EP1844015A2

EP1844015A2 - Novel heterocyclic oxime derivatives, method for preparing same and pharmaceutical compositions containing same

Info

Publication number: EP1844015A2
Application number: EP06709171A
Authority: EP
Inventors: Cécile PARMENON; Marie-Claude Viaud-Massuard; Jérôme GUILLARD; Catherine Dacquet; Alain Ktorza; Daniel-Henri Caignard
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2005-01-27
Filing date: 2006-01-26
Publication date: 2007-10-17
Also published as: FR2881137A1; MX2007008995A; JP2008528560A; BRPI0607087A2; US20090124656A1; WO2006079719A2; AR052891A1; MA29257B1; CN101133028A; CA2596156A1; KR20070103447A; FR2881137B1; NO20074347L; ZA200706249B; AU2006208812A1; WO2006079719A3; EA200701477A1

Abstract

The invention concerns compounds of formula (I), wherein: R1, R2, R3, R4 and X are such as defined in the description; A represents an alkylene chain such as defined in the description; B represents an alkyl or alkenyl group substituted by a group (a) or R7, or B represents a group (b) or R7. The invention is applicable to preparation of medicines.

Description

NOVEL HETEROCYCLIC OXIMIC DERIVATIVES, THEIR PREPARATION PROCESS AND

PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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.

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. These compounds also reduce insulin and lipid levels in these same animal models and in vitro induce differentiation of cell lines from preadipocytes to adipocytes (Hiragun et al., J.). Physiol., 1988, 134, 124-130, RF 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 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 ψ). These derivatives are likely to restore insulin sensitivity in tissues peripherals such as adipose tissue or skeletal muscles (JE 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 No. 2470, 1999, Sept. 8 ^th , 25).

Many hypoglycemic agents have significant side effects

(hepatic, cardiac, hematopoietic) that limit their long-term use in the treatment of non-insulin-dependent diabetes type II.

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 (Diabetes Care, 1995,

18 (Supplement 1), 86/8/93). The association of hyperglycemia with rhyperlipidemia promotes the risk of cardiovascular disease in diabetics. Hyperglycemia, hyperlipidemia and obesity have become pathologies of the modern world marked by a large amount of food intake and a 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)

in which :

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 branched or polyhaloalkyl (C ₁ -C ₆ ) linear or branched,

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 hétéroarylalkynyle (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:

* by a group of formula (II):

in which :

ZZ * R ⁵ represents a group U - QR '^ - NRR'

Z

-N (R) -C - R 'or N (R) -C - OR' in which Z represents an oxygen or sulfur atom and R and R ', which are identical or different, are as defined previously,

* and 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'

Z

-N (R) -C-OR ¹ or -O- C- R, ZO in which Z is as defined above and R and R ', which may be identical or different, may take the same values as previously defined,

4 or by a group R ⁷ where R ⁷ represents a CN, tetrazole group,

R ⁸ R ^

- N (R) CR ', - N (R) C - OR' or C- (CH ₂ ) - C- COOR

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,

or B represents a group of formula (II) or a group R ⁷ as defined above,

Being heard that :

the oxime R ¹ -C (= N-OR ² ) can be of Z or E configuration,

aryl means a phenyl, naphthyl or biphenyl group, these groups possibly being optionally partially hydrogenated,

with heteroaryl is meant 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,

their enantiomers and diastereoisomers as well as their addition salts 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. , oxalic, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

Preferably, the group R ¹ -C (= N-OR ² ) - is in position c

The preferred group for R ³ and R ⁴ is hydrogen.

X advantageously represents a hydrogen atom or an alkyl group such as the methyl group, for example.

Preferably, 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.

More particularly, the invention relates to the compounds of formula (I) for which B represents an alkyl or alkenyl group substituted by a

COOR _x group where R _x and R are as previously defined.

OR _y

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.

Very advantageously, 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,

B represents a group in which R _x and R ₅ , are as defined above.

Even more particularly, the invention relates to the compounds of formula (I) which are:

2-Ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} ethyl propanoate,

2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} ethyl propanoate,

2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid,

(25) -2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (271) -quinolinyl) ethyl ethoxy] phenyl} propanoate,

* (2_S) -2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) - quinolinyl) ethoxy] phenyl} propanoic acid, * 3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2- [ Ethyl 4- (trifluoromethyl) phenoxy] propanoate,

2- (acetyloxy) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-diniethyl-3,4-dihydro-1 (2H) -quinolinyl) étlioxy] phenyl} propanoic acid,

* 3- {4- [2- (6 - [(methoxyimino) (ρhényl) methyl] -4,4-dimethyl-3 ₅ 4-dihydro-l (2H) - quinolinyl) ethoxy] phenyl} -2- ( Ethyl 2,2,2-trifluoroethoxy) propanoate,

* 3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2 - (2,2,2-trifluoroethoxy) propanoic

2- (2-benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoate,

2- (2-benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) - quinolinyl) ethoxy] phenyl} propanoic acid,

(25) -3- {4- [2- (6 - [(4-cyanophenyl) (methoxyimino) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] ethyl phenyl-2-ethoxypropanoate,

4 - [[1- (2- {4 - [(25) -2,3-diethoxy-3-oxopropyl] phenoxy} ethyl) -4,4-dimethyl-1,2,3,4-tetrahydro- Ethyl 6-quinolinyl] (methoxyimino) methyl] benzoate,

* 4 - [[1- (2- {4 - [(2S) -2-carboxy-2-ethoxyethyl] phenoxy} ethyl) -4,4-dimethyl-1,2,3,4-tetrahydro- 6-quinolinyl] (methoxyimino) methyl] benzoic acid,

2-Ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4,7-trimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] ethylphenylpropanoate,

2-ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4,7-trimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, * 3- {4- [2- (6- [Cyclohexyl (hydroxyimino) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} 2 (jS) -ethoxypropanoate ethyl,

* 3- {4- [2- (6- [cyclohexyl (hydroxyimino) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} 2 () S ) -éthoxypropanoïque.

The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid 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 (III) is used as starting material:

in which R ¹ and X are as defined in formula (I),

on which a compound of formula (IV) is condensed in basic medium:

in which A, B, R ³ and R ⁴ are as defined in formula (I) and Ηal represents a halogen atom, to yield the compound of formula (V):

in which R ¹ , R ³ , R ⁴ , X, A and B are as defined in formula (I), which is subjected to the action of a compound of formula R ² O-NH ₂ in which R ² is as defined in formula (I) to yield the compound of formula (I):

which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique.

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:

(TS)

in which R ¹ and X are as defined in formula (I),

on which a compound of formula R 0 -NH ₂ in which R is as defined in formula (I) is condensed to yield the compound of formula (VI):

in which R ¹ , R ² and X are as defined in formula (I), on which a compound of formula (IV) is condensed in basic medium

in which A, B, R ³ and R ⁴ are as defined in formula (I) and Hal represents a halogen atom, to yield the compound of formula (I):

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:

in which 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,

on which a compound of formula (VIII) is condensed in basic medium:

in which B, R ³ and R ⁴ are as defined in formula (I), to yield the compound of formula (IX):

in which 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,

on which a compound of formula R ² O -NH ₂ in which R ² is as defined in formula (I) is condensed to yield the compound of formula (I / a), in particular the compounds of formula (I):

in which R ¹ , R ² , X, B, R ³ and R ⁴ are as defined in formula (I), and 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.

The compounds of formula (III) or (VII) are commercially available or readily accessible to those skilled in the art by conventional chemistry reactions, or described in the literature. The invention also relates to the compounds of formula (V)

in which 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.

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 insufficiency ), kidney diseases (including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, 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, 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.

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 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.

The use of 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.

They also exhibit activity in cancerous diseases 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, 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 preferred combinations according to the invention are:

(2S) -2-Ethoxy-3- {4- [2- (6 - [(methoxyiminino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) - quinolinyl) ethoxy] phenyl} propanoic acid and coenzyme Q ₁₀ ,

3- {4- [2- (6- (cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2-ethoxypropanoic acid and coenzyme Q ₁₀ . 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 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. Also in type I diabetes (insulin-dependent), Pinsulinothérapie 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).

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 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.

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 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.

Among the pharmaceutical 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.

In particular, 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.

The following preparations and examples illustrate the invention and in no way limit it.

Preparation 1: 3- {4- [2- (6-Benzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-1-quinolinyl) ethoxy] -phenyl} -2-ethoxy-propanoate ethyl

Step A: N- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline

Under Argon atmosphere, 5.1 ml of bromoacetyl bromide are added dropwise to a solution of 6.3 g of 4,4-dimethyl-1,2,3,4-tetrahydroquinoline in anhydrous THF at 0 °. vs. 8.2 ml of triethylamine are then added dropwise resulting in the formation of a precipitate. The mixture is stirred vigorously for one hour before being hydrolyzed and extracted with ethyl acetate. The organic phase is washed successively with water and with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Under Argon atmosphere, 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.

MS (IE): m / z = 267 (M ⁷⁹ Br); 268 (M Br ⁸⁰ ); 174. Step B: N- (2-Bromoethyl) -4,4-dimethyl-6-benzovl-1,2,3,4-tetmhydroquinoline

Under an inert atmosphere, 1.8 ml of titanium tetrachloride are added dropwise to a solution of 1.5 g of the compound obtained in Stage A and 1.9 ml of benzoyl chloride in 7 ml of anhydrous 1,2-DCE. . The medium is refluxed for 18 hours. 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 product is obtained after purification by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) in the form of a yellow oil.

MS (IS): m / z = 371 (M + H ⁷⁹ Br); 372 (M + H ⁸⁰ Br).

Stage C: 3- {4- [2- (6-Benzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-1-quinolinyl) ethoxy] -phenyl} -2-ethoxy-propanoate ethyl

Under an inert atmosphere, 2.15 g of potassium carbonate is added in one portion to a solution of 371 mg of ethyl 2-ethoxy-3- (4-hydroxy-phenyl) -propanoate in anhydrous DMF. The suspension is stirred for 30 minutes and then 870 mg of the compound obtained in stage B in solution in anhydrous DMF are added. The mixture is heated at 80 ^° C. for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) to yield the title product in the form of a yellow oil.

MS (IE): m / z = 529 (M); 307; 173.

Preparation 2: 3- {4- [2- (6-Benzoyl-4,4-dimethyl-1,2,3,4-tetrahydro-1-quinolinyl) ethoxy] -phenyl} -2 (S) -ethoxy- ethyl propanoate

Under an inert atmosphere, 5.69 g of potassium carbonate are added in one portion to a solution of 981 mg of ethyl 2 ( ₁ S) -ethoxy-3- (4-hydroxy-phenyl) -propanoate in the Anhydrous DMF. The suspension is stirred for 30 minutes and then 2.3 g of the compound obtained in Stage B of Preparation 1 dissolved in anhydrous DMF are added. The mixture is heated at 80 ^° C. for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) to yield the title product in the form of a yellow oil.

MS (IE): m / z = 529 (M); 307; 173.

Preparation 3; 3- {4- [2- (6-Benzoyl-4,4-dimethyl-3,4-dihydro (2 H) -1-quinolinyl) ethoxy] -phenyl} -2- (4-trifluoromethyl-phenoxy) -propanoate ethyl

Under an inert atmosphere, 2.19 g of potassium carbonate are added in one portion to a solution of 560 mg of ethyl 3- (4-hydroxy-phenyl) -2- (4-trifluoromethylphenoxy) propanoate in DMF. anhydrous. The suspension is stirred for 30 minutes and then 883 mg of the compound obtained in Stage B of Preparation 1 in solution in anhydrous DMF are added. The mixture is heated at 80 ° C for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) to yield the title product in the form of a yellow oil.

MS (IE): m / z = 645 (M); 278; 105.

Preparation 4: 2 (S) acetoxy-3- {4- [2- (6-benzoyl-4,4-dimethyl-3,4-dihydro (2 _J H) - l ~ quinolinyl) -ethoxy] -phenyl } propanoic

Under an inert atmosphere, 2.62 g of potassium carbonate are added in one portion to a solution of 425 mg of 2 (S) -acetoxy-3- (4-hydroxyphenyl) propanoic acid in DMF. Anhydrous. The suspension is stirred for 30 minutes and then 1.06 g of the compound obtained in Stage B of Preparation 1 in solution in anhydrous DMF are added. The mixture is heated at 80 ° C for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction crude is then purified by chromatography on silica gel (EP / AcOEt: 8/2) to yield the title product in the form of a yellow foam.

Melting point: 60-62 ^° C.

Preparation 5: 3- {4- [2- (6-Benzoyl-4,4-dimethyl-3,4-dihydro (2 H) -1-quinolinyl) -ethoxy] -phenyl} -2- (2.2.2 -trifluoroethoxy) ~ ethyl propanoate

Under an inert atmosphere, 1.79 g of potassium carbonate are added in one portion to a solution of 380 mg of ethyl 3- (4-hydroxy-phenyl) -2- (2,2,2-trifluoroethoxy) -propanoate in anhydrous DMF. The suspension is stirred for 30 minutes and then 725 mg of the compound obtained in Step B of Preparation 1 in solution in anhydrous DMF are added. The mixture is heated at 80 ° C for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) to yield the title product in the form of a yellow foam.

Melting point: 56-58 ° C.

Preparation 6; 3- {4- [2- (6-Benzoyl-4,4-dimethyl-3,4-dihydro (2 H _J) -l-quinolinyl) - ethoxy] -phenyl} ~ -2- (2-benzoyl-phényIamino) ethyl propanoate

Under an inert atmosphere, 1.23 g of potassium carbonate are added in one portion to a solution of 697 mg of ethyl 2- (2-benzoyl-phenylamino) -3- (4-hydroxy-p-phenyl) -propanoate in the solution. Anhydrous DMF. The suspension is stirred for 30 minutes and then 1 g of compound obtained in Stage B of Preparation 1 in solution in anhydrous DMF are added. The mixture is heated at 80 ° C for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 95/5 then 75/25) to yield the title product in the form of a yellow foam.

Melting point: 75-77 ° C.

Preparation 7: 3- (4- {2- [6- (4-Cyanobenzoyl) -4,4-dimethyl-3,4-dihydro (2H) -1-quinolinyl] -ethoxy} -phenyl) -2 (S) Ethyl ethoxy propanoate

Step A: 4- [1- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl] benzonitrile

Under an inert atmosphere, 0.74 ml of titanium tetrachloride is added dropwise to a solution of 900 mg of the compound obtained in Stage A of Preparation 1 and 1.11 g of 4-cyanobenzoyl chloride in 5 ml of 1, 2-DCE anhydrous. The medium is refluxed for 18 hours. 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 product is obtained after purification by chromatography on silica gel (EP / AcOEt: 9/1 then 8/2) in the form of a brown oil.

MS (IE): m / z = 397 (M); 303.

Step B: 3- (4- {2- [6- (4-Cyanobenzoyl) -4,4-dimethyl-3,4-dihydro (2H) -1-quinolinyl] -ethoxy} -phenyl) -2 (S) Ethyl ethoxy propanoate

Under an inert atmosphere, 2.15 g of potassium carbonate is added in one portion to a solution of 371 mg of ethyl 2 ( ₁ S) -ethoxy-3- (4-hydroxy-phenyl) -propanoate in the Anhydrous DMF. The suspension is stirred for 30 minutes and then 870 mg of the compound obtained in Step A dissolved in anhydrous DMF are added. The mixture is heated at 80 ^° C. for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 95/5 then 75/25) to yield the title product in the form of a yellow oil.

MS (IE): m / z = 554 (M); 303; 130.

Preparation 8: 4- (1- {2- [4- (2 (S) -Ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -4,4-dimethyl-1,2,3,4-tetrahydroquinoline Ethyl 6-carbonyl) benzoate

Step A: Ethyl 4- [1- (1- (2-Bromoethyl) -4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl] benzoate

Under Argon, 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.

MS (IE): m / z = 443 (M ⁷⁹ Br); 444 (M Br ⁸⁰ ); 350; 177; 149. Srade B: 4- (1- {2- [4- (2 (S) -Ethoxy-2-ethoxycarbonyl-ethyl) -phenoxy] -ethyl} -4,4-dimethyl-1,2,3,4-tetrahydroquinoline Ethyl 6-carbonyl) benzoate

Under an inert atmosphere, 5.24 g of potassium carbonate is added in one portion to a solution of 902 mg of ethyl 2 (E) -ethoxy-3- (4-hydroxyphenyl) -propanoate in anhydrous DMF. The suspension is stirred for 30 minutes and then 2.5 g of the compound obtained in Step A dissolved in anhydrous DMF are added. The mixture is heated at 80 ° C for 24 to 48 hours. After evaporation of a maximum of DMF, the residue is taken up in ethyl acetate and hydrolyzed. The organic phase is washed with a 10% aqueous sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on silica gel (EP / AcOEt: 95/5) to yield the title product in the form of a green oil.

MS (IE): m / z = 350; 177; 149; 107; 43.

Preparation 9: 3- {4- [2- (6-Benzoyl-4,4,7-trimethyl-3,4-dihydro-1 (1H-quinolinyl) ethoxy] phenyl} -2 (S) -ethoxypropanoate 'ethyl

Step A: 1- (2-Bromoethyl) -4,4,7-trimethyl-1,2,3,4-tetrahydroquinoline

The procedure is as for Stage A of Preparation 1, replacing 4,4-dimethyl-1,2,3,4-tetrahydroquinoline with 4,4,7-trimethyl-1,2,3,4-tetrahydroquinoline. Colorless oil.

MS (IE): m / z = 160; 281 (M ⁷⁹ Br); 283 (M ⁸¹ Br).

Stage B: N- (2-Bromoethyl) -4,4,7-trimethyl-6-benzoyl-1,2,3,4-tetrahydroquinoline

The procedure is as in Stage B of Preparation 1 starting from the compound obtained in Stage A. Orange oil.

MS (IE): m / z = 44; 77; 105; 292; 341; 385 (M ⁷⁹ Br); 387 (M ⁸¹ Br). Stage C: 3- {4- [2- (6-Benzoyl-4,4,7,7-trimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2 (S) -ethoxypropanoate ethyl

The procedure is as in Preparation 2 starting from the compound obtained in Stage B. Yellow oil.

MS (IE): m / z = 544 (M + H); 561 (M-HMH ₄ ); 566 (M + Na).

Preparation 10: 3- {4- [2- (6-Benzoyl-4,4,7-trimethyl-3,4-dihydro-1 (2 fl) -quinolinyl) ethoxy] phenyl} -2 (S) -ethoxypropanoic acid

The procedure is as in Preparation 2 starting from the compound obtained in Preparation 9 and replacing the ethyl 2 (iS) -ethoxy-3- (4-hydroxyphenyl) -projanoate with 2 (S) -ethoxy acid. 3- (4-hydroxyphenyl) propanoic acid.

Preparation 11; Ethyl 3- {4-r 2 - (6- (C 1-6 cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2-ethoxypropanoate

The procedure is as in Preparation 1, replacing in Step B benzoyl chloride with cyclohexylcarbonyl chloride.

MS (IE): m / z = 536 (M + H).

Preparation 12: 3- {4- [2- (6- (Cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2-ethoxypropanoic acid

The procedure is as in Preparation 2 starting from the compound obtained in Preparation 11. MS (IE): m / z = 508 (M + H); 530 (M + Na). Example 1; 2-Ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolmyl) ethoxy] phenyl} propanoate 'ethyl

Under an inert atmosphere, 350 mg of the compound obtained in Preparation 1 are solubilized in 5 ml of pyridine and then 460 mg of hydroxylamine hydrochloride are added in one portion. The solution is refluxed for 3 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a yellow foam.

Melting point: 46-48 ° C

Elemental microanalysis:

C H N

% theoretical 72, 77 7.40 5.14

% experimental 72.69 7.29 5.11

Example 2: 2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinoimyl) ethoxy ] ethyl phenyl} propanoate

Under an inert atmosphere, 550 mg of the compound obtained in Preparation 1 are solubilized in 10 ml of pyridine and then 868 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 2 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a yellow-orange oil. Elemental microanalysis:

C H N

% theoretical 73.09 7.58 5.01

% experimental 73,19 7,80 5,14

Example 3: 2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2 fl) -quinolinyl) ethoxy] phenyl} propanoic acid

200 mg of the compound obtained in Example 2 are solubilized in 5 ml of THF and the resulting solution is cooled to 0 ° C. before the portionwise addition of 2 ml of 20 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 sulfate, filtered and the 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.

Melting point: 62-64 ° C

Elemental microanalysis:

C H N

% theoretical 72.43 7.22 5.28

% experimental 72.17 7.07 5.21

Example 4: (2S) -2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2] -quinolinyl ) ethoxy] phenyl} propanoate ethyl

Under an inert atmosphere, 350 mg of the compound obtained in Preparation 2 are solubilized in 8 ml of pyridine and then 552 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 2 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a yellow-orange oil.

MS (IS): m / z = 559 (M + H); 581 (M + Na)

Elemental microanalysis:

C H N

% theoretical 73.09 7.58 5.01

% experimental 72.98 7.66 5.03

Example 5: (2S) -2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2] -3 -acid quinolinyl) ethoxy] phenyl} propanoic acid

270 mg of the compound obtained in Example 4 are solubilized in 7 ml of THF and the resulting solution is cooled to 0 ° C. before the portionwise addition of 2 ml of 26 ml of an aqueous lithium hydroxide solution 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 sulfate, filtered and the 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.

Melting point: 62-64 ° C

Elemental microanalvse:

C H N

% theoretical 72.43 7.22 5.28

% experimental 72.59 7.21 5.17 Example 6: 3- {4- [2- (6 - [(Methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2 H) -quolinolinyl) ethoxy] phenyl} -2- Ethyl [4 (trifluoromethyl) phenoxy] propanoate

Under an inert atmosphere, 300 mg of the compound obtained in Preparation 3 are solubilized in 7 ml of pyridine and then 388 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 3 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction crude is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a white foam.

Melting point: 44-46 ° C

Elemental microanalysis:

C H N

% theoretical 69.42 6.12 4.15

% experimental 69.81 6.23 4.32

Example 7: 2- (Acetyloxy) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid

Under an inert atmosphere, 530 mg of the compound obtained in Preparation 4 are solubilized in 8 ml of pyridine and then 858 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 5 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction crude is purified by chromatography on silica gel (heptane / AcOEt: 8/2) to yield the title product in the form of a pale yellow foam. Melting point: 64-66 ° C

Elemental microanalysis:

C H N

% Theoretical 70.57 6.66 5.14

% experimental 70.24 6.80 5.14

Example 8; 3- {4- [2- (6 - [(Methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2- (2, Ethyl 2,2-trifluoroethoxy) propanoate

Under an inert atmosphere, 500 mg of the compound obtained in Preparation 5 are solubilized in 10 ml of pyridine and then 858 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 2 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a yellow foam.

Melting point: 58-60 ° C.

Example 9: 3- {4- [2- (6 - [(Methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quolinyl) ethoxy] phenyl} -2 - (2,2,2-trifluoroethoxy) propanoic

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.

Melting point: 62-64 ° C

Elemental microanalvse:

C H N

% theoretical 65.74 6.03 3.79

% experimental 65.99 6.33 4.74

Example 10 2- (2-Benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) - ethyl quinolinyl) ethoxy] phenyl} propanoate

Under an inert atmosphere, 540 mg of the compound obtained in Preparation 6 are solubilized in 10 ml of pyridine and then 663 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 2 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 9/1) to yield the title product in the form of a yellow foam.

Melting point: 78-80 ° C.

Example 11: 2- (2-benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] - 4,4-dimethyl-3,4-dihydro-l (2 _J H ) -quinolinyl) ethoxy] pliényl} propanoic acid

198 mg of the compound obtained in Example 10 are solubilized in 3 ml of THF and the resulting solution is cooled to 0 ^° C. before the addition in portions of 2 ml of 16 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 extractions with dichloromethane, the combined organic phases are dried over magnesium sulphate, filtered and the 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 an orange foam.

Melting point: 100-102 ° C

Elemental microanalysis:

C H N

% Theoretical 75, 75 6.36 6.16

% experimental 75.51 6.59 5.92

Example 12; (25) -344- [2- (6 - [(4-Cyanophenyl) (methoxyimino) methyl] -4,4-dimethyl-3,4-dihydro-1 (2 H) -quinolinyl) ethoxy] phenyl} -2- ethyl ethoxypropanoate

Under an inert atmosphere, 175 mg of the compound obtained in Preparation 7 are solubilized in 6 ml of pyridine and then 263 mg of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 5 hours. After returning to ambient temperature, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The reaction crude is purified by chromatography on silica gel (heptane / AcOEt 95/5) to yield the title product in the form of a yellow oil.

MS (IS): m / z = 584 (M + H); 601 (M + NH ₄ ); 606 (M + Na).

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

Under an inert atmosphere, 1.15 g of the compound obtained in Preparation 8 are solubilized in 15 ml of pyridine and then 1.60 g of methoxylamine hydrochloride are added in one portion. The solution is refluxed for 6 hours. After return to temperature ambient, the solvents are evaporated under reduced pressure. The residue is taken up in ethyl acetate and washed with water and then with a saturated solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude reaction product is purified by chromatography on silica gel (heptane / AcOEt: 85/15) to yield the title product in the form of an orange-yellow oil.

MS (IS): m / z = 631 (M + H).

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

600 mg of the compound obtained in Example 13 are solubilized in 6 ml of THF and the resulting solution is cooled to 0 ^° C. before the addition in portions of 2 ml of 95 ml of an aqueous lithium hydroxide solution 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 sulfate, filtered and the solvents are evaporated under reduced pressure. The residue is purified by chromatography on silica gel (DCM / MeOH: 99/1) to yield the title product in the form of a pink foam.

Melting point: 83-85 ° C.

Example 15: 2-Ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4,7-trimethyl-3,4-dihydro-1 (2 H) -quinolmyl) ethoxy ] ethyl phenyl} propanoate

The procedure is as in Example 1 starting from the compound obtained in Preparation 9. Yellow oil.

MS (IS): m / z = 559 (M + H); 581 (M + Na). Example 16: 2-Ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4,7-trimethyl-5H-dihydro-1CZZ] -quinolinyl-ethoxylphenylpropanoic acid

The procedure is as in Example 3 starting from the compound obtained in Example 15. Yellow foam.

Melting point: 84-86 ° C.

Example 17: 3- {4- [2- (6- [Cyclohexyl (hy droxyimino) methyl] -4,4-dimethyl-3,4-dihydro-1 (2 fl) -quinolinyl) ethoxy] phenyl} 2 (S) Ethyl ethoxypropanoate

The procedure is as in Example 1 starting from the compound obtained in Preparation 11.

Example 18: 3- {4- [2- (6- [cyclohexyl (hydroxyimino) methyl] -4,4-dimethyl-3,4-dihydro-l (2 _J H) -quinolinyl) ethoxy] phenyl} 2 ( S) -éthoxypropanoïque

The procedure is as in Example 3 starting from the compound obtained in Example 17.

PHARMACGLOGICAL 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 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.

Example B: Effectiveness in Genetic Models

Mutations in laboratory animals and different sensitivities to diets have led to the development of animal models with non-insulin-dependent diabetes and hyperlipidemia associated with obesity and 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).

Antidiabetic and hypolipemic effect in ob / ob mice

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. By way of example, 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.

Example C: Pharmaceutical Composition

1000 tablets dosed with 5 mg of (2 "S) -2-ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-acid dihydro-l (2H) -quinolinyl) ethoxy] phenyl} propanoic acid

(Example 5) 5 g

Wheat starch 20 g

Corn starch 20 g

Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropyl cellulose 2 g Example D: Pharmaceutical Composition

1000 tablets containing 5 mg of 3- {4- [2- (6- (cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2 -ethoxypropanoic

(Preparation 12) 5 g

Wheat starch 20 g

Corn starch 20 g

Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropylcellulose 2 g

Example E: Variation 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 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:

that the combination according to the invention between a compound of formula (I) or of formula (V) 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 combination, the weight loss observed being much greater with the combination than with each component administered alone. Example F: Pharmaceutical Composition

100 tablets containing 30 mg of (25) -2-ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro 1- (2H) -quinolinyl) ethyloxy] phenyl} propanoic acid and 10 mg of coenzyme Q ₁₀

(2 <S) -2-Ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-

3,4-Dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid (Example 5) 3 g

Coenzyme Q ₁₀ 1 g

Wheat starch 20 g

Corn starch 20 g

Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropyl cellulose 2 g

Example G: Pharmaceutical Composition

100 tablets dosed with 30 mg of 3- {4- [2- (6- (Cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2 -ethoxypropanoic

3- {4- [2- (6- (Cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinylethoxy] phenyl} -2-ethoxypropanoic acid (Preparation 12) 3 g

Coenzyme Q ₁₀ 1 g

Wheat starch 20 g

Corn starch 20 g

Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropyl cellulose 2 g

Claims

1. Compounds of formula (I)

in which :

A represents a (C ₁ -C ₆ ) alkylene chain of which a CH ₂ group may be replaced by a heteroatom selected from oxygen or sulfur, or by a group NR _a (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 (C ₁ -C ₆ ) linear or branched or linear or branched polyhaloalkyl (C ₁ -C ₆ ),

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 grouping alkyl (C ₁ -C ₆₎ linear or branched, alkenyl (C ₂ -C ₆₎ -straight or branched alkynyl (C ₂ -C ₆₎ -straight 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 _O) ) 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 (C ₁₎ -C ₆ ) linear or branched or polyhaloalkyl (C ₁ -C ₆ ) linear or branched, or R ³ and R ⁴ together with the carbon atoms that carry them, when they are borne by two adjacent carbon atoms, a 5- or 6-membered ring and optionally containing a heteroatom selected from oxygen, sulfur and nitrogen,

* by a group of formula (II):

in which :

* R ⁵ represents a grouping

N (R) CR 'or N (R) C - OR' in which Z represents an oxygen or sulfur atom and R and R ', which are identical or different, are as defined previously, and R ⁶ represents an aryl, arylalkyl group in which the alkyl part contains from 1 to 6 carbon atoms and may be linear or branched, heteroaryl, heteroarylalkyl, the alkyl part of which contains from 1 to 6 carbon atoms and may be linear or branched. , CN, Tetrazole, - OR, NRR ¹ , - N (R) -C R '

Z

-N (R) -C-OR ¹ or O-C-R,

Z in which Z is as defined above and R and R ', which are identical or different, can take the same values as previously defined,

4 or by a group R ⁷ where R ⁷ represents a CN, tetrazole group,

R ⁸ R ⁹

N (R) CR ¹ , -N (R) C OR ¹ or -O- (CH ₂ ) CC-COOR

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 and R, 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,

or B represents a group of formula (II) or a group R ⁷ as defined above,

Being heard that :

the oxime R ¹ -C (= N-OR ² ) can be of Z or E configuration,

aryl means a phenyl, naphthyl or biphenyl group, these groups possibly being optionally partially hydrogenated, heteroaryl means any mono or bicyclic aromatic 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 chosen 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, NR _b R _c (wherein R _b 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 or nitro group, cyano, or halogen atoms,

2. Compounds of formula (I) according to claim 1 for which the group R ¹ -C (= N-OR ² ) - is in position c, their enantiomers and diastereoisomers and their addition salts with an acid or a pharmaceutically acceptable base.

3. Compounds of formula (I) according to claim 1 wherein R ³ and R ⁴ represent a hydrogen atom, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.

4. Compounds of formula (I) according to claim 1 wherein X represents a hydrogen atom, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

5. Compounds of formula (I) according to claim 1 wherein X represents an alkyl group, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1 wherein A represents an ethyleneoxy group, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

7. Compounds of formula (I) according to claim 1 wherein R ² represents a hydrogen atom, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.

8. Compounds of formula (I) according to claim 1 wherein R ² represents an alkyl group, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

9. Compounds of formula (I) according to claim 1 wherein R ¹ represents an unsubstituted or substituted phenyl group, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

10. Compounds of formula (I) according to claim 1, for which B represents a

COOR _x alkyl group substituted by a group / in which R _x and R _y ,

^The same or different ^radicals represent a hydrogen atom or an alkyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

H. Compounds of formula (I) according to claim 1, for which B represents a

COOR _x group CH- x in which R _x and R _y , identical or different, represent

OR _{y is} a hydrogen atom or an alkyl group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to claim 1 which are 2-ethoxy-3- {4- [2- (6- [(hydroxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dimethyl- Ethyl dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoate, 2-ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl- Ethyl 3,4-dihydro-1 (2H) -quolinyl) ethoxy] phenyl} propanoate, 2-ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] - 4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) -methoxy] phenyl} -propanoic acid, (25) -2-ethoxy-3- {4- [2- (6 - [(methoxyimino) ( ethyl (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoate, (2S) -2-ethoxy-3- {4- [ 2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, 3- {4- [2 - (6 - [(Methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2- [4- (trifluoromethyl) phenoxy] propanoate d 2- (acetyloxy) -3- {4- [2- (6 - [(methoxyimino) phenyl) ethyl thyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, 3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] - Ethyl 4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoate, the acid 3- {4- [2 - (6 - [(Methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) ) propanoic acid, 2- (2-benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3,4-dihydro-1 (2H) ethyl (quinolinyl) ethoxy] phenyl} propanoate, 2- (2-benzoylanilino) -3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4,4-dimethyl- 3,4-Dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, (2 S) -3- {4- [2- (6 - [(4-cyano-phenyl) (methoxyimino) methyl] -4 Ethyl 4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] p-phenyl} -2-ethoxypropanoate, 4 - [[1- (2- {4 - [(25) - 2, 3-Diethoxy-3-oxopropyl] phenoxy} ethyl) -4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl] (methoxyimmo) methyl ] ethyl benzoate, 4 - [[1- (2- {4 - [(25) -2-carboxy-2-ethoxyethyl] phenoxy} ethyl) -4,4-dimethyl-1,2,3 4-tetrahydro-6-quinolinyl] (methoxyimino) methyl] benzoic acid, 2-ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] -4,4,7-trimethyl- Ethyl 3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoate, 2-ethoxy-3- {4- [2- (6 - [(hydroxyimino) (phenyl) methyl] - 4,4,7-trimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, 3- {4- [2- (6- [cyclohexyl (hydroxyimmo) methyl] -4,4 Ethyl dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} 2 (SS) -ethoxypropanoate, 3- {4- [2- (6- [cyclohexyl (hydroxyimmo)) methyl] -4,4-dimethyl-3 ₃ 4-dihydro-l (2H) -quinolinyl) ethoxy] phenyl} 2 (S) -ethoxypropanoic acid, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

13. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (III) is used as starting material:

in which R ¹ and X are as defined in formula (I),

on which a compound of formula (IV) is condensed in basic medium

in which A, B, R ³ and R ⁴ are as defined in formula (I) and Hal represents a halogen atom, to yield the compound of formula (V):

in which R ¹ , R ³ , R ⁴ , X, A and B are as defined in formula (I), which is subjected to the action of a compound of formula R 0 -NH ₂ in which R is as defined in formula (I) to yield the compound of formula (I):

14. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (IH) is used as starting material:

in which R ¹ and X are as defined in formula (I),

on which a compound of formula R ² O -NH ₂ in which R ² is as defined in formula (I) is condensed to yield the compound of formula (VI):

in which R ¹ , R ² and X are as defined in formula (T), on which a compound of formula (IV) is condensed in basic medium

in which A, B, R ³ and R ⁴ are as defined in formula (I) and Hal represents a halogen atom, to yield the compound of formula (T):

which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique. 15. Process for the preparation of the compounds of formula (I) according to claim 1, for which A represents an alkyleneoxy chain, characterized in that the compound of formula (VII) used is the starting material:

in which R ¹ and X are as defined in formula (I), A 'represents a (C ₁ -C ₆ ) alkylene chain and Hal represents a halogen atom, on which a compound of formula (VIII):

in which R ¹ , X, B, R ³ and R ⁴ are as defined in formula (I), and A 'represents a (C ₁ -C ₆ ) alkylene chain, on which a compound of formula R ² O -NH ₂ in which R ² is as defined in formula (I) is condensed to yield the compound of formula (I / a), in particular the compounds of formula (I):

Compound of formula (V) according to claim 13:

in which R ¹ , R ³ , R ⁴ , X, A and B are as defined in the compounds of formula (I) according to claim 1, useful as synthesis intermediates of the compounds of formula (I) and in as hypoglycemic and lipid-lowering agents. 17. Pharmaceutical compositions containing as active ingredient at least one compound of formula (I) or of formula (V) according to any one of claims 1 to 12 and 16 or an acid or base addition salt thereof pharmaceutically acceptable, alone or in combination with one or more pharmaceutically acceptable excipients.

18. Pharmaceutical compositions according to claim 17 for the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycemia, dyslipidemia, and more particularly in the treatment of non-insulin-dependent diabetes type II, resistance to 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, inflammatory bowel diseases, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma, but also in the treatment or prevention of type I diabetes mellitus, obesity, regulation of appetite, anorexia, bulimia, anorexia nervosa, and cancerous diseases. These include hormone-dependent cancers such as breast cancer and colon cancer, and as angiogenesis inhibitors.

19. A combination containing a compound of formula (I) or formula (V) according to one of claims 1 to 12 and 16 and an antioxidant.

20. The combination of claim 19 wherein the compound of formula (I) is (25) -2-ethoxy-3- {4- [2- (6 - [(methoxyimino) (phenyl) methyl] -4 , 4-dimethyl-3,4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid, its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

21. The combination of claim 19 wherein the compound of formula (V) is 3- {4- [2- (6- (cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) ) -quinolinyl) ethoxy] phenyl} -2-ethoxypropanoic acid, its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

22. The combination of claim 19, 20 or 21 wherein the antioxidant is coenzyme Q ₁₀ .

The combination of claim 19, 20 or 21 wherein the antioxidant is vitamin E.

24. The combination of claim 19 which is (2 <S) -2-ethoxy-3- {4- [2- (6- [(methoxyimino) (phenyl) methyl] -4,4-dimethyl-3 , 4-dihydro-1 (2H) -quinolinyl) ethoxy] phenyl} propanoic acid and coenzyme Q 1 _O -

25. The combination of claim 19 which is 3- {4- [2- (6- (cyclohexylcarbonyl) -4,4-dimethyl-3,4-dihydro-1 (2H) -quinolmyl) ethoxy] phenyl} -2-Ethylpropanoic acid and coenzyme Q ₁₀ .

26. Pharmaceutical compositions containing as active ingredient an association according to any one of claims 19 to 25, alone or in combination with one or more pharmaceutically acceptable excipients.

27. Pharmaceutical compositions according to claim 26 useful for the manufacture of a medicament for the treatment and / or prevention of obesity.

28. Pharmaceutical compositions according to claim 26 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.

29. Use of an association according to any one of claims 19 to 25 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity. 30. Use of an association according to any one of claims 19 to 25 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by a therapeutic treatment.

31. Use of an association according to any one of claims 19 to 25 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by treatment of type I or II diabetes.

32. Use of an association according to any one of claims 19 to 25 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. .

33. Use of an association according to any one of claims 19 to 25 for obtaining pharmaceutical compositions intended for the treatment and / or prevention of weight overload characterized by a body weight index greater than 25 and less than 30. induced by a therapeutic treatment.

34. Use of a combination according to any one of claims 19 to 25 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 IL diabetes