MXPA06005838A - Novel salicylic anilides - Google Patents

Abstract

Novel salicylic anilides are chemical uncouplers useful e.g. for the treatment of obesity.

Description

NOVELTY SALICIICIAS ANILIDAS FIELD OF THE INVENTION The present invention relates to novel derivatives of salicylic anuide. The derivatives are effective chemical uncoupling and therefore are useful in the treatment, for example, of obesity.

BACKGROUND OF THE INVENTION Obesity is a well-known risk factor for the development of many very common diseases such as atherosclerosis, hypertension, type 2 diabetes, diabetes (non-insulin-dependent mellitus (NIDDM)), dyslipidemia, coronary heart disease and osteoarthritis and various cancers. It also causes considerable problems due to reduced mobility and a diminished quality of life. The number of obese people and the incidence of these diseases increases throughout the industrialized world. The term obesity indicates an excess of adipose tissue. In this context, obesity is best considered as any degree of excess of adiposity that produces a risk to health. The limit between normal and obese individuals can only be approximate, but the risk to health generated by obesity is probably continuous, as adiposity increases. In the context of Ref: 172567 present invention, persons with a body mass index (BMI) = body weight in kilograms divided by the square of their height in meters) greater than 25 are considered obese . Even moderate obesity increases the risk of premature death and diseases such as diabetes, dyslipidemia, hypertension, atherosclerosis, gallbladder disease and certain types of cancer. In the industrialized Western world the prevalence of obesity has increased significantly in recent decades. Due to the high prevalence of obesity and its consequences on health, its prevention and treatment should be a high priority for public health. With the exception of exercise, diet and limitation in foods, which is not feasible for a large number of patients, there is currently no convincing treatment to effectively and acceptable reduce body weight. However, not only in view of the considerable problems directly related to obesity such as those described above, but also due to the important effect of obesity as a risk factor in serious and even deadly and common diseases, they are important to find pharmaceutical compounds that are useful for the prevention and / or treatment of obesity.

When the energy intake exceeds the expenditure, the excess calories are stored predominantly in the adipose tissue and if this positive net balance is prolonged, it results in obesity, that is, there are components for weight balance and an anomaly. On either side (ingestion or expense) can lead to obesity. This process can be counteracted by increasing the energy expenditure (for example through exercise) or by decreasing the energy intake (for example with diets). The pharmacological treatment to date consists solely of Sibutramine (which acts on serotonergic mechanisms, Abbott) and Orlistat (which reduces the uptake of fat from the intestine, Roche Pharm), neither reduces body weight effectively or acceptably. Therefore, there is a need for pharmaceutical compounds which may be useful for the prevention and / or treatment of obesity, for example by increasing energy expenditure or by decreasing energy intake. One way to increase energy expenditure is by increasing the metabolic rate. Oxidative phosphorylation in the mitochondria, the energy of glucose metabolism and the oxidation of free fatty acids is used to activate the phosphorylation of ADP to ATP. When NADH and FADH2 are formed in the TCA cycle, they are oxidized back to NAD + and FAD, respectively, and protons are pumped out of the mitochondrial matrix. The resulting gradient of pH (the pH of the matrix -8 and the exterior pH -7) and the potential (~ -170 mV, negative interior) through the internal mitochondrial membrane constitute the electrochemical proton gradient. Taking into consideration that the effect of a difference of one pH unit corresponds to a potential of 61.5 mV, the proton electrochemical gradient exerts a proton motive force of approximately 230 mV, which is the driving force for the synthesis of mitochondrial ATP . When in this way the consumption of ATP, the cells respond by increasing the synthesis of ATP and consequently an influx of protons through ATP synthase, the enzyme responsible for the synthesis of ATP and therefore increases the metabolic rate. Chemical uncouplers are compounds which can transport protons through the membranes and when protons are transported through their inner mitochondrial membrane, ATP synthase is bypassed. On the side of the matrix (alkaline), the proton is released and the deprotonated uncoupling returns to the space between the membrane, where it captures another proton. The generation of the uncoupling cycle (or synthesis of ATP) and the resulting transport of protons generates an increased pumping out of protons through an increased oxidation of NADH and FADH2 by the respiratory chain. As a result, the concentration of NADH in the matrix will decrease.

Since the NADH feedback inhibits three stages in the TCA cycle (NADH is the main regulator of the TCA cycle), the flow through the TCA cycle will increase. Therefore, the metabolic rate will increase. Compounds such as chemical uncouplers, which act by increasing the metabolic rate in this way may be useful for treating obesity, but also for treating other diseases such as atherosclerosis, hypertension, diabetes, especially type 2 diabetes (NIDDM. English for non-insulin dependent diabetes mellitus), dyslipidemia, coronary heart disease, gallbladder disease, osteoarthritis and various types of cancer such as cancers of the endometrium, breast, prostate and colon as well as the risk of premature death and likewise other conditions such as diseases and disorders, conditions which improve by a reduced mitochondrial potential. In addition, chemical uncouplers can reduce reactive oxygen species (ROS) that are assumed (De Gray et al, Eur J. Biochem 269, 1995 ff (2002)) are involved in the aging process, in the damage of cardiac tissue as well as neuronal tissue. Therefore, it is also possible that the conditions affected by ROS are reversed or stopped by the intervention of chemical uncouplers. Examples of such conditions include diabetic microvascular diseases in the retina, glomerulrenal and peripheral nerve cells. The best-known chemical uncoupler "is 2,4-dinitrophenol (DNP), which has been shown to increase energy expenditure in humans as well as in animals.Side effects at high doses include increased perspiration , vasodilatation, skin flushes, cataracts, neuritis and death Two cases of deaths among the first and 100,000 people treated with DNP and the fact that the lowest dose can be fatal, given that only twice the average dose provides a desired increase 50% basal metabolic rate provides a very narrow safety interval combined with other factors, all this led to the withdrawal of DNP from the market.Since then nobody has tried to develop the market of uncoupling for the treatment of obesity.The DNP is the best known chemical uncoupling, but many other compounds that induce decoupling are known: DNP derivatives such as 4,6-dinitro-o-cresol (amar illo Victoria) and 2, -dinitro-l-naphthol (Martius yellow) also as structurally unrelated compounds such as 2,6-diterbutyl-4- (2 ', 2' -dicianovinyl) phenol) (SF6847) (also known as 2- (3, 5-diterbutyl-4-hydroxy-benzylidene) malonitrile), carbonylcyanide m-chlorophenylhydrazone (CCCP) and carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) (Miyoshi H et al. Quantitative releathionship between protenophoric and uncoupling activities of analogs of SF6847 (2, 6-di-t-butyl-4- (2 •, 2 '-dicyanovinyDphenol), Biochimica et Biophysica Acta 891, 293-299 (1987)) are uncoupling. Another class of chemical uncouplers are the salicylanilides of which S-13 is the most potent compound discovered so far (Terada H et al., Structural Requirements of Salicylanilides for Uncoupling Activity in Mitochondria, Quantitative Analysis of Structure, Uncoupling Relationships, Biochemistry and Biophysics, Acta 936). , 504-512 (1988)). WO00 / 06143 for Texas Pharmaceuticals Inc. is related to a method for inducing intracellular hyperthermia comprising a step of administering a mitochondrial uncoupling agent, such as 2,4-dinitrophenol. The document of E.U.A. 4,673,691 for Bachynsky is related to the use of 2,4-dinitrophenol to treat obesity. Various derivatives of salicylic anuide have been described in the literature. As an example, the document of E.U.A. 4,025,647 describes compounds of the formula: wherein R 1 can be hydrogen, X is the secondary or tertiary form of alkyl, R 2 alkanoyl, phenylsulfonynyl, phenylsulfonyl, etc., and Y is hydrogen or methyl. The compounds have anthelmintic activity, especially against hepatic atope. EP 322823 describes electrophotographic photoreceptors with the following formula halogen, etc. where A is a group of atoms necessary to condense the benzene ring with another ring. WO 01/44172 discloses compounds of the formula: wherein all X 'can be carbon, R1 can be hydroxyl, R2-R5 can be aryl, heteroaryl, alkylaryl, alkyl, ester, amide optionally substituted, etc. The compounds are inhibitors of serine proteases, urokinase, factor Xa, factor Vlla and have utility as anticancer and anticoagulant agents. R7 is amidine or guadinyl for all compounds specifically described in this application. WO 01/96944 describes compounds of the formula wherein R represents 0-4 substituents that are selected from alkyl, aryl, aralkyl, etc. The compounds are useful as components in colored photothermographic films. None of the specifically described compounds has an alkyl or branched phenyl as a substituent on the phenyl ring which is further to the left. WO 01/82924 describes compounds of the formula wherein R 1 -3 represents hydrogen, alkyl, halo, alkoxy, etc. The compounds are inhibitors of phosphate transport.

SUMMARY OF THE INVENTION The present inventors have surprisingly found that the salicylic aniidas of the formula I are potent chemical uncouplers. Accordingly, the present invention relates to compounds according to formula I wherein X represents: -c = c- R4 R2 or -C = C-, and m is 0, 1 or 2; R 1 represents alkyl of 1 to 6 branched carbon atoms or phenyl; R2 and R4 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R5, R6 and R7 independently represent hydrogen, nitro, cyano, halogen, -0R8, haloalkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, -C (0) OR8, -COR8, -C (0) NR8R8, -SH, -S (0) 20R8, -S (0) 2 (R8) 2, -S (0) nR9, aryl, heteroaryl, wherein the aryl and heteroaryl optionally they may be substituted with one or more alkyl of 1 to 6 carbon atoms, oxo or phenyl wherein the phenyl is substituted with one or more of halogen or alkyl of 1 to 6 carbon atoms; n is 0, 1, 2 and each R 8 represents independently hydrogen or alkyl of 1 to 6 carbon atoms and R 9 represents alkyl of 1 to 6 carbon atoms; R3 represents alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, arylalkenyl of 1 to 6 carbon atoms, arylalkynyl of 1 to 6 carbon atoms, heteroarylalkyl of 1 to 6 carbon atoms, heteroarylalkenyl of 1 to 6 carbon atoms, heteroarylalkynyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heteroaryl; wherein R3 optionally can be substituted with up to four substituents, RIO, Rll, R12 and R13 independently represent alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, oxo, cyano, nitro, - (CH2) rOR14, -SH, -S (0) pR15, -S (0) pN (R14) ( R15), -C (0) OR14, -OC (0) R14, -C (0) R14, -C (0) N (R14) (R15), - (CH2) rN (R14) C (O) R15 -, -B (OR14) (OR15), - (CH2) rN (R14) (R15) or phenyl, wherein the phenyl is optionally substituted with one or more substituents that are selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, cyano, nitro, -OR16-, -S (0) SR16, -C (0) OR16, -OC (0) ) R16, -C (0) R16, -C (0) N (R16) (R17), -N (R16) (R17), - (CH2) SN (R16) C (O) R17, -B (0R16) ) (0R17) -, - (CH2) tOR16 or - (CH2) tN (R16) (R17); each R14 independently represents hydrogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 atoms carbon and cyano; R15 represents haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms and cyano; or wherein R14 and R15, when attached to a nitrogen atom, together with the nitrogen atom form a cycloalkyl ring of 3 to 8 carbon atoms or heteroaryl, optionally substituted with one or more alkyl substituents of 1 to 6 carbon atoms. carbon; each R16 and R17 independently represents hydrogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 -Carbon or cycloalkyl atoms of 3 to 8 carbon atoms; or R16 and R17, when attached to a nitrogen atom, together with the nitrogen atom form a cycloalkyl or heteroaryl ring, optionally substituted with one or more alkyl substituents; p and s, independently of each other, are an integer of 0, 1 or 2; r and t, independently of each other, are an integer of 0, 1, 2 or 3; q is 0, 1 or 2; with the proviso that the compound is not N- (2-chloro-4-nitrophenyl) -3-tert-butyl-6-methylsalicylanilide, 3,5-diterbutyl-N- (2-chloro-4-nitrophenyl) -2-hydroxybenzamide or 3-tert-butyl-N- (2-chloro-4-nitrophenyl) -2-hydroxy-5-methylbenza-mide; and pharmaceutically acceptable salts, solvates and prodrugs thereof. The present invention also relates to the use of compounds of formula I in treatment or therapy and in particular with pharmaceutical compositions comprising said compounds. In another aspect, the invention relates to therapeutic methods comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof. In a further aspect, the invention relates to the use of compounds of formula I in the manufacture of medicaments.

DEFINITIONS In the present context, the term "alkyl" is intended to indicate a straight or branched chain of a saturated monovalent hydrocarbon radical having 1 to 12 carbon atoms, also indicated as alkyl of 1 to 12 carbon atoms. Typical alkyl groups are alkyl groups with 1 to 8 or 1 to 6 carbon atoms and are also indicated as alkyl of 1 to 8 carbon atoms and alkyl of 1 to 6 carbon atoms, respectively. Typical alkyl groups of 1 to 6 carbon atoms include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, n-pentyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl (neopentyl), 1,2,2-trimethylpropyl and the like, while Typical alkyl groups of 1 to 8 carbon atoms include the same groups as well as alkyl groups having 7 or 8 carbon atoms, such as heptyl, octyl, 2,2-dimethylhexyl and the like. The term "C 1-6 alkyl", as used herein, also includes alkyl of 3 to 6 secondary carbon atoms and alkyl of 4 to 6 tertiary carbon atoms. The term "alkyl of 1 to 8 carbon atoms" as used herein also includes alkyl of 3 to 8 carbon atoms and alkyl of 4 to 8 tertiary carbon atoms. The term "C 1 -C 12 alkyl", as used herein, also includes alkyl of 3 to 12 secondary carbon atoms and alkyl of 4 to 12 tertiary carbon atoms. In the present context, the term "alkenyl" is meant to indicate a straight or branched chain monovalent hydrocarbon radical having from 2 to 6 carbon atoms and at least one carbon-carbon double bond, for example 3 to 5 alkenyl. carbon atoms. Typical alkenyl groups of 3 to 5 carbon atoms include vinyl, allyl, 1-propenyl, 1,3-butadien-1-yl and the like. The term "conjugated alkenyl" as used herein, alone or in combination, refers to an alkenyl having consecutive double bonds such as, for example, 1,3-butadiene-1-yl. In the present context, the term "alkynyl" is intended to indicate a straight or branched chain monovalent hydrocarbon radical having from two to six carbon atoms and at least one carbon-carbon triple bond and optionally one or more double bonds carbon-carbon. Examples include ethynyl, propynyl and 3,4-pentadien-l-ynyl. The term "halogen" is intended to indicate members of the seventh major group of the periodic system, i.e. fluoro, chloro, bromo and iodo. In the present context, the term "aryl" is intended to indicate a carbocyclic aromatic ring radical which optionally may be fused to another ring, which may be aromatic or non-aromatic, aromatic or non-aromatic. Typical aryl groups include phenyl, biphenylamyl, indenyl, fluorene, naphthyl (1-naphthyl, 2-naphthyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), 1,2,4,4-tetrahydroquinolyl, 1, 2, 3, 4-tetrahydronaphthyl and the like The term "heteroaryl", as used herein, alone or in combination, refers to an aromatic ring radical with, for example, 5 to 7 constituent atoms, or an aromatic ring system radical fused with, for example, 7 to 18 constituent atoms, wherein at least one ring is aromatic, containing one or more heteroatoms that are selected from heteroatoms of nitrogen, oxygen or sulfur, wherein the N-oxides and sulfur monoxides - and the sulfur dioxides are perishable heteroaromatic substitutions Examples include furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazoyl, isothiazolyl pyridinyl, pi ridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl and indazolyl, thienyl (2-thienyl, 3-thienyl), furanyl (2-furanyl, 3-furanyl), indolyl, oxadiazolyl, isoxazolyl, thiadiazolyl oxatriazolyl, thiatriazolyl quinazolinyl, fluorenyl, xanthenyl, isoinda nyl , benzhydryl, acridinyl, thiazolyl, pyrrolyl (1-pyrro-lyl, 2-pyrrolyl, 3-pyrrolyl), pyrazolyl (1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl 5-pyrazolyl), imidazolyl (1-imidazolyl, 2- imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1, 2, 3-triazol-1-yl, 1, 2, 3-triazol-4-yl, 1,2,3-triazol-5-yl, 1 , 2,4-triazol-3-yl, 1, 2,4-triazol-5-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (isoxazo-3-yl, isoxazo-4 -yl, isoxazo-5-yl), isothiazolyl (isothiazo-3-yl, isothiazo-4-yl, isothiazo-5-yl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridinyl (2- pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinoli-nyl) , 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinoli-nyl, 8-quinolinyl), isoquinolinyl (1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), benzo [b] furanyl (2-benzo [b] furanyl, 3-benzo [b] furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), 2,3-dihydrobenzo [b] furanyl (2- (2,3-dihydrobenzo [b] furanyl), 3- (2,3-dihydro-benzo [b] furanyl), 4- (2,3-dihydro-benzo [b] furanyl), - (2,3-dihydro-benzo [b] furanyl), 6- (2,3-dihydro-benzo [b] furanyl), 7- (2,3-dihydro-benzo [b] furanyl)), benzo [b ] thiophenyl, (benzo [b] thiophen-2-yl, benzo [b] thiophen-3-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophene 6-yl, benzo [b] thiophen-7-yl), 2,3-dihydro-benzo [b] thiophenyl (2,3-dihydro-benzo [b] thiophen-2-yl,, 3-dihydrobenzo [b] thiophen-3-yl, 2,3-dihydro-benzo [b] thiophen-4-yl, 2,3-dihydro-benzo [b] thiophen-5-yl, 2,3-dihydrobenzo [b] thiophen-6-yl, 2,3-dihydro-benzo [b] thiophen-7-yl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl 2-benzimidazolyl, 4-benzimidazolyl, -benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl) benzoxazolyl (2-benzoxazolyl, 3-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 66-bbeennzzooxxaazzoolliilloo 7-benzoxazolyl), benzothiazolyl (2-benzothiazolyl, -benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, "2-carbazolyl, 3-carbazolyl 4-carbazolyl), 5H-dibenz [b, f] azepinyl (5H-dibenz [b , f] azepin-1-yl, 5H-dibenz [b, f] azepin-2-yl, 5H-dibenz [b, f] azepin-3-yl, 5H-dibenz [b, f] azepin-4-yl , 5H-dibenz [b, f] azepin-5-yl), 10, 11-dihydro-5H-dibenz [b, f] azepinyl, (10,11-dihydro-5H-dibenz [b, f] azepin-1 -yl, 10, 11-dihydro-5H-dibenz [b, f] azepin-2-yl, 10, 11-dihydro-5H-dibenz [b, f] azepin-3-yl, 10, 11-dihydro-5H -dibenz [b, f] azepin-4-yl, 10, 11-dihydro-5H-dibenz [b, f] azepin-5-yl), benzo [1, 3] dioxol, (2-benzo [1,3] dioxol, 4-benzo [1,3] dioxol, 5-benzo [1, 3] dioxol, 6-benzo [1,3] dioxol, 7-benzo [1, 3] dioxol), and tetrazolyl (5-tetrazolyl, N-tetrazolyl). A "fused ring system", as used herein alone or in combination, refers to a carbocyclic or heterocyclic ring radical fused to another carbocyclic or heterocyclic ring radical, the two rings having two common carbon atoms. Typical fused aromatic ring systems include, but are not limited to naphthalene, quinoline, isoquinoline, indole and isoindole. In the present context, the term "cycloalkyl" is intended to indicate a cyclic saturated monovalent hydrocarbon radical having 3, 4, 5, 6, 7 or 8 carbon atoms in the ring.

In the present context, the term "alkoxy" is intended to indicate a radical of the formula -OR ', wherein R' represents alkyl, as indicated in the foregoing. The term "haloalkoxy" is intended to indicate an alkoxy as defined above substituted with one or more of halogen, such as fluoro, chloro, bromo or iodo. In the present context, the term "to the uilamino" is intended to indicate a radical of the formula -NH-R 'or -N (R') 2, wherein each R 'represents alkyl as indicated in the above. The term "nitro" will mean the radial -N02. The term "cyano" will mean the radical -CN. In the present context, the term "haloalkyl" is intended to indicate an alkyl, as defined above, substituted with one or more halogens as defined above. Examples include trihalomethyl, such as trifluoromethyl and trichloromethyl and 2,2,2-trichloro-l-ethyl. In the present context, the term "hydroxyalkyl" is intended to indicate an alkyl, as defined above, substituted with one or more hydroxyl groups. Examples include hydroxymethyl, 1-hydroxy-1-ethyl and 2-hydroxy-1-ethyl. As used herein, the term "solvate" is a complex of defined stoichiometry formed by a solute (in each case, a compound according to the present invention) and a solvent. The solvents may be, by way of example, water, ethanol or acetic acid. As used herein, the term "prodrug" includes biohydrolyzable amides and biohydrolyzable esters and also comprises: a) compounds in which the biohydrolyzable functionality in such a precursor is encompassed in the compound according to the present invention, and b) compounds which can be oxidized or biologically reduced in a given functional group to provide drug substances according to the present invention. Examples of these functional groups include 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, terbutyl and the like. In the present context, the term "pharmaceutically acceptable salt" is intended to indicate salts which are not harmful to the patient. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable inorganic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic acids , methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene-salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts that are included in J. Pharm, Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include salts of lithium, sodium, potassium, magnesium and the like. Examples of alkylated ammonium and ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetrabutylammonium and the like. A "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially suppress the clinical manifestations of a given disease and its complications. A suitable amount to accomplish this is defined as a "therapeutically effective amount". The effective amounts for each purpose will depend on the severity of the disease or damage as well as the weight and general condition of the subject. It will be understood that the determination of an appropriate dosage can be obtained using routine or systematic experimentation by constructing a matrix of values and by testing different points in the matrix, all of which are within the usual skills of a trained physician or veterinarian. The term "treatment" and "treating" as used herein means the administration and care of a patient for the purpose of combating a condition, such as a disease or disorder. The term is intended to include a full spectrum of treatments for a given condition that a patient suffers from, said administration of the active compound to alleviate the symptoms or complications, to delay the progress of the disease, disorder or condition, to alleviate or release the symptoms and complications and / or to cure or eliminate the disease, disorder or condition and equally to avoid the condition, wherein the prevention should be understood as the administration and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of the active compounds to prevent the onset of symptoms or complications. The patient to be treated is preferably a mammal, in particular a human being, but may also include animals such as dogs, cats, cows, sheep and pigs.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, m is 0. In another embodiment m is 1 and in another additional embodiment m is 2. In one embodiment, R 1 represents phenyl, neopentyl, tertbutyl, isopropyl or 1,1-dimethylpropyl and in particular terbutyl. In one embodiment, R2 and R4 independently represent hydrogen or methyl. In one embodiment, R3 represents alkenyl of 1 to 6 carbon atoms or alkynyl of 1 to 6 carbon atoms, both optionally substituted. Particular examples of R3 include styryl. In one embodiment, R3 represents optionally substituted aryl. Particular examples of R3 include phenyl, 4-chlorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-cyano-phenyl or radicals with the following structures wherein R is selected from the list consisting of hydrogen, methyl, CF 3, Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano and phenyl, wherein the phenyl may optionally be substituted with Cl, Br , F, CF3 or methoxy. Particular examples of R3 include phenyl and 4-cyanophene. In another embodiment, R3 represents an optionally substituted heteroaryl. In particular, R3 can be selected from: wherein R is selected from the list consisting of hydrogen, methyl, CF3, Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano and phenyl, wherein the phenyl may optionally be substituted with Cl, Br, F, CF3 or methoxy. Particular mention is made of thiophen-2-yl, 5-cyanothiophen-2-yl and benzo [b] thiophen-2-yl. In another embodiment, one or more of R5, R6 and R7 are selected from nitro, cyano, halogen, haloalkyl, haloalkoxy, optionally substituted alkyl or optionally substituted heteroaryl. In particular, R5, R6 and R7 together can constitute the following substitution patterns: 2-chloro-4-nitro; 2-trifluoromethoxy-4-nitro; 4- (1-imidazolyl); 2-trifluoromethyl-4- (1-imidazolyl); and 2-methyl-4- (1-imidazo-lyl). Particular mention is made of 2-chloro-4-nitro and 2-trifluoromethoxy-4-nitro. In one embodiment, the compound of formula I is selected from the list consisting of 5-tert-butyl-4-hydroxy-2-methylbiphenyl-3-carboxylic acid (2-chloro-4-nitrophenyl) amide; E) 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -2-hydroxy-5-styryl-benzamide; 5-tert-butyl-4-hydroxy-2-methylbiphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxyphenyl) amide; (4-Cyano-2-trifluoromethoxyphenyl) -amide of acid -tert-butyl-4'-cyano-4-hydroxy-2-methylbiphenyl-3-carboxylic acid; 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -5- (5-cyanothiophen-2-yl) -2-hydroxybenzamide; and 5-benzo [b] thiophen-2-yl-3-tert-butyl-N- (2-chloro-4-cyanophenyl) -2-hydroxybenzamide. The compounds according to formula I can comprise chiral carbon atoms or carbon-carbon double bonds which can generate stereoisomeric forms, for example enantiomers, diastereoisomers and geometric isomers. The present invention relates to all of said isomers as either pure form or as mixtures thereof. The pure isomeric forms can be prepared from intermediates which in themselves are pure isomers, by purification of a mixture of isomers after synthesis or by combination of two methods. The purification of the isomeric forms is well known in the art, for example as described in Jaques in Enantiomers, Racemates and resolution, Wiley. 1981. The compounds of the present invention are useful in the treatment of diseases or conditions that benefit from an increase in mitochondrial respiration. The compounds of the present invention are considered to be particularly suitable for the treatment of obesity as such or to prevent weight gain for the treatment of diseases or disorders where obesity is involved in the etiology. In one embodiment, the invention in this manner provides a method for treating 1 metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, type 1 diabetes, late diabetic complications that include cardiovascular diseases, cardiovascular disorders, lipid metabolism disorders, neurodegenerative and psychiatric disorders, lack of regulation of intraocular pressure that includes glaucoma, atherosclerosis, hypertension, coronary heart disease, gallbladder disease, osteoarthritis and cancer. More specifically, such conditions include the metabolic syndrome, type 2 diabetes (especially in obese patients), diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsulinemia, impaired glucose tolerance (IGT, by its acronym in English), glucose impaired fasting (IFG, for its acronym in English), increased production of hepatic glucose, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia (especially in obese patients), diabetic dyslipidemia, hyperlipidemia , hypertriglyceridemia, hyperlipoproteinemia, micro- / macroalbuminuria, nephropathy, retinopathy,. neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, coronary arthropathy, cardiac hypertrophy, myocardial ischemia, heart failure, congestive heart failure, stroke, myocardial infarction, arrhythmia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurodegenerative and psychiatric disorders, Alzheimer's disease, neuronal death, impaired cognitive condition, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsy, addiction to chemical substances, intraocular pressure disorders, bacterial infections, mycobacterial infections. In the present context it is intended that the cancer include forms such as hematological cancer such as leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphatic leukemia, myelodysplasia, multiple myeloma, Hodking disease or forms of solid tumors such as fibrosarcoma, small or non-small cell lung carcinoma, gastric, intestinal or colorectal cancer, prostate, endometrial, ovarian or breast cancer, brain, head or neck cancer, cancer of the urinary tract such as kidney or bladder cancer , malignant melanoma, liver cancer, uterine and pancreatic cancer. In another embodiment, the invention relates to the use of a chemical decoupling according to the present invention to maintain a weight loss. The use of the compounds according to the present invention in the treatment of obesity in the same way can reduce or eliminate side effects such as skin irritation, glaucoma, etc., which are known from the treatment of obesity with DNP and Other chemical uncouplers with narrow safety intervals. Uncoupling can also reduce the release of insulin from the β-cells and therefore may be useful in providing rest to the β-cells. Rest induction of ß-cells may be useful in relation to ß-cell transplantation, and it has also been reported to induce ß-cells which may be useful in preventing diabetes. Anti-obesity drugs which regulate appetite and reduce food intake often have a lack of long-term efficacy in terms of body weight loss because the body, in response to treatment, slows down metabolism. In contrast, the compounds of the present invention increase metabolism and therefore are considered to be particularly suitable for maintaining weight loss. The compounds of the present invention are also considered to be particularly suitable for the treatment of diseases or disorders where reactive oxygen species are involved in the etiology, where a reduction in the amount of reactive oxygen species is beneficial. In a modality, the invention thus provides a method for treating, and in particular preventing, aging and damage to the heart, endothelial cells and neuronal tissue, diabetic microvascular diseases in the retina, renal glomeruli and peripheral nerve cells. The method comprises administering to a patient in need thereof a therapeutically effective amount of one or more compounds of the present invention to a patient in need thereof. The subject can be any mammal that suffers from a condition that benefits from increased mitochondrial respiration. Such mammals may include, for example, horses, cows, sheep, pigs, mice, rats, dogs, cats, primates such as chimpanzees, gorillas, macaques and, most preferably, humans. It is well known that many compounds used to fight insects and parasites, that is, insecticides and parasiticides, are chemical uncoupling. It is therefore considered that uncoupling devices accor to the present invention can be used as insecticides or parasiticides. In the methods of the present invention, the compounds of the present invention can be administered alone or in combination with other therapeutically active compounds, either concomitantly or sequentially, and in any suitable ratio. Such additional active compounds may be selected from antidiabetic agents, antihyperlipidemic agents, anti-obesity agents, antihypertensive agents and agents for the treatment of complications resulting or associated with diabetes. Suitable antidiabetic agents include insulin, GLP-1 (glucagon-1-like peptide), derivatives such as those described in WO 98/08871 (Novo Nordisk A / S), which is incorporated herein by reference, as well as hypoglycemic agents active orally. Suitable orally active hypoglycemic agents preferably include imidazolines, sulfonylureas, biguanides, meglitinides, oxadiazolidiones, thiazolidiones, insulin sensitizers, α-glucosidase inhibitors, agents that act on the ATP-dependent potassium channel of pancreatic β-cells, for example, potassium channel openers such as those described in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A / S), which are incorporated herein by reference, channel openers. potassium such as ormitiglinide, potassium channel blockers such as nateglinide or BTS-67582, glucagon antagonists such as those described in WO 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.) , all of which are incorporated herein by reference, GLP-1 agonists such as those described in WO 00/42026 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), the These are incorporated herein by reference, inhibitors of DPP-IV (dipeptidyl-peptidase IV), PTPase inhibitors (protein tyrosine phosphatase), glucokinase activators such as those described in WO 02/08209 for Hoffmann La Roche, enzyme inhibitors. liver enzymes involved in the stimulation of gluconeogenesis and / or glycogenolysis, glucose uptake modulators, GSK-3 inhibitors (glycogen synthase kinase-3), compounds that modify lipid metabolism such as antihyperlipidemic agents and antilipidemic agents, compounds that decrease the food ingestion and PPAR (peroxisome proliferator activated receptor) and RXR agonists (retinoid X receptor) such as ALRT-268, LG-1268 or LG-1069.

In one embodiment of the methods, the compound of the present invention can be administered in combination with insulin or insulin analogues. In one embodiment, the compound of the present invention can be administered in combination with a sulfonylurea, for example tolbutamide, chlorpropamide, tolaza-mide, glibenclamide, glipizide, glimepiride, glycazide or glyburide. In one embodiment, the compound of the present invention can be administered in combination with a biguanide, for example metformin. In one embodiment of the methods of the present invention, the compounds of the present invention can be administered in combination with meglitinide, for example repaglinide or senaglinide / nateglinide. In one embodiment, the compound of the present invention can be administered in combination with an insulin sensitizer of the thiazolidinedione type, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / CI-1037 or T174 or the compounds described in WO 97/41097 (for example 5- [[4- [3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidin-2,4-dione), WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292, which are incorporated herein by reference.

In one embodiment, the compound of the present invention can be administered in combination with an insulin sensitizer for example such as Gl 262570, YM-440, MCC-555, JTT-501, AR-H03942, RP-297, GW-409544 , CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds described in WO 99/19313 (NN622 / DRF-2725), WO 00/50414, WO 00/63191, WO 00/63192, WO 00/63913 and WO 00/23425, WO 00/23415, WO 00/23451, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, WO 00/63209, WO 00/63190 and WO 00/63189, which are incorporated herein by reference. In one embodiment, the compound of the present invention can be administered in combination with an α-glucosidase inhibitor, for example voglibose, emiglytate, miglitol or acarbose. In one embodiment, the compound of the present invention can be administered in combination with a glycogen phosphorylase inhibitor, for example the compounds described in WO 97/09040. In one embodiment, the compound of the present invention can be administered in combination with a glucokinase activator. In one embodiment, the compound of the present invention can be administered in combination with an agent that acts on the ATP-dependent potassium channel of pancreatic β cells, for example tolbutamide, glibenclamide, glipizide, glycoside, BTS-67582 or repaglinide. In one embodiment, the compound of the present invention can be administered in combination with nategli-nide. ~ r. In one embodiment, the compound of the present invention can be administered in combination with an antihyperlipidemic agent or an antilipidemic agent for example cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrotirroxin. In one embodiment, the compound of the present invention can be administered in combination with one or more of the compounds mentioned above, for example in combination with metformin and a sulfonylurea such as glyburide; a sulfonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulfonylurea, metformin and troglitazone; insulin and a sulfonylurea; insulin and metformin; insulin, metformin and sulfonylurea; insulin and troglitazone; insulin and lovastatin; etc. In one embodiment, the compound of the present invention can be administered in combination with one or more anti-obesity agents or appetite regulating agents. Such agents can be selected from the group consisting of CART agonists (cocaine and amphetamine-regulated transcript), NPY agonists (neuropeptide Y), MC3 agonists (melanocortin 3), MC4 agonists (melano-curtain 4), antagonists of orexin, TNF agonists (tumor necrosis factor), CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 adrenergic agonists such as CL-326243, AJ-9677, GW-0604, LY362884 , LY377267 or AZ-40140, agonists of MHS (melanocyte stimulating hormone), MCH (melanocyte concentrating hormone) antagonists, CCK agonists (cholecystokinin), serotonin reuptake inhibitors (fluoxetine, seroxat or citalopram), inhibitors of reuptake of noradrenaline (eg sibutramine), 5HT agonists (serotonin), bombesin agonists, galanin antagonists, growth hormone, growth factors such as prolactin or placental lactogen, growth hormone releasing compounds, HRT agonists (hormone of thyrotropin release), modulators of UCP 2 or 3 (protein 2 or 3 uncoupling), leptin agonists, DA (dopamine) agonists (bromocriptine, di prexin), lipase / amylase inhibitors, PPAR modulators, RXR modulators, TR ß agonists, CNS adrenergic stimulating agents, AGRP inhibitors (agouti-related protein), histamine H3 antagonists such as those described in WO 00 / 42023, WO 00/63208 and WO 00/64884, which are incorporated herein by reference, exendin-4, GLP-1 agonists and ciliary neurotrophic factor. Additional anti-obesity agents are bupropion (antidepressant), topiramate (anticonvulsant), ecopipam (dopamine antagonist D1 / D5), naltrexone (opioid antagonist) and peptide YY3-36 (Batterham et al, Nature 418, 650-654 (2002)) . In one embodiment, the anti-obesity agent is leptin. In one embodiment, the anti-obesity agent is a lipase inhibitor, for example orlistat. In one embodiment, the anti-obesity agent is an adrenergic CNS stimulating agent, for example dexan-fetamine, amphetamine, phentermine, mazindol phendimetrazine, diethylpropion, fenfluramine or dexfenfluramine. In a further embodiment, the compounds of the present invention can be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol propanolol and metoprolol; ACE inhibitors (angiotensin-converting enzyme) such as benazepril, captopril, enalapril, fosinopril, lisonopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodi-pina, diltiazem and verapamil; and blockers such as doxazosin, urapidil, prazosin and terazosin. It should be understood that any suitable combination of the compounds according to the invention with diet and / or exercise, one or more of the compounds mentioned above and optionally one or more of the additional active substances is considered to be within the scope of the present invention. . The present invention also provides pharmaceutical compositions comprising as an active ingredient at least one compound of the present invention, preferably in a therapeutically effective amount, suitable for any of the methods according to the present invention together with one or more carriers or excipients. pharmaceutically acceptable Such pharmaceutical compositions may also comprise another additional active compound as indicated in the foregoing. The pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 m9 and particularly preferably from about 0.5 mg to about 200 mg of a suitable compound for any of the methods described in the above.

PHARMACEUTICAL COMPOSITIONS The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or excipients, either in single or multiple doses. The pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as with any other adjuvant and excipient known in accordance with conventional techniques such as those described in Remington: The Science and Practice of Pharmacy, twentieth edition, Gennaro , Ed., Mack Publishing Co., Easton, PA, 2000. The pharmaceutical compositions can be formulated specifically for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal , intra-cisternal, intraperitoneal, vaginal and parenteral (which includes subcutaneous, intramuscular, intrathecal, intravenous and intra-dermal), are preferred orally. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient selected. Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, lozenges, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs. The pharmaceutical compositions for administration. parenteral include sterile, aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders that are diluted (reconstituted) in sterile injectable solutions or dispersions before use. Depot injectable formulations are also contemplated and considered to be within the scope of the present invention. Other suitable forms of administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, etc. A typical oral dosage is in the range of from about 0.001 to about 100 mg / kg of body weight per day, preferably from about 0.01 to about 50 mg / kg of body weight per day and more preferably from about 0.05 to about 10 mg / kg of body weight per day administered in one or more dosages such as one to three dosages. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant disease that is treated as well as other factors evident to the experts in the treatment. technique. The formulations can conveniently be presented in a unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times a day, such as 1 to 3 times a day, may contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and most preferably from about 0.5 mg to about 200 mg. For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, the doses typically are of the order of about half the dose used for oral administration. Compounds for use in accordance with the present invention are generally used as the free substance or as a pharmaceutically acceptable salt thereof. Examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid. The term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds for use in accordance with the present invention, salts which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. When a compound for use according to the present invention contains a free base, such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid. When a compound for use according to the present invention contains a free acid, such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as a sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be useful in the preparation of the compounds of the invention and these form a further aspect of the invention. For parenteral administration, the solutions of the compounds for use according to the present invention in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil can be used. Such aqueous solutions may suitably be quenched if necessary and the liquid diluent first becomes isotonic with a sufficient amount of saline or glucose solution. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used are all available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers (carriers) include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, alabaster, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia gum, magnesium stearate, stearic acid and lower cellulose alkyl ethers. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. Pharmaceutical compositions formed by combining the compounds for use according to the present invention and pharmaceutically acceptable carriers are then easily administered in a variety of dosage forms suitable for the routes of administration described. The formulations can conveniently be presented in a unit dosage form by methods known in the pharmacy art. Formulations of the present invention suitable for oral administration may be presented as separate units such as capsules or tablets, each with a predetermined amount of the active ingredient and which may include a suitable excipient. In addition, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid or a liquid emulsion oil in water or water in oil. Compositions designed for oral use can be prepared according to any known method if such compositions may contain one or more agents that are selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically elegant preparations pleasant to the palate. The tablets may contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or acacia gum; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action for a prolonged period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. They can also be coated by the techniques described in the U.S. Patents. numbers 4,356,108; 4,166,452 and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules wherein the active ingredient it is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil. The aqueous suspensions may contain the compound for use according to the present invention mixed with excipients suitable for the preparation of aqueous suspensions. Such excipients are agents that improve the suspension, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents which may be phosphatides as found in nature such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with chain aliphatic alcohols long, for example, heptade-caetyl-eneoxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and an exitol such as oxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, an agent that improves the suspension and one or more preservatives. Suitable dispersing or humidifying agents and agents that improve the suspension are exemplified by those already mentioned above. Additional excipients, for example, flavoring sweetening agents and coloring agents may also be present. Pharmaceutical compositions comprising compounds for use in accordance with the present invention may also be in the form of oil-in-water emulsions.

The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example a liquid paraffin or a mixture thereof. Suitable emulsifying agents can be gums as found in nature, for example gum acacia or gum. of tragacanth, phosphatides as found naturally, for example soybeans, lecithin and esters or partial esters of fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of said partial esters with ethylene oxide, example polyoxyethylene sorbitan monooleate. The emulsions may also contain adulterating and flavoring agents. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleoginous suspension. This suspension can be formulated according to known methods using suitable dispersing agents or humectants and agents that improve the suspension as described above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a diluent or solvent. parenterally acceptable non-toxic, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conveniently used as a solvent or improving suspension. For this purpose, any combination of fixed oil can be used using monoglycerides or synthetic diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compositions may also be in the form of suppositories for rectal administration of the compounds of the invention. These compounds can be prepared by mixing the medicament with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the medicament. Such materials include cocoa butter and polyethylene glycols, for example. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are contemplated. For the purpose of this application, topical applications will include mouth rinses and liquids for gargling. The compounds of the present invention can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine and phosphatidylcholines. In addition, some of the compounds of the present invention can form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the invention.

Therefore, in a further embodiment, there is provided a pharmaceutical composition comprising a compound for use according to the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and one or more pharmaceutically acceptable carriers, excipients or diluents. If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as a suspension or aqueous or non-aqueous liquid solution. A typical tablet can be prepared by conventional tableting techniques which may contain: Core: Active compound (as free compound 5.0 mg or salt thereof) Lactose Ph. Eur. 67.8 mg Microcrystalline cellulose (Avicel) 31.4 mg Amberlite ™ IRP88 * 1.0 mg Magnesium stearate Ph. Eur. C.s.

Coating: Hydroxypropylmethylcellulose approximately 9 mg Mywacett 9-40 T ** approximately 0.9 mg * Poliacrilin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as a plasticizer for film coating. If desired, the pharmaceutical composition comprising a compound for use according to the present invention may comprise a compound for use according to the present invention in combination with additional active substances such as those described in the foregoing. The present invention also provides methods for the preparation of compounds for use in accordance with the present invention. The compounds can be prepared easily according to the following general procedures (in which all variables are as defined above, unless otherwise specified) using readily available starting materials, reagents and conventional synthesis procedures. . In these reactions, it is also possible to make use of variants which in themselves are known to those usually skilled in the art but which are not mentioned in greater detail.

EXAMPLES CLAR-MS (Method A) The following instruments were used. • Hewlett Packard 1100 G1312A Series Bin Pump • Hewlett Packard 1100 Series Header Compartment • Hewlett Packard 1100 G1315A DAD Diode Distribution Detector • Hewlett Packard 1100 MSD Series • Sedere 75 Evaporative Light Dispersion Detector The instrument is controlled by the program HP Chemstation Software The CLAR pump is connected to two eluent tanks containing: A: 0.01% TFA in water B: 0.01% TFA in acetonitrile The analysis is performed at 40 ° C by injecting an appropriate volume of the sample (preferably 1 μl) on the column which is diluted with an acetonitrile gradient.

The CLAR conditions, the detector settings and the mass spectrometer settings used are given in the following table. Column: Waters Xterra MS C-18 X 3 mm internal diameter 5 μm Gradient: 5% -100% linear acetonitrile for 7.5 min at 1.5 ml / min Detection: 210 nm (analog output of a DAD (diode distribution detector) ) ELS (analog output of ELS) EM ionization mode API-ES Scanning 100 - 1000 urn, stage of 0.1 urn After DAD, the flow is divided giving approximately 1 ml / min to the ELS and 0.5 ml / min to the EM .

General Procedure (A) To a solution of the salicylanilide I substituted with bromine (1 equivalent) in dioxane is added the appropriate substituted arylboronic acid. The appropriate palladium catalyst is added together with the appropriate base and the reaction mixture is heated at reflux for 5-20 hours. The reaction mixture is evaporated. Water is added to the residue and the aqueous phase is extracted with an organic solvent such as ethyl acetate, diethyl ether or dichloromethane. The organic phase is dried over sodium sulphate and evaporated. Stage A: Aqueous treatment followed by crystallization. Step B: Aqueous treatment followed by column chromatography.

General Procedure (B) To a solution of the substituted salicylanilide I with bromine (1 equivalent) in acetonitrile is added the appropriate substituted aryltin compound. The appropriate palladium catalyst is added together with the appropriate base and the reaction mixture is heated at reflux for 5-20 hours. The reaction mixture is evaporated. Water is added to the residue and the aqueous phase is extracted with an organic solvent such as ethyl acetate, diethyl ether or dichloromethane. The organic phase is dried over sodium sulphate and evaporated. Stage A: Aqueous treatment followed by crystallization Eyapa B: Aqueous treatment followed by column chromatography.

General Procedure (C) To a solution of bromine compound A (1 equivalent) is added an organic solvent such as dioxane or tetrahydrofuran, 0.01 equivalent of Pd2 (dba) 3 and 0.02 equivalents of Pd (P (t-bu) 3) 2. This solution is add the appropriate vinyl B compound (1 equivalent) followed by 1.1 equivalent of dicyclohexylmethylamine. The reaction mixture is stirred at room temperature for 1-3 days. The compounds are isolated by aqueous treatment followed by column chromatography.

General Procedure (D) The substituted salicyclic acid I is protected with a dialkyldichlorosilane II after reflux in toluene to form a compound of formula III. The brominated derivative III is reacted with boronic acid of formula IV under palladium catalyzed cross-coupling reaction conditions to provide compounds of formula V. The compounds of formula V are hydrolyzed to free salicylic acid with aqueous base of tetrabutylammonium fluoride ( TBAF) The free acid is reacted with a Vi aniline under standard conditions to provide compounds of formula VII.

General Procedure (E) The substituted salicyclic acid I is protected with a dialkyldichlorosilane II after reflux in toluene to form a compound of formula III. The bromine derivative III is reacted with an appropriate alkene or alkyne compound of formula IV under palladium catalyzed cross coupling reaction conditions to provide compounds of formula V. The compounds of formula V are hydrolyzed to free salicylic acid with aqueous base or fluoride of tetrabu-tilamonio (TBAF). The free acid is reacted with an aniline VI under standard conditions to provide compounds of formula VII.

Example 1 (General Procedure (A)) (5-tert-butyl-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (2-chloro-4-nitrophenyl) -amide) Step B: To a solution of 3-bromo-5-tert-butyl-N- (2-chloro-4-nitrophenyl) -6-hydroxy-2-methylbenzamide (0.18 g, 0.4 mmole "B) in 5 ml of dioxane under nitrogen phenylboronic acid (50.0 mg, 0.4 mmol), tetrakis (triphenylphosphine) palladium (0) (10 mg, 0.009 mmol) and sodium carbonate (1.41 ml, 2 M solution in water) are added, the reaction mixture is heated to 100 C for 6 hours The reaction mixture is evaporated, diluted with ethyl acetate and the organic phase is washed with a citric acid solution (10%) The organic phase is dried over sodium sulphate and evaporated. The crude compound is purified by column chromatography XH (400 MHz, CHLOROFORM-D): d ppm: 1.42 (s, 9 H), 7.31 (s, 1 H), 2.45 (s, 3 H), 7.25-7.35 ( , 4 H), 7.40-7.50 (m, 2 H), 8.25 (dd, 1 H), 8.32 (d, 1 H), 8.50 (s, 1 H), 8.90 (d, 1 H), 9.60 (s, 1H); CLAR-MS (Method A): M / Z = 439, 441 (M + 1); Rt = 5.99.

Example 2 (General procedure (B)) (E) 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -2-hydroxy-5-styrylbenzamide Step B: To a solution of 3-bromo-5-tert-butyl-N- (2-chloro-4-nitrophenyl) -6-hydroxy (0.2 g, 0.5 mmol) in 5 ml of acetonitrile are added, under a nitrogen atmosphere , phenylethenyltin (0.25 g, 0.63 mmole) and bis (triphenylphosphine) palladium (II) chloride (Acros organics, 35.0 mg, 0.05 mmole). The mixture is sent to microwaves (Emry's Optimizer EXP, single-mode instrument of Personal Chemistry, 130 ° C, 300 sek). The reaction is evaporated, dissolved in water and dichloromethane and then acidified with trifluoroacetic acid. The organic layer is evaporated and the crude compound is purified by column chromatography. XH (400 MHz, CHLOROFORM-D): d ppm: 1.49 (s, 9H), 6.99 (d, 1H), 7.08 (d, 1H), 7.47 (s, 1H), 7.50-7.55 (m, 5H), 7.60 (s, 1H), 7.64 - 7.68 (, 1H), 7.73 (s, 1H), 8.67 (d, J = 8.59 Hz, 1H), 8.77 (s, 1H), 12.21 (s, 1H) CLAR-EM (Method A): m / z = 409 (M + l); Rt = 5.65.

Example 3 (General Procedure (A)) 5-tert-butyl-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxyphenyl) amide Step B: To a solution of 3-bromo-5-tert-butyl-N- (2-trifluoromethoxy-4-cyanophenyl) -6-hydroxy-2-methylbenzamide (0.141 g, 0.3 mmoles) in 5 ml of dioxane under nitrogen are added phenylboronic acid (37.0 mg, 0.3 mmol), tetrakis (triphenylphosphine) palladium (0) (7 mg, 0.006 mmol) and sodium carbonate (1.05 ml, 2 M solution in Water). The reaction mixture is heated at 100 ° C for 48 hours. The reaction mixture is evaporated, diluted with ethyl acetate and the organic phase is washed with a solution of citric acid (10%). The organic phase is dried over sodium sulphate and evaporated. The crude compound is purified by column chromatography.

XH (400 MHz, CHLOROFORM-D): d ppm: 1.43 (s, 9H), 2. 39 (s, 3H), 7.27 - 7.41 (m, 5H), 7.45 (dd, 1H), 7.48 (s, 1H), 7.61 (s, 1H), 7.68 (d, J = 8.59 Hz, 1H), 8.21 (s, 1H), 8. 87 (d, J = 8.59 Hz, 1H), 9.77 (s, 1H); HPLC-MS (Method A): m / z = 469 (M + 1); Rt = 5.65.

Example 4 (General procedure (A)) 5-tert-butyl-4'-cyano-4-hydroxy-2-methylbiphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxyphenyl) amide Step B: To a solution of 3-bromo-5-tert-butyl-N- (2-trifluoromethoxy-4-cyanophenyl) -6-hydroxy-2-methylbenzamide (0.141 g, 0.3 mmol) in 5 ml of dioxane under nitrogen are added 4-cyanophenylboronic acid (44.0 mg, 0.3 mmol), tetrakis (triphenylphosphine) palladium (0) (7 mg, 0.006 mmol) and sodium carbonate (1.05 ml, 2 M solution in water). The reaction mixture is heated at 100 ° C for 6 hours. The reaction mixture is evaporated, diluted with ethyl acetate and the organic phase is washed with a solution of citric acid (10%). The organic phase is dried over sodium sulphate and evaporated.

The crude compound is purified by column chromatography. XH (400 MHz, CHLOROFORM-D): d ppm: 1.43 (s, 9H), 2. 37 (s, 3H), 7.24 (s, 1H), 7.41 (d, J = 8.08 Hz, 2H), 7.62 (s, 1H), 7.66 - 7.72 (m, 1H), 7.74 (d, J = 8.08 Hz, 2H), 8.16 (s, 1H), 8.85 (d, J = 8.59 Hz, 1H), 9.75 (s, 1 HOUR); CLAR-EM (Method A): m / z = 494 (M + l); Rt = 5.27.

Example 5 (General procedure (A)) 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -5- (5-cyanothiophen-2-yl) -2-hydroxybenzamide Step B: To a solution of 3-bromo-5-tert-butyl-N- (2-chloro-4-cyanophenyl) -6-hydroxybenzamide (0.141 g, 0.34 mmol) in 15 ml of dimethoxyethane under nitrogen are added 4-cyanophenylboronic acid (44.0 mg, 0.3 mmol), tetrakis (triphenylphosphine) palladium (0) (63 mg, 0.055 mmol) and sodium hydrogen carbonate (5.5 ml, saturated solution in water). The reaction mixture is heated at 80 ° C for 23 hours.

The reaction mixture is evaporated, diluted with ethyl acetate and the organic phase is washed with a 10% citric acid solution. The organic phase is dried over sodium sulphate and evaporated. The crude compound is purified by column chromatography. 1H (400 MHz, CHLOROFORM-D): d ppm: 1.50 (s, 9H), 7.20 (d, J = 4.04 Hz, 1H), 7.61 (m, 2H), 7.67 (dd, J = 2.02 Hz, 1H) , 7.70 (d, J = 2.02 Hz, 1H), 7.78 (s, 1H), 8.65 (d, J = 8.59 Hz, 1H), 8.74 (s, 1H), 12.35 (s, 1H); HPLC-MS (Method A): m / z = 436, 438 (M + 1); Rt = 5.65.

Example 6 (General procedure (A)) 5-benzo [b] thiophen-2-yl-3-terbutyl-N- (2-chloro-4-cyanophenyl) -2-hydroxybenzamide Step B: The title compound is prepared from 3-bromo-5-tert-butyl-N- (2-chloro-4-cyanophenyl) -6-hydroxybenzamide and benzothiophen-2-boronic acid. HPLC-MS (Method A): m / z = 462 (M + 1); Rt = 6.05. By the methods described in the above, the following compounds can be prepared.

PHARMACOLOGICAL METHODS Assay (I): Use of glucose in a human epithelial cell line (FSK-4 cells) Description of the assay: The assay indirectly measures the activity of the respiratory chain in FSK-4 cells using D- (63- H (N) -glucose The 3H proton will first be released to the TCA cycle and transported to the respiratory chain where it will be incorporated into the water, then the water is separated from the D- (6-3H (N)) -glucose by evaporation Finally the radioactivity in the water is determined using a Topcounter equipment Method: FSK-4 cells obtained from ATCC (Maryland, USA) are grown in growth medium (McCoy's medium with the following addition: 100 units / ml of penicillin and streptomycin and fetal bovine serum ((FCS) 10%) at 37 ° C and 5% C02 All media are obtained from Gibco (Life Technologies, Maryland, USA) unless mentioned In another sense, on day zero, crops are harvested. cells using trypsin-EDTA and washed in assay medium (MEM medium with the following addition Ix of non-essential amino acids (M7145, 2 mM glutamine, 100 units / ml of penicillin and streptomycin, 0.0075% sodium bicarbonate, 1 mM sodium pyruvate and 2% horse serum) using centrifugation. Cells are plated in wells of single StripPlates vessels (Corning BV Life Sciences, The Netherlands) which are placed in 24 well plates (Corning BV Life Sciences, The Netherlands) with a concentration of 1.5 x 10 4 cells / 100 μl of assay medium / well. The cells are then incubated at 37 ° C and 5% C02 overnight. The next day the compounds to be tested are diluted to different concentrations in DMSO (Sigma, Missouri, E.U.A.) at 100 times the final concentration. They are then diluted to a final concentration in a test medium containing 10 μCi / ml of D- (6-3H (N)) -glucose (PerkinElmer Life Sciences Inc., Boston, E.U.A.). The medium is separated from the cells and 200 μl of the dilutions of the compound are added in duplicate. The cells are then incubated for a further 24 hours at 37 ° C and 5% C02. Finally, the cells are used when adding 50 μl of trichloroacetate (TCA, 10%). Subsequently, 300 μl of sterile water is added to the 24 wells surrounding the Strip-Plate wells. The plate is sealed with a Top-seal-tape top seal tape (Packard, PerkinElmer Life Sciences Inc., Boston, USA) and the plate is incubated in a 50 ° C heating cabinet at the equilibrium of the radioactive water formed in the Respiratory chain in the water in the 24-well plate by evaporation. The plates are incubated for 8 hours and then the cabinet heating is switched off. The upper seal is removed when the samples have reached room temperature. 1 ml of scintillation liquid (Packard Microscient, PerkinElmer Life Sciences Inc., Boston, U.S.A.) is added to all samples and the radioactivity is determined using a computer Topcounter (Packard, PerkinElmer Life Sciences Inc., Boston, U.S.A.). The non-specific activity is determined by evaporation of 200 μl of the dilution medium containing D- (6-3H (N)) -glucose in 300 μl of sterile water, and the total radioactivity is determined by making a count of 5 μl of assay medium with 10 μCi / ml of D- (6-3H (N)) -glucose. Calculations: The half-maximal concentration (EC50) and the maximum efficiency (Emax) are calculated using the Hill equation and the GraphPad Prism 3.0 program (GraphPad software, Inc.). In studies where the linear slope is determined, the following concentrations of the compounds are used: 5x, 3x, 2x, 1.5x, 1.25x, lx, 0.85x, 0.7x, 0.5x, 0.3x, 0.2x and Ox CE50. From the increase in the percentage in the utilization of glucose, the linear slope is calculated using the Michaelis-Menten equation.

Test (II). Effect of chemical uncouplers on mitochondrial respiration using isolated mitochondria. This test is used to investigate whether the increase in glucose utilization caused by the test compounds observed in the glucose utilization test is due to an increase in respiration of the mitochondria. This is done by determining the oxygen uptake in rat hepatic isolated mitochondria. A Clark oxygen electrode is used to determine oxygen consumption. The isolated mitochondria are added to assay medium (D-Mannitol, 220 mM, 5 mM magnesium chloride, 2 mM HEPES and 5 mM potassium phosphate, pH = 7.4) containing rotenone (a complex 1 inhibitor) and oligomycin ( an inhibitor of ATP-synthase) and the rate of oxygen consumption is measured when a stabilized nutrient (for example succinate) is added and the increase in the rate of oxygen consumption is measured. When the rate of oxygen consumption has stabilized again, the test compound is added and the oxygen consumption is measured. If the test compound stimulates the speed of oxygen consumption, it is considered to be a chemical uncoupling.

Test (III): Identification of chemical uncouplers that increase energy expenditure in vivo The effect of chemical uncouplers on energy expenditure (oxygen consumption) in vivo is determined by indirect calorimetry. Briefly, the animals are placed in air-tight chambers. Air is continuously administered and extracted from the chambers. The concentrations of oxygen gas (C02) and carbon dioxide in the air circulated in the chambers (inlet and outlet air) are recorded and the consumption of 02 and the production of CO2 are calculated. Based on the amount of 02 consumed and C0 produced, the energy expenditure is calculated. The compounds which, at a given dose, increase the total expenditure of body energy without obvious detrimental effects are considered to be chemical uncoupling which increases the expenditure of energy. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (28)

CLAIMS Having described the invention as above, property is claimed as contained in the following claims:

1. A compound according to formula I characterized in that X represents: 0 -C = C-, and m is 0, 1 or 2; R 1 represents alkyl of 1 to 6 branched carbon atoms or phenyl; R2 and R4 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms; R5, R6 and R7 independently represent hydrogen, nitro, cyano, halogen, -OR8, haloalkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, -C (0) 0R8, -C0R8, -C (0) NR8R8, -SH, -S (0) 20R8, -S (0) 2N (R8) 2, -S (0) nR9, aryl, heteroaryl, wherein the aryl and heteroaryl optionally they may be substituted with one or more alkyl of 1 to 6 carbon atoms, oxo or phenyl wherein the phenyl is substituted with one or more of halogen or alkyl of 1 to 6 carbon atoms; n is 0, 1, 2 and each R8 independently represents hydrogen or alkyl of 1 to 6 carbon atoms and R9 represents alkyl of 1 to 6 carbon atoms; R3 represents alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, arylalkyl of 1 to 6 carbon atoms, arylalkenyl of 1 to 6 carbon atoms, arylalkynyl of 1 to 6 carbon atoms, heteroarylalkyl of 1 to 6 carbon atoms, heteroarylalkenyl of 1 to 6 carbon atoms, heteroarylalkynyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl or heteroaryl; wherein R3 optionally can be substituted with up to four substituents, RIO, Rll, R12 and R13 independently represent alkyl of 1 to 6 carbon atoms, alkylaryl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, oxo, cyano, nitro, - (CH2) r0R14, -SH, -S (0) PR15, -S (0) PN (R14) ( R15), -C (0) 0R14, -0C (0) R14, -C (0) R14, -C (0) N (R14) (R15), - (CH2) rN (R14) C (O) R15 -, -B (0R14) (OR15), (CH2) rN (R14) (R15) or phenyl, wherein the phenyl is optionally substituted with one or more substituents that are selected from the group consisting of alkyl of 1 to 6 atoms carbon, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, cyano, nitro, -0R16-, -S (0) SR16, -C (0) 0R16, -0C (0) R16, -C (0) R16, C (0) N (R16) (R17), -N (R16) (R17), - (CH2) SN (R16) C (0) R17, B (0R16) (0R17) ) -, - (CH2) tOR16 or - (CH2) tN (R16) (R17); each R14 independently represents hydrogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 atoms carbon and cyano; R15 represents haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms and cyano; or wherein R14 and R15, when attached to a nitrogen atom, together with the nitrogen atom form a cycloalkyl ring of 3 to 8 carbon atoms or heteroaryl, optionally substituted with one or more alkyl substituents of 1 to 6 carbon atoms; each R16 and R17 independently represents hydrogen, haloalkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkynyl of 1 to 6 atoms carbon or cycloalkyl of 3 to 8 carbon atoms; or R16 and R17, when attached to a nitrogen atom, together with the nitrogen atom form a cycloalkyl or heteroaryl ring, optionally substituted with one or more alkyl substituents; p and s, independently of each other, are an integer of 0, 1 or 2; r and t, independently of each other, are an integer of 0, 1, 2 or 3; q is 0, 1 or 2; with the proviso that the compound is not N- (2-chloro-4-nitrophenyl) -3-tert-butyl-6-methylsalicylanide, 3,5-diterbutyl-N- (2-chloro-4-nitrophenyl) -2-hydroxybenzamide or 3-tert-butyl-N- (2-chloro-4-nitrophenyl) -2-hydroxy-5-methylbenza-mide; and pharmaceutically acceptable salts, solvates and prodrugs thereof.

2. The compound according to claim 1, characterized in that m is 0.

3. The compound according to claim 1, characterized in that m is 1.

4. The compound according to claim 1, characterized in that m is 2

5. The compound according to any of claims 1-4, characterized in that R1 represents phenyl, neopentyl, terbutyl, isopropyl or 1,1-dimethylpropyl.

6. The compound according to claim 5, characterized in that R1 represents terbu-tyl.

7. The compound according to any of claims 1-6, characterized in that R2 and R4 independently represent hydrogen or methyl.

8. The compound according to any of claims 1-7, characterized in that R3 represents alkenyl of 1 6 carbon atoms or alkynyl of 1 to 6 carbon atoms, both of which are optionally substituted.

9. The compound according to claim 8, characterized in that R3 represents styryl.

10. The compound according to any of claims 1-6, characterized in that R3 represents optionally substituted aryl.

11. The compound according to claim 10, characterized in that R3 is selected from phenyl, 4-cyanophenyl, 4-chlorophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl or radicals with the following structures: wherein R is selected from the list consisting of hydrogen, methyl, CF3, Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano and phenyl, wherein the phenyl may optionally be substituted with Cl, Br, F, CF3 or methoxy.

12. The compound according to any of claims 1-7, characterized in that R3 represents an optionally substituted heteroaryl.

13. The compound according to claim 12, characterized in that R3 is selected from wherein R is selected from the list consisting of hydrogen, methyl, CF3, Cl, Br, F, methoxy, ethoxy, methylcarbonyl, nitro, cyano and phenyl, wherein the phenyl may optionally be substituted with Cl, Br, F, CF3 or methoxy. The compound according to claim 13, characterized in that R3 is selected from thiophen-2-yl, 5-cyanothiophen-2-yl and benzo [b] thiophen-2-yl. 15. The compound according to any of claims 1-14, characterized in that one or more of R5, R6 and R7 are selected from nitro, halogen, haloalkyl, optionally substituted alkyl or optionally substituted heteroaryl. 16. The compound according to claim 15, characterized in that R5, R6 and R7 together constitute the substitution pattern: 2-chloro-4-nitro or 2-trifluoromethoxy-4-nitro. 17. The compound according to claim 1, characterized in that it is selected from the list consisting of 5-tert-butyl-4-hydroxy-2-methylbiphenyl-3-carboxylic acid (2-chloro-4-nitrophenyl) amide; E) 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -2-hydroxy-5-styryl-benzamide; 5-tert-butyl-4-hydroxy-2-methylbiphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxyphenyl) amide; 5-tert-butyl-4'-cyano-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxyphenyl) -amide; 3-tert-butyl-N- (2-chloro-4-cyanophenyl) -5- (5-cyanothio-phen-2-yl) -2-hydroxybenzamide; and 5-benzo [b] thiophen-2-yl-3-tert-butyl-N- (2-chloro-4-cyanophenyl) -2-hydroxybenzamide. 18. The compound according to any of claims 1-17, characterized in that it is for use in therapy. 19. A pharmaceutical composition characterized in that it comprises one or more compounds according to any of claims 1-17. 20. A method for treating a disease that benefits from an increase in mitochondrial respiration, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound according to any of claims 1-17 optionally in combination with other therapeutically active compounds. 21. A method to treat obesity, atherosclerosis, hypertension, type 2 diabetes, dyslipidemia, coronary heart disease, osteoarthritis, gallbladder disease, cancer of the endometrium, breast, prostate or colon or to prevent weight gain or maintain weight loss or to treat diabetic microvascular diseases in the retinal, glomerulorrenal or peripheral nerve cell apoptosis, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any of claims 1-17 optionally in combination with other therapeutically active compounds, wherein the another compound can be administered concomitantly or sequentially. 22. The method according to claim 21, characterized in that the disease is selected from atherosclerosis, hypertension, type 2 diabetes, dyslipidemia and wherein the patient is obese. 23. The method according to claim 21, characterized in that it is used for the prevention of weight gain or the maintenance of weight loss. 24. The method according to claim 21, characterized in that the disease is obesity. 25. The use of a compound according to any of claims 1-17, in the manufacture of a medicament for use in the treatment of a disease that benefits from an increase in mitochondrial respiration. 26. The use of a compound according to any of claims 1-17 for the preparation of a medicament for the treatment of obesity, atherosclerosis, hypertension, type 2 diabetes, dyslipidemia, coronary heart disease, osteoarthritis, gallbladder diseases. , cancer of endometrium, breast, prostate or colon, or prevention of weight gain or maintenance of a weight loss or to treat diabetic microvascular diseases in the retina, glomerulorrenales or apoptosis of peripheral nervous cells. 27. A method for increasing mitochondrial respiration in a subject, characterized in that it comprises administering an effective amount of a compound according to any of claims 1-17 to the subject, optionally in combination with one or more additional therapeutically active compounds, wherein the other compound can be administered sequentially or concomitantly. 28. A method for reducing the amount of reactive oxygen species in a subject, characterized in that it comprises administering an effective amount of a compound according to any of claims 1-17 to the subject, optionally in combination with one or more therapeutically active compounds , wherein the other compound can be administered sequentially or concomitantly.