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  • A61K31/47—Quinolines; Isoquinolines
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Definitions

• the present invention relates to novel heterocyclic oximes derivatives, process for their 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.
• 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.
• thiazolidinedione Rosiglitazone induces the expression of genes specific for lipid metabolism such as aP2 and adipsin as well as the expression of glucose transporters GLUT1 and GLUT4, suggesting that the effect of thiazolidinediones observed in vivo can be mediated via adipose tissue.
• This specific effect is obtained by the stimulation of nuclear transcription factors: "peroxisome proliferator-activated receptor gamma" (PPAR ⁇ ).
• PPAR ⁇ peroxisome proliferator-activated receptor gamma
• 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)
• A represents an alkylene chain (C 1 -C 6 ) in which a CH 2 group may be replaced by a heteroatom selected from oxygen or sulfur, or by a group NR 3 (where R a represents a hydrogen atom or an alkyl group (C 1 -C 6 ) linear or branched), or with a phenylene or naphthylene group,
• R 1 and R 2 identical or different, represent a hydrogen atom or an alkyl group (C 1 -C 6) linear or branched, alkenyl (C 2 -C 6) -straight or branched alkynyl (C 2 -C 6 ) linear or branched, aryl, aryl (C 1 -C 6 ) alkyl linear or branched, arylalkenyl (C 2 -C 6 ) linear or branched, arylalkynyl (C 2 -C 6 ) linear or branched, heteroaryl, heteroarylalkyl (C 1 -C 6 ) linear or branched, linear or branched heteroarylalkenyl (C 2 -C 6 ), linear or branched heteroarylalkynyl (C 2 -C 6 ), cycloalkyl (C 3 -C 8 ), cycloalkyl (C 3 -C 8 ) alkyl (dC 6 ) linear or
• R 3 and R 4 which may be identical or different, represent a hydrogen or halogen atom, or a group R, OR or NRR ', in which R and R', which may be identical or different, represent a hydrogen atom or a hydrogen atom; alkyl (C 1 -C 6) linear or branched, alkenyl (C 2 - C 6) linear or branched alkynyl (C 2 -C 6) linear or branched, aryl, aryl (C 1 -C 6) -straight or branched , arylalkenyl (C 2 -C 6) -straight or branched arylalkynyl (C 2 -C 6) linear or branched, heteroaryl, heteroaryl (C 1 -C 6) linear or branched, - AT -
• heteroarylalkenyl C 2 -C 6) -straight or branched hgruroarylalkynyle (C 2 -C 6) -straight or branched alkenyl, (C 3 -C 8) cycloalkyl (C 3 -C 8) alkyl (C 1 -C 6) linear or branched or polyhalo (C 1 -C 6 ) alkyl linear or branched, or R 3 and R 4 together with the carbon atoms that carry them, when carried by two adjacent carbon atoms, a ring comprising 5 or 6 linkages and optionally containing a heteroatom selected from oxygen, smile and nitrogen,
• X represents a hydrogen or halogen atom, or a linear or branched (C 1 -C 6 ) alkyl group
• B represents a linear or branched (C 1 -C 6 ) alkyl or linear or branched (C 2 -C 6 ) alkenyl group, these groups being substituted:
• ZZ * R 5 represents a group U - QR ' ⁇ - NRR'
• R 6 represents an aryl, arylalkyl group whose alkyl part contains from 1 to 6 carbon atoms and can be linear or branched, heteroaryl, heteroarylalkyl, the alkyl portion of which contains 1 to 6 carbon atoms and may be linear or branched, CN, tetrazole, OR, - NRR ', - N (R) -C - R'
• R 7 represents a CN, tetrazole group
• ZZ in which Z is as defined above, and R and R ', which may be identical or different, may take the same values as defined above
• n represents O, 1, 2, 3, 4, 5 or 6, and R 8 and R 9 , identical or different, represent a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group, it being understood that R and R can not simultaneously represent a hydrogen atom
• aryl means a phenyl, naphthyl or biphenyl group, these groups possibly being optionally partially hydrogenated,
• heteroaryl any aromatic mono- or bicyclic group containing 5 to 10 members, which may be optionally partially hydrogenated on one of the rings in the case of bicyclic heteroaryls, and containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur,
• the aryl and heteroaryl groups thus defined which may be optionally substituted with 1 to 3 groups, which may be identical or different, chosen from linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) polyhaloalkyl, and (C 1 -C 6 ) alkoxy; 1 -C 6) linear or branched, hydroxy, carboxy, alkoxycarbonyl (C 1 -C 6) linear or branched, acyloxy (C 1 -C 6) linear or branched, formyl, acyl (C 1 -C 6) -straight or branched , aroyl, NRbR O (wherein Rb and R 0 , which may be identical or different, represent a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl, aryl or heteroaryl), amido, nitro or cyano group, or halogen atoms,
• hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic and camphoric acids. , oxalic, etc.
• R 3 and R 4 are hydrogen.
• X advantageously represents a hydrogen atom or an alkyl group such as the methyl group, for example.
• A represents an alkylene chain of which a CH 2 group may be replaced by a heteroatom and more particularly by an oxygen atom. More particularly, the invention relates to the compounds of formula (I) for which A represents an ethyleneoxy group.
• the preferred R 2 groups are the hydrogen atom and the alkyl group, such as, for example, the methyl group.
• R 1 advantageously represents a phenyl group which is unsubstituted or substituted by one or more substituents chosen from groups such as alkyl, alkoxy, cyano, alkoxycarbonyl, carboxy or halogen atoms.
• Preferred B groups are alkyl or alkenyl groups, and more particularly alkyl groups, substituted by a group, COOR x / COOR x / COOR x / COOR x or NHCOR y OR y NR y R 2 NHCOOR y in which R x , R y and R 2 , which may be identical or different, represent: a hydrogen atom or an alkyl group such as, for example, the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl groups, a grouping polyhaloalkyl such as for example trifluoromethyl or trifluoroethyl groups, or a phenyl group which is unsubstituted or substituted with an alkyl, polyhaloalkyl, acyl or aroyl group.
• the invention relates to the compounds of formula (I) for which B represents an alkyl or alkenyl group substituted by a
• B also advantageously represents a group wherein n and R x are as defined above. Even more preferably, B represents a wherein R x and R 7 are as previously defined.
• the invention relates to the compounds of formula (I) for which A represents a CH - CH O chain.
• R 3 and R 4 simultaneously represent a hydrogen atom
• R 2 represents a hydrogen atom or an alkyl group
• R 1 represents an unsubstituted phenyl group
• R x and R 5 are as defined above.
• the present invention also relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (III) is used as starting material:
• An advantageous variant relates to the process for preparing the compounds of formula (I), characterized in that a compound of formula (III) is used as starting material:
• Another advantageous variant relates to the process for preparing the compounds of formula (I) for which A represents an alkyleneoxy chain, characterized in that the compound of formula (VII) used is the starting material:
• R 1 and X are as defined in formula (I)
• a ' represents an alkylene chain (C 1 -C 6 ) and HaI represents a halogen atom
• R 1 , X, B, R 3 and R 4 are as defined in formula (T), and A 'represents a (C 1 -C 6 ) alkylene chain,
• R 1 , R 2 , X, B, R 3 and R 4 are as defined in formula (I)
• a ' represents a (C 1 -C 6 ) alkylene chain, which can be purified according to a technique conventional separation, which is converted, if desired in its addition salts with a pharmaceutically acceptable acid or base and the isomers are optionally separated by a conventional separation technique.
• R 1 , R 3 , R 4 , X, A and B are as defined in the compounds of formula (I), useful as synthetic intermediates for the compounds of formula (I) and as agents hypoglycemic and lipid-lowering agents.
• the compounds of the present invention possess very valuable pharmacological properties.
• They can be used as inhibitors of aldose reductase, to improve cognitive functions in dementia and complications of diabetes, diseases intestinal inflammatory, 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 diabetics, hyperlipidemia , hypercholesterolemia, high blood pressure, heart failure, cardiovascular diseases including atherosclerosis.
• diseases including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, dyslipidemia in diabetics, hyperlipidemia , hypercholesterolemia, high blood pressure, heart failure, cardiovascular diseases including atherosclerosis.
• 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.
• these compounds can be used in 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.
• these compounds reduces total cholesterol, body weight, leptin resistance, plasma glucose, triglycerides, LDL, VLDL and 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.
• compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal, peroral administration. or transcutaneous, rectal, perlingual, ocular or respiratory and especially single or coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels and drinkable 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 possibly associated treatments and ranges between 0.1 mg and 1 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) or of formula (V) as defined above and an antioxidant agent for obtaining pharmaceutical compositions useful in the treatment and / or prevention of obesity and overweight 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 agent of the combination according to the invention is more preferably represented by quinone derivatives such as ubiquinone or coenzyme Q 10 , which acts as a scavenger of free radicals but which is also capable of regenerating vitamin E .
• 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 significant reduction. 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% of women.
• Patients with body weight index (EVIC weight (kg) / height 2 (m 2 )) greater than or equal to 30 are considered to be obese (J 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 deregulation of food intake, hormonal dysregulation or following administration of treatment: Type II anti-diabetic therapy with sulfonylureas results in weight gain in patients.
• Pinsulinobab is also a source of body weight gain in patients (In Progress in Obesity Research, 8 th International Congress on Obesity, 1999, 739-746; Annals 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 because they predispose to insulin resistance , dyslipidemia and the onset of macrovascular diseases (nephropathies, retinopathies, angiopathies).
• the combination according to the invention achieves a weight loss that even moderate significantly reduces all the risk factors associated with obesity (Int, J. Obes, 1997, 21, 55-9, MJ Obes, 1992). , 21, S5-9).
• the combination according to the invention thus finds its utility in the treatment and / or prevention of obesity and overweight characterized by a body index greater than 25.
• the invention thus relates to the use of the combination between a compound of formula (I) or of formula (V) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and overloads characterized by a body index greater than 25 and less than 30.
• 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 Type I or IL diabetes
• the invention thus relates to the use of the combination between a compound of formula (I) or of formula (V) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and weight overloads 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 IL diabetes
• the invention also relates to pharmaceutical compositions containing the combination of a compound of formula (I) or of formula (V) and an antioxidant as defined above in combination with one or more pharmaceutically acceptable excipients.
• compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, single or sugar-coated tablets, sublingual tablets, capsules, lozenges, suppositories, creams, ointments , dermal gels, etc.
• the invention relates to pharmaceutical compositions containing a compound of formula (I) or of formula (V) as defined above and an antioxidant agent such as coenzyme Q 10 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 from 0.1 mg to 1 g of each component of the combination per 24 hours in one or more doses.
• Step A N- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline
• the residual oils are solubilized in anhydrous toluene and cooled to 0 ° C.
• 98 ml of a solution of borohydride complexed with THF at 1M in THF are added slowly. After returning to ambient temperature, the solution is stirred for 2 hours and then hydrolysed with a saturated solution of sodium hydrogencarbonate. After stirring for 15 minutes, the mixture is extracted with ethyl acetate. The organic phase is washed with water and with a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The solvents are evaporated under reduced pressure and the crude reaction product is purified by chromatography on silica gel to yield the title compound in the form of a colorless oil.
• Step B N- (2-Bromoethyl) -4,4-dimethyl-6-benzovl-1,2,3,4-tetmhydroquinoline
• Step A 4- [1- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl] benzonitrile
• Step B 3- (4- ⁇ 2- [6- (4-Cyanobenzoyl) -4,4-dimethyl-3,4-dihydro (2H) -1-quinolinyl] -ethoxy ⁇ -phenyl) -2 (S) Ethyl ethoxy propanoate
• Step A Ethyl 4- [1- (1- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl] benzoate
• the 2.5 g of the compound obtained in Stage A of Preparation 1 are solubilized in 15 ml of anhydrous 1,2-DCE, then 4.73 g of terephthaloyl chloride and 2.56 ml of sodium tetrachloride are added successively. titanium drip. The resulting solution is refluxed for 18 hours. After returning to ambient temperature, 20 ml of absolute ethanol are added and the mixture is refluxed again for 1 hour. After returning to ambient temperature, the medium is hydrolyzed on ice water and extracted twice with dichloromethane. The combined organic phases are washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The title compound is obtained after chromatography on silica gel (EP / AcOEt: 95/5 then 8/2) in the form of a green oil.
• Step A 1- (2-Bromoethyl) -4,4,7-trimethyl-1,2,3,4-tetrahydroquinoline
• Example 8 400 mg of the compound obtained in Example 8 are solubilized in 10 ml of THF and the resulting solution is cooled to 0 ° C. before the portionwise addition of 2 ml of 36 ml of an aqueous solution of lithium hydroxide to 0.1N. After returning to ambient temperature, the medium is stirred for 24 hours and then the pH of the solution is brought to 2 by addition of an aqueous solution of 1N hydrochloric acid. After extraction with dichloromethane, the combined organic phases are dried over magnesium sulphate, filtered and filtered. solvents are evaporated under reduced pressure. The residue is purified by chromatography on silica gel (Heptane / AcOEt: 8/2 + 1% AcOH) to yield the title product in the form of a brown foam.
• Example 13 4 - [[1- (2- ⁇ 4 - [(2S) -2,3-Diethoxy-3-oxopropyl] phenoxy ⁇ ethyl) -4,4-dimethyl-1,2,3,4-tetrahydro Ethyl 6-quinolinyl] (methoxyimino) methyl] benzoate
• Example 14 4 - [[1- (2- ⁇ 4 - [(2S) -2-Carboxy-2-ethoxyethyl] phenoxy ⁇ ethyl) -4,4-dimethyl-1,2,3,4-tetrahydro- 6-quinolmyl] (methoxyimino) methyl] benzoic
• Example 3 The procedure is as in Example 3 starting from the compound obtained in Example 15. Yellow foam.
• Example 18 3- ⁇ 4- [2- (6- [cyclohexyl (hydroxyimino) methyl] -4,4-dimethyl-3,4-dihydro-l (2 J H) -quinolinyl) ethoxy] phenyl ⁇ 2 ( S) -éthoxypropano ⁇ que
• Acute toxicity was assessed after oral administration to batches of 8 mice (26 ⁇ 2 g). The animals were observed at regular intervals during the first day and daily for two weeks following treatment. The LD 50 , resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.
• the 10-week old ob / ob (Harlan) female mouse is used for in vivo testing. These animals are kept under a 12-hour light-dark cycle at 25 ° C. This mouse has a basal hyperglycemia of 2 g / l.
• the animals are randomized to their blood glucose levels to form groups of six.
• the compounds tested intraperitoneally are dissolved in a mixture of dimethylsulfoxide (10%) and solutol (15%) to be administered at 10 mg / kg in a volume of 2.5 ml / kg, twice daily for four days. Orally, the compounds are tested at 30 mg / kg administered in a volume of 2.5 ml / kg of 1% HEC, twice daily for four days.
• the control groups receive 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, insulinemia and triglyceridemia comparable to the effects obtained with the reference substance Rosiglitazone, but with a change in non-significant body weight. In addition, no side effects were observed during the in vivo tests.
• 3- ⁇ 4- [2- (6- (cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl ⁇ -2- ethoxy propanoic shows after treatment at 3 mg / kg for 4 days a reduction of 57% of triglyceridemia, 32% of glycemia and 56% of insulinemia.
• mice 8 to 12 weeks old 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 different combinations to be tested are injected intraperitoneally once a day for 7 days. The molecules are injected into a 5% DMSO / 15% Solutol / H 2 O 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:
• Example F Pharmaceutical Composition

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