EP1966204A1

EP1966204A1 - Novel heterocyclic oxime derivatives, process for the preparation thereof and pharmaceutical compositions containing them

Info

Publication number: EP1966204A1
Application number: EP06847063A
Authority: EP
Inventors: Franck Suzenet; Gérald Guillaumet; Christelle Pillard; Carine Bassene; Catherine Dacquet; Alain Ktorza; Daniel-Henri Caignard
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2005-12-20
Filing date: 2006-12-19
Publication date: 2008-09-10
Also published as: NO20082821L; CN101374837A; US20090274674A1; EA014317B1; FR2894965B1; CA2634320A1; WO2007077313A1; ZA200805976B; JP2009520007A; AU2006334310A1; AR058573A1; BRPI0620190A2; MA30068B1; FR2894965A1; KR20080077030A; EA200801566A1

Abstract

Compounds of formula (I), in which: X represents a hydrogen or halogen atom or an alkyl group, R1, R2, R3 and R4 are as defined in the description, A represents an alkylene chain as defined in the description, B represents an alkyl or alkenyl group substituted with a group D which represents a pyridine ring, as blood-glucose-lowering and blood-lipid-lowering agents.

Description

NOVEL HETEROCYCLIC OXIMINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS THEREOF

CONTAIN

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 ^ 2). These derivatives are capable of restoring insulin sensitivity in peripheral tissues 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 ^tb , 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 hyperlipidemia 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 :

R ¹ represents an aryl, heteroaryl or cycloalkyl (C ₃ -C ₈ ) group,

> R ² represents a hydrogen atom, or an alkyl group (C ₁ -C ₆₎ linear or branched, aryl, or aryl- (C ₁ -C ₆₎ linear or branched,

X represents a hydrogen or halogen atom, or a linear or branched (C ₁ -C ₆ ) alkyl group,

> R ³ and R ^4, identical or different, represent a hydrogen or halogen atom, or an alkyl group (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆₎ linear or branched alkylamino (Ci-C ₆ ) linear or branched, or dialkylamino (C ₁ -C ₆ ) linear or branched, -

> D represents a pyridine ring,

> 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 Ra represents a hydrogen atom or an alkyl group ( C ₁ -C ₆ ) linear or branched),

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 (H):

in which R ⁵ represents a group -COOR and R ⁶ represents a group -OR 'where R and R', which are identical or different, each represent a hydrogen atom, or a linear or branched (C ₁ -C ₆ ) alkyl group unsubstituted or substituted by one or more halogen atoms,

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 being able to be partially hydrogenated,

"heteroaryl" means any mono or bicyclic aromatic group containing 5 to 10 members, which may be partially hydrogenated on one ring in the case of bicyclic heteroaryls, and containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur,

the aryl and heteroaryl groups so defined may be substituted by 1 to 3 groups selected from alkyl (C ₁ -C ₆₎ linear or branched polyhaloalkyl (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆₎ linear or branched hydroxy, carboxy, formyl, NR _b R _c (wherein R _b and R ₀ , identical or different, represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl, aryl or heteroaryl ), ester, amido, nitro, cyano, 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. Examples of pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine and the like.

The preferred compounds of the invention are the compounds of formula (I) for which R ¹ represents an aryl group and more particularly phenyl.

The preferred R ² group of the compounds of formula (I) according to the invention is the alkyl group and more particularly methyl.

More particularly, the compounds of formula (I) according to the invention are derivatives for which D with the ring to which it is fused represent an 1H-pyrrolo [2,3-b] pyridine system. The preferred group for R ³ and R ⁴ is hydrogen.

Preferably, A represents an alkylene chain in which a CH ₂ group is replaced by an oxygen atom.

More particularly, the invention relates to the compounds of formula (I) for which A represents an ethyleneoxy group.

X preferably represents a hydrogen atom.

The preferred R ⁵ group is the COOH or COOMe group.

The preferred group R ⁶ is the group OEt or OCH ₂ CF ₃ .

The preferred group B is the group -CH ₂ -CH (R ⁵ ) (R ⁶ ) and more particularly the group -CH ₂ -CH (R ⁵ ) (R ⁶ ) in which R ⁵ represents a group COOH, COOMe or COOEt and R ⁶ represents a methoxy, ethoxy or trifluoroethoxy group.

Very advantageously, the invention relates to the compounds of formula (I) having a 1H-pyrrolo [2,3-e] pyridine structure in which: X represents a hydrogen atom,

R ¹ represents a phenyl, cyclopropyl, cyclopentyl or cyclohexyl group,

A represents a chain -CH ₂ -CH ₂ -O-,

R ² represents a methyl group,

R ³ and R represent simultaneously a hydrogen atom,

B represents a group -CH ₂ -CH (R ⁵ ) (R ⁶ ) in which R ⁵ represents a grouping

COOMe, COOEt or COOH, and R ⁶ represents an ethoxy or trifluoroethoxy group.

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

2-Ethoxy-3- [4- (2- {6 - [(E) - (methoxy-imino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl ] methyl propanoate,

(2S) -2-Ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-y] pyridin-1 methyl (ethoxy) phenyl] propanoate,

3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyrid-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate methyl,

(25) -3- [4- (2- {6 - [(E) - (Methoxyimmo) (phenyl) methyl] -1H-pyrrolo [2,3-ό] pyridin-1-yl} ethoxy) phenyl ] -2- (2,2,2-trifluoroethoxy) propanoate methyl,

* The 2-ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -LH ^"-ρyrrolo [2,3 ôjpyridin- 1-yl} ethoxy) phenyl] propanoic acid,

(25) 2-Ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] -pyridine-1-en yl} ethoxy) phenyl] propanoic acid,

* 3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -4H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2 - (2,2,2-trifluoroethoxy) propanoic (25) -3-4- [2- {6 - [(E) - (methoxyimino) phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid,

2-Ethoxy-3- [4- (2- {6 - [(Z) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy) phenyl ] methyl proρanoate,

2-Ethoxy-3- [4- (2- {6 - [(2) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-p] pyridin-1-yl} ethoxy) phenyl) ] propanoic

Methyl 2-ethoxy-3- [4- (2- {5 - [(methoxy-imino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy) phenyl] propanoate ,

3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-ό] pyrid-1-yl} ethoxy) phenyl] -2- (2.2) Methyl 2-trifluoroethoxy) propanoate

2-ethoxy-3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-p] pyridin-1-yl} ethoxy) phenyl] propanoic acid,

* 3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl] -LH ^'-ρyrrolo [2,3-b] pyridin-l- yl} ethoxy) phenyl] -2- ( 2,2,2-trifluoroethoxy) propanoic

* 3- [4- (2- {4-chloro-5 - [(Z) - (methoxyimino) (phenyl) methyl] -LH ^"-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate methyl,

3- [4- (2- {4-chloro-5 - [(2) - (methoxy-imino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy acid ) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid,

methyl 3- [4- (2- {6- [cyclopropyl (methoxyimino) methyl] -1H-pyrrolo [2,3- 6] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate,

* 3- [4- (2- {6- [cyclopropyl (methoxyimino) methyl] - H ^"-pyrrolo [2,3-b] pyridin-1 - yl} ethoxy) phenyl] -2- (2,2, 2-trifluoroethoxy) methyl ρropanoate, * 3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -LH ^'-pyrrolo [2,3-Z "] pyridin-l- yl} ethoxy) phenyl] -2-ethoxypropanoate,

(2 R) -3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate methyl,

3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2 methyl trifluoroethoxy) propanoate,

(2 S) -3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- Methyl (2,2,2-trifluoroethoxy) propanoate,

* 3- [4- (2- {6- [cyclopropyl (methoxyimino) methyl] -l ^//: pyrrolo [2,3-Z '] pyridin-l- yl} ethoxy) phenyl] -2- ethoxypropanoic,

* 3- [4- (2- {6- [cyclopropyl (methoxyimino) methyl] ^-LH: pyrrolo [2,3-b] pyridin-l- yl} ethoxy) phenyl] -2- (2, 2,2-trifluoroethoxy) propanoic acid,

3 - [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid,

* The acid (25) -3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -l _J H-pyrrolo [2,3-b] ρyridin- 1-yl} ethoxy) phenyl] - 2-ethoxypropanoic acid,

3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2.2) , 2-trifluoroethoxy) propanoic acid,

(2S) -3- [4- (2- {6- [Cyclohexyl (methoxy-imino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] - 2- (2,2,2-trifluoroethoxy) propanoic acid,

2-Ethoxy-3- [4- (2- {6 - [(methoxyimino) (4-pyridinyl) methyl] -1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy) phenyl ] methyl propanoate, 2-Ethoxy-3- [4- (2- {6 - [(methoxyimino) (4-pyridinyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid ,

* The (2 _1S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -LH-pyrrolo [2,3-b] ρyridin-yl} ethoxy) phenyl] - 2- (2,2,2-trifluoroethoxy) propanoate methyl,

(2S) -3- [4- (2- {6 - [(methoxy-imino) (phenyl) methyl] -1-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] - 2- (2,2- _D -trifluoroethoxy) propanoic acid,

Methyl 2-ethoxy-3- [4- (2- {6 - [(pheiioxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] propanoate ,

2-ethoxy-3- [4- (2- {6 - [(phenoxyimmo) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid,

methyl 3 - [4- (2- {6- [cyclopentyl (methoxyimino) methyl] -1H-pyrrolo [2,3-di-pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate,

3 - [4- (2- {6- [cyclopentyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid,

Methyl 2-ethoxy-3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoate ,

2-Ethoxy-3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid

3- [4- (2- {6- [Cyclopropyl (hydroxy-imino) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] -2- (2.2) , 2-trifluoroethoxy) propanoic acid,

2-Ethoxy-3- [4- (2- {6 - [(hydroxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy) phenyl] propanoic acid , 3- [4- (2- {6- [Cyclopropyl (hydroxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid.

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 D, 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 , A, B, D and X are as defined in formula (I), which is subjected to the action of a compound of formula R ² O-NHa 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:

(M)

in which D, 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 lead to compound of formula (VI):

in which R ¹ , R ² , D 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):

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

Another aspect of the invention also relates to the compounds of formula (V):

in which D, X, A, R ¹ , R ³ , R ⁴ and B are as defined in the compounds of formula (I), useful as synthetic intermediates for the compounds of formula (I) and as hypoglycemic and hypolipidemic agents.

The preferred compounds of formula (V) according to the invention are those for which R ¹ represents a (C ₃ -C ₈ ) cycloalkyl group.

Even more particularly, the preferred compounds of formula (V) are:

methyl 3- (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrolo [2,3-a] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate,

3- (4- {2- [6- (Cyclopropylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) propanoate methyl, methyl 3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate,

methyl (2S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate,

3- (4- {2- [6- (Cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) propanoate methyl,

(2S) -3- (4- {2- [6- (Cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2 methyl trifluoroethoxy) propanoate,

3- (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid,

3- (4- {2- [6- (Cyclopropylcarbonyl) -1H-pyrrolo [2,3-ό] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) ) propanoic acid,

3- (4- {2- [6- (cyclohexylcarbonyl) -1-pyrrolo [2,3-a] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid,

(2S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid,

3- (4- {2- [6- (Cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) ) propanoic acid,

2 (S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2, 2,2-trifluoroethoxy) propanoic acid,

methyl 3- (4- {2- [6- (cyclopentylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate, 3- (4- {2- [6- (cyclopentylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid,

3- [4- (2- {6- [Cyclopropyl (hydroxyimmo) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} -methoxy) phenyl] -2- (2.2) , 2-trifluoroethoxy) propanoic acid,

2-Ethoxy-3- [4- (2- {6 - [(hydroxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] propanoic acid ,

3- [4- (2- {6- [Cyclopropyl (hydroxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid.

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 Paldose 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 Pinsulin 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, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels and oral or injectable ampoules.

The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or 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 (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 combination according to the invention is (2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridine 1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic 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 (BMI = weight (kg) / height ² (m ² )) greater than or equal to 30 are considered to be obese (Int.JO Obes., 1998, 22, 39-47; Obesity Lancet , 1997, 350, 423-426). Obesity (BMI> 30) and overweight (25 <BMI <30) can have several origins: they can occur as a result of 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), insulin therapy is also a source of body weight gain in patients (In Progress in Obesity Research, 8 ^th International Congress on Obesity, 1999, 739-746; Armais of Internai 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, non-msulino-dependent diabetes because they predispose to insulin resistance , dyslipidemia and the appearance of macro-vascular diseases (nephropathies, retinopathies, angiopathies).

Other pathologies are the consequence of obesity or overweight: vesicular stones, respiratory dysfunction, several forms of cancer and, in cases 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 weight overload characterized by a body index greater than 25. The invention therefore relates to the use of the association between a compound of formula (I) or (V) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and overweight characterized by a body index greater than 25 and less than 30 . In particular, the combination according to the invention is useful in the treatment and / or prevention of obesity and overweight characterized by a body index greater than 25 and less than 30 induced by a therapeutic treatment, such as the treatment of type I or IL diabetes The invention therefore relates to the use of the combination between a compound of formula (I) or (V) and an antioxidant agent for obtaining pharmaceutical compositions intended for treatment and / or prevention obesity and overweight characterized by a body index greater than 25 and less than 30 induced by a therapeutic treatment, such as treatment of type I or IL diabetes

The invention also relates to pharmaceutical compositions containing the combination of a compound of formula (I) or (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 (V) as defined above and an antioxidant 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 between 0.1 mg and 1 g of each component of the association by 24 hours in one or more catches.

The following Examples and Preparations illustrate the invention and do not limit it in any way. Preparation 1: Methyl 3- (4- {2- [6- (Cyclopropylcarbonyl) -1 H -pyrrolo [2,3-b] pyrid-1-yl} ethoxy} phenyl) -2-ethoxypropanoate

Step A: Cyclopropyl (1H-pyrrolo [2,3-b] pyridin-6-yl) methanone

In a flask under an argon atmosphere, 3 g (21 mmol) of 1H-pyrrolo [2,3-e] pyridine-6-carbonitrile are dissolved in 35 mL of anhydrous tetrahydrofuran. Then, 5.35 mL (42 mmol) of trimethylsilyl chloride and 126 mL (126 mmol) of phenylmagnesium bromide (1 M in tetrahydrofuran) are added. The reaction is stirred overnight at room temperature. Then, it is hydrolysed with 100 ml of a 2M ammonium chloride solution. The pH is then acidified to 1 with 10% hydrochloric acid and the mixture is stirred for 2 hours at room temperature. The pH of this solution is then reduced to 9 with a concentrated solution of ammonia. The aqueous phase is extracted twice with 100 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 9/1 then 8/2) to yield the title product in the form of a beige solid.

Melting point: 159 ^° C. MS: m / z = 187 [M + H] ⁺ .

Stage B: 3- (4 ~ {2-β- (Cychpropylcarbonyl) -1H-pyiro [2,3-b] pyridin-1-yl] -thio [phenyl] -2-methoxypropanoate methyl

In a flask under argon, 0.500 g (2.68 mmol) of the compound obtained in Step A are dissolved in 30 ml of anhydrous N, N-dimethylformamide. Then, 0.161 g (4.02 mmol) of sodium hydride are added. This mixture is stirred for 1 hour at room temperature and cooled to 0 ° C. This solution is then added to 1 g (3.48 mmol) of methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate dissolved in N, N-dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature. Then it is hydrolyzed with 50 ml of a saturated solution of ammonium chloride. The aqueous phase is extracted 3 times with 50 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product obtained is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 9/1 and 8/2) to give the title product as a yellow solid.

Melting point: 159 ° C. MS: m / z = 437 [M + H] ⁺ .

Preparation 2: 3- (4- {2- [6- (Cyclopropyïcarbonyl) -lJÏ-pyrrolo [2,3-b] pyridin-l- yl] êtnoxy} phenyl) -2- (2 ₅ 2.2-trifluoroethoxy) methyl prαpanoate

In a bicol under an inert atmosphere, the compound obtained in Stage A of Preparation 1 (0.600 g) is dissolved in 30 ml of anhydrous Λζ N-dimethylformamide, then 0.193 g (5.31 mmol) of sodium hydride (60% in oil) are added. The mixture is stirred for 1 hour and 30 minutes at room temperature and cooled to 0 ° C. The anion obtained is then added to 0.485 g of methyl 3- [4- (2-bromoethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate (1.26 mmol) dissolved in 15 ml of N Anhydrous N-dimethylformamide. The reaction is stirred for 7 hours at room temperature. The solvent is then evaporated and the residue taken up in 40 ml of water. It is extracted 3 times with 40 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 10/0, 9/1 and 8/2) to yield the title product in the form of a red solid.

Melting point: 123 ^° C. MS: m / z = 513 [MH-Na] ⁺ .

Preparation 3: 3- (4- {2- [6- (Cyclohexykarbonyl) -l _J H-pyrrolo [2,3 ^ pyridin-l- yl] ethoxy} phenyl) -2-ethoxypropanoate

Stage A: 6- (1-Cychhexyhinyl) ~ 1H ~ pyrrolo [2,3-b] pyridme

Under argon atmosphere, 1.5 g (10.48 mmol) of H ^"-pyrrolo [2,3-b] pyridme-6-carbonirrile are dissolved in 20 mL of anhydrous tetrahydrofuran. Then 2.66 mL (20, 96 mmol) of trimethysilyl chloride are added. This mixture is then added to 31 ml (62.87 mmol) of cyclohexylmagnesium chloride dissolved in 20 ml of anhydrous tetrahydrofuran. The reaction is stirred for 20 hours at room temperature. It is then hydrolysed with 50 ml of 2M ammonium chloride. After acidification to pH 1 with 6M hydrochloric acid, the mixture is stirred for 2 hours at room temperature. It is then basified to pH 8 with aqueous ammonia and extracted 3 times with 20 mL of dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated.

The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 9/1, 8/2 then 7/3) to yield the title product in the form of a yellowish solid.

Melting point: 160 ° C. MS: m / z = 229 [M + H] ⁺ .

Step B: 3- {4- {2- [6 ~ (cyclohexylcarbonyl) LII ~ ~ ^f pyn olo [2, 3-bJpyridin-yl] ethoxy} phenyl) -2-ethoxypropanoate of métkyle

In a bicol under argon, 0.376 g (1.65 mmol) of the compound obtained in Step A are dissolved in 20 mL of anhydrous N, N-dimethylformamide and 0.091 g (3.79 mmol) of sodium hydride (60% in oil) are added. The mixture is stirred for 1 hour at room temperature. Then, it is then added to a solution containing 0.616 g (2.15 mmol) of methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate and 10 mL of anhydrous N, N-dimethylformamide. The reaction is stirred for 4 hours at room temperature. It is then hydrolysed with 30 ml of a saturated solution of ammonium chloride and extracted 3 times with 30 ml of ethyl acetate. The organic phases are washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated under reduced pressure to yield the title product in the form of a yellow oil.

MS: m / z = 479 [M + H] ⁺ . Preparation 4: (2S) -3- (Methyl 4- {2- [6- (Cyclohexylcarbonyl) -1H-pyrrolo [2,3-triphenyl] -1-ylethoxy} phenyl) -2-ethoxypropanoate

The procedure is as in Preparation 3, replacing in Step B methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with (2S) -3- [4- (2-bromoethoxy) phenyl] - Methyl 2-ethoxypropanoate.

[α] o = -7 (methanol, c = 1).

Preparation 5: 3- (4- {2- [6- (cyclohexylcarbonyl) -lJÎ-pyrroIα [2 ₅ 3-6] pyridin-l- yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) methyl propanoate

The procedure is as in Preparation 2 from Stage A of Preparation 3. Yellow oil.

MS: m / z = 533 [M + H] ⁺ .

Preparation 6: (2S) -3- (4- {2-6- (cyclohexylcarbonyl) -1H-pyrrolo [2 _s 3-t] pyridin-1-yl] ethoxy} phenyl) -2- (2.2.2 methyl trifluoroetloxy) propanoate

The procedure is as in Preparation 3, replacing in Step B methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with (2S) -3- [4- (2-bromoethoxy) phenyl] - 2- (2,2,2-Trifluoroethoxy) propanoate methyl.

[α] o = -15 (methanol, c = 1).

Preparation 7; 3- (4- {2- [6- (Cyalopropylcarbonyl) -1H-pyrrolo [2,3-felpyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid

The compound obtained in Preparation 1 (0.340 g) is dissolved in 20 mL of tetrahydrofuran. Then, 0.102 g (2.34 mmol) of lithium hydroxide dissolved in 20 mL of water are added. The mixture is stirred for 2 hours at room temperature. The solvent is then evaporated and the residue acidified to pH 3 with aqueous acetic acid. The aqueous phase is extracted 3 times with dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (dichloromethane / methanol: 97/3) to yield the title product in the form of a yellow gum.

+

MS: m / z = 423 [M + H].

Preparation 8: 3- (4- {2- [6- (cyclopropyIcarbonyï) -lif-pyrrolo [2,3-ft] pyrWm-yl] ethoxy} phenyl) -2- (2 ^ _{»2-trifluoroethoxy)} propanoic

The compound obtained in Preparation 2 (0.200 g) is dissolved in tetrahydrofuran and cooled to 0 ° C. Then 0.052 g (1.23 mmol) of lithium hydroxide monohydrate dissolved in 10 mL of water are added. The reaction is stirred for 1 hour and 30 minutes from 0 ° C to room temperature. The solvent is evaporated and the white residue obtained is dissolved in 20 ml of water. After acidification to pH 3 with aqueous acetic acid, it is extracted 3 times with 10 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (dichloromethane / methanol 95/5) to yield the title product in the form of a white solid.

Melting point: 113 ^° C. MS: m / z = 475 [MH] ⁺ .

Preparation 9: 3- (4- {2- [6- (cyclohexykarbonyl) -l _J ET-pyrrolo [2,3-b] pyridin-l- yl] ethoxy} phenyl) -2-ethoxypropanoic

In a flask under an argon atmosphere, 0.200 g (0.42 mmol) of the compound obtained in

Preparation 3 are dissolved in 30 mL of a 50/50 water / tetrahydrofuran mixture. Then, 53 mg (1.26 mmol) of lithium hydroxide are added. The reaction is stirred 1 hour to ambient temperature. Tetrahydrofuran is then evaporated under reduced pressure. The residue is acidified to pH 3 with aqueous acetic acid and extracted 3 times with 20 mL of ethyl acetate. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (pure dichloromethane and then dichloromethane / methanol: 95/5 then 90/10) to yield the title product in the form of a yellow oil.

MS: m / z = 465 [M + H] ⁺ .

Preparation 10: (2S) -3- (4- {2- (6- (cyclohexylcarbonyl) -l _J Fit-pyrrolo [2.3-6] pyridin-l-yl | ethoxy} phenyl) '2-ethoxypropanoic

In a flask, 0.180 g (0.38 mmol) of the compound obtained in Preparation 4 are dissolved in 4 mL of tetrahydrofuran and cooled to 0 ° C. Then 0.048 g (1.14 mmol) of lithium hydroxide dissolved in 7 mL of water are added. The reaction is stirred for 9 hours at 0 ° C. at room temperature. The solvent is evaporated. The residue is washed with 10 mL of diethyl ether. The aqueous phase is acidified to pH 3 with acetic acid. It is extracted 3 times with 10 mL of ether. The organic phases are washed with 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated under reduced pressure to yield the title product in the form of an oil.

[α] _D = -11 (methanol, c = 1). EC: purity>99%; ee ≥98%.

Preparation 11; 3- (4- {2- [6- (cyclohexylcarbonyl) -l _J H-pyrrolo [2,3 - &] pyridin-l- yl] ethoxy} phenyl) -2- (2,2,2-triflιιoroéthoxy) propanoic

The procedure is as in Preparation 9 from the compound obtained in Preparation 5. Yellow oil.

MS: m / z = 519 [M + H] ⁺ . Preparation 12: 2 (S) -3- (4- {2- [6- (Cyclohexycarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-ylethoxy} phenyl) -2- (2,2,2 -trîfluoroéthoxy) propanoic

The procedure is as in Preparation 9 starting from the compound obtained in Preparation 6. Oil. [OC] _D = -11 (methanol, c = 1).

EC: purity> 99%; ee> 98%.

Preparation 13: Methyl 3- (4- {2- [6- (Cydopentylcarbonyl) -1H] -pyrrolo [2,3-dichloro-1-yl] ethoxy} phenyl) -2-ethyl-propoxy] -acetate

The procedure is as in Preparation 3, replacing in Step A cyclohexylmagnesium chloride by cyclopentylmagnesium chloride.

Preparation 14: 3- (4- {2- [6- (Cyclopentylcarbonyl) -1H] -Pyrrolo [2,3-olpyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid

The procedure is as in Preparation 9 starting with the compound obtained from the compound obtained in Preparation 13.

EXAMPLE 1 2-Ethoxy-3- [4- (2- {6 - [(jB) ~ (mêtlioxyimmo) (phenyl) métliyl] -l _J H- pyrrolo [2 ^ 3- lpyπdin _s-l-yl} ethoxy ) Methyl phenylpropanoate

Stage A: Phenyl (1H-pyrrho [2,3-b] pyridin-6-yl) metkanone

In a flask under argon, 25.2 mL of 1M phenylmagnesium bromide in tetrahydrofuran are dissolved in 7 mL of anhydrous tetrahydrofuran. In another flask under argon, 0.6 g of 1H-pyrrolo [2,3-e] pyridine-6-carbonitrile and 1.07 mL of trimethylsilyl are dissolved in 7 mL of tetrahydrofuran. This solution is then canulated on the magnesium solution at room temperature. After stirring overnight, the mixture is hydrolyzed with 20 ml of a 2N ammonium chloride solution. The pH is then brought to 1 with 10% hydrochloric acid and the resulting solution is stirred for 2 hours at room temperature. ambient temperature. The pH of the solution is brought to 9 with a concentrated solution of ammonia and the aqueous phase extracted twice with 20 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. After purification by chromatography on silica gel (pure dichloromethane and then dichloromethane / methanol: 99/1), the title compound is obtained in the form of a yellow solid.

Melting point: 174 ° C.

Stage B: (E) -Phenyl (1H-pyrrolo [2,3-h] pyridin-6-yl) meihanone Q-methyloxime

In a flask under an argon atmosphere, 4.5 g of the compound obtained in Stage A, 2.26 g of methoxyammonium chloride and 2.2 ml of pyridine are dissolved in 200 ml of absolute ethanol. The reaction is stirred for 24 hours at room temperature. The solvent is then evaporated and the residue taken up in 150 ml of water. The aqueous phase is extracted 3 times with 100 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 5/1). The two isomers Z and E are thus separated and isolated.

Isomer E: white solid.

Melting point: 158 ° C.

Step C: 2-Ethoxy-S- [4- (2 ~ {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyr} -olo [2 _t- b] pyridin-1-yl Methyl ethoxy) phenyl] propanoate

In a flask under an inert atmosphere, 0.400 g of the compound obtained in Stage B are dissolved in 16 ml of anhydrous N-dimethylformamide. Then, 0.096 g of sodium hydride (60% in oil) are added and the mixture is stirred for 1 hour at room temperature. This solution is then added to 0.690 g of methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate dissolved in 8 ml of N, N-dimethylformamide. The reaction mixture is stirred 4 hours at room temperature. It is then hydrolyzed with 30 ml of a saturated solution of ammonium chloride. The aqueous phase is extracted twice with 30 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product obtained is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 8/2) and gives the title product in the form of a yellow oil.

MS: m / z = 502 [M + H] ⁺ .

EXAMPLE 2: (2S) -2-Ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (plenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy methyl phenylpropanoate)

The procedure is as in Example 1, replacing in Step C methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with (2S) -3- [4- (2-bromoethoxy) phenyl] Methyl 2-ethoxypropanoate.

[α] o = -5 (methanol, c = 1).

EXAMPLE 3 3- [4- (2- {6-1 (E) - (Methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl-2- (2) Methyl 2,2-trifluoroethoxy) propanoate

The procedure is as in Example 1, replacing in Step C methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with 3- [4- (2-bromoethoxy) phenyl] -2- ( Methyl 2,2,2-trifluoroethoxy) propanoate.

EXAMPLE 4 (2S) -3- [4- (2- [6 - [(E) - (Methoxyimino) (phenyl) methyl-1H-pyrrolo [2,3-b] pyrimid-1-yl} ethoxy) phenyl ] -2- (2,2,2-trifluoroethoxy) methyl propylate

The procedure is as in Example 1, replacing in Step C methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with (2S) -3- [4- (2-bromoethoxy) phenyl] Methyl 2- (2,2,2-trifluoroethoxy) propanoate.

EXAMPLE 5 2-Ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phéiιyl] propanoïqiιe

The compound obtained in Example 1 (0.360 g) is dissolved in 20 ml of a 50/50 water / tetrahydrofuran mixture. Then, 0.094 g of lithium hydroxide is added. The reaction is stirred for 2 hours at room temperature. The tetrahydrofuran is then evaporated and the residue obtained is acidified to pH 3 with aqueous acetic acid. This aqueous phase is extracted 3 times with 50 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (dichloromethane / methanol: 97/3) and leads to the title product in the form of a slightly yellow gum.

+

MS: m / z δ 488 [M + H].

EXAMPLE 6 (2S) -2-ethoxy-3- [4- (2- {6 - [(E) - (inéthoxyîmino) (pIιényl) methyl] - lH-pyrrolα [2,3 _{'blpyridin-l-} yl} ëtlιoxy) pliényI] propaiιoïque

The compound obtained in Example 2 (0.140 g) is dissolved in 3 ml of tetrahydrofuran and cooled to 0 ^° C. Then 0.035 g (0.84 mmol) of lithium hydroxide monohydrate dissolved in 5 ml of water are added. . The reaction is stirred for 3 hours at 0 ^° C. at room temperature. The solvent is evaporated. The residue obtained is washed with 10 mL of diethyl ether. The aqueous phase is acidified to pH 3 with aqueous acetic acid. It is then extracted 3 times with 10 mL of ether. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (dichloromethane / methanol 95/5).

[α] p = -10 (methanol, c = 1). EC: purity ≥ 99%; ee ≥ 98%.

EXAMPLE 7 3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo acid

[23-b] pyridin-l-yl} ethoxy) phenyl] -2- (2 ^ _{»2-trifluoroethoxy)} propaiioïque

The title acid is obtained from the compound obtained in Example 5 (0.900 g) according to the procedure used for Example 6, in the form of a yellow foam.

MS: m / z = 541 [M + H] ⁺ .

EXAMPLE 8 (2S) -3-14- (2- {6 - [(E) - (methyl) xylimino) (phenyl) methyl-1H-pyrrol

[2 _s 3-b] pyridin-l-yl} ethoxy) phenyl] -2- (2,2 ₅ 2-trifluoroethoxy) piOpauoïque

In a flask, 0.070 g (0.13 mmol) of the compound obtained in Example 4 are dissolved in 1.5 mL of tetrahydrofuran and cooled to 0 ° C. Then, 0.016 g (0.39 mmol) of lithium hydroxide dissolved in 2.5 mL of water are added. The reaction is stirred for 2 hours at room temperature. The solvent is evaporated and the residue acidified to pH 3 with acetic acid. The aqueous phase is extracted 3 times with 10 ml of ether. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (dichloromethane / methanol 95/5). [α] _D = -15 (methanol, c ≈ 1).

EC: purity>99%; ee ≥ 98%. EXAMPLE 9: 2-Ethoxy-3- [4- (2- {6 - [(4) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy] phenyl] methyl propanoate

Stage A; (Z) ~ Pkenyl (1H-pyrro [2,3-b] pyridin-6-yl) methyl-O-methyloxime

In a flask under an argon atmosphere, 4.5 g of the compound obtained in Step A of Example 1, 2.26 g of méthoxyammom ^'um and 2.2 mL of pyridine are dissolved in 200 ml of ethanol absolute. The reaction is stirred for 24 hours at room temperature. The solvent is then evaporated and the residue taken up in 150 ml of water. The aqueous phase is extracted 3 times with 100 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 5/1). The two isomers Z and E are thus separated and isolated.

Isomer Z: white solid. Melting point: 189 ° C.

Stage B; 2-Ethyl-3- [4- (2- {6 - [(Z) - (methoxyimino) (phenyl) methyl] -1H-pyrrolσ [2,3-b] pyridin-1-yl} ethoxy) phenyl] methyl propanoate

The procedure is as in Step C of Example 1. Yellow oil

MS: m / z = 502 [M + H] ⁺ .

EXAMPLE 10 Acid 2-ethoxy-3- [4- (2- {6-l (Z) - (methoxyimino) (phenyl) nιéthyl] -lH- pyrrolo [2 ₅ 3-b] pyridin-l-yl} ethoxy) phényllpropanoïqιιe

The title acid is obtained from the compound obtained in Example 9 according to the procedure of Example 5. Yellow gum

MS: m / z = 488 [M + H] ⁺ . EXAMPLE 11: Methyl 2-Ethyl-3-yl-2- (5-formamethoxymethyl) (phenyl) methyl-1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanate

Stage A: Phenyl (1H-pyrrolo [ _2h 3-b] pyridin-5-yl) methanone

In a flask, 31 mg (0.31 mmol) of chromium trioxide are dissolved in 140 ml of dichloromethane then 3.43 ml (24.99 mmol) of tert-butanol hydroperoxide (70% in water). ) are added slowly. The solution becomes dark red. Phenyl (1H-pyrrolo [2,4-b] pyridin-5-yl) methanol (1.4 g) is slowly added. The reaction, which turns yellow, is stirred for 21 hours at room temperature and in the open air. The peroxides are neutralized with 30 ml of a solution of sodium bisulfite and the mixture is extracted 3 times with 50 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and then evaporated under reduced pressure.

The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4 then 5/5) to yield the title product in the form of a pink solid. Melting point: 174 ° C. MS: m / z = 223 [M + H] ⁺ .

Stage B: Phenyl (1H-pyrrolo [2,3-b] pyridin-5-yl) methanone O-methyloxime

In a flask under an inert atmosphere, 1 g (4.50 mmol) of the compound obtained in Stage A are dissolved in 40 ml of absolute ethanol. Then 0.55 mL (6.75 mmol) of pyridine and 0.564 g (6.75 mmol) of the O-methylhydroxylamine hydrochloride are added. The reaction is stirred for 15 hours at reflux and then allowed to return to ambient temperature. The ethanol is evaporated off under reduced pressure and the residue is taken up in a water / dichloromethane mixture (50 ml). It is extracted 3 times with 50 ml of dichloromethane and the organic phases are then dried over magnesium sulphate, filtered and evaporated. Chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) makes it possible to obtain a mixture of the two expected isomers in a 50/50 ratio in the form of a white solid.

Melting point: 145 ° C. MS: m / z = 252 [M + H] ⁺ .

Stage C: 2-Ethoxy-3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoate methyl

In a flask under an argon atmosphere, 0.800 g (3.18 mmol) of the compound obtained in Stage B are dissolved in 15 ml of N, N-dimethylformamide and then 0.191 g (4.77 mmol) of sodium hydride ( 60% in the oil) are added. The mixture is stirred for 1.5 hours at room temperature. The anion formed is then cooled to 0 ^° C. It is then transferred to the mixture consisting of 52 mg (10 mol%) of potassium iodide, 1.47 g (3.82 mmol) of 3- [4- Methyl (2-bromoethoxy) phenyl] -2-ethoxypropanoate and 25 mL of N, N-dimethylformamide. The reaction mixture is stirred for 2 hours at 0 ^° C. at room temperature. The solvent is then evaporated. The residue is taken up in 20 ml of water and extracted with ethyl acetate (3 times 20 ml). The organic phases are washed with 30 ml of brine, dried over magnesium sulphate, filtered and evaporated. Chromatography on silica gel (petroleum ether / ethyl acetate: 7/3 and then 6/4) makes it possible to obtain the title product as a mixture of the 2 isomers in a Z / E 50/50 proportion in the form of a yellow oil.

MS: m / z = 502 [M + H] ⁺ .

EXAMPLE 12 344-2- {5 - [fMéthθCTimmQ ¥ phénynméthyn-lH-pvrrolor23 b1pvridm--l-yl.} Ethoxy) phenyl] -2- (2 _{"2,2-trîflworoétlioxy)} methyl propaHoate

In a flask under an argon atmosphere, 0.800 g (3.18 mmol) of the compound obtained in Step B of Example 11 are dissolved in 15 ml of anhydrous N, N-dimethylformamide and then 0.191 g (4.77 mmol). sodium hydride (60% in oil) are added. The mixture is stirred for 1.5 hours at room temperature. The anion formed is then cooled to 0 ^° C. It is then transferred to the mixture consisting of 52 mg (10 mol%) of potassium iodide, 1.47 g (3.82 mmol) of 3- [4- Methyl (2-bromoethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate and 25 mL of anhydrous N, N-dimethylformamide. The reaction mixture is stirred for 2 hours at 0 ° C. at room temperature. The solvent is then evaporated. The residue is taken up in 20 ml of water and extracted with ethyl acetate (3 times 20 ml). The organic phases are washed with 30 ml of saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated.

Chromatography on silica gel (petroleum ether / ethyl acetate: 7/3 and then 6/4) makes it possible to obtain the title product as a mixture of the 2 isomers in a Z / E 50/50 proportion, in the form of a yellow oil.

MS: m / z = 556 [M + H] ⁺ .

EXAMPLE 13 2-Ethoxy-3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl-1H-pyrrolo [ ₂₅ -b] pyridin-1-yl} ethoxy) phenyl] propanoic acid

The compound obtained in Example 11 (0.500 g) is dissolved in 10 mL of tetrahydrofuran and cooled to 0 ° C. Then 0.113 g (2.70 mmol) of lithium hydroxide monohydrate dissolved in 17 mL of water are added. The reaction is stirred for 2 hours at 0 ° C and the solvent is evaporated. The residue is taken up in 10 ml of water and acidified to pH 3 with aqueous acetic acid. It is extracted 3 times with 10 mL of dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica gel (dichloromethane / methanol: 9/1) and the title product is obtained in the form of a white gum. MS: m / z = 488 [M + H] ⁺ .

EXAMPLE 14: S-O-C 1-6 -alkyl-8-hydroxy-1-ylmethyl-1H-pyrrolo [p -benzyl-1-yl] ethoxy] phenyl-2- (2,2,2-trifluoroethoxy) propanoic acid

The compound obtained in Example 12 (0.500 g) is dissolved in 10 mL of tetrahydrofuran and cooled to 0 ° C. Then 0.113 g (2.70 mmol) of lithium hydroxide monohydrate dissolved in 17 mL of water are added. The reaction is stirred for 2 hours at 0 ° C and the solvent is evaporated. The residue is taken up in 10 ml of water and acidified to pH 3 with aqueous acetic acid. It is extracted 3 times with 10 mL of dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica gel (dichloromethane / methanol: 9/1) to yield the title product in the form of a white solid. Melting point: 182 ° C (degradation). MS: m / z = 542 [M + H] ⁺ .

EXAMPLE 15 3- [4- (2- {4-CWoro-5 - [(Z) - (methoxyimino) (phenyl) methyl-1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) methyl phenyll-2- (2,2 _s- trifluoroethoxy) propanoate

Step A: 4-C-chloro-1- (triisopropylhilyl) -1H-pyrrolo [2, S-b] pyridine

In a flask under argon, 6 g (39.32 mmol) of 4-chloro-1H-pyrrolo [2,3-e] pyridine are dissolved in 90 mL of tetrahydrofuran and cooled to 0 ° C. Then 1.73 g (43.25 mmol) of sodium hydride (60% in oil) are added in portions. The mixture is stirred for 15 minutes at 0 ° C. Finally, 8.42 mL (39.32 mmol) of triisopropylsilyl chloride are added.

The reaction is stirred for 3 hours under reflux. It is hydrolysed with 50 ml of a saturated solution of ammonium chloride and extracted 3 times with 50 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure.

The residue is purified by chromatography on silica gel (pure petroleum ether and then petroleum ether / ethyl acetate 95/5) to yield the title product in the form of a yellowish oil. MS: m / z = 309 [M + H] ⁺ Cl; 311 [M + H] ^{+ 37} Cl.

Step B: [4-Chloro-1- (triisopropylsilyl) -1H-pyrrolo [2,3-h] pyrimid-5-yl] phenyfymethanil

In a three-necked stream under argon, 1.5 g (4.86 mmol) of the compound obtained in Step A are dissolved in 50 mL of anhydrous tetrahydrofuran and cooled to -78 ° C. Then 8.2 ml (10.69 mmol) of sec-butyllithium (1.3 M in solution in hexane / cyclohexane) are added dropwise. The reaction mixture is stirred for 30 minutes at -78 ° C. 1.3 ml (12.15 mmol) of distilled benzaldehyde are then added. The mixture is stirred for 14 hours at room temperature. It is hydrolyzed with 50 mL of a saturated solution of ammonium chloride and extracted with dichloromethane (3 x 50 mL). The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 98/2) to give the title product as a colorless oil. MS: m / z = 416 [M + H] ⁺ Cl; 418 [M + H] ^{+ 37} Cl.

Stage C: [4-Chloro-1 - (triisopropyl) -1H-pyrrolo [2,3-h] pyridin-5-yl] (phenyl) methanone

The compound obtained in Step B (1.4 g) is dissolved in 90 ml of toluene and 2.93 g (33.70 mmol) of manganese dioxide are added. Dean Stark's camera is positioned. The reaction is stirred for 18 hours under reflux and then allowed to return to ambient temperature. The mixture is then filtered on celite and the filtrate is evaporated.

The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate 95/5) to obtain the title compound as a white solid. Melting point: 104 ° C.

MS: m / z = 413 [M + H] ⁺ Cl; 415 [M + H] ^{+ 37} Cl.

Stage D: (Z) ~ [4-chloro-1- (triisopropyl) -1H-pyrrolo [2] b] pyridin-S-yl] pkenytymethanone Q-methylethylamine

In a flask under argon, 2.3 g (5.57 mmol - 1 eq) of the compound obtained in Step C are dissolved in 90 ml of absolute ethanol. Then 0.68 mL (8.36 mmol) of pyridine and 0.698 g

(8,36 mmol) of O-methylhydroxylamine hydrochloride are added. The reaction is stirred for 46 hours under reflux. The solvent is then evaporated. The residue is taken up in 100 ml of water and extracted 3 times with 50 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude is purified and the 2 oximes separated on a BIOTAGE column by fraction of 250 mg (petroleum ether / ethyl acetate: 500 mL 8/2, 150 mL 8/2 to 7/3 and 400 mL 7/3).

Isomer Z: white solid. Melting point: 110 ^° C. Stage E: (Z) - (4-Chloro-1H-pyrro [2,3-h] pyridin-5-yl) (phenyl) methanone Q-methyloxime

In a flask under an argon atmosphere, 0.800 g (1.81 mmol) of the compound obtained in Step D are dissolved in 8 mL of tetrahydrofuran. Then 4 mL (3.98 mmol) of tetrabutylammonium fluoride (1 M in tetrahydrofuran solution) are added. The reaction mixture is stirred for 19 hours at room temperature. It is then hydrolyzed with 10 ml of water and extracted 3 times with 10 ml of dichloromethane. The organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure.

The residue obtained is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 8/2, 7/3 then 6/4) to yield the title product in the form of a white solid.

Melting point: 176 ° C.

MS: m / z = 286 [M + H] ⁺ Cl; 288 [M + H] ^{+ 37} Cl.

Methyl F-α-β-Fe-Cmoro-δ- [2 H -methylimino-1-yl] ethoxy] phenyl] -2- (2,2,2-trifluoroethyl) propanoate

In a bicol under an argon atmosphere, the compound obtained in Stage E (0.300 g) is dissolved in 5 ml of anhydrous ΛζN-dimethylformamide, then 0.063 g (1.58 mmol) of sodium hydride (60% in theory). oil) are added. The mixture is stirred for 1 hour and 30 minutes at room temperature and cooled to 0 ^° C. The anion obtained is then added to a mixture containing 0.485 g (1.26 mmol) of 3- [4- (2-bromoethoxy) -phenyl). ] -2- (2,2,2-trifluoroethoxy) propanoate methyl, 17 mg of potassium iodide and 8 ml of anhydrous N ₁ N-dimethylformamide. The reaction is stirred for 2 hours at room temperature. The solvent is then evaporated and the residue taken up in 10 ml of water. It is extracted 3 times with 10 mL of ethyl acetate. The combined organic phases are washed with 20 ml of a saturated solution of sodium chloride, then dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude is purified by chromatography on silica gel (ether of petroleum / ethyl acetate: 8/2, 7/3 then 6/4) to yield the title product in the form of a colorless oil.

MS: m / z = 590 [M + H] ⁺ Cl; 592 [M + H] ^{+ 37} Cl.

EXAMPLE 16: 3- [4- (2- {4-Chloro-5 - [(Z) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b-pyrrolidin-1-yl} ethoxy) phenyl] -2- (2,2-Trifluoroethoxy) propanoic

The compound obtained in Example 15 (0.300 g) is dissolved in tetrahydrofuran and cooled to 0 ° C. Then 0.064 g (1.53 mmol) of lithium hydroxide monohydrate dissolved in 10 mL of water are added. The reaction is stirred 1 hour and a half from 0 ° C to room temperature. The solvent is evaporated and the residue is dissolved in 10 mL of water. After acidification with aqueous acetic acid, it is extracted 3 times with 10 ml of dichloromethane. The organic phases are dried over magnesium sulfate, filtered and evaporated. The white powder obtained is washed with hexane, filtered on sintered glass and dried under vacuum. Melting point: 186 ^° C.

MS: m / z = 576 [M + H] ⁺ Cl; 578 [M + H] ^{+ 37} Cl.

EXAMPLE 17: Methyl 3- [4-α- {6-rCγcIopropyl (methoxymethyl) methy] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxyproperpate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 1. EXAMPLE 18 3- [4- (2- {6- [Cyclopropyl (methoxy) mannyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2.2, Methyl 2-trifluoroethoxy) propaaoate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 2.

EXAMPLE 19 Methyl 3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 3.

EXAMPLE 20: (2S) -3- [4- (2- {6- [Cyclohexyl (methoiminimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy] phenyl] -2- methyl ethoxypropanoate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 4.

EXAMPLE 21 3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl-2- (2,2,2-trifluoroethoxy) ) methyl propanoate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 5. EXAMPLE 22: Methyl (2SV) 344-22-{64Cydohexy (Methoxyimino) niethyn-1H-pyrrolo [2,3-b] pyrid-1-yl} ethoxy) phenyl-2- (2,2,2-trifluoroethoxy) propanoate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 6.

EXAMPLE 23: 3- [4- (2- {6- [cydopropyl (méthoxyinuno) methyl] -LH-pyrrolo [2 _'3-b] pyridin-l-yl} ethoxy) phéiιyI] -2-ethoxypropanoic

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 7.

EXAMPLE 24 3- [4- (2- {6- [Cyclopropyl (methoxyimino) methyl] -1H-pyrroloacid

[2,3-b] pyridin-l-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 8.

EXAMPLE 25 3- [4- (2- {6- [Cyclohexyl (methoxyimino) -ethyl-1H-pyrrolo [2 _S- b] pyrimid-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 9. EXAMPLE 26 (2S) -3- [4- (2- {6- [Cyclohexyl (methoxyimino) -ethyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy] phenyl] -2 -éthoxypropanoïque

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 10.

EXAMPLE 27 3- [1-4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2) , 2,2-trifluoroethoxy) propanoic acid

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

EXAMPLE 28 (2S) -3- [4- (2- {6- [Cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2) 2,2-trifluoroet hoxy) propanoic

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 12.

EXAMPLE 29: 2-Ethoxy-3- [4- (2- {6 - [(methoxyimino) (4-pyridinyl) methyl-1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) ph methyl enyl] propanoate

The procedure is as in Stages B and C of Example 1 starting from 4-pyridinyl (1H-pyrrolo [2,3-b] pyrid-6-yl) methanone.

EXAMPLE 30 2-Ethoxy-3- [4- (2- {6 - [(methoxyimino) (4-pyridinyl) -nithiyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl ] propanoic

The procedure is as in Example 5 starting from the compound obtained in Example 29. EXAMPLE 31: (2S) -3- [4- (2- {6 - [(Methoxyimino) phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2) Methyl 2,2-trifluoroethoxy) propanoate

The procedure is as in Example 1 without separating the isomers obtained in Step B and replacing in Step C methyl 3- [4- (2-bromoethoxy) phenyl] -2-ethoxypropanoate with (2S) -3- [ Methyl 4- (2-bromoethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate.

EXAMPLE 32 (2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrroloic acid

[2,3-b] pyridin-1-yl} ethoxy) phenyl] -2,2,2,2-trifluoroethoxy) propaiioïq "e

The procedure is as in Example 5 starting from the compound obtained in Example 31.

EXAMPLE 33: 2-Ethoxy-3- [4- (2- {6 - [(phenoxyimino) (phenyl) methyl] -1H-pyrrolo

_[2, 3-b] pyridin-1-yl} ethoxy) phenyl] propanoate

The procedure is as in Example 1, replacing in Stage B the methoxyammonium chloride with phenoxyammonium chloride and without separating the isomers obtained.

EXAMPLE 34: 2-Ethoxy-3- [4- (2- {6 - [(phenoxyimino) (phenyl) methyl] -1H-pyrroloic acid

[2,3-b] pyridin-1-yl} ethoxy) phênyIlpropanoique

The procedure is as in Example 5 starting from the compound obtained in Example 33. EXAMPLE 35: Methyl 3- [4- (2- {6-yl) pyropentyl (methoxyimino) methyl] -1β-pyrrolo [2,3-δ] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 13.

EXAMPLE 36 3- [4- (2- {6- [Cyclopentyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethyloxy) phenyl] -2-ethoxypropanoic acid

The procedure is as in Step B of Example 1 starting from the compound obtained in Preparation 14.

EXAMPLE 37 Methyl 2- (Ethoxy-3-yl) -2-methyl-trimethoxvinyl) phenyl-methyl-1-pyrrolo [2,3-di] pyrimidin-1-yl} methyl) phenyl] propanoate

The procedure is as in Example 1 without separating the isomers obtained in Step B.

EXAMPLE 38 2-Ethoxy-3- [4- (2- {6 - [(methoxy) amino) (phenyl) methyl-1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propattoïque

The procedure is as in Example 5 starting from the compound obtained in Example 37.

EXAMPLE 39 3- [4- (2- {6- [Cyclopropyl (hydroxyimmo) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2.2) , 2-trîfliιoroêthoxy) propanoic

In 30 ml of methanol, add the compound obtained in Preparation 8 (0.00198 mol), hydroxylamine hydrochloride (0.00594 mol) and pyridine (0.00594 mol). Heat at reflux for 3 hours. Evaporate to dryness. Add 100 ml of hydrochloric acid (IN) and then extract with twice 50 ml of dichloromethane, and evaporate under reduced pressure to yield the title product in the form of a white solid. EXAMPLE 40 2-ethoxy-3- [4- (2- {6 - [(hydroxyimino) (phenyl) méthyll4 _J Θ ^r - pyrrolo [2,3-élpyrîdin-l-yl} ethoxy) phenyl] propanoic

The procedure is as in Example 1, replacing in Stage B the methoxy ammonium chloride with hydroxylamine hydrochloride. Yellowish oil.

EXAMPLE 41 acid-3-T4- ({2- [6-ethoxy cyclopropyI (hydroxyimino) métliyll-LiI-pyrrolQ [2 3- d] _{pyridin-l-yl}?)} Phenyl] -2-ethoxypropanoic

The procedure is as in Example 39 starting from the compound obtained in Preparation 7. Solid amide.

MS: m / z = 438.5 [M + H] ⁺ .

PHARMACQLOGICAL 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; Efficiency 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 male mouse (Harlan) 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. Animals are randomized to their blood glucose levels to form groups of eight. The orally tested compounds are dissolved in a mixture of hydroxyethyl cellulose (1% HEC) to be administered at 3 mg / kg in a volume of 10 ml / kg, once a day for four days. The control group receives the solvents under the same conditions as the treated groups. Product activity is assessed by measuring blood glucose, triglyceride and insulin levels 24 hours after the last administration and by daily measurement of body weight.

The compounds of the invention show a very good ability to reduce blood glucose comparable to the effects obtained with Rosiglitazone, the reference substance.

By way of example, the compound of Example 32, administered at a dose of 3 mg / kg, shows a 37% reduction in triglyceride level compared with the control group, a reduction of insulinemia of 23% compared to control group and a 43% reduction in blood glucose compared to control.

In addition, no side effects were observed during the in vivo tests.

Example C: Pharmaceutical Composition

1000 tablets dosed with 5 mg of (2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (Example 32) 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: Body Weight Variation

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 (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 E: Pharmaceutical Composition

100 tablets dosed with 30 mg of (2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid (Example 32) and 10 mg of coenzyme Q ₁₀

(2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- ( 2,2,2-trifluoroethoxy) propanoic acid (Example 32) 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

REVENBICATIONS

1. Compounds of formula (I):

in which :

R ¹ represents an aryl, heteroaryl or cycloalkyl (C ₃ -C ₈ ) group,

> R ³ and R ^4, identical or different, represent a hydrogen or halogen atom, or an alkyl group (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆₎ linear or branched alkylamino (C ₁ -C ₆ ) linear or branched, or dialkylamino (C ₁ -C ₆ ) linear or branched,> D represents a pyridine ring,

> 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), 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 R ⁵ represents a group -COOR and R ⁶ represents a grouping

Where R and R ', which may be identical or different, each represent a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group which is unsubstituted or substituted with one or more halogen atoms,

Being heard that :

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

the aryl and heteroaryl groups thus defined may be substituted with 1 to 3 groups chosen from linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) polyhaloalkyl or linear or branched (C ₁ -C ₆ ) alkoxy; hydroxy, carboxy, formyl, NR _b R _c (in which R ₁ and R ₀ , which may be identical or different, represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl group, aryl or heteroaryl), ester, amido, nitro, cyano, or halogen atoms,

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

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

4. 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.

5. Compounds of formula (I) according to claim 1 wherein D with the ring to which it is fused represent an 1H-pyrrolo [2,3-b] pyridine system, their enantiomers and diastereoisomers and their addition salts with a acid or a pharmaceutically acceptable base.

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

7. 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 thereof with a pharmaceutically acceptable acid or base.

8. Compounds of formula (I) according to claim 1 wherein B represents a group -CH ₂ -CH (R ⁵ ) (R ⁶ ), their enantiomers and diastereoisomers and their addition salts with an acid or a base pharmaceutically acceptable.

9, Compounds of formula (I) according to claim 1 which are 2-ethoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2, 3-ό] pyridin-l-yl} ethoxy) phenyl] Methyl propanoate, (2S) -2-ethoxy-3- [4- (2- {6 - [(E) - (methoxyiminino) (phenyl) methyl] -1H-pyrrolo [2,3-ό] methyl pyridin-1-yl} ethoxy) phenyl] propanoate, methyl 3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [trifluoroethoxy] propanoate, (2 S) -3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] -2- (2 ₃ 2,2-trifluoroethoxy) propanoate acid, 2-é1hoxy-3- [4- (2- {6 - [(E) - (methoxyimino) (phenyl) methyl] - lh- pyrrolo [2,3-6] pyridin-1-yl} ethoxy) phenyl] propanoic acid, (25) -2-ethoxy-3- [4- (2- {6 - [(E) - (memoxymmo)) (phenyl) methyl] -1H-pyrrolo [2,3-β] pyridin-1-yl} ethoxy) phenyl] propanoic acid, 3- [4- (2- {6 - [(E) - ( (Phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, (25) -3 - [4-

(2- {6 - [(E) - (Memoxy-imino) (phenyl) -methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2- trifluoroethoxy) ρropanoic acid, 2-ethoxy-3- [4- (2- {6 - [(Z) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl Methyl ethoxy) phenyl] propanoate, 2-emoxy-344- (2- {6 - [(Z) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-ό] pyridinic acid. 1-yl} ethoxy) phenyl] propanoic acid, 2-ethoxy-3- [4- (2- {5 - [(methoxyimino)

Methyl (phenyl) methyl] -1-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoate, 3- [4- (2- {5 - [(memoxymino) (phenyl) methyl) Methyl 1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate, 2-ethoxy-3- [4- (2- {5 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid, 3- [4- (2- { 5 - [(Memoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, the 3- [ 4- (2- {4-chloro-5 - [(2) - (methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- ( Methyl 2,2,2-trifluoroethoxypropanoate, 3- [4- (2- {4-chloro-5 - [(2) - (methoxyiraino) (phenyl) methyl] -1H-pyrrolo [2], 3-ό] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, 3- [4- (2- {6- [cyclopropyl (memoxyimino) methyl] -1H- Methyl pyrrolo [2,3 - &] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate, 3- [4- (2- {6- [cyclopro] pyl (methoxycin) methyl) -1H-pyrrolo [2,3-5] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate methyl, 3- [4- (2- Methyl {6- [cyclohexyl (methoxy mimo) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate, (25) -3- [4- ( Methyl 2- {6- [cyclohexyl (memoxy-immo) -methyl] -1H-pyrrolo [2,3-i] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoate, 3- [4- (2- { 6- [cyclohexyl (methoxy-imino) -methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2- Methyl trifluoroethoxy) propanoate, (25) -3- [4- (2- {6- [cyclohexyl (methoxy) amino] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] Methyl 2- (2- (2,2,2-trifluoroethoxy) propanoate, 3- [4- (2- {6- [cyclopropyl (methoxy) amino] methyl] -1H-pyrrolo [2,3-δ] pyridinic acid, 1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid, 3- [4- (2- {6- [cyclopropyl (methoxy) tert-methyl] -1H-pyrrolo [2,3-y] pyridin-1-yl} } ethoxy) phenyl] -2-

(2,2,2-trifluoroethoxy) propanoic acid, 3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-a] pyridin-1-yl} ethoxy acid; ) phenyl] -2-ethoxypropanoic acid, (2 S) -3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid, 3- [4- (2- {6- [cyclohexyl (methoxyimino) me & yl] -LH-pyrrolo [2 ₅ 3-b] pyridin-l-yl} ethoxy) phenyl ] -2- (2,2,2-trifluoroethoxy) propanoic acid, (25) -3- [4- (2- {6- [cyclohexyl (methoxyimino) methyl] -1H-pyrrolo [2,3-Z] pyridine 1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, 2-ethoxy-3 - [4- (2- {6 - [(methoxyimino) (4-pyridiyl) methyl] Methyl-1H-pyrrolo [2,3-6] pyrid-1-yl} ethoxy) phenyl] propanoate, 2-emoxy-3- [4- (2- {6 - [(memoxyimino)) acid pyridinyl) methyl] -1-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid, the (25) -3- [4- (2- {6-

Methyl [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoate, the acid ( 2S) -3- [4- (2- {6 - [(methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2); 2,2-trifluoroethoxy) propanoic acid, 2-emoxy-3- [4- (2- {6- [φhenoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy ) methyl phenyl] propanoate, 2-ethoxy-3- [4- (2- {6-

[(Phenoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid, 3- [4- (2- {6- [cyclopentyl (methoxyimino) methyl] ] -LH ^'-pyrrolo [2,3-b] pyridin-l-yl} ethoxy) phenyl] -2-ethoxypropanoate, 3- [4- (2- {6- [cyclopen1yl (méthoxyimmo) methyl ] -1-pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] -2-ethoxypropanoic acid, 2-ethoxy-3- [4- (2- {6 - [(methoxyimino) phenyl) methyl] -LH-pyrrolo

Methyl [2,3-έ] pyridin-1-yl} ethoxy) phenyl] propanoate, 2-ethoxy-3- [4- (2- {6- [(methoxy-imino) phenyl) -methyl] -l pyrrolo [2,3-b] pyridin-1-yl} ethoxy) phenyl] propanoic acid, 3- [4- (2- {6- [cyclopropyl (hydroxyimino) methyl] -1H-pyrrolo [2,3 - [ό] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, 2-ethoxy-3- [4- (2- {6 - [(hydroxyimino)) phenyl) methyl] -LH ^"-pyrrolo [2,3 - &] pyridin-l-yl} ethoxy) phenyl] propanoic acid, 3- [4- (2- {6- [cyclopropyl (hydroxyimino) methyl] - 1H-pyrrolo [2,3-β] pyridin-1-yl} (ethoxy) phenyl] -2-ethoxypropanoic acid.

10. 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 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 , A, B, D and X 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):

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

wherein D, R ¹ and X are as defined in formula (I), which is condensed with a compound of formula R 0 -NH ₂ wherein R is as defined in formula (I) to yield a compound of formula (VI):

12. Compounds of formula (V) according to claim 10:

(V)

wherein X, B, D, A, R ¹ , R ³ and R ⁴ are as defined in claim 1 useful as synthetic intermediates for the compounds of formula (I).

Compounds of formula (V) according to claim 12 which are 3- (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrolo [2,3-b] pyrid-1-yl] ethoxy} phenyl Methyl 2-ethoxypropanoate, 3- (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} prienyl) -2- (2); Methyl 2,2-trifluoroethoxy) propanoate, 3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-6] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate methyl, (2S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoate methyl, the Methyl 3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) propanoate (2S) -3- (4- {2- [6- (Cyclohexylcarbonyl) -1H-pyrrolo [2,3-di] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) methyl propanoate, 3- (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrolo [2,3-a] pyridin-1-yl] ethoxy} phenyl) -2-ethoxypropanoic acid, 3 - (4- {2- [6- (cyclopropylcarbonyl) -1H-pyrrole acid [2,3-b] pyrid-1-yl] ethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) propanoic acid, 3- (4- {2- [6- (cyclohexyl) carbonyl) 1H-pyrrolo [2,3-b] pyridin-1-yl] ethoxy) phenyl) -2-ethoxypropanoic acid, (2S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H- pyrrolo [2,3-b] pyridin-1-yl] ethoxy) phenyl) -2-ethoxypropanoic acid, 3- (4- {2- [6- (cyclohexylcarbonyl) -1H-pyrrolo [1H] pyridin-1-yl] ethoxy} phenyl) -2- (2,2,2-trifluoroethoxy) propanoic acid, 2 (S) -3- (4- {2- [6- (cyclohexylcarbonyl) -1H- pyrrolo [2,3-b] pyridin-1-yl] ethoxy) phenyl) -2- (2,2,2-trifluoroethoxy) propanoic acid, 3- (4- {2- [6- (cyclopentylcarbonyl) -1H); Methyl pyrrolo [2,3-b] pyridin-1-yl] ethoxy) phenyl) -2-ethyloxypropanoate, 3- (4- {2- [6- (cyclopentylcarbonyl) -1H-pyrrolo [P] pyridine -l-yyéthoxylphény ^^ - ethoxypropanoic.

14. Pharmaceutical compositions containing as active principle at least one compound of formula (I) or of formula (V) according to any one of claims 1 to 9, 12 or 13 or an addition salt thereof to an acid or a pharmaceutically acceptable base, alone or in combination with one or more pharmaceutically acceptable excipients.

15. Pharmaceutical compositions according to claim 14 for the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycaemia, dyslipidemias, and more particularly in the treatment of non-insulin-dependent diabetes type II, insulin resistance, glucose intolerance, syndrome X-related disorders, coronary artery disease and other cardiovascular diseases , renal diseases, 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, obesity, appetite regulation, anorexia, bulimia, anorexia nervosa, as well as cancerous pathologies including hormone-dependent cancers such as breast cancer and colon cancer, and as inhibitors of angiogenesis.

16, Association containing a compound of formula (I) or (V) according to one of claims 1 to 9, 12 or 13 and an antioxidant.

17, The combination according to claim 16, wherein the compound of formula (I) is (2S) -3- [4- (2- {6 - [(methoxyinimo) phenyl) -methyl] -1H-pyrrolo [2, 3-b] pyridin-1-yl} ethoxy) phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid, its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

18, Association according to claim 16 or 17 wherein the antioxidant is coenzyme Q ₁₀ .

The combination of claim 16 or 17 wherein the antioxidant is vitamin E.

20. Combination according to claim 16 or 17 which is (2S) -3- [4- (2- {6- [6-methoxyimino) (phenyl) methyl] -1H-pyrrolo [2,3-b] pyridine 1-yl} ethyl) -2-phenyl-2- (2,2,2-trifluoroethoxy) propanoic acid and coenzyme Q ₁₀ -

21, Pharmaceutical compositions containing as active ingredient a combination according to any one of claims 16 to 20 alone or in combination with one or more pharmaceutically acceptable excipients.

22, Pharmaceutical compositions according to claim 21 useful for the manufacture of a medicament for the treatment and / or prevention of obesity.

23, Pharmaceutical compositions according to claim 21 useful for the manufacture of a medicament for the treatment and / or prevention of overweight characterized by a body weight index of greater than 25 and less than 30.

24, Use of an association according to any one of claims 16 to 20 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity.

25, Use of an association according to any one of claims 16 to 20 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by a therapeutic treatment.

26. Use of an association according to any one of claims 16 to 20 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by treatment of type I diabetes or IL

27. Use of an association according to any one of claims 16 to 20 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. .

28. Use of an association according to any one of claims 16 to 20 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 a therapeutic treatment.

29. Use of an association according to any one of claims 16 to 20 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