FR2909379A1 - New quinoline derivatives are aldose reductase inhibitors useful to treat and/or prevent e.g. hyperglycemia, dyslipidemia, insulin resistance, glucose intolerance, diabetes, kidney disease, retinopathies or obesity - Google Patents

Abstract

Quinoline derivatives of formula (I), their enantiomers, diastereoisomers, and their acid or base addition salts, are new. Quinoline derivatives of formula (I), their enantiomers, diastereoisomers, and their acid or base addition salts, are new. R 11-6C alkyl (substituted by COOR 3 or -NR 4R 5), preferably -(CH 2) 3-COOR 3, -(CH 2) 2-C(Me) 2-COOR 3 or -CH 2-NR 4R 5; R 4-COOR 3 a or 1-6C alkyl (substituted by COOR 3 a); R 3, R 3 aH or 1-6Calkyl; R 51-6C alkyl (substituted by phenyl (optionally substituted by 1-3 substituents of 1-6C alkoxy, 1-6C (polyhalo)alkyl or halo)); R 2phenyl (optionally substituted by 1-6C alkyl, 1-6C alkoxy or 1-6C polyhaloalkyl or halo); and n : 0-8. Independent claims are included for: (1) the preparation of (I); and (2) a combination containing (I) and an antioxidant agent. [Image] ACTIVITY : Antidiabetic; Antilipemic; Metabolic; Cardiovascular-Gen.; Cardiant; Vasotropic; Nephrotropic; Ophthalmological; Antipsoriatic; Gynecological; Nootropic; Osteopathic; Gastrointestinal-Gen; Antiarteriosclerotic; Anorectic; Eating-Disorders-Gen.; Cytostatic; Muscular-gen; Anabolic. MECHANISM OF ACTION : Aldose reductase inhibitor.

Description

The present invention relates to novel heterocyclic derivatives, their

  method of preparation and pharmaceutical compositions containing them. The compounds described in the present invention are new and have particularly advantageous pharmacological properties: they are excellent hypoglycemic and lipid-lowering agents. The treatment of non-insulin-dependent type II diabetes remains unsatisfactory despite the placing on the market of numerous oral hypoglycemic agents intended to facilitate the secretion of insulin and to promote its action at the peripheral target tissues. In the last ten years, a class of compounds of thiazolidinedion structure (US 5089514, US 5306726) has shown marked antidiabetic activity by promoting insulin sensitivity in target peripheral tissues (skeletal muscle, liver, adipose tissue) of models. non-insulin-dependent diabetes type II animals. These compounds also reduce insulin and lipid levels in these same animal models and induce in vitro the differentiation of preadipocyte cell lines, adipocytes (A.

  Hiragun et al., J. Cell. Physiol., 1988, 134, 124-130; R. F. Kleitzen et al., Mol. Pharmacol., 1992, 41, 393-398). The treatment of preadipocyte cell lines with the thiazolidinedione Rosiglitazone induces the expression of genes specific for lipid metabolism such as aP2 and adipsin as well as the expression of GLUT1 and GLUT4 glucose transporters, suggesting that the effect of thiazolidinediones observed in vivo can be mediated via adipose tissue. This specific effect is achieved by the stimulation of nuclear transcription factors: peroxisome proliferator-activated receptor gamma (PPAR 12). These derivatives are capable of restoring insulin sensitivity in peripheral tissues such as adipose tissue or skeletal muscles (J. E. Gerich, New Engl.

  Med., 19, 321, 1231-1245). Nevertheless, derivatives of thiazolidinediones structure (troglitazone, rosiglitazone) have shown in humans disturbing side effects, including liver problems (Script N 2470, 1999, Sept. 8th, 25). Many hypoglycemic agents have significant side effects (hepatic, cardiac, hematopoietic) that limit their long-term use in the treatment of non-insulin-dependent type II diabetes. The development of new therapeutic agents that are less toxic and active in the long term is absolutely necessary in this pathology. In addition, hyperlipidemia is often observed in diabetics (Diabete Care, 1995, 18 (supplement 1), 86/8/93). The association of hyperglycemia with hyperlipidemia promotes the risk of cardiovascular disease in diabetics. Hyperglycemia, hyperlipidemia and obesity have become pathologies of the modern world marked by high food intake and chronic lack of exercise. The increase in the frequency of these pathologies calls for the development of new therapeutic agents active in these diseases: compounds having excellent hypoglycemic and hypolipidemic activity while avoiding the side effects observed with thiazolidinediones are therefore very useful in the treatment and / or prophylaxis of these pathologies and particularly indicated in the treatment of non-insulin-dependent type II diabetes to reduce peripheral insulin resistance and normalize glucose control. The compounds of the present invention, in addition to their novelty, meet these pharmacological criteria and are excellent hypoglycemic and lipid-lowering agents. The present invention relates more particularly to the compounds of formula (I): wherein R 1 represents a linear or branched (C 1 -C 6) alkyl group substituted with one or more COOR 3 or NR 4 R 5 groups, in which: R 1 2 (I) 2909379 3 R3 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, R4 represents a COOR'3 group or a linear or branched (C1-C6) alkyl group substituted with a COOR 'group Wherein R'3 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, R5 represents a linear or branched (C1-C6) alkyl group substituted by a phenyl group which is unsubstituted or substituted with 1 to 3 linear or branched (C1-C6) alkyl groups, linear or branched (C1-C6) alkoxy, linear or branched (C1-C6) polyhaloalkyl or halogen atoms, R2 represents a phenyl group which is unsubstituted or substituted by a or more alk grouping linear or branched (C 1 -C 6) yl, linear or branched (C 1 -C 6) alkoxy, linear or branched (C 1 -C 6) polyhaloalkyl or halogen atoms, - nvaut 0, 1, 2, 3, 4, 5, 6 7 or 8, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic and camphoric acids. Examples of pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc. Preferred compounds of the invention are the compounds of formula (I) for which R1 represents a group - (CH2) 3 -COOR3, - (CH2) 2-C (Me) 2 -COOR3 or a CH2-NR4R5 group. Advantageously, the group NR4R5 represents -N (CH2-COOR) (CH2-.Ar) in which R represents a linear or branched (C1-C6) alkyl group such as, for example, the tert-butyl group, and represents an unsubstituted or substituted phenyl group, preferably with a halogen atom or a CF3 group. Even more particularly, the invention relates to the compounds of formula (I) which are: methyl 8- [2- (benzyloxy) -3-quinolinyl] -8-hydroxy-5-octynoate, 5-8-hydroxy Methyl 8- (3-phenylpropoxy) -3-quinolinyl] -5-octynoate, 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5 Methyl octynoate, methyl 8-hydroxy-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy] -3-quinolinyl] -5-octynoate, - 8-hydroxy Methyl 8- (2 - {[5- (4-methoxyphenyl) pentyl] oxy} -3-quinolinyl) -octynoate, 8- (2- {[5- (3,5-dimethoxyphenyl)} Methyl pentyl] oxy-3-quinolinyl-8-hydroxy-5-octynoate, 8-hydroxy-8- (2 - {[5- (3,5-trimethoxyphenyl) p-octyl] oxy} Methyl 3-quinolinyl) -5-octynoate, 8- [2- (benzyloxy) -3-quinolinyl] -8-hydroxy-5-octynoic acid, - 8- [2- (benzyloxy) -3 sodium -quinolinyl] -8-hydroxy-5-octynoate, 8-hydroxy-8- [2- (3-phenylpropoxy) -3-quinolinyl] -5-octynoic acid, 8-hydroxy-8 [2- (3-phenylpropoxy) -3-quinoliny sodium 1 -5-octynoate, 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoic acid, 20-8-hydroxy-8- Sodium 2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate, 8-hydroxy-8- [2- ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy acid; ) -3-quinolinyl] -5-octynoic, 8-hydroxy-8- [2 - ({5- [4- (trifluoromethyl) phenyl] p-octyl} oxy) -3-quinolinyl] -5-octynoate sodium, 8-hydroxy-8- (2 - {[5- (4-methoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoic acid, 8-hydroxy-8- (2- Sodium {[5- (4-methoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate, - 8- (2 - {[5- (3,5-dimethoxyphenyl) pentyl] oxy} - 3-quinolinyl) -8-hydroxy-5-octynoic acid, 8- (2 - {[5- (3,5-dimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -8-hydroxy-5- sodium octynoate, 8-hydroxy-8- (2 - {[5- (3,4,5-trimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoic acid, 8-hydroxybenzoyl Sodium 8- (2 - {[5- (3,4,5-trimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate; Methyl 2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate, - 8-hydroxy-2,2-dimethyl-8- [2 - ({ Methyl 5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoate, 8-hydroxy-2,2-dimethyl-8- {2 - [(5- phenylpentyl) oxy].-3-quinolinyl} -5-octynoic acid, 8-hydroxy-2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate, sodium, 15-hydroxy-2,2-dimethyl-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoic acid, sodium 8-hydroxy-2,2-dimethyl-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoate; fluorobenzyl) (5-hydroxy-5- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -2-20 pentynyl) amino] tert-butyl acetate, - (benzyl {5-hydroxy-5- Tert-Butyl [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -2-pentynyl} amino) acetate, - ((4-fluorobenzyl) 5- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -2-pentynyl} amino) ac tert-butyl acetate. The enantiomers, diastereoisomers as well as the addition salts with a pharmaceutically acceptable acice or base of the preferred compounds of the invention form an integral part of the invention. The present invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (II) is used as starting material: 2909379 -6-CHO Cl which is converted into a compound of formula (III): OMe OMe on which is condensed in the presence of sodium hydride the compound of formula (IV): ## STR3 ## in which R 2 and n are as defined in formula (I) ), to yield the compound of formula (V): ## STR2 ## wherein R 2 and n are as defined above, which are placed in acidic medium to yield the compound of formula (VI): CHO N Wherein R2 and n are as defined above, on which the propargyl magnesium bromide is condensed, to yield the compound of formula (VII): wherein R2 and n are as defined previously, that tert-butyldimethylsilyl chloride is subjected to the action of formula (VIII): wherein R 2 and n are as defined above, on which the compound of formula (IX): OMe OMe (IX) OMe in which A represents an alkylene chain (C1- C6) linear or branched ,. To obtain the compound of formula (X): wherein R 1, R 2 and A are as defined above and Ra represents a linear or branched (C1-C6) alkyl group, 2909379 -s which is in the presence of tetrabutylammonium chloride, to give the compound of formula (Pa), a particular case of compounds of formula (I): ## STR5 ## in which n, Ra, R 2 and A are as defined above, saponifies to yield the compound of formula (Pb), in particular the compounds of formula (I): embedded image in which n, R 2 and A are as defined above, or a compound of formula (VIII) on which in a basic medium, the compound of formula (XI): embedded image in which A is as defined above, to give the compound of formula (XII): embedded image in which n, R 2 and A are as defined above, which is subjected to the action of methyl tetrabromide to lead to the compound of formula (XIII): embedded image in which n, R 2 and A are as defined above, on which the compound of formula HNR '4 R 5 in which R 5 is as defined in the formula is condensed ( I), and R'4 represents a group R4 as defined in formula (I) in which R'3 represents a linear or branched (C1-C6) alkyl group, to yield the compound of formula (XIV): AiNR 4R5 (XIV) wherein n, R2, R'4, R5 and A are as previously defined, which are placed in the presence of tetrabutylammonium chloride, to yield compound 10 of formula (I / c), case of the compounds of formula (I): embedded image in which n, R 2, R '4, R 5 and A are as defined above, which are saponified to yield the compound of formula (Pd), a particular case of compounds of formula (I): ## STR2 ## wherein n, R 2, R 5 and A are as defined above and R "4 represents a group R 4 t As defined in formula (I) in which R '3 represents a hydrogen atom, the compounds (I / a) to (Ud) constitute the set of compounds of formula (I), which can be purified according to a conventional separation technique, which, if desired, is converted into their addition salts with a pharmaceutically acceptable acid or base and the isomers are optionally separated therefrom according to a conventional separation technique. The compounds of formula (II) are commercially available or readily accessible to those skilled in the art by conventional chemistry reactions or described in the literature. The compounds of the present invention possess very valuable pharmacological properties. These compounds show in particular an excellent activity in the reduction of blood glucose levels. These properties justify their therapeutic application in the treatment and / or prophylaxis of hyperglycemia, dyslipidemia and more particularly in the treatment of non-insulin-dependent diabetes type II, glucose intolerance, disorders related to syndrome X ( including hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia), coronary artery disease and other cardiovascular diseases (including high blood pressure, heart failure, venous), renal diseases (including glomerulonephritis, glomerulosclerosis, nephrotic syndromes, hypertensive nephrosclerosis), retinopathies, disorders related to endothelial cell activation, psoriasis, ovarian polycystic syndrome, dementia, diabetic complications and osteoporosis. They can be used as inhibitors of aldose reductase, to improve cognitive functions in dementia and complications of diabetes, inflammatory bowel diseases, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma. The activity of these compounds is also recommended for the treatment and / or prophylaxis of other diseases including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, dyslipidemia in diabetic, hyperlipidemias, hypercholesterolemia, arterial hypertension, heart failure, cardiovascular diseases including atherosclerosis. In addition, these compounds are indicated for use in the regulation of appetite, particularly in the regulation of food intake in subjects suffering from disorders such as obesity, anorexia, bulimia and anorexia nervosa. . Thus, these compounds can be used for prevention or for the treatment of hypercholesterolemia, obesity with beneficial effects on hyperlipidemia, hyperglycemia, osteoporosis, glucose intolerance, resistance to insulin or diseases in which insulin resistance is a secondary pathophysiological mechanism. The use of these compounds reduces total cholesterol, body weight, leptin resistance, plasma glucose, triglycerides, LDL, VLDL as well as plasma free fatty acids. They can be used in combination with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol, probucol, GLP1, metformin, biguanides or glucose reabsorption inhibitors, and may be administered together or at different times to act synergistically in the treated patient. They also exhibit activity in cancerous pathologies and in particular hormone-dependent cancers such as breast cancer and colon cancer, as well as an inhibitory effect of the angiogenesis processes involved in these pathologies. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets. , sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels and oral or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges from 0.1 mg to 1 mg. g per 24 hours in 1 or more takes. The present invention also relates to a new combination between a heterocyclic derivative of formula (I) as defined above and an antioxidant agent for obtaining pharmaceutical compositions useful in the treatment and / or prevention of obesity and overweighting. characterized by a body weight index greater than 25. The antioxidants according to the invention are more particularly anti-free radical scavengers or free radical scavengers, antilipoperoxidizing agents, chelating agents or agents capable of regenerating endogenous antioxidants such as glutathione , vitamin C or vitamin E, as well as their addition salts with a pharmaceutically acceptable acid or base. The antioxidant of the combination according to the invention is more preferably represented by quinone derivatives such as ubiquinone or coenzyme Qlo, which acts as a scavenger of free radicals but is also capable of regenerating vitamin E The preferred combination according to the invention is methyl 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate and coenzyme Q10. Moreover, the combination according to the invention has quite surprising pharmacological properties: the Applicant has in fact demonstrated the existence of a synergy between the two compounds of the combination which makes it possible to obtain a very low reduction. significant body fat making it useful in the treatment and / or prevention of obesity and overweight characterized by a body weight index greater than 25. Obesity in the United States reaches 20% of men and 25 % women. Patients with body weight index (BMI = weight (kg) / height2 (m2)) greater than or equal to 30 are considered to be obese (Int.JO Obes., 1998, 22, 39-47; Obesity Lancet, 1997, 350, 423-426). Obesity (BMI 30) and overweight (25 <BMI <30) can have several origins: they can occur as a result of a dysregulation of food intake, a hormonal dysregulation or following the administration of a treatment: an antidiabetic treatment Type II with sulfonylureas results in weight gain in patients. Similarly in type I (insulin-dependent) diabetes, insulin therapy is also a source of body weight gain in patients (In Progress in Obesity 5 Research, 8th International Congress on Obesity, 1999, 739-746; of Internal Medicine, 1998, 128, 165-175). Obesity and overweight are well-established risk factors for cardiovascular disease: they are associated with an increased significance of the risk of stroke, of non-insulin-dependent diabetes as they predispose to insulin-dependent diabetes. resistance, dyslipidemia and the appearance of macrovascular diseases (nephropathies, retinopathies, angiopathies). Other pathologies are the consequence of obesity or overweight: vesicular stones, respiratory dysfunctions, several forms of cancer and, in the case of very severe obesity, premature death (N. Engl. J. Med., 1995, 333, 677-385, JAMA, 1993, 270, 2207-2212). The combination of the invention achieves a weight loss that even moderate significantly reduces all risk factors associated with obesity (Int, J. Obes., 1997, 21, 55-9; Obes., 1992, 21, S5-9). The combination according to the invention thus finds its utility in the treatment and / or prevention of obesity and weight overload characterized by a body index greater than 25. The invention therefore relates to the use of the association between a compound of formula (I) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and overweight characterized by a body index greater than 25 and less than 30. In particular, the combination according to the invention is useful in the treatment and / or prevention of obesity and overweight characterized by a body index greater than 25 and less than 30 induced by a therapeutic treatment, such as the treatment of diabetes. type I or II. The invention therefore relates to the use of the combination between a compound of formula (I) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and overloads. Weights characterized by a body index greater than 25 and less than 30 induced by a therapeutic treatment, such as the treatment of type I or II diabetes. The invention also relates to pharmaceutical compositions containing the combination of a compound of formula (I) and an antioxidant as defined above in combination with one or more pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention, mention may be made especially of those which are suitable for oral, parenteral, nasal administration, single or sugar-coated tablets, sublingual tablets, capsules, lozenges, suppositories, creams, In particular, the invention relates to pharmaceutical compositions containing a compound of formula (I) as defined above and an antioxidant agent such as coenzyme Qlo or vitamin E in combination with one or more pharmaceutically acceptable excipients. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments and ranges between 0.1 mg and 1 g of each component of the association by 24 hours in a 20 or more shots. The following examples illustrate the invention and do not limit it in any way. EXAMPLE 1 Methyl 8- [2- (Benzyloxy) -3-quinolinyl] -8-hydroxy-5-octynoate Step A: 2-Chloro-3- (dimethoxymethyl) quinoline In a pellet under argon topped with a condenser, 6.0 g of 2-chloroquinoline-3-carbaldehyde are suspended in 30 ml of distilled methanol. Trimethylorthoformate (4.12 mL) and ammonium nitrate (126 mg) are then added and the mixture is refluxed for 4 hours. After cooling to room temperature, the reaction medium is hydrolysed by adding a saturated aqueous solution of sodium carbonate and the phases are separated. The aqueous phase is extracted with diethyl ether and then the organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and the solvent is evaporated. The crude reaction is purified by filtration on silica gel (AcOEt 30/70 Pentane) to yield the title product as a white solid. Step B: 2- (Benzyloxy) -3- (dimethoxymethyl) quinoline In a bicol under argon, the sodium hydride (60% in suspension in the mineral oil, 400 mg), previously washed, is suspended in the N Methylpyrrolidone (6 ml) at 0 ° C. The benzyl alcohol (1.03 ml) is then added slowly and stirring is maintained for 30 minutes. The compound obtained in Step A (1.2 g) is added and stirring is continued for 12 hours, the temperature slowly rising to room temperature. The reaction medium is hydrolysed by adding distilled water and after separation of the phases, the aqueous phase is extracted with diethyl ether. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration and evaporation of the solvent, the reaction crude is purified by chromatography on silica gel (eluent AcOEt / pentane 10/90) to yield the title product in the form of a beige solid. Stage C: 2- (Benzyloxy) -3-quinolinecarbaldehyde In a flask surmounted by a condenser, the compound obtained in Stage B (1.43 g) is placed in solution in a mixture of tetrahydrofuran / water (31 ml / 13 ml) . The p-toluenesulfonic acid (132 mg) is added and the mixture is refluxed for 4 hours. After cooling to room temperature, the reaction medium is hydrolysed by adding a saturated aqueous solution of sodium carbonate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with distilled water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. After filtration and evaporation of the solvent, the title compound is obtained pure, no purification being necessary. Stage D: 1- [2- (Benzyloxy) -3-quinolinyl] -3-butyn-1-ol Magnesium (121 mg) is activated by heat-etching in a bicol placed under vacuum and after cooling and placing under argon, mercuric chloride (13 mg)) and a minimum of freshly distilled diethyl ether are added. The propargyl bromide (610 'a1) is then added slowly until the reaction starts. The addition is then continued dropwise to maintain a slight reflux. After the addition is complete, stirring is continued for about 30 minutes until all the magnesium is consumed. The reaction mixture is then brought to -78 ° C. after diethyl ether is added (40 ml). The compound obtained in Step C (1.11 g) in solution in anhydrous diethyl ether (5 ml) is then added dropwise to the magnesium. The temperature rose slowly (in about 2 hours) to 0 C and the bath is removed and stirring is maintained for 15 minutes at room temperature. The reaction medium is then hydrolysed with a saturated aqueous solution of ammonium chloride and after phase separation, the aqueous phase is extracted with diethyl ether. The organic phases are combined, washed with a saturated aqueous solution of ammonium chloride and dried over magnesium sulfate. After filtration and evaporation of the solvents, the crude reaction product is isolated and purified by chromatography on silica gel (eluent AcOEt / pentane 20/80) to yield the title product in the form of a beige solid. Step E: 2- (Benzyloxy) -3- (1 - {[tert-butyl (dimethyl) silyl] oxy} -3-butynyl) quinoline In a bicol under argon, the compound obtained in Step D (4 mmol) is dissolved in 12 ml of anhydrous dimethylformamide. The reaction medium is brought to 0 ° C. and the imidazole (682 mg) and then the tert-butyldimethylsilyl chloride (790 mg) are added. Stirring is maintained for 12 hours while allowing the temperature to rise slowly to room temperature. The hydrolysis of the reaction medium is carried out by adding an aqueous solution saturated with sodium chloride and after separation of the phases, the aqueous phase is extracted with diethyl ether. The organic phases are combined, washed with distilled water and then with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration and evaporation of the solvent, the crude reaction product is purified by chromatography on silica gel eluent AcOEt / pentane 5/95, to give the title product in the form of a colorless oil. Stage F: Methyl 8- [2- (Benzyloxy) -3-quinolinyl] -8 - {[tert-butyl (dimethyl) silyl] oxy} -5-octynoate In a bicol under argon, the compound obtained in Step E ( 1.28 g) is placed in solution in 8 ml of freshly distilled tetrahydrofuran and the reaction medium is brought to -78 ° C. A solution of 1.6 M n-butyllithium in tetrahydrofuran (2.25 ml) is then slowly added and the stirring is maintained 30 minutes after the end of the addition, during which time the temperature is brought to about -65 / -60 C. The hexamethylphosphoramide then the trimethyl orthobutyrate (1.5 eq) are then added rapidly . The temperature rose to room temperature extremely slowly and stirring continued for 12 hours. The reaction medium is hydrolysed by adding a saturated aqueous solution of ammonium chloride and the phases are separated. The aqueous phase is extracted with diethyl ether and the organic phases are then combined, washed with a saturated aqueous solution of ammonium chloride. After drying over magnesium sulphate, filtration on celite and evaporation of the solvents, the crude product of the reaction is purified by chromatography on silica gel, eluent AcOEt / pentane 10/90, to yield the title product in the form of a colorless oil. Stage G: Methyl 8- [2- (Benzyloxy) -3-quinolinyl] -8-hydroxy-5-octynoate In a bicol under argon, the compound obtained in Stage F (1.47 mmol) is dissolved in 8 ml of distilled tetrahydrofuran. The tetrabutylammonium chloride in 1M solution in tetrahydrofuran (2.05 mmol) is then added and the reaction mixture is stirred for 2 hours at 45 ° C. After evaporation of the solvent, the residue is taken up in ethyl acetate. and is filtered on celite. After evaporation of the filtrate and purification by chromatography on silica gel (eluent AcOEt / pentane: 10/90 then 40/61)), the title compound is obtained in the form of a white solid. Elemental Microanalysis: C% H% N% Calculated: 74.42 6.25 3.47 Found: 74.5 7.64 3.44 EXAMPLE 2: 8-Hydroxy-8- [2- (3-phenylpropoxy) Methyl 3-quinolinyl-5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 3-phenylpropanol. The title compound is obtained as a white solid. Elemental Microanalysis Calculated: 75.15 6, 77 3.25 Found: 74.88 6, 93 3.19 EXAMPLE 3: 8-Hydroxy-8- {2 - [(5-phenylpentyl) oxy Methyl 3-quinolinyl-5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 5-phenylpentan-1-ol. The title compound is obtained in the form of a pale yellow oil which crystallizes cold. Elemental Microanalysis: Calculated: 75.79 7.24 3.05 Found: 76, 03 7.24 3.28 EXAMPLE 4: 8-Hydroxy-8- [2 - ({5-4 Methyl (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 5- (4-trifloromethylphenyl) ) pentan-l-ol. The title compound is obtained in the form of a fine white powder. Elemental Microanalysis: C% H% N% Calculated: 68.30 6.11 2.65 Found: 68.55 6.33 2.86 EXAMPLE 5: 8-Hydroxy-8- (2 - {[5- (4 methyl (methoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 5- (4-methoxyphenyl) pentan-1-ol. . The title compound is obtained as a beige solid. Elemental Microanalysis: C% H% N% Calculated: 73.59 7.21 2.86 Found: 73.45 7.30 3.07 EXAMPLE 6: 8- (2 - {[5- (3,5-Dimethoxyphenyl) Methyl pentyl] oxy-3-quinolinyl-8-hydroxy-5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 5-20 (3,5-dimethoxyphenyl) pentan. -1-ol. The title compound is obtained as a white solid. Elemental Microanalysis: C% H% N% Calculated: 71, 65 7.18 2, 70 Found: 71.91 7.19 2, 80 EXAMPLE 7: 8-Hydroxy-8- (2- {[5- (3 Methyl 4,5-trimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate The procedure is as in Example 1, replacing in Step B benzyl alcohol with 5- (3, 4,5-trimethoxyphenyl) 1-pentanol. The title compound is obtained in the form of a very viscous pale yellow oil. Elemental Microanalysis: Calculated: 69.92 7.15 2, 55 Found: 69.54 7.13 2.52 EXAMPLE 8: 8- [2- (Benzyloxy) -3-quinolinyl] - 8-hydroxy-5-octynoic The compound obtained in Example 1 (155 mg) is placed in solution in a mixture of methanol (7.3 ml) / distilled water (0.8 ml). Lithium hydroxide monohydrate (564 mg) is added and stirring is maintained for 48 hours. Oxalic acid (173 mg) is then added and stirring is continued for 15 minutes. The solvents are evaporated and the residue is taken up in ethyl acetate and washed with a minimum of distilled water. After drying the organic phase with magnesium sulfate and evaporation of the solvent, the crude product is purified by chromatography on silica gel (eluent: AcOEt) to yield the title product as a beige solid. EXAMPLE 8a: sodium 8- [2- (Benzyloxy) -3-quinolinyll-8-hydroxy-5-octynoate The compound obtained in Example 8 is placed in distilled methanol and sodium hydroxide (12 mg) is added. After stirring until complete dissolution of the sodium hydroxide, the solvent is evaporated and the product is dried several days under vacuum. The title product is obtained in the form of a hygroscopic beige solid obtained and is then handled only in a glove box. EXAMPLE 9: 8-Hydroxy-8- [2- (3-phenylpropoxy) -3-quinolinyl] -5-octynoic acid The procedure is as in Example 8 starting with the compound obtained in Example 2. The compound of title is obtained in the form of a white solid. EXAMPLE 9a: sodium 8-hydroxy-8- [2- (3-phenylpropoxy) -3-quinolinyl] -5-octynoate The procedure is as in Example 8a from the compound obtained in Example 9 The title compound is obtained as a hygroscopic white solid. EXAMPLE 10 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoic acid The procedure is as in Example 8 starting from the compound obtained in Example 3. The title compound is obtained as a beige solid. EXAMPLE 10a: sodium 8-Hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate The procedure is as in Example 8a from the compound obtained in Example 10 The title compound is obtained as a hygroscopic white solid. EXAMPLE 11 8-Hydroxy-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoic acid The procedure is as in Example 8, starting from the compound obtained in Example 4. The title compound is obtained as a colorless oil. EXAMPLE IIa: sodium 8-hydroxy-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoate The procedure is as in Example 8a to from the compound obtained in Example 11. The title compound is obtained as a hygroscopic white solid. EXAMPLE 12: 8-Hydroxy-8- (2 - {[5- (4-methoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoic acid The procedure is as in Example 8 starting from the compound obtained in Example 5. The title compound is obtained as a white solid. EXAMPLE 12a: sodium 8-hydroxy-8- (2 - {[5- (4-methoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate The procedure is as in Example 8a from the compound obtained in Example 12. The title compound is obtained as a white, potentially hygroscopic solid. EXAMPLE 13 8- (2- {[5- (3,5-Dimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -8-10-hydroxy-5-octynoic acid The procedure is as in Example 8 starting with the compound obtained in Example 6. The title compound is obtained as a light yellow solid. EXAMPLE 13a: sodium 8- (2- {[5- (3,5-Dimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -8-hydroxy-5-octynoate The procedure is as in Example 8a from compound obtained in Example 13. The title compound is obtained in the form of a hygroscopic white solid. EXAMPLE 14 8-Hydroxy-8- (2 - {[5- (3,4,5-trimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoic acid The procedure is as in Example 8 starting from compound obtained in Example 7. The title compound is obtained as a colorless oil. EXAMPLE 14a: Sodium 8-Hydroxy-8- (2 - {[5- (3,4,5-trimethoxyphenyl) pentyl] oxy} -3-quinolinyl) -5-octynoate 2909379 The procedure is as in US Pat. Example 8a from the compound obtained in Example 14. The title compound is obtained as a potentially hygroscopic white solid. EXAMPLE 15 Methyl 8-Hydroxy-2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate Step A: 8 - {[Tert-butyl (dimethyl) Methyl silyl] oxy} -8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate The procedure is as in Steps A to F of Example 1, replacing in Step B benzyl alcohol with 5-phenylpentanol. The title compound is obtained in the form of a pale yellow oil which crystallizes cold. Step B: Methyl 8 - {[tert-butyl (dimethyl) silyl] oxy} -2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate A 1M lithium diisopropylamide solution (LDA) in tetrahydrofuran (1.2 eq) at -90 ° C is slowly cannulated to a solution of the compound obtained in Step A (500 mg) in distilled tetrahydrofuran (0.5 ml) at room temperature. C. The stirring is maintained 30 minutes after the end of the addition and the methyl iodide (45 l) is then added. The temperature is slowly raised to room temperature and stirring is maintained for 12 hours. The reaction medium is hydrolysed by adding distilled water and the phases are separated. The aqueous phase is extracted with ethyl acetate and the organic phases are then combined, washed with a saturated aqueous solution of sodium chloride. After drying over magnesium sulphate and evaporation of the solvents, the product of the reaction is directly engaged in the second methylation, carried out under the same conditions. The crude product is purified by chromatography on silica gel (eluent AcOEt / pentane 7/93) to yield the title product as a yellow oil. Stage C: 8-Hydroxy-2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-25 methyl octynoate In a bicol under argon, the compound obtained in Stage B (245 mg) is dissolved in distilled tetrahydrofuran (2.5 ml). The tetrabutylammonium chloride in 1M solution in tetrahydrofuran (1.4 eq) is then added and the reaction mixture is stirred for 2 hours at 45 ° C. After evaporation of the solvent, the residue is taken up in ethyl acetate and is filtered on celite. The crude product is then obtained after evaporation of the filtrate and is purified by chromatography on silica gel (eluent AcOEt / pentane 10/90 then 50/50) to yield the title product in the form of a clear yellow oil. EXAMPLE 16 Methyl 8-Hydroxy-2,2-dimethyl-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl-5-octynoate The procedure is as in US Pat. Example 15, replacing in Stage A 5-phenylpentan-1-ol with 5- (4-trifluoromethylphenyl) pentan-1-ol. The title product is obtained in the form of a colorless oil. EXAMPLE 17 8-Hydroxy-2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoic acid The procedure is as in Example 8 starting with the compound obtained in Example 15. The title compound is obtained as an orange-yellow oil. EXAMPLE 17a: sodium 8-hydroxy-2,2-dimethyl-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate The procedure is as in Example 8a from the compound obtained in Example 17. The title compound is obtained as a very viscous colorless oil. EXAMPLE 18: 8-Hydroxy-2,2-dimethyl-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoic acid 2909379 as in Example 8 from the compound obtained in Example 16. The title compound is obtained as a colorless oil. EXAMPLE 18a: Sodium 8-Hydroxy-2,2-dimethyl-8- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -5-octynoate The procedure is as in Example 8a from the compound obtained in Example 18. The title compound is obtained as a very viscous colorless oil. EXAMPLE 19: tert-Butyl [(4-Fluorobenzyl) (5-hydroxy-5- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -2-pentynyl) amino] acetate Step A: 3- ( 1- {[Tert-Butyl (dimethyl) silyl] oxy} -3-butynyl) -2 - [(5-phenylpentyl) oxy] quinoline The procedure is as in Steps A to E of Example 1, substituting at Step Benzyl alcohol with 5-phenylpentan-1-ol. The title compound is obtained as a colorless oil. Step B: 5 - {[Tert-butyl (dimethyl) silyl] oxy} -5- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -15 2 -pentyn-1-ol In a bicol under argon the compound obtained in Step A (877 mg) is dissolved in anhydrous tetrahydrofuran (4.5 ml) and the reaction medium is then brought to -78 ° C. The n-butyllithium in 1.6 M solution in tetrahydrofuran (1.85 ml) ) is then added dropwise and stirring is maintained for about 15 minutes. Paraformaldehyde (111 mg) is then added all at once and stirring is continued for 12 hours while allowing the bath to slowly rise to room temperature. The reaction medium is then hydrolysed by adding distilled water and the phases are separated. The sentence

  The aqueous solution is extracted with ethyl acetate and the organic phases are combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration and evaporation of the solvent, the crude reaction product is purified by chromatography on silica gel (eluent AcOEt / pentane 10/90) to give the title product as a colorless oil. Step C: 3- (5-Bromo-1 - {[tert-butyl (dimethyl) silyl] oxy} -3-pentynyl) -2- [(5-phenylpentyl) oxy] quinoline In a bicol under argon, the compound obtained in Stage B (482 mg) and triphenylphosphine (427 mg) are dissolved in anhydrous dimethylformamide (5 ml). Methyl tetrabromide (540 mg) is added and stirring is continued for 7 hours. The reaction medium is then hydrolysed by adding distilled water and after separation of the phases, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with distilled water and then with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulphate. After filtration and evaporation of the solvents, the crude reaction product is isolated and purified by chromatography on silica gel (eluent AcOEt / pentane 2/98) to yield the title product in the form of a colorless oil. Step D: [(5 - {[Tert-Butyl (dimethyl) silyl] oxy} -5- {2 - [(5-phenylpentyl) oxy] -3-15-quinolinyl} -2-pentynyl) (4-fluorobenzyl) amino ] butyl acetate In a bicol under argon with a condenser, tertbutyl (4-fluoro-benzylamino) acetate (236 mg) and potassium carbonate (158 mg) are suspended in anhydrous dimethylformamide ( 3 ml) and the compound obtained in Stage C (428 mg) in solution in anhydrous dimethylformamide is added. The suspension is stirred at 45 ° C. for 12 h and after cooling, the reaction medium is hydrolysed by addition of distilled water. After separation of the phases, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporation of the solvent, the crude is purified by chromatography on silica gel (eluent AcOEt / pentane 10/90) to give the title product as a colorless oil. Step E: [(4-Fluorobenzyl) (5-hydroxy-5- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -2-pentynyl) amino] tert-butyl acetate 2909379 bicol under argon, the compound obtained in Stage D (82 mg) is dissolved in distilled tetrahydrofuran (3 ml). The tetrabutylammonium chloride in 1M solution in tetrahydrofuran (1.4 eq) is then added and the reaction mixture is stirred for 2 hours at 45 ° C. After evaporation of the solvent, the residue is taken up in ethyl acetate and is filtered on 5 celite. The crude product is then obtained after evaporation of the filtrate and is purified by chromatography on silica gel (eluent AcOEt / pentane 20/80) to yield the title product in the form of a colorless oil. EXAMPLE 20: (Benzyl {5-hydroxy-5- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -2-pentynyl} amino) tert-butyl acetate 10 Stage A: 3- (1 - {[Tert-butyl (dimethyl) silyl] oxy} -3-butynyl) -2 - ({5- [4 (trifluoromethyl) phenyl] pentyl} oxy) quinoline The procedure is as in Stages A to E of Example 1, replacing in Step B benzyl alcohol with 5- (4-trifloromethylphenyl) pentan-1-ol. The compound of. title is obtained in the form of a colorless oil.

Step B: (Benzyl {5-hydroxy-5- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -2-pentynyl} amino) tert-butyl acetate proceeds as in Steps B to E of Example 19 from the compound obtained in Step A and replacing in Step D (4-fluoro-benzylamino) tert-butyl acetate with tert-butyl benzylaminoacetate. The title compound is obtained as a colorless oil. EXAMPLE 21: ((4-Fluorobenzyl) {5-hydroxy-5- [2 - ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) -3-quinolinyl] -2-pentynyl} amino) acetate serves Butyl Step A: 3- (1- {[Tert-Butyl (dimethyl) silyl] oxy} -3-butynyl) -2- ({5- [4- (trifluoromethyl) phenyl] pentyl} oxy) quinoline 2909379-28 - The procedure is as in Steps A to E of Example 1, replacing in Step B benzyl alcohol with 5- (4-trifloromethylphenyl) pentan-1-ol. The title compound is obtained as a colorless oil. Stage B: ((4-Fluorobenzyl) {5-hydroxy-5-12 - ({5- [4- (trifluoromethyl) phenyl] pentylloxy) -3-quinolino-2-pentynylamino) t-butyl acetate The procedure is as in Stages B to E of Example 19 from the compound obtained in Step A. The title compound is obtained as a colorless oil. PHARMACOLOGICAL STUDY Example A: Acute Toxicity Study Acute toxicity was assessed after oral administration to batches of 8 mice (26 ± 2 g). The animals were observed at regular intervals on the first day and daily for two weeks after treatment. The LD50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention. Example B: Efficacy in Genetic Models Mutations in laboratory animals as well as different dietary sensitivities allowed the development of animal models with non-insulin-dependent diabetes and hyperlipidemia associated with obesity and disease. insulin resistance. Mouse (ob / ob) genetic models (Diabetes, 1982, 31 (1), 1-6) and Zucker rats (fa / fa) have been developed by different laboratories to understand the pathophysiology of these diseases and to test the efficacy of new antidiabetic compounds (Diabetes, 1983, 32, 830-838).

Anti-diabetic and lipid-lowering effect in the ob / ob mouse The 10-week old ob / ob male mouse (Harlan) is used for the in vivo tests. These animals are kept under a 12-hour light-dark cycle at 25 ° C. This mouse has a basal hyperglycemia of 2 g / l. Animals are randomized to their blood glucose levels to form groups of eight. The orally tested compounds are dissolved in a mixture of hydroxyethyl cellulose (1% HEC) to be administered at 3 mg / kg in a volume of 10 ml / kg, once a day for four days. The control group 5 receives the solvents under the same conditions as the treated groups. The activity of the products is evaluated by a measurement of the blood glucose level 24 hours after the last administration and by the daily measurement of the body weight. The compounds of the invention show a very good ability to reduce blood glucose comparable to the effects obtained with Rosiglitazone, the reference substance.

In addition, no side effects were observed during the in vivo tests. Example C: Pharmaceutical composition 1000 tablets dosed with 5 mg of methyl 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate 5 g (Example 3) Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g Example D: Change in body weight Male C57 Black 6 ob / ob mice 8 to 12 weeks old were used. After quarantine for one week, they were weighed and randomized according to their weight, and 6 homogeneous groups (not significantly different starting weight) were formed.

After being weighed, the various combinations according to the invention between a compound of formula (I) and an antioxidant agent to be tested are injected intraperitoneally once a day for 7 days. The molecules are injected into a 5% DMSO / Solutol 15% / H 2 H 2 O solution heated to 65 ° C. to ensure good dissolution. The solution is further preheated before injection. The mice are weighed daily and the weight obtained after 7 days of treatment is recorded. The results obtained clearly show that the combination according to the invention between a compound of formula (I) and an antioxidant agent makes it possible to significantly reduce the weight of obese mice, that there is a synergy between the 2 components of the association, the loss (the weight observed being much greater with the combination than with each component administered alone) Example E: Pharmaceutical composition 100 tablets dosed with 30 mg of 8-hydroxy-8- {2 - [(5 methylphenylpentyl) oxy] -3-quinolinyl} -5-octynoate (Example 3) and 10 mg of coenzyme Qlo 8-Hydroxy-8 {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5 Methyl octynoate (Example 3) 3g Coenzyme Qio 1g Wheat starch 20g Corn starch 20g Lactose 30g Magnesium stearate 2g Silica 1g Hydroxypropylcellulose 2g 2909379 wherein: 5 - R1 represents a grouping linear or branched (C1-C6) alkyl substituted with one or more COOR3 or NR4R5 groups, in which: - R3 represents embedded image A hydrogen atom or a linear or branched (C1-C6) alkyl group, R4 represents a COOR'3 group or a linear or branched (C1-C6) alkyl group substituted with a COOR'3 group where R'3 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, R5 represents a linear or branched (C1-C6) alkyl group substituted with a phenyl group which is unsubstituted or substituted with 1 to 3 (C1-C6) alkyl groups; ) linear or branched, linear or branched (C1-C6) alkoxy, linear or branched polyhaloalkyl (C1-C6) or halogen atoms, R2 represents a phenyl group which is unsubstituted or substituted by one or more C1-C6 alkyl groups; ) linear or branched, linear or branched (C1-C6) alkoxy, linear or branched polyhaloalkyl (C1-C6) or halogen atoms, 20 n0, 1, 2, 3, 4, 5, 6, or 8, their enantiomers and diastereoisomers and their addition salts with an acid or a pharmaceutical base acceptable.

Claims (20)

  1. Compounds of formula (I): 2 (I) 10 2909379 - 32 -   2. Compounds of formula (I) according to claim 1 wherein R1 represents a - (CH2) 3 -COOR3 group, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.   3. Compounds of formula (I) according to claim 1 wherein R1 represents the - (CH2) 2-C (Me) 2 -COOR3 group, their geometrical, enantiomeric and diastereoisomeric isomers and their addition salts with an acid or to a pharmaceutically acceptable base.   4. Compounds of formula (I) according to claim 1 wherein R1 represents a -CH2-NR4R5 group, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.   5. Compound of formula (I) according to claim 1, which is methyl 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate, its enantiomers and diastereoisomers, and its addition salts with a pharmaceutically acceptable acid or base.   6. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II): CHO Cl which is converted into a compound of formula (III) is used as starting material. On which the compound of formula (IV) is condensed in the presence of sodium hydride: R 2 OH (IV) in which R 2 and n are as defined in formula (I), for to give the compound of formula (V): in which R2 and n are as defined above, which are placed in acidic medium to yield the compound of formula (VI): in which R2 and n are as defined above, on which the propargyl magnesium bromide is condensed to give the compound of formula (VII): ## STR2 ## in which R2 and n are as defined above, which are subjected to effect of tert-butyldimethylsilyl chloride to give the compound of formula (VIII): embedded image wherein R2 and n are as defined above, on which the compound of formula (IX): OMe OMe (IX) OMe 5 in which A represents a linear or branched (C1-C6) alkylene chain, is condensed to obtain the compound of formula (X): wherein R 1, R 2 and A are as defined above and Ra represents a linear or branched (C 1 -C 6) alkyl group, which is placed in the presence of tetrabutylammonium, to give the compound of formula (Fa), a particular case of the compounds of formula (I): ## STR2 ## in which n, Ra, R2 and A are as defined above, which are saponified to lead to compound of formula (Pb), in particular the compounds of formula (I): ## STR5 ## in which n, R 2 and A are as defined above, or - compound of formula (VIII) on which is condensed in medium basic of the compound of formula (XI): embedded image in which A is as defined above, to give the compound of formula (XII): ## STR2 ## wherein n, R 2 and A are as previously defined, which are subjected to the action of methyl tetrabromide to yield the compound of formula (XIII Embedded image in which n, R2 and A are as defined above, on which the compound of formula HNR'4R5 in which R5 is as defined in formula (I) is condensed, and R'4 represents a group R4 as defined in formula (I) in which R'3 represents a linear or branched (C1-C6) alkyl group, to yield the compound of formula (XIV): AiNR'4R5 (XIV In which n, R2, R'4, R5 and A are as defined above, which are placed in the presence of tetrabutylammonium chloride, to yield the compound of formula (Uc), a particular case of compounds of formula ( In which n, R2, R'4, R5 and A are as defined above, which are saponified for to give the compound of formula (Ud), in particular the compounds of formula (I): ## STR1 ## in which n, R 2, R 5 and A are as defined above and R "4 represents a group R 4 as defined in the formula (I) in which R '3 represents a hydrogen atom, the compounds (Ua) to (Ud) constitute the set of compounds of formula (I), which can be purified according to a conventional separation technique, that If desired, their addition salts are converted to a pharmaceutically acceptable acid or base and the isomers are optionally separated therefrom by a conventional separation technique.   7. Pharmaceutical compositions containing as active ingredient at least one compound of formula (I) according to any one of claims 1 to 5, or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable excipients.   8. Pharmaceutical compositions according to claim 7, useful for the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycaemia, dyslipidemia, and more particularly in the treatment of type II non-insulin dependent diabetes mellitus, resistance insulin, glucose intolerance, syndrome X-related disorders, coronary artery disease and other cardiovascular diseases, kidney disease, retinopathies, disorders related to endothelial cell activation, psoriasis ovarian polycystic syndrome, dementia, osteoporosis, intestinal inflammatory diseases, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma, but also in the treatment or prevention of type I diabetes, obesity, appetite regulation, anorexia, bulimia, anorexia nervosa, and cancerous conditions s including hormone-dependent cancers such as breast cancer and colon cancer, and as angiogenesis inhibitors.   9. Association containing a compound of formula (I) according to one of claims 1 to 5, and an antioxidant.   10. The combination of claim 9 wherein the compound of formula (I) is methyl 8-hydroxy-8- {2 - [(5-phenylpentyl) oxy] -3-quinolinyl} -5-octynoate, its enantiomers and diastereoisomers and that its addition salts with a pharmaceutically acceptable acid or base.   The combination of claim 9 wherein the antioxidant is coenzyme Qlo. 2909379 - 38 -   12. Pharmaceutical compositions containing as active ingredient an association according to any one of claims 9 to 11 alone or in combination with one or more pharmaceutically acceptable excipients.   13. Pharmaceutical compositions according to claim 12 useful for the manufacture of a medicament for the treatment and / or prevention of obesity.   Pharmaceutical compositions according to claim 12, useful for the manufacture of a medicament for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30.   15. Use of an association according to any one of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity.   16. Use of an association according to any one of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by a therapeutic treatment. 15   17. Use of an association according to any one of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by treatment of type I diabetes or. II.   18. Use of a combination according to any of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 25. 30.   19. Use of a combination according to any one of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 25. Induced by a therapeutic treatment. 2909379 - 39 -   20. Use of an association according to any one of claims 9 to 11 for obtaining pharmaceutical compositions for the treatment and / or prevention of weight overload characterized by a body weight index greater than 25 and less than 30. induced by treatment of type I or II diabetes.