assays, in which preparations of plasma membranes and rat liver nuclei are used. Certain oxamic acids and their derivatives are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain oxamic acids to prevent immediate type hypersensitivity reactions; U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids to suppress pests on animals and plants; U.S. Pat. No. 5,232,947 describes the use of certain oxamic acids to improve brain damaged brain functions; and the memory of the European Patent published as EP-580,550 discloses certain oxamic acid derivatives as hypocholesterolemic agents. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama et al. in an article published in the Journal of Medicinal Chemistry, 38 (4): 695-707 (1995) describe the substitution of a -CH2 group in a natural metabolite of T3 by a -NH group resulting in -HNCOCO2H. Likewise, R.E. Steele et al. in an article published in International Congressional Service. { Atherosclerosis X) 1066: 321-324 (1995) and Z.F. Stephan and cpj. in an article published in Atherosclerosis, 126: 53-63 (1996), describe certain oxamic acid derivatives useful as thyromimetic agents for lowering lipids and devoid, however, of undesirable cardiac activities. All documents cited here, including the foregoing, are hereby incorporated by reference herein in their entirety.

SUMMARY OF THE INVENTION The present invention provides compounds of Formula (i) their prodrugs, their geometric and optical isomers, and pharmaceutically acceptable salts of said compounds, said prodrugs and said isomers, wherein: R1 and R2 are independently halogen, C ^ g alkyl, -CN or perfluoroalkyl C-j_g; provided that at least one of R 'and R2 is -CN; R3 is hydrogen or C < j_g; R ^ is halogen, perfluoroalkyl C ^ g, alkyl Cj.g, C 1-8 alkanoyl hydroxy- (C-g alkyl), aryl optionally substituted with Y and Z, aryl- (C-g alkyl), carbocyclic aroyl optionally substituted with Y and Z, cycloalkyl C ^ .- \ Q optionally substituted with Y and Z, or cycloalkyl C-μg); or R ^ is the radical R 10 R 11 wherein: R "is hydrogen, C-μg alkyl, aryl optionally substituted with Y and Z, aryl- (C-j_g alkyl), cycloalkyl 03.10 optionally substituted with Y and Z, or C3_? n- cycloalkyl (C- | g alkyl); R ^ is -OR ^; R ^ is hydrogen or C ^ g alkyl; or R ^ and R "'" can be taken together with the carbon atom to which they are attached to form a carbonyl group; R ^ is hydroxy, esterified hydroxy or etherified hydroxy; R ^ is hydrogen, halogen, C-μg alkyl or perflu-alkylalkyl C-μg; R7 is hydrogen, C-μg alkyl or perfluoroalkyl C-j.g; R8 is -OR12 or -NR12R13; They are each independently hydrogen or C ^ _ alkyl; R ^ 4 is hydrogen, C-μg alkyl or C- | g acyl; X is O, S (0) a, C = O or NR15; a is 0, 1 or 2; R1 5 is hydrogen or C < \ _g; Y and Z, each time they appear, are independently (a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) -OCF3, (e) -CN, (f) C ^ g alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF3 and phenyl, (g) C5-5 alkoxy, (h) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF 3, C 1-4 alkyl and C 1-4 alkoxy, (i) -C (0) 2 R 16, (j) C (0) NR 16 R 17, (k) -C (0) R 16, (I) -NR16C (O) NR16R17 or (m) -NR16C (O) R17; or Y and Z, each time they appear, can be taken together to form (a) a carbocycle of the formula -. { C ^) ^, or (b) a heterocycle selected from the group consisting of 0 (CH2) cO, (C ^^ NH- and CH = CHNH-; b is 3, 4, 5, 6 or 7; c and d are each independently 2, 3, 4, 5 or 6: R16 and R17J once they appear, are independently hydrogen, C-μg alkyl, C2_ß alkenyl - (C C_g alkyl) -alcoxy Cg, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (C C4 alkyl) -aryl optionally substituted with X and Y, - (C 1 4 4 alkyl) -heterocycle optionally substituted with X and Y, - (C C alkyl; | _4) -h¡drox¡, - (alkyl C? _4) -halo, - (alkyl C- | _4) -poly-halo, - (C 1 alkyl) -CONR 18 R 19 or C 1 Q cycloalkyl; het, each time it appears, is a ring of 4, 5, 6, 7 or 8 members partially or totally saturated, or unsaturated, containing one to four heteroatoms independently selected from the group consisting of N, O and S, and which includes any bicyclic group in which any of the above heterocyclic rings is fused with a benzene ring or other heterocycle which is a 4, 5, 6, 7 or 8 membered ring, partially or fully saturated, or unsaturated, which contains from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and R18 and R19; Once they appear, they are independently hydrogen, alkyl C < μg, C3..10 ° C aryl cycloalkyl optionally substituted with Y and Z. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, designated Group A, contain the compounds of Formula I and the pharmaceutically acceptable salts of such compounds, as indicated above, wherein X is oxygen. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group A, designated Group B, contains the compounds of Formula I and the pharmaceutically acceptable salts of such compounds, as indicated above, wherein R3 is located in the position 2 ', R4 is located in the 3' position, R ^ is located in the position 4 'and R ^ is located at the 5' position. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group B, designated Group C, contains the compounds of Formula I and the pharmaceutically acceptable salts of such compounds, as indicated above, wherein R3, R5 and R7 they are hydrogen, and R6 is hydroxy. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group C, designated Group D, contains the compounds of Formula I and the pharmaceutically acceptable salts of such compounds, as indicated above, wherein R1 and R2 are each one independently -CN, methyl or chloro, provided that at least one of R1 and R2 is -CN. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group D, designated Group E, contains the compounds of Formula I and pharmaceutically acceptable salts of such compounds, as indicated above, wherein R8 is -OR12. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group E, designated Group F, contains the compounds of Formula I and the pharmaceutically acceptable salts of such compounds, as indicated above, wherein R 12 is hydrogen, methyl or ethyl, and R 4 is -CH (CH 3) 2. A preferred group of compounds and pharmaceutically acceptable salts of such compounds, from Group D, designated Group G, contains the compounds of Formula I and pharmaceutically acceptable salts of such compounds, as indicated above, wherein R8 is -NR1 R13 . A preferred group of the pharmaceutically acceptable salts of the compounds of Formula I, and the prodrugs, geometric and optical isomers thereof, contains the pharmaceutically acceptable salts of the compounds, prodrugs, and geometric and optical isomers in which the salt is a salt of sodium or potassium. A preferred group of compounds of Formula I, prodrugs and geometric and optical isomers thereof, and pharmaceutically acceptable salts of the compounds, prodrugs and isomers, designated Group H, includes the specific compounds N- [3-cyano-4- ( 4-hydroxy-3-isopropyl-phenoxy) -5-methyl-phenyl] -oxamic acid and N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -oxamic acid , and its ethyl esters. A preferred group of the pharmaceutically acceptable salts of the compounds, prodrugs, and geometric and optical isomers of Group H, designated Group I, contains the pharmaceutically acceptable salts of the compounds, prodrugs and geometric and optical isomers in which the salt is a salt of potassium or sodium. This invention provides methods of treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug or said isomer, as described above. In another aspect, this invention provides methods of treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), which comprise administering to said mammal therapeutically effective amounts of a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug or said isomer, as described above, and an anorexic agent. In another aspect, this invention provides methods of treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), which comprise administering to said mammal therapeutically effective amounts of a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug or said isomer, as described above, and a lipase inhibitor. In a preferred aspect, this invention provides methods of treating obesity in mammals (including a human), comprising administering to said mammal an effective amount to treat obesity of a compound of Formula I, or a prodrug thereof, or an isomer geometric or optical thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above. In another aspect, this invention provides methods of treating obesity in mammals (including a human), comprising administering to said mammal amounts effective to treat obesity of a compound of Formula I, or a prodrug thereof, or a geometric isomer or optical thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, and an anorectic agent. In another aspect, this invention provides methods of treating obesity in mammals (including a human), comprising administering to said mammal amounts effective to treat obesity of a compound of Formula I, or a prodrug thereof, or a geometric isomer or optical thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, and a lipase inhibitor. In another aspect, this invention provides pharmaceutical compositions comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above. , and a pharmaceutically acceptable carrier, diluent or carrier. In another aspect, this invention provides pharmaceutical compositions comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above. , an anotonic agent and a pharmaceutically acceptable carrier, diluent or carrier. In another aspect, this invention provides pharmaceutical compositions comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above. , a lipase inhibitor and a pharmaceutically acceptable carrier, diluent or carrier. In another aspect, this invention provides pharmaceutical compositions for treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, and a pharmaceutically carrier, diluent or carrier acceptable. In another aspect, this invention provides pharmaceutical compositions for treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometrical or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, an anorectic agent, and a pharmaceutically acceptable carrier, diluent or carrier.

In another aspect, this invention provides pharmaceutical compositions for treating a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, a lipase inhibitor, and a carrier , diluent or pharmaceutically acceptable carrier. In another preferred aspect, this invention provides pharmaceutical compositions for treating obesity in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically salt acceptable of said compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, diluent or carrier. In yet another preferred aspect, this invention provides pharmaceutical compositions for treating obesity in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a salt thereof. pharmaceutically acceptable of said compound, prodrug or isomer, as described above, an anorectic agent, and a pharmaceutically acceptable carrier, diluent or carrier.

Yet another preferred aspect, this invention provides pharmaceutical compositions for treating obesity in a mammal (including a human), comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically salt acceptable of said compound, prodrug or isomer, as described above, a lipase inhibitor, and a pharmaceutically acceptable carrier, diluent or carrier. In another aspect, this invention provides kits for the treatment of a condition selected from obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis comprising: a first compound, said first comprising a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, carrier or diluent. , in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable carrier, carrier or diluent, in a second unit dosage form; and a container. In another preferred aspect, this invention provides kits for the treatment of obesity comprising: a first compound, said first compound being a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically salt acceptable of said compound, prodrug or isomer, as described above, and a pharmaceutically acceptable carrier, carrier or diluent, in a first unit dosage form; a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable carrier, carrier or diluent, in a second unit dosage form; and a container. Unless otherwise indicated, in this context: "acyl" means an organic radical derived from an organic acid by elimination of the hydroxyl group, including, as the case may be, for example, acetyl, alkanoyl C- | _g, aryl carbocyclic-alkanoyl C -μ carbocyclic aroyl; "alkanoyl" means a univalent or bivalent acyl radical formed by hydroxyl removal of the carboxyl group which substituted the methyl group at the end of the acyclic hydrocarbon backbone chain; "alkanoyl C- |" g " It includes, as the case may be, for example, acetyl, propionyl, butyryl or pivaloyl; "alkanoylamino" of "alkanoyl C ^ .g-amino" includes, as the case may be, for example, acetamido or propionamido; "alkoxy" means an alkyl radical that is attached to the rest of the molecule by oxygen, including, as the case may be, for example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; "alkoxycarbonyl" of "C 1 -g-carbonyl alkoxy" preferably contains one to four carbon atoms in the alkoxy moiety and includes, as the case may be, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl; "alkyl" means a straight or branched chain hydrocarbon radical, including, as the case may be, for example, methyl, ethyl, / 7-propy, isopropyl, n-butyl and the like; "Aroyl" means aryl acyl, including, as the case may be, for example, benzenesulfonyl, benzoyl and naphthoyl; preferably benzoyl and benzoyl substituted on the benzene ring with C? _g alkyl, C- |g alkoxy, halogen or trifluoromethyl; "Aryl" includes carbocyclic aryl and heterocyclic aryl, and is preferably phenyl optionally substituted by one or two of C Cg alkyl, C ?g alkoxy, hydroxy, C-μg alkanoyloxy, halogen, trifluoromethyl, cyano, C alca alkanoyl; 12-amino or C 1 -g-carbonyl alkoxy; "aryl" of aryl-C-μg alkyl "is preferably benzyl or phenethyl optionally substituted with one or two of C C l alkyl, C-μg alkoxy, hydroxy, C alca_g alkanoyloxy, halogen or trifluoromethyl" carbocyclic "(carbocycle) means an unsaturated ring, or partially or totally saturated, having only carbon atoms in its nucleus, including, as the case may be, an aryl (an organic radical derived from an aromatic hydrocarbon by removal of an atom, eg, phenyl from of benzene, also including, for example, naphthyl); "carbocyclic aryl" includes, as the case may be, for example, optionally substituted phenyl or optionally substituted naphthyl; "cycloalkane" means a saturated monocyclic hydrocarbon, including, as the case may be, for example, cyclohexane; "C3_-jo cycloalkyl" means a monocyclic or polycyclic radical derived from a cycloalkane, including, as the case may be, for example, cyclopentyl and cyclohexyl; "C3_alkyl cycloalkyl U.sub.i.sup.-g)" optionally includes, for example, 1- or 2- (cyclopentyl or cyclohexyl) ethyl, 1-, 2- or 3- (cyclopentyl or cyclohexyl) propyl, or 1-, 2-, 3- or 4- (cyclopentyl or cyclohexyl) butyl; "Esterified hydroxy" means acyloxy, e.g., acyloxy derived from an organic carboxylic acid, preferably C 1-4-2 alkanoyl; aroyloxy, or aryl- (alkanoyl C- | _g-oxy); also, 3,7,12 (3a, 5β, 7a, 12a) -trihydroxy-co -an-24-oyloxy (derived from cholic acid), and the like; "Etherified hydroxy" includes, as the case may be, for example, C 1 alkoxy, C 1 .g-oxy alkenyl, C 1 _ -oxo cycloalkyl, carbocyclic aryl-C-μg alkoxy, tetrahydropyranyl-oxy, C5_7 cycloalkyl- alkoxy C < | _g, and the like; "halo" and "halogen" mean a radical derived from the elements fluorine, chlorine, bromine or iodine; "heterocyclic" ("heterocycle") means a radical derived from an unsaturated ring, or partially or totally saturated, consisting of different types of atoms, including heterocyclic aromatic and non-aromatic groups containing one or more heteroatoms, each of them selected between O, S and N; examples of heterocyclic groups include, as the case may be, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, piperazinyl, piperidyl, pyranyl, pyrazinyl, pyrazolyl, pyridyl. , pyrimidyl, pyrrolyl, quinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydrothienyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl, thiophenyl and triazolyl; when the heterocyclic groups are specifically mentioned or embraced as substituents for the compounds of Formula I, it is understood, unless otherwise specified, that all suitable isomers of such heterocyclic groups are intended; "heterocyclic aryl" includes, as the case may be, for example, monocyclic heterocyclic aryl, e.g., thienyl, furanyl, pyridyl, pyrrolyl or N- (C-alkyl alkyl) ) pyrrolyl optionally substituted; optionally substituted thienyl includes 2- or 3-thienyl and 2- or 3-thienyl preferably substituted with optionally substituted furanyl alkyl includes 2- or 3-furanyl and 2- or 3-furanyl preferably substituted with C-alkyl. -μ ^; optionally substituted pyridyl includes 2-, 3- or 4-pyridyl and 2-, 3- or 4-pyridyl preferably substituted with C 1 -g alkyl or halogen; a "hydrate" is a crystalline substance that contains one or more water molecules of crystallization, ie, a substance containing water combined in the molecular form, and all suitable hydrates are part of the present invention; "hydroxy- (C ^ g alkyl)" includes, as the case may be, for example, hydroxymethyl; "perfluoroalkyl" means that all suitable hydrogen atoms are substituted by fluorine atoms, e.g., perfluoropentyl, CF3 (CF2) 3CF2-; "Pharmaceutically acceptable" means that the excipients which act as carrier, diluent, carrier, excipients, and / or salt must be compatible with the other ingredients of the formulation, and not deleterious to the patient receiving them; "pharmaceutically acceptable salts" of the compounds of this invention can be formed by the compound itself, prodrugs, e.g., esters, isomers and the like, and include all pharmaceutically acceptable salts that are very often used in pharmaceutical chemistry; for example, salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, carboxylic acids, sulfonic acids including agents such as naphthalenesulfonic, ethanesulfonic, hydroxyethanesulfonic, methanesulfonic ("mesylate"), benzenesulfonic ("besylate") acids can be formed. ") and toluenesulfonic, eg paratoluenesulfonic acid (" tosylate "), sulfuric acid, nitric acid, phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric acid, succinic acid, formic acid, phthalic acid, malic acid, maleic acid, lactic acid, ascorbic acid, glycolic acid, gluconic acid, mandelic acid, glutamic acid, aspartic acid, fumaric acid, pyruvic acid, phenylacetic acid, pamoic acid, nicotinic acid, and the like; pharmaceutically acceptable salts also include alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg magnesium and calcium salts), salts with amines (eg, ammonium, alkylammonium, dialkylammonium, trialkylammonium salts) , tetraalkylammonium, diethanolamine, triethanolamine and guanidinium); preferred salts include salts of organic acids selected from formic, acetic, trifluoroacetic, propionic, benzoic, citric, maleic, tartaric, methanesulfonic, benzenesulfonic or toluenesulfonic acids, salts of inorganic acids selected from hydrochloric, hydrobromic, sulfuric or phosphoric, selected amino acids between aspartic and glutamic acid; and sodium and potassium salts; A "polymorph" is a substance that appears in two or more forms; a "prodrug" is a precursor of a drug which, upon administration, releases the drug in vivo via some chemical or physiological process (eg, a prodrug being brought to physiological pH or by enzymatic action becomes the desired drug form) ); Exemplary prodrugs after their cleavage release the corresponding free acid, and such hydrolyzable ester-forming moieties of the compounds of Formula I include, but are not limited to, those having a carboxyl moiety where the free hydrogen is substituted by C ^ alkyl. , C2_7-oxymethyl, 1- (alkanoyloxy) ethyl alkanoyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di- N, N-alkyl (C? _2) -amino (C2_3) alkyl (such as b-dimethylaminoethyl), carbamoyl-alkyl (C «| _2), N, N-di-alkyl (C ^) - carba moil-alkyl (C <; | 2) and piperidino-, pyrrolidino- or morpholino-alkyl (C2_3); a "radical" is a group of atoms that behaves like a single atom in a chemical reaction, ie, an organic radical is a group of atoms that confers characteristic properties to a compound that contains it, or that remains unchanged during a series of reactions; a "solvate" is a molecular or ionic complex of molecules or ions of a solvent with those of a solute; a "solvate" in which the solvent is water, forms "hydrates" or hydrated ions, and all suitable solvates form part of the present invention; and "treating", "treating" or "treatment" includes, among others, preventive (e.g., prophylactic), palliative and curative treatment.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise indicated, throughout this document: ° C means degrees centigrade,% is percent, Ci is Curies, cm is centimeter or centimeters, DEE is diethyl ether, DMF is dimethylformamide, DMSO is dimethylsulfoxide, EtOH is ethanol, " found "refers to data found, g is gram or grams, h is hour or hours, kg is kilograms or kilograms, I is liter or liters, M is molar (concentration), MeOH is methanol, mg is milligram or milligrams, min is minute or minutes, ml is milliliter or milliliters, mmol is millimole or millimoles, mM is millimolar (concentration), MS is mass spectrum, N is normal (concentration), nM is nanomolar (concentration), psi is pounds per inch at square, RT is room temperature, TEA is triethylamine, THF is tetrahydrofuran, μg is microgram or micrograms and μl is microliter or microliter. As described herein, it will be understood that a compound within the scope of Formula I always includes all active forms of such compounds, including, for example, their free form, eg, the free acid or base form and also, all the prodrugs, polymorphs, hydrates, solvates, stereoisomers, eg, diastereomers and enantiomers, and the like, and all pharmaceutically acceptable salts described above. It will also be appreciated that suitable active metabolites of compounds within the scope of Formula I are included herein, in any suitable form. More specifically, certain compounds suitable for use in the present invention such as, for example, certain compounds of Formula I may have asymmetric centers and, therefore, exist in different enantiomeric forms. All suitable optical isomers and stereoisomers of such compounds, and mixtures thereof, are considered to be within the scope of the invention. With respect to such compounds, the present invention includes the use of a racemate, an individual enantiomeric form, an individual diastereomeric form, or mixtures thereof, whichever is suitable. In addition, such compounds can also exist as tautomers. Accordingly, the present invention relates to the use of all these suitable tautomers and their mixtures. In addition, those skilled in the art will readily recognize that physiologically active compounds having accessible hydroxy groups are often administered in the form of pharmaceutically acceptable esters. The compounds of this invention can be administered as esters, formed in the hydroxy groups. Although the mechanism has not been investigated yet and no connection is desired to any particular theory, it is believed that such esters are metabolically cleaved in the body, and that the actual drug is the hydroxylated compound itself. It is possible, as has been known for some time in pharmaceutical chemistry, to adjust the speed or duration of action of the compound by appropriate choice of ester groups. Those skilled in the art will understand from this specification how to prepare the compounds of the present invention using any suitable known method. In addition, the reaction of SCHEME A of the present specification illustrates the preparation of the compounds of the present invention and, unless otherwise indicated, R, R3, R4 and R ^ in SCHEME A are as described above. In addition, the EXAMPLES provided herein, as well as the description of the common intermediate, further illustrate the preparation of the compounds of the present invention. The present invention also includes isotopically-labeled compounds, which are identical to those cited in Formula I, except for the fact that one or more atoms are substituted by an atom having an atomic mass or a mass number different from the atomic mass. or of the mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F and 36CI, respectively. The compounds of the present invention, their compounds, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or tissue substrate distribution assays. The tritiated, i.e., 3H, and carbon-14 isotopes, i.e., 14C, are particularly preferred for their ease of preparation and detectability. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, may provide certain therapeutic advantages resulting from their greater metabolic stability, for example increased in vivo half-life or decreased dosage requirements and, therefore, may be preferred in some circumstances . In general, the compounds of Formula I of this invention and their isotopically-labeled prodrugs can be prepared by carrying out the procedures described in SCHEME A and / or in the following EXAMPLES, using an isotopically-labeled reagent readily available instead of a non-reactive reagent. marked isotopically The starting materials for SCHEME A, common intermediates a and a-1 and the Examples of the present specification are either available in the label or can be prepared according to methods known to those skilled in the art, such as those described , for example, in U.S. Pat. No. 5,401,772; 5,569,674; and 5,654,468, and in the specification of the European Patent published as EP 580,550, mentioned above. For example, immediately below, and also in the Examples provided herein, methods are described for preparing various starting materials that those skilled in the art will appreciate as suitable for preparing the compounds of Formula I of the present invention: (1) 4-Chloro-3-cyano-5-methylenetriobenzene: can be prepared using the procedure described by S.W. Wright in an article published in the OPPI Briefs, 29 (1): 128-131 (1997) or as described in the Patents of the USA No. 5,401,772; 5,569,674; and 5,654,468 and in the specification of the European Patent published as EP 580,550, mentioned above; (2) 3-cyano-4,5-dichloron-tetrabenzene: can be prepared using the above mentioned procedures, or as described by G. Casiraghi et al, in an article published in J.C.S. Perkin Trans.l: 1862-1.865 (1980), from 3-chloro-2-hydroxybenzaldehyde; Y (3) 3-isopropyl-4-methoxyphenol: can be prepared using the conditions described by K.S. Webb and D. Levy in an article published in Tetrahedron Lett., 36 (29): 5.117-5.118 (1995), starting from 3-isopropyl-4-methoxy-benzene-boronic acid. As discussed above, the compounds of the present invention can be prepared from a common intermediate to, as described below which can be synthesized according to any suitable methods known in the art. More specifically, those skilled in the art will understand, based on the present disclosure, how to prepare the common intermediate a in which X is oxygen, (S? 2) a. C = 0, or NR1 ^ where a and R are as described above. It is particularly preferred that X is oxygen. For example, the common intermediate a in which X is oxygen ("a-1") can be prepared, or (a) 1 2 a-1 coupling a 4-nitrophenol (or a corresponding thiophenol) 1 with a bis-aryl-iodonium tetrafluoroborate 2 at approximately RT in a suitable organic solvent such as, for example, dichloromethane, chloroform, DMF or DMSO, in the presence of a suitable copper catalyst such as, for example, copper bronze and a suitable base such as, for example, TEA, potassium tert-butoxide or sodium hydride. { J. Med. Chem, 38: 695-707 (1995)): (b) coupling a 4-halonitrobenzene 3 such as, for example, a 4-iodonitrobenzene, a 4-bromonitrobenzene or a 4-chloronitrobenzene, with a phenol (or a thiophenol) 4 at a suitable elevated temperature (greater than about 120 ° C) in the presence of a suitable base such as, for example, potassium carbonate or potassium tert-butoxide, in a polar inert solvent such as, for example, DMSO or N-methylpyrrolidone; or (c) a-1 coupling (to RT in dichloromethane) a phenylboronic acid 2 with a 4-nitrophenol 5 in the presence of copper (II) acetate and a suitable base such as, for example, triethylamine, pyridine or a mixture of triethylamine and pyridine. . { Tetrahedron. Lett., 39: 2,933-2,936, 2,937-2,940 (1998)). In SCHEME A described hereinafter, the common intermediate a-2 generated in Step a is the common intermediate a-1 in which R2 is -CN and R5 is methoxy. As discussed above, those skilled in the art will understand, based on the present disclosure, e.g., SCHEME A, the manner of preparing compounds of Formula I of the present invention. For example, those skilled in the art will understand from the present description how to modify SCHEME A, and the details of the Examples described hereinafter to prepare any specific compound of Formula I of the present invention that is desired. It will be understood that SCHEME A is provided for the purpose of illustration only and does not limit the invention as defined by the claims.

SCHEME fifteen SCHEME A (continued) Step a of scheme A As discussed above, the common intermediate a-2 wherein X is oxygen, R2 is -CN and R ^ is methoxy can be prepared a-2 coupling 4-chloronitrobenzene 6 with a phenol 7 at a suitable elevated temperature (greater than about 120 C) in the presence of a suitable base such as, for example, potassium carbonate or potassium tert-butoxide, in an inert solvent polar such as, for example, DMSO or N-methylpyrrolidone.

Step b of Scheme A Demethylation to the phenol can be effected by reaction with a suitable boron trihalide such as, for example, boron tribromide or boron trichloride, in a suitable organic solvent such as, for example, dichloromethane or chloroform .

Step c of Scheme A The reduction of the nitro group to the aniline can be effected using methods well known in the art such as, for example, hydrogenation or chemical reduction with zinc powder or tin (II) chloride.

Step d of Scheme A Aniline can be converted to oxamate by reaction with diethyl oxalate at elevated temperature (eg, about 120 C) for a suitable period of time (eg, about 5 h), or with ethyl oxalyl chloride at about RT in a suitable anhydrous aprotic solvent such as, for example, DEE, dichloromethane, chloroform or THF.

Step e of Scheme A Oxamate can be converted to oxamic acid using conventional methods well known in the art. For example, the ester can be hydrolyzed to the acid using suitable aqueous alkali such as, for example, alkali metal carbonates or hydroxides in an aqueous solution of MeOH. In the preparation of the compounds of Formula I it is noted that, as will be appreciated by those skilled in the art, some of the methods useful for the preparation of such compounds may require protection of a particular functionality, eg, to prevent interference with such functionality in reactions at other sites within the molecule or to preserve the integrity of such functionality. The need and type of such protection are easily determined by one skilled in the art and will vary depending, for example, on the nature of the functionality and the conditions of the selected preparation method, see, eg, T.W. Greene, Protective Groups in Orqanic Svnthesis. John Wiley & Sons, New York, 1991. Suitable protecting groups for any particular functionality would include those which are not chemically substantially reactive under the described reaction conditions and which can be eliminated without substantially chemically altering other functionalities of any given intermediate of the compound of Formula I, or of the compound of Formula I itself. The protecting group can be removed if desired in any given preparation method, eg, in a subsequent step.

Some of the compounds of Formula I of this invention have an acid nature and form a salt with a pharmaceutically acceptable cation. Some of the compounds of Formula I of this invention have a basic nature and form a salt with a pharmaceutically acceptable anion. All such salts are within the scope of this invention and may be prepared by conventional methods such as combining the acidic and basic entities, usually in a stoichiometric or relationship in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. The compounds can be obtained in crystalline form by dissolution in one or more appropriate solvent (s) such as ethanol, hexanes or water / ethanol mixtures. Preferred in the compositions, methods and kits of this invention anorectic agents include phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, an antagonist of neuropeptide Y, a cholecystokinin A, an inhibitor of monoamine reuptake, a sympathomimetic agent, a serotoninergic agent , a dopamine agonist, agonist or mimetic receptor stimulating hormone melanocytes, an antagonist of cannabinoid receptors, an analogue of melanocyte-stimulating hormone, an antagonist of concentrating hormone melanin, the OB protein , an analogue of leptin, a galanin antagonist and an orexin receptor antagonist.

A preferred monoamine resorption inhibitor is sibutramine. Preferred serotonergic agents include dexfenfluramine and fenfluramine. A preferred dopamine agonist is bromocriptine. A preferred lipase inhibitor is tetrahydrolipstatin. Suitable anotonic agents for the compositions, methods and kits of this invention can be prepared using methods known to those skilled in the art, for example, phentermine can be prepared as described in US Pat. No. 2,408,345; sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; fenfluramine and dexfenfluramine can be prepared as described in U.S. Pat. No. 3,198,834; and bromocriptine can be prepared as described in U.S. Pat. N2§3,752,814 and 3,752,888. Suitable lipase inhibitors can be prepared using methods known to those skilled in the art, for example, tetrahydrolipstatin can be prepared. { Lactone 1, 3 (2S, 3S, 5S) 5 - [(S) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic acid} as described, e.g., in U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917 and 5,643,874. The administration of a compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and an anorectic agent or a lipase inhibitor, as the case according to this invention can be sequential in time or simultaneous with, generally being preferred method simultaneous. For sequential administration, a compound, a prodrug, an isomer or a pharmaceutically acceptable salt of the present invention and an anorectic agent or a lipase inhibitor may be administered in any order, as the case may be. In addition, for sequential administration, the compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and the anorectic agent (or the lipase inhibitor as the case may be), can be administered in any order. It is generally preferred that said administration be oral. It is even more preferred that the administration be oral and simultaneous. However, for example, if the patient being treated is unable to swallow, or the oral absorption is impaired or is undesirable for other reasons, parenteral or transdermal administration will be appropriate. When the administration is sequential, the administration of a compound, prodrug, isomer or pharmaceutically acceptable salt of the present invention and an anorectic agent or a lipase inhibitor, as the case may be, can be carried out by the same method or by different methods. The dose of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention to be administered to a human or animal is variable between fairly broad limits and is subject to the judgment of the attending physician or veterinarian. As would be understood by those skilled in the art, it may be necessary to adjust the dose of a compound, prodrug or isomer of this invention when administered in the form of a salt, e.g., when the salt-forming moiety thereof has an appreciable molecular weight.

The general range of effective rates of administration of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention is from about 0.001 mg / kg of body weight to about 100 mg / kg of body weight of the patient per day. A preferred range of effective administration rates of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention is from about 0.01 mg / kg of body weight to about 50 mg / kg of body weight of the patient per day. While it may be practical to administer the daily dose of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, in portions, at various times of the day, in any given case, the amount of compound, prodrug, isomer or pharmaceutically acceptable salt administered will depend on such factors as the solubility of the compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, the formulation used and the route of administration (eg, orally, transdermally, parenterally or topically). The dosages of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of the present invention can be administered to humans by any suitable route, oral administration being preferable. The tablets or individual capsules will generally contain from about 0.1 mg to about 100 mg of the compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, in a suitable carrier, diluent or carrier. Dosages for intravenous administration are, generally, within the range of about 0.1 mg to about 10 mg per individual dose, as necessary. For intranasal or inhalation administration, the dosage is formulated, generally, as a solution at a concentration of from about 0.1% to about 1% (w / v). In practice, the physician will determine the actual dosage which will be the most suitable for an individual patient and will vary, e.g., with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but, of course, there may be individual cases where higher or lower dosage ranges are necessary, and all of these dosages of compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention are within the scope of the present invention. Any suitable dosage of an anorectic agent can be used in aspects of the present invention comprising such agents. The dosage of the anorectic agent is generally in the range of from about 0.01 to about 50 mg / kg of the patient's body weight per day, preferably from about 0.1 to about 10 mg / kg of the patient's body weight per day. , administered in a single dose or as divided doses. For example, when the anorectic agent is phentermine, the dosage of phentermine is from about 0.01 to 50 mg / kg of body weight of the patient per day, preferably from about 0.1 to about 1 mg / kg of the patient's body weight. per day. In addition, when the anorectic agent is sibutramine, the dosage range is from about 0.01 to about 50 mg / kg of the patient's body weight per day, preferably from about 0.1 to about 1 mg / kg of the patient's body weight. per day; When the anorectic agent is dexfenfluramine or fenfluramine, the dosage range is from about 0.01 to about 50 mg / kg of body weight of the patient per day, preferably from about 0.1 to about 1 mg / kg of the patient's body weight. per day; and when the anorectic agent is bromocriptine, the dosage range is from about 0.01 to about 10 mg / kg of the patient's body weight per day, preferably about 0, 1 to about 10 mg / kg of body weight of the patient per day. In practice, the physician will determine the actual dosage of an aetiological agent that will be most suitable for an individual patient and will vary, e.g., with the age, weight and response of the particular patient. The above dosages of anorectic agents are exemplary but, of course, there may be individual cases where higher or lower dosage ranges of such annealing agents are required, and such dosages are within the scope of the present invention. Any suitable dosage of a lipase inhibitor can be used in aspects of the present invention comprising such inhibitors. The dosage of the lipase inhibitor is generally in the range of from about 0.01 to about 50 mg / kg of body weight of the patient per day, preferably from about 0.05 to about 10 mg / kg of the patient's body weight per day, administered in a single dose or as divided doses. For example, when the lipase inhibitor is tetrahydrolipstatin, the dosage of tetrahydrolipstatin is preferably about 0.05 to 2 mg / kg of body weight of the patient per day. In practice, the physician will determine the actual dosage of lipase inhibitor that will be most suitable for a particular patient and will vary, e.g., with the age, weight and response of the particular patient. The above dosages of lipase inhibitors are exemplary but, of course, there may be individual cases where higher or lower dosage ranges of such lipase inhibitors are required, and all these dosages are within the scope of the present invention. In the present invention, any suitable route of administration can be used. It is usually preferred to administer the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention orally for reasons of convenience; however, they can be administered, for example, percutaneously, or as suppositories to be absorbed by the rectum, as desired in a specific case. As described above, administration can be carried out in single or multiple doses, as appropriate. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered alone, and are preferably administered as pharmaceutical compositions comprising a pharmaceutically acceptable carrier, carrier or diluent. The pharmaceutical compositions of the invention will comprise a suitable amount of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, i.e., an amount sufficient to provide the desired dosage. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered in a wide range of different dosage forms, that is, they can be combined with various inert pharmaceutically acceptable carriers in any suitable form. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. The pharmaceutical compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which can be a single tablet or a capsule or a convenient volume of a liquid. All common types of pharmaceutical compositions can be used in the present invention, including tablets, lozenges, hard candies, chewable tablets, granules, powders, sprays, capsules, pills, microcapsules, solutions, parenteral solutions, tablets, injectables (eg, intravenous , Intraperitoneal, intramuscular or subcutaneous), suppositories, elixirs, syrups and suspensions. For parenteral administration, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be used as solutions in sesame or peanut oil, or as aqueous solutions (eg, aqueous propylene glycol), as the case may be, and it is best to use them in the form of a sterile aqueous solution which may contain other substances; for example, sufficient amount of salts or glucose to make the solution isotonic, the pH of the solution being suitably adjusted and buffered, when necessary, and surfactants such as, for example, hydroxypropylcellulose. Such oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. Such aqueous solutions are suitable for intravenous injection purposes. The compounds of this invention can also be administered topically and this can be done by means of, e.g., creams, jellies, ointments, lotions, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice. The compounds of the present invention can also be administered transdermally (e.g., by the use of a patch). Any formulation suitable for transdermal application comprising a compound of the present invention can be employed and, generally, such formulations would also contain a suitable transdermal carrier, eg, a pharmacologically acceptable absorbable solvent to stimulate and facilitate the passage of the compounds through of the skin of the individual. For example, suitable transdermal devices may comprise the form of a dressing with a support member and a reservoir containing the subject compound. These apposite-type transdermal devices may further include carriers, barriers to control speed and means for securing the transdermal device to the subject's skin that are suitable. As will be described in detail hereinafter, the pharmaceutical compositions can be prepared by commonly employed methods using conventional organic or inorganic additives., such as an excipient (eg, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate or calcium carbonate), a binder (eg, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), a disintegrant (eg, starch, carboxymethylcellulose, hydroxypropylstarch, hydroxypropylcellulose with low molecular weight substituents, sodium bicarbonate, calcium phosphate, or calcium citrate), a lubricant (eg, stearate magnesium, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (eg, citric acid, menthol, glycine or orange powder), a preservative (eg, sodium benzoate, sodium bisulfite, methylparaben or propylparaben) , a stabilizer (eg, citric acid, sodium citrate or acetic acid), a suspending agent (eg, methylcellulose, polyvinylpyrrolidone or aluminum stearate) , a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), a coloring agent, an emulsifying agent, and a base wax (e.g., cocoa butter, petrolatum, or polyethylene glycol). Any of the compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention can be easily formulated as tablets, capsules, and the like. It is preferable to prepare solutions from water-soluble salts, such as the hydrochloride salt.

In general, all pharmaceutical compositions are prepared according to customary methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound, prodrug, isomer or pharmaceutically acceptable salt of the invention with a suitable diluent and filling the capsules with a suitable amount of the mixture. Typical diluents include inert powdered substances, such as starch of very different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. The tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrants as well as a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives can also be used. Common binders for tablets include substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Also suitable are natural and synthetic gums, including gum arabic, alginates, methylcellulose, polyvinylpyrrolidine and the like. Also serve as binders polyethylene glycol, ethylcellulose and paraffins. Generally, a lubricant is necessary in the tablet formulation to prevent the tablet and punches from adhering to the die. The lubricant is chosen from sliding solids such as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants include substances that swell when wetted to disintegrate the tablet and release a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention. These include starches, clays, celluloses, algines and gums. More particularly, for example, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, natural powder sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose can be used, as well as sodium lauryl sulfate. Often the tablets are coated with sugar as a flavoring and sealing agent, or with film forming protective agents to modify the dissolution properties of the tablet. The compounds of the invention can also be formulated as chewable tablets, using large amounts of pleasant tasting substances such as mannitol in the formulation, as is now well established in the art. When it is desired to administer a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention as a suppository, any suitable base can be used. Cocoa butter is a traditional base for suppositories, which can be modified by the addition of paraffins to raise its melting point. Bases of water-miscible suppositories comprising, in particular, polyethylene glycols of various molecular weights are widely used. As discussed above, the effect of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention can be delayed or prolonged by convenient formulation. For example, a slowly soluble pellet of a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention can be prepared and incorporated into a tablet or capsule. The technique can be improved by preparing pellets of different dissolution rates and filling capsules with a mixture of the pellets. The tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Parenteral preparations can also be made long-acting by dissolving or suspending a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention, as the case may be, in oily or emulsified vehicles that allow it to be dispersed only slowly in the serum. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention may also be administered to a mammal other than a human. The method of administration and the dosage to be administered to said mammal will depend, for example, on the species of animal and the disease or disorder being treated. The compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered to animals in any suitable manner, eg, orally, parenterally or transdermally, in any suitable form such as, for example, a capsule, bolus, tablet, pellet, eg, prepared by mixing a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention with a suitable diluent such as carbowax or caranday wax together with a lubricant, soaking liquid or paste, eg, prepared by dispersing a compound, prodrug, isomer or pharmaceutically acceptable salt of this invention in a pharmaceutically acceptable oil such as peanut oil, sesame oil or corn oil. The compounds, prodrugs, isomers or pharmaceutically acceptable salts of this invention can also be administered to animals as an implant. Such formulations are prepared in a conventional manner in accordance with classical veterinary practice. Alternatively, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention can be administered with the water supply, e.g., in the form of a liquid or water-soluble concentrate. In addition, the compounds, prodrugs, isomers and pharmaceutically acceptable salts of this invention, eg, within the pharmaceutical compositions of the invention, can be administered in the animal feed, eg, a concentrated feed additive or a premix can be prepared for mix it with the animal's normal feed, usually together with a suitable carrier for it. The carrier facilitates the uniform distribution of the compound, prodrug, isomer or pharmaceutically acceptable salt of this invention in, e.g., the finished feed with which the premix is combined. Suitable carriers include, but are not limited to, liquids, eg, water, oils such as soybean, corn, cottonseed, or volatile organic solvents, and solids, eg, a small portion of the feed or various suitable flours including alfalfa, soybeans, cottonseed oil, linseed oil, corn cob, corn, molasses, urea and bones, and mineral mixtures. As the present invention has an aspect that relates to the treatment of diseases / conditions described herein with a combination of active ingredients that can be administered separately, the invention also relates to combining separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, prodrug, or isomer, and a second compound as previously described. The kit comprises a package for containing the separate compositions such as a divided bottle or a divided box. Typically the kit comprises instructions for the administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when the titration of the individual components of the combination by facultative prescription is desired. An example of this case is the so-called bubble container. Bubble containers are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules and the like). Bubble containers are generally constituted by a sheet of relatively stiff material covered with a sheet of preferably transparent plastic material. During the packaging operation, depressions are formed in the plastic sheet. The depressions have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the depressions and the sheet of relatively stiff material is sealed against the plastic sheet by the face of the sheet which is opposite to the direction in which the depressions were formed. As a result, the tablets or capsules are hermetically enclosed in the depressions between the plastic sheet and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the bubble container by applying pressure manually on the depressions, whereby an opening is formed in the sheet at the depression site. The tablet or capsule can then be drawn through said opening. It may be desirable to provide a memory aid in the kit, e.g., in the form of numbers following the tablets or capsules, whereby the numbers correspond to the days of the regimen that the tablets or capsules thus specified should be ingested. Another example of such memory aid is a calendar printed on the card, e.g., as follows: "First Week, Monday, Tuesday, ... etc. .. Second Week, Monday, Tuesday, ..." etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several tablets or capsules that are taken on a given day. Also, a daily dose of a compound of Formula I, or a prodrug thereof, or a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of such a compound, prodrug or isomer, may consist of a tablet or capsule although a Daily dose of a second compound may consist of several tablets or capsules, and vice versa. Help for memory will reflect this. In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the intended order of use is provided. Preferably, the dispenser is provided with a memory aid, in order to further facilitate compliance with the regime. An example of such memory aid is a mechanical meter that indicates the number of daily doses that have been dispensed. Another example of such memory aid is a battery-operated microchip memory coupled with a liquid crystal reader, an audible reminder signal that, for example, reads the date on which the last daily dose was taken and / or remembers when you have to take the next dose. The utility of the compounds of Formula I, or their isomers, or the pharmaceutically acceptable salts of such compounds, or their isomers, can be evidenced by the activity in at least one of the two assays described below.

TEST 1 Oxygen consumption As will be appreciated by those skilled in the relevant art, during an increased energy expenditure, animals generally consume more oxygen. In addition, metabolic fuels such as, for example, glucose and fatty acids, are oxidized to CO2 and H2O with consequent heat release, which is commonly known in the art as thermogenesis. Thus, the measurement of oxygen consumption in animals, including humans and companion animals, is an indirect measure of thermogenesis. Normally indirect calorimetry is used in animals, e.g., humans, by those skilled in the relevant art to measure such energy expenditure. Those skilled in the art understand that the increased energy expenditure and the consequent burning of metabolic fuels that result in the production of heat may be effective in relation to the treatment of, e.g., obesity. As is well known to those skilled in the art, thyroid hormones affect cardiac function, for example, by causing an increase in heart rate and, consequently, an increase in oxygen consumption with the consequent production of heat. The ability of the compounds, their isomers, and the pharmaceutically acceptable salts of said compounds and isomers of this invention to generate a thermogenic response can be demonstrated according to the following protocol.

A. Experimental part This in vivo test is designed to evaluate the efficacy and cardiac effects of compounds that are tissue-selective thyroid hormone agonists. The measured endpoints of efficacy are total body oxygen consumption and activity of hepatic mitochondrial alpha-glycerophosphate dehydrogenase ("mGPDH"). The cardiac end points that are measured are the heart weight and the mGPDH activity in the heart. The protocol consists of: (a) dosing obese Zucker rats for approximately 6 days, (b) measuring oxygen consumption and (c) collecting tissue for the preparation of mitochondria and the subsequent analysis of enzymatic activity.

B. Preparation of rats Obese, male, Zucker rats with a body weight range of about 400 g to about 500 g are housed for about 3 to about 7 days in individual cages under classical laboratory conditions before the start of the study. A compound of Formula I, or an isomer thereof, or a pharmaceutically acceptable salt of said compound or isomer, vehicle or T3 sodium salt, is administered by oral gavage as a single daily dose administered between about 3 p.m. and approximately 6 p.m. for about 6 days. A compound of Formula I, or an isomer thereof, or a pharmaceutically acceptable salt of said compound or isomer, or sodium salt of T3 is dissolved in a suitably small volume of about 1 N NaOH and then brought to an appropriate volume with NaOH. about 0.01 N containing about 0.25% methylcellulose (0.01 N NaOH / MC: 1 N NaOH 10: 1). The dosage volume is approximately 1 ml.

C. Oxygen consumption Approximately 1 day after the last dose of the compound is administered, the oxygen consumption is measured using an indirect, open circuit calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204). The Oxymax gas sensors are calibrated with N2 gas and a gas mixture (approximately 0.5% C? 2, approximately 20.5% O2, approximately 79% N2) before each experiment. The object rats are removed from their habitat and their body weights are recorded. The rats are placed in the hermetically sealed chambers (43 x 43 x 10 cm) of the Oxymax, the chambers are placed in the activity monitors, and then the air flow through the chambers is adjusted to a value of about 1, 6 l / min at approximately 1.7 l / min. Then the Oxymax program calculates the oxygen consumption (ml / kg / h) by the rats based on the air flow through the chambers and the difference in oxygen content at the entry and exit gates. Activity monitors have 15 infrared rays of light separated approximately 2, 54 cm on each axis, and ambulatory activity is recorded when two consecutive rays are broken, and the results are recorded as counts. Oxygen consumption and walking activity are measured approximately every 10 min from approximately 5 h to approximately 6.5 h. Resting oxygen consumption is calculated for the individual rats by calculating the average of the values excluding the first five values and the values obtained during periods of time in which the ambulatory activity exceeds approximately 100 counts.

ASSAY 2 Union with thyroid hormone receptors The ability of a compound of Formula I, or an isomer thereof, or a pharmaceutically acceptable salt of said compound or isomer ("the thyromimetic test compounds") to bind to the thyroid hormone receptors can be demonstrated in the following protocol.

A. Preparation of nuclear extracts from insect cells Sediments of High Five cells (BTI-TN-5B1-4, number in catalog B855-02, Invitrogen®, Carlsbad, California) obtained approximately 48 h after infection with baculovirus (GibcoBRL®, Gaithersburg, Maryland), which express either TRa or human TRβ, were suspended in ice-cold Sample buffer (10 mM Tris, pH 8.0, 1 mM MgCl 2, 1 mM DTT; 0.05% Tween 20; 1 mM 4- (2-aminoethyl) -benzenesulfonyl fluoride; 25 μg / ml leupeptin). After approximately 10 min incubation on ice, the suspension was homogenized for 20 strokes with a Dounce homogenizer (VWR® Scientific Products, West Chester, Pennsylvania) and centrifuged at 800 x g for approximately 15 min at 4 ° C. The pellet (cores) was suspended in a hypertonic buffer (0.4 M KCl, 10 mM Tris, pH 8.0, 1 mM MgCl2, 1 mM DTT, 0.05% Tween 20) and incubated for approximately 30 min on ice. The suspension was centrifuged at 100,000 x g for approximately 30 min at 4 ° C. The supernatant liquid (nuclear extract) was stored in aliquots of 0.5 ml at -80 ° C.

B. Binding assay Competitive binding assays are carried out to measure the interaction of the test thyromimetic compounds with the a1 and β1 receptors of thyroid hormones (TRa and TRβ) according to the following protocol. Solutions of the test thyromimetic compounds (final concentration of 20 mM compound) are prepared using 100% DMSO as solvent. Each compound is serially diluted in a test buffer (5 mM Tris-HCl, pH 8.0, 50 mM NaCl, 2 mM EDTA, 10% (v / v) glycerol; 1 mM DTT, "assay buffer") containing 0.4 nM 1 ^ I-T3 (specific activity of about 220 Ci / mmol) to give solutions whose compound concentration ranges from about 10 μM to about 0.1 nM. A nuclear extract of High Five insect cells containing either TRa or TRβ is diluted to a total protein concentration of 0.0075 mg / ml using the assay buffer as a diluent. One volume (100 μl) of each dilution of thyromimetic compound (containing 2 ^ I-T3 0.4 nM) is combined with an equal volume (100 μl) of diluted nuclear extract containing TRa1 or TRβ1, and incubated at RT for approximately 90 min. A 150 μl sample of the binding reaction is removed and placed in a 96-well filter plate (Millipore®, Bedford, Massachusetts) that had previously been washed with ice-cold assay buffer. The plate is subjected to vacuum filtration using a filtration manifold (Millipore®). Each well is washed five times by the addition of 200 μl of ice-cold assay buffer and subsequent vacuum filtration. The plate is removed from the vacuum filtration manifold, the bottom of the plate is dried briefly with paper towels, then 25 μl of Optiphase Supermix Wallac® scintillation liquid (EG &G Wallac®, Gaithersburg, Maryland) is added to each well and the top of the plate is covered with plastic sealing tape (Microplate Press-on Adhesive Sealing Film, Packard® Instrument Co., Inc., Downers Grove, Illinois) and the radioactivity is quantified using a scintillation counter for plates of 96 wells Wallac® Microbeta. The following EXAMPLES are provided solely for purposes of illustration and do not limit the invention that is defined by the claims.

EXAMPLE 1 2-Cyano-6-methylphenol A solution of 2-hydroxy-3-methylbenzaldehyde (18.6 g), hydroxylamine hydrochloride (14.2 g) and sodium formate (19.2 g) in formic acid (200 ml) was heated to reflux for 18 h , then cooled and partitioned between DEE / water. The organic layer was washed with water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo to give a solid. Recrystallization from diethyl ether / petroleum ether gave the title compound as colorless crystals (15.0 g).

EXAMPLE 2 3-Cyano-4-hydroxy-5-methylnitrobenzene To a stirred and heated solution (45 ° C) of 2-cyano-6-methylphenol (5 g) in glacial acetic acid (32 ml) was added a solution of fuming nitric acid (3.2 ml) in acetic acid (12 ml). ml). After 1 h at an elevated temperature (45 ° C), the reaction mixture was cooled (to 0 ° C), water was added and partitioned between DEE / water. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to give a solid. Recrystallization from DEE gave the title compound as yellow crystals (3.6 g).

EXAMPLE 3 3-lsopropyl-4-methoxybromobenzene A solution of 2-methoxyisopropylbenzene (2 g) and N-bromosuccinimide (2.6 g) in acetonitrile (20 ml) was stirred at room temperature for 18 h. The reaction was concentrated in vacuo, suspended in carbon tetrachloride and filtered. The filtrate was concentrated in vacuo. The residue was subjected to flash chromatography (5% dichloromethane / hexanes) to give the title compound as an oil (2.5 g).

EXAMPLE 4 3-Isopropyl-4-methoxybenzene boronic acid To a stirred and cooled solution (-78 ° C) of 3-isopropyl-4-methoxybromobenzene (2.5 g) was added n-butyllithium (4.8 ml of a 2.5 M solution in hexanes) drop a drop. After 30 min, triisopropyl borate (5 ml) was added and the reaction solution was allowed to warm to RT and then stirred for 18 h. The reaction solution was concentrated in vacuo, saturated aqueous sodium bicarbonate was added and the resulting mixture was stirred for 30 min. The reaction was extracted with ethyl acetate. The organic layer was washed with water and then brine, dried over sodium sulfate, and concentrated in vacuo to give a solid, which was triturated with hexanes to give the title compound as colorless flakes (1.1 g).

EXAMPLE 5 4-Methoxy-5,6,7,8-tetrahydronaphthalene-1-ol To a stirred and cooled solution (0 ° C) of 5-hydroxy-8-methoxy-3,4-dihydro-2H-naphthalen-1-one (1.7 g) in trifluoroacetic acid (20 ml) was added triethylsilane ( 4.2 ml) and the reaction was warmed to RT and then stirred for 1.5 h. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate / water, the organic layer was washed with water, brine and then dried over sodium sulfate and concentrated in vacuo. The resulting oil was subjected to flash chromatography (10% ethyl acetate / hexanes) to give the title compound as a colorless solid (1.6 g).

EXAMPLE 6 Ethyl ester of N-r3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) 5-methyl-phenin-oxamic acid Step A A mixture of 3-isopropyl-4-methoxyphenol (200 mg), 4-chloro-3-cyano-5-methyl-nitrobenzene (200 mg) and potassium carbonate (211 mg) in methyl ethyl ketone (8 ml) was heated refluxed for 18 h. The dark mixture was concentrated in vacuo, partitioned between ethyl acetate / water, the organic layer was washed with about 2 N sodium hydroxide, brine, dried over sodium sulfate and concentrated to give a dark oil. Flash chromatography (10% ethyl acetate / hexanes) gave 2- (3-isopropyl-4-methoxy-phenoxy) -3-methylene-5-nitrobenzonitrile as a yellow oil (300 mg).

Step BA a stirred and cooled solution (-78 C) of 2- (3-isopropyl-4-methoxy-phenoxy) -3-methyl-5-nitrobenzontromile (308 mg) in dichloromethane (5 ml) was added tribromide boron (0.31 ml) drop by drop. The reaction was allowed to warm to RT and was stirred for 1 h, stopped by the addition of water and stirred for 20 min. The reaction was extracted with ethyl acetate, the organic phase was washed with water, saturated aqueous brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography (20% ethyl acetate / hexanes) on silica gel gave 2- (3-isopropyl-4-hydroxyphenoxy) -3-methyl-5-nitrobenzonitrile as a yellow oil (215 mg) .

Step C A solution of 2- (3-isopropyl-4-hydroxy-phenoxy) -3-methyl-5-nitrobenzonitrile (215 mg) and stannous chloride (776 mg) in ethanol (5 ml) was heated to reflux for 2 hours. After cooling, the reaction was stopped by the addition of saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was extracted with ethyl acetate, the organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography (40% ethyl acetate / hexanes) to give 5-amino-2- (3-isopropyl-4-hydroxy-phenoxy) -3-methyl-benzonitrile as a colorless foam (150 mg).

Step D: A solution of 5-amino-2- (3-isopropyl-4-hydroxy-phenoxy) -3-methylbenzonitrile (150 mg) in diethyl oxylate (0.7 ml) was heated at 130 C for 18 h. Flash chromatography (40% ethyl acetate / hexanes) of the reaction solution gave N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methyl-phenyl] ethyl ester] -oxamic as a colorless solid (118 mg). MS found: 381.

EXAMPLE 7 N-R3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methyl-pheno-oxamic acid Stage A Stage A of Example 6.

Stage B Stage B of the example 6.

Stage C Stage C of the example 6.

Stage D Stage D of the example 6.

Step E A solution of N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methyl-phenyl] -oxamic acid ethyl ester (110 mg) and 1 N aqueous sodium hydroxide solution (0.6 ml) in EtOH (1 ml) was stirred at room temperature for 10 min, partitioned between ethyl acetate / 1N aqueous hydrochloric acid, the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a colorless solid (9 mg). MS: 353. Using the appropriate starting materials, the N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -oxamic acid compound was prepared in a manner analogous to sequence of reactions described for EXAMPLE 7. MS found: 373.

Claims (34)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of Formula (i) a prodrug thereof, an optical and geometrical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug and said isomer, wherein: R1 and R2 are independently halogen, C < | _g, -CN or perfluoroalkyl C-μg; provided that at least one of R1 and R2 is -CN; R3 is hydrogen or C ^ g alkyl; R4 is halogen, perfluoroalkyl C < | g, C 1 -g alkyl, C 1 alkanoyl, hydroxy- (C 1 -g alkyl), aryl optionally substituted with Y and Z, aryl- (C 1 -g alkyl), carbocyclic aroyl optionally substituted with Y and Z, cycloalkyl Cg. ^ G optionally substituted with Y and Z, or C3_i0- cycloalkyl (C-μg alk); or R4 is the radical R 10 - C- Rb, 11 wherein: R9 is hydrogen, alkyl C < | g, aryl optionally substituted with Y and Z, aryl- (C- ^ g alkyl), Cg cycloalkyl optionally substituted with Y and Z, or C3_iQ- cycloalkyl (C-μg alkyl); R10 is -OR14; R1 1 is hydrogen or C-μg alkyl; or R1 ^ and R1 1 may be taken together with the carbon atom to which they are attached to form a carbonyl group; R ^ is hydroxy, esterified hydroxy or etherified hydroxy; R "is hydrogen, halogen, C-g alkyl or perflu-alkylalkyl C? _; R7 is hydrogen, C-μg alkyl or perfluoroalkyl C- | _g; R8 is -OR12 or -NR12R13; R 12 and R 13 are each independently hydrogen or C-μg alkyl; R 4 is hydrogen, C-j alkyl. or acyl C ^.; X is O, S (0) a, C = O or NR1 5; a is 0, 1 or 2; R 5 is hydrogen or C- | g alkyl; Y and Z, each time they appear, are independently (a) hydrogen, (b) halogen, (c) trifluoromethyl, (d) -OCF3, (e) -CN, (f) C ^ _ alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF3 and phenyl, (g) C2.g. alkoxy, (h) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OCF3, -CF 3, C1.4 alkyl and C1-4 alkoxy, (i) -C (0) 2R16, 0) C (0) NR16R17, (k) -C (0) R16, (I) -NR16C (0) NR16R17 or (m) -NR16C (0) R17; or Y and Z, each time they appear, can be taken together to form (a) a carbocycle of the formula - (^ 2) 5, or (b) a heterocycle selected from the group consisting of 0 (CH2) cO, (C ^^ NH- and CH = CHNH-; b is 3, 4, 5, 6 or 7; c and d are each independently 2, 3, 4 , 5 or 6: R16 and R17, each time they appear, are independently hydrogen, C-μg alkyl, C2_ alkenyl, - (C- | g alkyl) -alcoxy C -g, aryl optionally substituted with X and Y, het optionally substituted with X and Y, - (alkyl C- | _4) -aryl optionally substituted with X and Y, - (alkyl C- | _4) -heterocycle optionally substituted with X and Y, - (alkyl C- | _4) - hydroxy, - (alkyl C- | _4) -halo, - (C 1 - 4 - alkyl) - halo, - (C 1 -C 4 alkyl) -CONR 8R 19 or C 3 -C 6 cycloalkyl; het, each time it appears, is a heterocyclic ring selected from the group consisting of heterocyclic ring of 4, 5, 6, 7 or 8 partially or fully saturated, or unsaturated, members containing one to four heteroatoms independently selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above heterocyclic rings is fused with a benzene ring or another heterocycle which is a ring of 4, 5, 6, 7 or 8 members, partially or totally saturated, or unsaturated, containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; and R18 and R1 9, each time they appear, are independently hydrogen, alkyl C-μg, cycloalkyl 03. ^ 0 ° aryl optionally substituted with Y and Z.

2. A compound or pharmaceutically acceptable salt according to claim 1, wherein X is oxygen.

3. A compound or pharmaceutically acceptable salt according to claim 2, wherein R3 is located at the 2 'position, R4 is located at the 3' position, R ^ is located at the 4 'position and R ° is located at the 5 'position.

4. A compound or pharmaceutically acceptable salt according to claim 3, wherein R3, R ^ and R7 are hydrogen, and R ^ is hydroxy.

5. A compound or pharmaceutically acceptable salt according to claim 4, wherein R1 and R2 are independently in each case -CN, methyl or chloro.

6. A compound or pharmaceutically acceptable salt according to claim 5, wherein R8 is -OR12.

7. - A compound or pharmaceutically acceptable salt according to claim 6, wherein R12 is hydrogen, methyl or ethyl, and R4 is -CH (CH3) 2-

8. A compound or pharmaceutically acceptable salt according to claim 5, wherein R8 is -NR12R13.

9. A pharmaceutically acceptable salt according to the claim 1, wherein said salt is a potassium or sodium salt.

10. A compound, prodrug, isomer or pharmaceutically acceptable salt according to claim 1, wherein said compound is N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5- acid. methyl-phenyl] -oxamic acid or N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -oxamic acid.

11. A compound, prodrug, isomer or pharmaceutically acceptable salt according to claim 10, wherein said compound is N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methyl] -phenyl] -oxamic.

12. A pharmaceutically acceptable salt of N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methyl-phenyl] -oxamic acid according to claim 11, wherein said salt is a potassium salt.

13. A pharmaceutically acceptable salt of N- [3-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -5-methylene-phenyl] -oxamic acid according to claim 12, wherein said salt It is a sodium salt.

14. A compound, prodrug, isomer or pharmaceutically acceptable salt according to claim 10, wherein said compound is N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) acid. ) -phenyl] - oxamic.

15. A pharmaceutically acceptable salt of N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -oxamic acid according to claim 14, wherein said salt is a potassium salt.

16. A pharmaceutically acceptable salt of N- [3-chloro-5-cyano-4- (4-hydroxy-3-isopropyl-phenoxy) -phenyl] -oxamic acid according to claim 14, wherein said salt is a sodium salt.

17. The use of a compound, prodrug, isomer or pharmaceutically acceptable salt according to claim 1, for the manufacture of a medicament for treating a condition selected from the group consisting of obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal.

18. The use according to claim 17, wherein said condition is obesity.

19. The use according to claim 17, which further includes an anorectic agent.

20. The use according to claim 18, further including an anorectic agent.

21. The use according to claim 19, wherein said anorectic agent is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a neuropeptide Y antagonist, a cholecystokinin A agonist, an inhibitor of monoamine reabsorption, a sympathomimetic agent, a serotoninergic agent, a dopamine agonist, an agonist or mimetic of melanocyte-stimulating hormone receptors, a cannabinoid receptor antagonist, an analogue of the hormone stimulating melanocyte, a hormone antagonist which concentrates melanin, the OB protein, a leptin analogue, a galanin antagonist and an orexin receptor antagonist.

22. The use according to claim 21, wherein said anorectic agent is phentermine.

23. The use according to claim 21, wherein said inhibitor of the monoamine resorption is sibutramine, said serotonergic agent is dexfenfluramine or fenfluramine and said dopamine agonist is bromocriptine.

24. The use according to claim 17, which further includes administering a lipase inhibitor.

25. The use according to claim 18, which further includes administering a lipase inhibitor.

26. The use according to claim 25, wherein said lipase inhibitor is tetrahydrolipstatin.

27. A pharmaceutical composition comprising a compound, prodrug, isomer or pharmaceutically acceptable salt according to claim 1, and a pharmaceutically acceptable carrier, diluent or carrier.

28. A pharmaceutical composition according to claim 27, further comprising an an- otic agent.

29. - A pharmaceutical composition according to claim 27, further comprising a lipase inhibitor.

30. A pharmaceutical composition for treating a condition selected from the group consisting of obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis, in a mammal, comprising a compound, prodrug , isomer or pharmaceutically acceptable salt according to claim 1, and a pharmaceutically acceptable carrier, diluent or carrier.

31. A pharmaceutical composition according to claim 30, wherein said condition is obesity.

32. A pharmaceutical composition according to claim 30, which also includes an an- otic agent.

33. A pharmaceutical composition according to claim 31, which also includes an an- otic agent.

34. A pharmaceutical composition according to claim 33, wherein said anorectic agent is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a neuropeptide Y antagonist, a cholecystokinin A agonist, an inhibitor of monoamine reabsorption , a sympathomimetic agent, a serotoninergic agent, a dopamine agonist, an agonist or mimetic of melanocyte-stimulating hormone receptors, a cannabinoid receptor antagonist, an analogue of the melanocyte-stimulating hormone, an antagonist of the hormone that concentrates melanin, the OB protein, a leptin analogue, a galanin antagonist and an orexin receptor antagonist. 35.- A pharmaceutical composition according to claim 34, wherein said anorectic agent is phentermine. 36.- A pharmaceutical composition according to claim 34, wherein said inhibitor of the reabsorption of monoamines is sibutramine, said serotonergic agent is dexfenfluramine or fenfluramine, and said dopamine agonist is bromocriptine. 37.- A pharmaceutical composition according to claim 30, which further includes a lipase inhibitor. 38.- A pharmaceutical composition according to claim 31, which also includes a lipase inhibitor. 39.- A pharmaceutical composition according to claim 38, wherein said lipase inhibitor is tetrahydrolipstatin. 40.- A kit for the treatment of a condition selected from the group consisting of obesity, hyperlipidemia, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis comprising: a first compound, said first compounding a pharmaceutically acceptable compound, prodrug, isomer or salt according to claim 1, and a pharmaceutically acceptable carrier, carrier or diluent, in a first unit dosage form; a second of the melanocytes, a cannabinoid receptor antagonist, an analogue of the melanocyte-stimulating hormone, an antagonist of the hormone that concentrates melanin, the OB protein, a leptin analogue, a galanin antagonist and an antagonist of the orexin receptors. 43. A kit according to claim 42, wherein said anorectic agent is phentermine. 44. A kit according to claim 42, wherein said inhibitor of the reabsorption of monoamines is sibutramine, said serotonergic agent is dexfenfluramine or fenfluramine, and said dopamine agonist is bromocriptine. 45. A kit according to claim 41, wherein said lipase inhibitor is tetrahydrolipstatin. APPENDIX SHEET SUMMARY OF THE INVENTION The present invention provides novel compounds of Formula (l) and their prodrugs, their geometric and optical isomers, and pharmaceutically acceptable salts of said compounds, prodrugs and isomers, wherein R1-R ° and X are as described herein; Also provided are pharmaceutical compositions containing said compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and methods, pharmaceutical compositions and kits for treating obesity, hyperlipidemia, thyroid disease, hypothyroidism and related disorders and diseases such as diabetes. mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis.