MXPA99006358A - Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to a novel class of compounds for treating hyperlipidemia, obesity and impaired glucose tolerance/noninsulin dependent diabetes mellitus without adversely affecting energy metabolism, and pharmaceutical compositions comprising th e aforementioned compounds for the treatment of obesity, hyperlipidemia and maturity-onset diabetes.

Description

CARBOXYLIC CIDOS AND DERIVATIVES OF THE SAME AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM FIELD PE INVENTION A novel class of compounds has been found that are effective in treating hyperlipidemia, obesity and impaired glucose tolerance / diabetes mellitus not dependent on insulin, without adversely affecting energy metabolism. The active compounds have the general formula: HOOC-C-CH,, -C-COOH (i) R < R. R.

R-R4 independently represent, each, a hydrogen or a substituted or unsubstituted hydrocarbyl or a heterocyclyl radical; wherein R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chloro, bromo, cyano, nitro, lower alkoxy or trifluoromethyl; Q represents a di-radical consisting of a linear chain of 2 to 14 carbon atoms, of which one or more can be replaced by heteroatoms, the chain is optionally substituted P-4 & 2./29IX by inert substituents and one or more of the members of the carbon or heteroatom chain are optionally part of a ring structure and, where one or both carboxyl groups can be substituted by a physiologically acceptable hydrolysable substituent in vi. The invention also provides pharmaceutical compositions comprising the aforementioned compounds of formula (I) for the treatment of obesity, hyperlipidemia and diabetes onset at maturity.

BACKGROUND OF THE INVENTION The dyslipoproteinemia (hypercholesterolemia-hypertriglyceridemia combined), the low level of HDL cholesterol, obesity (in particular, obesity J in the upper part of the body), the impaired tolerance to glucose (? GT) What leads to diabetes mellitus and your non-dependence on insulin (NIDDM) and essential hypertension are common diseases that afflict individuals living in westernized societies. When initiated and ligated through hyperinsulinemia, these four diseases often coexist and precipitate independently as well as the sialerologically atherosclerotic vascular disease that leads to coronary heart disease. The incidence of the Mortal Quartet (X-Syndrome, Metabolic Syndrome) that OHIn iHM-JT comprises the four diseases, increases as the population ages and reaches epidemic proportions for the age of 70 years. The combat to the individual categories of the Mortal Quartet, as well as the offer of a holistic therapeutic approach to the Syndrome are considered the most important challenges of medicine in the opulent western society. Many hypercholesterolemic / hypertriglyceridemic individuals are individuals who respond poorly or who do not respond to dietary measures and, therefore, are candidates for long-term treatment with hypolipidemic drugs. HMG-CoA reductase inhibitors and bile acid sequestrants designed to upregulate the LDL receptor are very effective in isolated hypercholesterolemia. However, both are ineffective in reducing plasma triglycerides and scarcely effective in increasing plasma HDL, thus failing to offer an adequate mode of treatment for hypertriglyceridemia combined with hypercholesterolemia. (comprising> 70% of dyslipoproteinemic patients) or for isolated hypertriglyceridemia with reduced HDL in plasma, as well as for the phase rich in postprandial chylomicrons granted as an independent risk for atherosclerotic cardiovascular disease. However, the Isolated hypertriglyceridemia P1402 / 99MX can be treated either with nicotinic acid or with drugs of the fibrate family. However, the flexibility of nicotinic acid is very low and the advantage of fibrate drugs to reduce overall mortality has been seriously questioned since the exhaustive study of WHO clofibrates. As well, nicotinic acid is not effective, while fibrate drugs are only scarcely effective in reducing plasma cholesterol, thus leaving the patient with hypertriglyceridemia-hypercholesterolemia combined only with the option of a combined treatment mode (for example, with inhibitor of HMG-CoA reductase / nicotinic acid). The measures for weight reduction are essentially based on the promotion of a dietary or behavioral resource for weight reduction. However, it turns out that most obese people respond inadequately to dietary or behavioral measures, especially if they are examined for long periods of time. The odds of maintaining 5 years of weight reduction initiated by dietary or behavioral changes are less than 10%. This overwhelming failure is mainly metabolic, since the reduction in weight as a result of diet is always accompanied by a decrease in the basal metabolic rate and the overall expense of DQuery QQMY energy, thus bringing the diet of the obese patient to a genuine impasse. Anti-obesity drugs based on the modulation of energy intake are usually based on anorexics designed to depress the center of satiety in the hypothalamus. It is reported that these drugs are ineffective in the medium and long term and some may induce primary pulmonary hypertension. Similarly, antiobesity drugs based on the modulation of total body caloric expenditure are currently not available, while allowing free access to calorie consumption. The peripheral-acting β3-adrenergic agonists were selected based on their ability to stimulate the adipose-adrenoceptor brown-adrenoreceptors and can, of course, induce thermogenesis in rodents. However, the efficacy of these agents in humans insofar as it allows free access to calories is still questionable and it can be expected that their broad specificity to tissues (eg, skeletal muscle, myocardial and colon) will result in non-specific induced adrenergic effects. The pharmacological measures currently available to treat IGT and manifest NIDDM consist of two types of oral hypoglycemic drugs that have been in use for 30 years. Sulfonylureas promote insulin secretion Pancreatic P1402 / 99MX to face peripheral resistance to insulin, while it is claimed that biguanides improve the peripheral action of insulin. The popularity of sulfonylurea results from the old conviction that the blood glucose that precipitates diabetic microvascular disease in the retina, the kidney, the nerves and in some other tissues, should be normalized by all means even at the expense of increased secretion of pancreatic insulin. This therapeutic approach began at a time when the hyperinsulinemic phase that dominates the natural history of NIDDM development or the course of IGT induced by obesity was not granted, nor was the pathological sequelae dictated by prolonged hyperinsulinemia. In addition, sulfonylurea (in a similar way to insulin) tends to promote weight gain, thus further promoting insulin resistance and compensatory hyperinsulinemia leading to macrovascular disease induced by diabetes (atherosclerotic cardiovascular disease). The biguanides are claimed to reinforce insulin-mediated glucose depletion without stimulation of pancreatic insulin secretion. However, the use of biguanides as monotherapy is not recommended unanimously except for very obese patients in light of their low rate P1402 / 99MX therapeutic / toxicity and the induction of lactic acidosis. During the period of the last ten years, the scientific community gradually became more aware of the etiological-pathophysiological link between dyslipidemia, obesity, NIDDM, hypertension, reduced fibrinolysis and some other pathologies (for example, hyperuricemia), realizing now that the related pathologies are only reflections of a unifying Syndrome. Leading to atherosclerotic cardiovascular disease, the syndrome is currently conceived as the main risk factor for mortality and morbidity in Western societies. The pharmacological treatment of the syndrome demands a holistic approach instead of treating it separately from each of its different categories. No drug designed with these principles is yet available. The long chain α, β-dialkanoic acids of 14-20 carbon atoms with hydrocarbyl substitutions at the β, β 'carbon atoms, as well as their salts and steric derivatives thereof, in U.S. Patent Nos. 4,634,795 , 4,689,344 and 4,711,896 of Bar-Tana were revealed to possess hypolipidemic, weight-reducing and anti-diabetogenic activity. However, the conception that the treatment of the Metabolic Syndrome and its • n i / related pathologies would require a chronic dosage has initiated an extensive search for new compounds that have a higher efficiency compared to acids a ,? -dialkanoic ß, ß '- substituted previously revealed.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES A novel class of compounds has now been found, in accordance with the present invention, which are surprisingly effective in reducing blood lipids. It was also found that the novel compounds of the invention have an antidiabetic calorigenic activity (NIDDM) without adversely affecting the energy metabolism. In addition, the efficacy of some of these compounds is much better compared to the α, β-dialkanoic, β-β-substituted acids previously reported. The novel compounds provided by the present invention are α, α-dialkanoic acids having the general formula: HOOC OOH > and hydrolysable functional derivatives in vi vo P14 (1J / 99MX) the carboxylic groups thereof, wherein R ~ R4 each independently represents a hydrogen or a substituted or unsubstituted hydrocarbyl, wherein R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chlorine, bromine, cyano, nitro, lower alkoxy or trifluoromethyl; Q represents a di-radical consisting of a linear chain of 2 to 14 carbon atoms, of which one or more can be replaced by heteroatoms, the chain will be optionally substituted by inert substituents and one or more of the members of the carbon or heteroatom chain optionally form part of a ring structure Included within the scope of the invention are those derived from the a and / or? carboxy groups of the compounds of the above formula I , which have the ability to hydrolyze in vi to produce free diacids of formula I. Among these suitable derivatives should be mentioned, firstly, alcohols with pharmaceutically acceptable organic or inorganic cations, in particular, alkali metal salts, alkaline earth metal salts, ammonium salts and substituted ammonium salts; esters, particularly lower alkyl esters; amides, mono- and di-substituted amides; and, anhydrides, for example, with lower alkanoic acids; and lactones GAVE ? n / q Q and formed by the ring closure of either or both carboxylic groups, with a free hydroxy substituent (or substituents) in the molecule of the formula (I). The term "hydrocarbyl" in the definition of R1-R4, includes, for example, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, and the like. A preferred group of compounds, according to the invention, are those of the formula (I) above, wherein R? ~ Are each lower alkyl and Q is a straight chain of polymethylene of 2 to 14 carbon atoms; and the hydrolysable functional derivatives in vi ve thereof. The especially preferred compounds of the present invention are those of the general formula: HOOC-C? 2-CH2-C- (CH2) n-C CH2-CH2-COO? (H) CH- CH- and its hydrolysable functional derivatives in vi, where n is an integer from 6 to 12; or of the general formula: P1402 / 99MX HOOC-O- (CH2) p-C-COOH (III) EC. CH- where n is an integer from 10 to 16; and its hydrolysable function derivatives in vi vo. The novel compounds of the formula (I), according to the invention, can be prepared by methods known per se, some of which are illustrated in the examples herein. In another aspect, the present invention provides pharmaceutical compositions for the treatment of obesity, hyperlipidemia, diabetes or Metabolic Syndrome, which comprises as active ingredients the novel compounds of the above formula (I) together with pharmaceutical carriers or diluents. The pharmaceutical compositions are mainly for oral administration but, they can also be for parenteral or topical administration. These pharmaceutical compositions, which are preferably in unit dosage form, can be in the form of, for example, tablets, capsules, troches, pills, powders and aqueous and non-aqueous solutions or suspensions. The pharmaceutical compositions of this invention also preferably comprise conventional solid or liquid pharmaceutical carriers or diluents, for example, gelatin, sugars, starches, derivatives of P 1402 / 99_MX cellulose, fatty acids and their salts, vegetable oils, glycerin, glycols, water, aqueous saline solution or phosphate buffer and the like. The compositions may also comprise other compatible substances normally used in pharmaceutical formulations and also other additives, such as coloring agents, flavoring agents and preservatives. The pharmaceutical compositions according to the invention are preferably in unit dosage form, each unit containing 50 to 500 mg of the active ingredient of the above formula (I). The daily dose of the compounds of the above formula (I), according to the invention, will depend on the age, needs and tolerance of the individual patient but will normally vary from 50 mg to 5,000 mg per day. The pharmacological activities of the compounds of formula (I) according to the invention could be demonstrated by means of experiments in rats and experiments in vi tro in liver cells, in accordance with the standard methods. Some of these experiments are described in detail below.

P1402 / 99MX EXPERIMENTS ON TN VIVO AND E CELLS EXPERIMENT AI a group of rats (n = 5 for each treatment group) were fed ad libi tum with Purina Chow for 6 days, the diet was supplemented with 0.1% (w / w) of acids,? - dioic Y / Y '- methylsubstituted of formula (II) (Example 1, Example 3, Example 4). The biological effect in vivo was evaluated by monitoring dietary intake, plasma triglycerides, plasma cholesterol and plasma glucose. The results are shown in the following Table I.

P1402 / 99MX TABLE I Not treated? 1 Axis. 3 Axis 4 Triglycerides 63.9 + 24.1 24.8 + 3.9 28.8 + 7.4 29.3 + 10.4 plasma (mg%) Plasma cholesterol 66.3 + 5.6 64.1 + 12.0 62.4 + 13.3 56.8 + 10. (mg%) Plasma glucose 141.2 + 10.7 127.8 + 6.6 138.8 + 2.7 139.0 + 9.0. { mg%) Dietary intake 19.1 + 1.7 18.6 + 2.1 19.3 + 1.1 19.1 + 1.2 (9 / d) H EXPERIMENT II A group of rats (n = 5 for each treatment group) were fed ad l ibi tum with Purina Chow for 5 days, the diet was supplemented with either a,? - hexadecanedioic acid Y / Y'- methylsubstituted (formula (II), Example 3) or α, β-hexadecanedioic acid β, β '-methyl substituted (U.S. Patent No. 4,634,795) at a dose of 0.09% (w / w). The biological effect in vi was evaluated by monitoring plasma triglycerides, plasma apolipoprotein (apo) C-III, plasma insulin and steady state concentrations (Sss) of the respective drugs in the plasma. The multiplication in the effectiveness of the compound?,? - Substituted (Example 3) with respect to the compound β, β '- substituted was calculated by normalizing the effect observed in the respective obtained Css. The results are shown in the following Table II.

P1402 / 99MX TABLE II Not treated ß, ß'- acid?,? '- Methyl- Multiplica- ethylhexadecane a,? - tion of hexadecane dioxide (Example efficacy,? - dioic 3) (?,? /?) Triglycerides 61.0 + 13.5 19.7 ± 4.0 19.9 + 7.4 8.2 plasma (mg%) apo C-III plasma 33.0 + 10.0 11.0 ± 3.7 12.0 + 4.6 7.7 (mg%) Plasma insulin 31.0 + 6.5 23.0 ± 3.4 16.0 + 6.1 15.2 (U / ml) Css (g / ml) 97.4 + 12.6 12.0 + 1.2 EXPERIMENT III Conditions equal to those of EXPERIMENT II, using acid a ,? -tetradecanodioico a, a -methyl-substituted. The results are shown in the following Table III.

The multiplication of the efficiency represents the respective effect induced by the compound a, -'-substituted (Example 6) with respect to that of the compound β, β'-substituted.

TABLE III Not treated ß, ß'- acid a, a'-methyl- Multiplicamefcil-hexadecane, hexadecane dioxide (Example oc,? - dioic 6) (a, a / b) 5 Triglycerides 211.0 + 81.5 79.5 ± 9.2 44.5 ± 14.0 1.78 plasma (mg) Plasma cholesterol 101.5 + 15 84.0 ± 9.3 69.5 ± 9.7 1.2 (mg%) apo C-III plasma 276 + 31 63 ± 10 17 ± 14 3.7 (mg%) Plasma glucose (mg 112 114 + 6 104 + 4 1.1 Plasma insulin 28.9 + 13.1 25.4 + 5.5 24.2 + 7.3 1.0 (U / ml) EXPERIMENT IV The decoupling of oxidative phosphorylation by compounds of formula I was evaluated in isolated liver cells loaded with JC-1 dye (as described by M. Reers et al., Meth. Enzymol 260, 406 (1995))) and incubated in the presence of added compounds of formula I, as specified, JC-1 fluorescence was determined by FACSCAN flow cytometry. While the cytosolic monomeric dye emits at 530 nm (when excited at 488 nm), the fluorescence of the aggregated intramitochondrial dye is shifted to the 590 nm. The 530/590 fluorescence ratio thus reflects the cytosolic / mitochondrial distribution of the dye as a result of the inner membrane potential of the mitochondria prevalent in the affected cells. The greater the 530/590 ratio, the greater the degree of decoupling and the induced calorigenesis by aggregated effectors. The results are shown in the following Figure 1.

SUMMARY OF THE INVENTION The following conclusions were reached with respect to the biological effects of the compounds of formula 1: (a) The active compounds are potent hypolipidemic. The global hypolipidemic effect is based on the activation of the purification P1402 / 99MX of plasma lipoproteins resulting from the decrease in apo C-III. (b) The active compounds are potent sensitizers to insulin, as reflected by the plasma insulin concentrations required to maintain euglycemia. Insulin sensitization may form the basis for using these compounds in the treatment of IGT / NIDDM. (c) The active compounds induce an increase in calorigenesis as a result of the decrease in mitochondrial membrane potential. The decoupling induced by these compounds can form the basis for using these compounds in the treatment of obesity. (d) These compounds may offer a holistic therapeutic approach to the Metabolic Syndrome. Its effectiveness is by far superior compared to the compounds ß, ß '-substituted homologs.

EXAMPLES Example 1: 4,4,11,11-tetramethyl etradecanedioic acid Ethyl bromoacetate (14.4 g, 0. 094 mol) for 30 minutes to a stirred solution of 26.2 g (0.1 mol) of triphenylphosphine in 120 ml of benzene maintained at 35-38 ° C. After shaking P1402 / 99MX for an additional 12 hours at room temperature, the precipitate was filtered and washed twice with hexane to provide 34.7 g (86%) of (carboethoxymethyl) -triphenylphosphonium bromide, m.p. 159-160 ° C. 115 ml of 10% aqueous sodium hydroxide solution were added dropwise with cooling at 5 ° C to a stirred suspension of 118.4 g (0.276 mol) of the bromide in 500 ml of water and 200 ml of chloroform containing a small amount of phenolphthalein. Stirring was continued for a period of 30 minutes without external cooling followed by the addition of 500 ml of chloroform to provide clear layers. The aqueous phase was extracted three times with 100 ml of chloroform and the combined chloroform fractions were dried over sodium sulfate and concentrated in vacuo. Crystallization of the 180 ml residue from a 1: 1 mixture of benzene and hexane provided 86.2 g (90%) of Pure (carboethoxymethylene) triphenylphosphorane, m.p. 119-120 ° C. Potassium carbonate was added in portions (56 g) for 1 hour to a stirred mixture of 68 g (0.94 mol) of freshly distilled isobutyraldehyde and 70 ml of 40% formalin in argon. During the addition, the temperature was maintained at 10-15 ° C. The temperature was allowed to rise to 25 ° C while further stirring in argon was continued for 12 hours, followed by the P1402 / 99MX addition of 100 ml of water to the white suspension. The mixture was extracted four times with 40 ml of chloroform and the combined extracts were dried over magnesium sulfate and concentrated in vacuo. Distillation of the remaining liquid (solidified upon cooling) through a 20 cm Vigreux column gave 93.0 g (97%) of 2,2-dimethyl-3-hydroxy-propanol, e.g. 83-86 ° C / 15 Torr, p.f. 90-93 °. A solution of 2,2-dimethyl-3-hydroxypropanal (22 g, 0.22 mol) and (carboethoxymethylene) triphenylphosphorane (75 g, 0.22 mol) in dry dichloromethane (150 ml) was refluxed for 46 hours. The solvent was then evaporated and the crude product distilled at 15 Torr through a very short column. The distillate was separated into two fractions by ilation networks through a 40 cm idmer column. The first fraction gave 22.3 g (60%) of ethyl trans-4, 4-dimethyl-5-hydroxypent-2-enoate, e.g. 133-136 ° C / 15 Torr, nD23 1.4641. 1H NMR (CDC13): (= 1.10 [s, 6H, C (CH3) 2], 1.25 (t, 3H, CH3CH2), 3.40 (s, 2H, CH2), 3.80 (broad s, 1H, OH), 4.15 (q, 2H, CH2CH3), 5.80 (d, 1H, J = 16 Hz, 3-H), 6.94 (d, 1H, J = 16 Hz, 2-H) Analyze Calculated for C9H1603: C , 62.76; H, 9.36. Found: C, 62.92; H, 9.50 .. Ethyl trans-4, 4-dimethyl-5-hydroxypent-2-enoate (8.6 g, 0.05 mol) in 100 ml of dichloromethane P1402 / 99MX was added to a stirred suspension of 70 g (0.27 mol) of chromium pyridine trioxide complex in 900 ml of anhydrous dichloromethane. The insoluble black gum residue was washed thoroughly three times with 100 ml portions of ether. The combined organic solutions were passed through a column (3.5 cm, 25 cm) of silica gel and the solvent was removed by distillation. Distillation of the residual oil through a 20 cm Widmer column provided 8.0 g (94%) of ethyl 4-methyl-4-formylpent-2-enoate, e.g. 110-111 ° C / 15 Torr, nD18 1.4605. 1H NMR (CDC13): (= 1.30 [s, 6H, C (CH3) 2], 1.45 (t, 3H, CH3CH2), 4.15 (q, 2H, CH2CH3), 5.85 (d, 1H, J = 16 Hz, 3-H), 6.90 (d, 1H, J = 16 Hz, 2-H), 9.45 (s, 1H, CHO), Analysis i Calculated for C9H1403: C, 63.51; H, 8.29. 63.53; H, 8.38 8.64 g (0.04 mol) of dibromobutane and five drops of formic acid were added to a solution of 26.2 g (0.1 mol) of triphenylphosphine in 125 ml of dimethylformamide and the mixture was refluxed for 3 hours it was then cooled and diluted with 150 ml of ether The precipitate formed was filtered, washed with ether and dried The crude product was dissolved in 35 ml of methanol and precipitated with 80 ml of ether to yield 25.2 g (85.2 g. % yield) of butane-1,4-bis (triphenylphosphonium) dibromide, mp 302-303 ° C.

P1402 / 99MX Butane 1,4 bis (triphenyl-phosphonium) dibromide (13.4 g, 0.018 mol) (dried in phosphorus pentoxide for at least 3 days) and 600 ml of dry tetrahydrofuran (refluxed in lithium aluminum hydride and distillate at atmospheric pressure) were placed in a dry 1-liter three-necked flask, argon-washed and vigorously stirred in argon until a fine suspension formed. Then, 20 ml of 1.80 M solution of phenyl lithium was added to the flask. ether drop by drop for 1 hour. The red solution was stirred at room temperature for 4 hours and 6.12 g (0.036 mol) of ethyl 4-methyl-4-formylpent-2-enoate were added in one portion. The resulting white suspension was stirred at room temperature for 10 hours and refluxed for 2 hours. The reaction mixture was filtered and concentrated to yield a viscous yellow oil. After the addition of 150 ml of ether to the oil, the solution was filtered once more. The filtrate was concentrated to yield 5.82 g of an oil which was diluted with 30 ml of toluene and filtered through Al203 and silica gel eluted in toluene. The solvent was evaporated to provide 3.82 g of diethyl 4,4,11,11-tetramethyltetradeca-2, 5,9,12-tetranediodate. A solution of 2.98 g (8.1 mmol) of diethyl 4,4,11,11-tetramethyltetradeca-2, 5,9,12-tetra-tranedioneate in 50 ml of methanol was hydrogenated with 0.2 g of Pt (prepared according to R. Adams, V.

P1402 / 99MX Voorhees and R. L. Shriner, Org. Synth, 8, 92 (1928)) until the theoretical volume of hydrogen had been absorbed. It was concentrated to the filtrate to yield an oil which was diluted with 30 ml of toluene and filtered through Al203 and silica gel eluted in toluene. The solvent was evaporated to provide an oil. To the resulting oil, 25 ml of 25% NaOH solution and several drops of ethanol were added, the resulting mixture was heated for 2 hours at 50-60 ° C, acidified with concentrated HCl and extracted with chloroform. The combined chloroform extracts were dried in sodium sulfate. After distilling off the solvent, the residue was recrystallized from hexane to provide 2.06 g (81%) of 4,4,11,11-tetramethyl-tetradecanedioic acid, m.p. 88-89 ° C. 1H NMR (CDC13): (= 0.86 [s, 12H, C (CH3) 2], 1.05 1.38 (m, 16H, CH2), 1.52 (m, 4H, 3.12-CH2), 2.30 (t, 4H, 2.13 CH2), 9. 50 (broad s, 2H, COOH). Anál i si s Cal culado para C18H3404: C, 68.75; H, 10.90. Found: C, 68.95; H, 10.96.

E ng 2; Diethyl 4,4,13,13-tetramethylhexadeca- 2, 5, 11, 14-te rarenßdionato 4.88 g (0.02 mol) of 1,6-dibromohexane and one drop of formic acid were added to a solution of 13. 1 g (0.05 mol) of triphenylphosphine in 60 ml of dimethylformamide and the mixture was refluxed for 3 hours, then cooled and diluted with 20 ml.

P1402 / 99MX of ether. The formed precipitate was filtered, washed with 30 ml of ether and dried. The crude product was dissolved with heating in 25 ml of methanol and precipitated with 40 ml of ether to yield 12.6 g (82.0%) hexane-1,6-bis (triphenylphosphonium) dibromide, m.p. 312-313 ° C. Hexane-1,6 bis (triphenyl-phosphonium) dibromide (8.28 g, 0.011 mol) (dried over phosphorus pentoxide for at least 36 hours) and 550 ml of dry tetrahydrofuran (refluxed in lithium-aluminum hydride and distilled atmospheric pressure) were placed in a 1 liter dry neck flask with argon and vigorously stirred under argon until a fine suspension formed. Then, 17 ml of 1.375 M solution of phenyllithium was added dropwise in ether for 30 min. The red solution was stirred at room temperature for 4 hours and 3.6 g (0.021 mol) of ethyl 4-methyl-4-formylpent-2-enoate (prepared as in Example 1) in 50 ml of dry tetrahydrofuran were added in one portion. portion. The resulting white suspension was stirred at room temperature for 10 hours and refluxed for 2 hours. The reaction mixture was filtered and concentrated to yield a yellow viscous oil. After the addition of 100 ml of ether to the oil, the solution was filtered once more. The filtrate was concentrated to yield 3.7 g of an oil which was diluted with 20 ml of toluene, filtered P1402 / 99MX through Al203 and then subjected to silica gel column chromatography (100 g, eluted in toluene) to yield 25 g (59% yield) of diethyl 4, 4, 13, 13-tetra ethylhexadeca- 2, 5, 11, 14 -tetraenodionate. The ester gave a spot on TLC (Silufol UV 254, CHC13, Rf 0.75). 1H NMR (CDC13): (= 1.18 [s, -12H, C (CH3) 2], 1.25 (t, J = 6Hz, 6H, CH3CH2), 1.05-1.38 (m, 4H, 8.9-CH2), 1.85-2.05 (m, 4H, 7.10-CH2), 4.15 (q, 2H, J = 6 Hz, CH2CH3), 5.22-5.30 (m, 4H, 5, 6, 11, 12 -CH), 5.75 ( d, 2H, J = 14 Hz, 3.14-CH), 7.05 (d, 2H, 2.15-CH).

On 3; 4,4,13,13-tetramethylhexadecanedioic acid A solution of 5.43 g (0.014 mol) of Example 2 in 50 ml of methanol containing 0.3 g of Pt was hydrogenated and hydrolyzed as described in Example 1, to yield 3.52. g (74%) of 4, 4, 13, 13 -tetramethylhexadecandioic acid pf 85-86 ° C. 1 H NMR (CDCl 3): (= 0.86 [s, 12 H, C (CH 3) 2], 1.05-1.38 (m, 20 H, CH 2), 1.52 (m, 4 H, 3.14-CH 2), 2.30 (t, 4 H , 2.15-CH2), 9.50 (broad s, 2H, COOH) Calcined Analysis for C20H38O4: C, 70.13; H, 11.18. Found: C, 70.07; H, 11.02.

Ei em 1o 4; 4,4,15,15-te rame iloc adeno-dioic acid 10.88 g (0.04 mol) of 1,8-dibromo-octane and P1402 / 99MX Five drops of formic acid were added to a solution of 26.2 g (0.1 mol) of triphenyl phosphine in 125 ml of dimethylformamide and the mixture was refluxed for 3 hours, then cooled and diluted with 150 ml of ether. The formed precipitate was filtered, washed with ether and dried. The crude product was dissolved in 35 ml of methanol and precipitated with 80 ml of ether to yield 27.1 g (85.2%) of octane-1,8-bis (triphenylphosphonium) dibromide, m.p. 255-257 ° C. 1H NMR (CDC13): (= 0.7-1.3 [m, 12H, (CH2) 6], 3.0-3.3 (m, 4H, 2PCH2), 7.1-7.5 (m, 30H, 2PPh3) Calcined Analysts for C44H46Br2P2 : Br, 20.06, found: Br, 20.22 Octane-1,8 bis (triphenyl-phosphonium) dibromide (14.34 g, 0.018 mol) (dried in a vacuum desiccator in phosphorus pentoxide for at least 10 days) and 400 ml of dry tetrahydrofuran (refluxed in lithium-aluminum hydride and distilled at atmospheric pressure) were placed in a dry 1-liter three-necked flask, argon-washed and vigorously stirred in argon until a fine suspension formed. Then, 20 ml of 1.86 M solution of phenyllithium in ether was added dropwise over 30 minutes. The red solution was stirred at room temperature for 2.5 hours and 6.12 g (0.036 mol) of ethyl 4-methyl-formylpent-2-enoate (prepared as in Example 1) was added in one portion. The white suspension The resulting P1402 / 99MX was stirred at room temperature for 14 hours and refluxed for 1 hour. The reaction mixture was filtered and concentrated to yield a viscous yellow oil. After the addition of 150 ml of ether to the oil, the solution was filtered once more. The filtrate was concentrated to yield 6.69 g of an oil which was diluted with 30 ml of toluene and filtered through Al203 and silica gel eluted in toluene. The solvent was evaporated to provide 4.33 g of diethyl 4,4,15,15-tetra-methyl-octadeca-2,5,13,16-tetranediodate. A solution of 2.26 g (5.4 mmol) of diethyl 4,4,15, 15-tetramethyl octadeca-2, 5,13, 16-tetraenodio-nate in 50 ml of ethanol containing 0.5 g of Ni (prepared in accordance with H. Adkins, Org Syntheses Coll., 3, 180 (1955)) was hydrogenated until the theoretical volume of hydrogen had been absorbed and filtered. The filtrate was processed as described in Example 1 to yield 1.24 g (62% yield) of acid, m.p. 71-72 ° C. 1H NMR (CDC13): (= 0.86 [s, 12H, C (CH3) 2], 1.05-1.38 (m, 24H, CH2), 1.52 (m, 4H, 3.16-CH2), 2.30 (t, 4H , 2.17-CH2), 9.50 (broad S, 2H, COOH) Analysis Calcd for C22H4204: H, 11.42 Found: C, 71.35: H, 11.35.

E p plo 5: 2,2,13,13-e radecanode dioic acid 43 ml (80 mmol) of 1.88 N solution of butyl- P1402 / 99MX lithium in hexane were added dropwise to 8.1 g (80 mmol) of diisopropylamine in 60 ml of THF. After stirring for 30 minutes at the same temperature, 3.5 g (40 mmol) of isobutyric acid was added dropwise. The mixture was gradually warmed to room temperature and stirred for 3 hours, then cooled to 15 ° C again followed by the addition of 1, 10 -dibromodecane (4.5 g, 15 mmol) in one portion. After stirring for 3 hours at room temperature, the reaction was stopped by 40 ml of 12% hydrochloric acid while cooling with ice water. The aqueous phase was extracted with benzene, washed with water and dried in MgSO4. After removing the solvent, the residue crystallized. The product was recrystallized from hexane to yield 3.4 g (72%) of 2,2,13,13-tetra-methyl-tetradecanedioic acid, m.p. 86-87.5 ° C. 1H NMR (CDC13) delta 1.18 (s, 12H, CH3), 1.20-1.32 (m, broad 16H, CH2), 1.52 (br.T, 4H, ß-CH2).

Example 6; 2,2,15,15-tetraethyhexadecanedioic acid 3.5 g (40 mmol) of isobutyric acid were added at 15 ° C in Ar to a solution of lithium diisopropylamide prepared from 8.1 g (80 mmol) of diisopropylamine in 60 ml of THF and 38.3 ml (80 mmol) of 2.1 N hexane solution of butyl-lithium.

P1402 / 99MX The mixture was stirred at room temperature for 3 hours and cooled again to 15 ° C. 3.3 g (10 mmol) of 1, 12 -dibromododecane were then added in one portion, the temperature was gradually raised to 20 ° C and the reaction was stirred overnight. The reaction was quenched on ice with 12% hydrochloric acid, extracted with benzene, washed with water and dried. The product was crystallized from hexane to yield 2.6 g (71%) of 2, 2, 15, 15-tetramethylhexadecanedioic acid, m.p. 90-91 ° C. Found%: C 69.75; H 11.14; Calculated%: C 70.13; H 11.18. 1 H NMR (CDC13) delta 1.18 (s, 12 H, CH 3), 1.20-135 (broad m, 20 H, CH 2), 1.50 (broad t, 4 H, ß-CH 2).

Example 7: Acid 2, 2, 17, 17-tetrame-iloc-adeno-dioic 1, 14 -Dibromotetradecane was prepared by adding HBr to a solution of 4.0 g (20.6 mmol) of 1, 13-tetradecadiene and 0.5 g of benzoyl peroxide in benzene at room temperature. The mixture was stirred for two hours and subjected to chromatography on Al203 (412 cm) with eluent of benzene. The 1,14-dibromotetradecane was isolated and recrystallized from hexane to yield 6.8 g (93.1%), m.p. 50 ° C. The acid 2, 2, 17, 17 -Tetra-metilocta-decanodioic acid was synthesized by adding dropwise 17.5 ml (30 mmol) of 1.72 N solution of butyllithium in P1402 / 99MX hexane at 3.0 g (30 mmol) of diisopropylamine in 40 ml of THF in an Ar atmosphere at 15-5 ° C. After 30 minutes, the mixture was cooled to 20 ° C and 1.3 g (15 mmol) of isobutyric acid were added. The temperature was gradually increased to 20 ° C and the stirring continued for three hours. The reaction mixture was again cooled to -15 ° C followed by the addition of 1,14 -dibromotetradecane (0.2 g, 3.4 mmol) in one portion. The temperature was increased to 20 ° C and the reaction was stirred overnight. The reaction was quenched on ice with 12% hydrochloric acid, extracted with benzene, washed with water and dried. The product was crystallized from hexane to yield 1.0 g (80%) of 2,2,17,17-tetramethyl octadecanedioic acid, m.p. 94-96 ° C (from hexane). Found%: C 71.10; H 11.40. Calculated%: C 71.30; H 11.42. 1 H NMR (CDC13) delta 1.18 (s, 12 H, CH 3), 1.25 (broad s, 24 H, CH 2), 1.51 (broad t, 4 H, ß-CH 2).

P1402 / 99MX

Claims (22)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. A composition of the general formula: wherein 3-R4 independently represent, each, a hydrogen or a substituted or unsubstituted hydrocarbyl or heterocyclyl radical; wherein R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chloro, bromo, cyano, nitro, lower alkoxy or trifluoromethyl; Q represents a di-radical consisting of a linear chain of 2 to 14 carbon atoms, of which one or more can be replaced by heteroatoms, the chain will be optionally substituted by inert substituents and one or more of the chain members carbon or heteroatoms optionally form part of a ring structure and, where one or both groups
2. P1402 / 99MX carboxyl can be substituted by a hydrolyzable substituent in vi tro and physiologically acceptable; with the proviso that: compounds wherein Rx-R4 and 5-R6 represent all hydrogen are excluded; compounds where R 5 -R 6 represent CH 3 and R 3 -4 represent H and, Q represent a linear chain of 2-6 or 10 carbon atoms, are excluded; compounds where R3.-R4 represent CH3 and R5-R6 represent H and, Q represent a linear chain of 2-3 carbon atoms, are excluded; and compounds wherein R5-R6 represent chlorine or bromine and R? -R4 represent H and, Q represents a linear chain of 2-12 carbon atoms, are excluded. 2. A compound according to claim 1, wherein R5-Rs independently represent hydroxyl, methyl, ethyl, methoxy or chloro. 3. A compound of the formula:
3. HOOC-CH2-CH2-C- (CH2) n-C CH2-CH2-C00H (EL)
4. CH. CH, where n is an integer from 6 to 12; and its hydrolysable functional derivatives in vi. 4. A compound of the formula:
5. P1402 / 99MX CH, CH, HOOC-C- (CH2) n-C-COOH CIID CH, CH, where n is an integer from 11 to 13 and from 15 to 18; and, its hydrolysable function derivatives in vi vo. A compound according to claim 1, wherein the hydrolysable derivative is a pharmaceutically acceptable organic or inorganic cation, ester, amide or anhydride of a lower alkanoic acid or an internal ester, amide or anhydride of said acid.
6. 6. The 4,4,11,11-tetramethyltetradecanedioic acid compound.
7. 7. The diethyl compound 4,4,13,13-tetramethylhexadeca-2, 5,11,14-tetranediodate.
8. 8. The 4,4,13,13-tetramethylhexadecanedioic acid compound.
9. 9. The 4,4,15,15-tetramethyl octadecanedioic acid compound.
10. 10. The 2, 2, 15, 15-tetramethylhexadecanedioic acid compound.
11. 11. A pharmaceutical composition containing as active ingredient a compound claimed in claim 1.
12. 12. A pharmaceutical composition for the treatment of obesity, hyperlipidemia and diabetes onset at maturity, comprising P140 / 99MX as an active ingredient is an efficient amount of a compound of the formula (I) wherein R? ~ R4 independently represents, each a hydrogen or a substituted or unsubstituted hydrocarbyl or heterocyclyl radical; wherein R5 and R6 independently represent hydrogen, hydroxyl, lower alkyl, chloro, bromo, cyano, nitro, lower alkoxy or trifluoromethyl; Q represents a di-radical consisting of a linear chain of 2 to 14 carbon atoms, of which one or more can be replaced by heteroatoms, the chain will be optionally substituted by inert substituents and one or more of the chain members carbon or heteroatoms optionally form part of a ring structure and, wherein one or both carboxyl groups may be substituted by an in vi tro and physiologically acceptable hydrolyzable substituent; with the proviso that the compounds wherein R? -R4 and Rs-6 represent all hydrogen are excluded.
13. 13. A pharmaceutical composition for the treatment of obesity, hyperlipidemia and diabetes onset at maturity, which comprises as an active ingredient an efficient amount of a compound claimed in claim 1. I heard 4n9 / q OMTG
14. 14. A pharmaceutical composition according to claim 11, wherein the amount of the active ingredient per unit dosage form is about 50 to 500 mg.
15. 15. A pharmaceutical composition according to claim 12, wherein the amount of the active ingredient per unit dosage form is from about 50 to 500 mg.
16. 16. A pharmaceutical composition wherein the active ingredient is a compound claimed in claim 2.
17. 17. A pharmaceutical composition wherein the active ingredient is a compound claimed in claim 3.
18. 18. A pharmaceutical composition wherein the active ingredient is a The compound claimed in claim 4.
19. 19. A pharmaceutical composition wherein the active ingredient is a compound of the formula (III), wherein n = 14 and its hydrolysable derivatives in vivo.
20. 20. A method for the treatment of obesity, hyperlipidemia and diabetes of onset at maturity in patients, comprising administering to the patient a pharmaceutical composition according to claim 12.
21. 21. A method according to claim 20, wherein the compound is administered to the patient of P1402 / 99MX oral, parenteral or topical form.
22. 22. A method according to claim 20, wherein the compound is administered in a dose ranging from 50 mg to 5,000 mg per day. P1402 / 99MX