WO2008006969A2

WO2008006969A2 - Novel tetracyclic derivatives, process for the preparation thereof and pharmaceutical compositions which contain them

Info

Publication number: WO2008006969A2
Application number: PCT/FR2007/001174
Authority: WO
Inventors: Jean-Martial L'helgoual'ch; Morgan Le Naour; Pascal Berthelot; Nicolas Lebegue; Véronique Leclerc; Pascal Carato; Catherine Dacquet; Alain Ktorza; Daniel-Henri Caignard
Original assignee: Les Laboratoires Servier
Priority date: 2006-07-10
Filing date: 2007-07-09
Publication date: 2008-01-17
Also published as: WO2008006969A3; AR061835A1; FR2903404A1; FR2903404B1

Abstract

Compounds of formula (I): in which: > R1, R2 and R3, as described in the description, form a ring of formula (II) where R6 is a hydrogen or halogen atom, or an alkyl, alkoxy, amino, alkylamino or dialkylamino group, and X is a hydrogen atom or an N-OR7 group, > R4 and R5 are a hydrogen or halogen atom, or an alkyl, alkoxy, alkylamino or dialkylamino group, > A is as defined in the description, > B is an alkyl or alkenyl group substituted with a [-CHR8R9 group.

Description

NEW TETRACYCUECALDES,

PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to novel tetracyclic 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 the insulin and lipid levels in these same animal models and in vitro induce the differentiation of cell lines from preadipocytes to adipocytes (A. Hiragun et al., J. . Ceil Physiol, 1988, 134, _124-130;... Kleitzen RF 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 II). 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 ^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, JJS (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 (T)

CO

in which :

> R ₁ represents a hydrogen atom and R ₂ and R ₃ together with 2 adjacent carbon atoms carrying them a ring of formula (II):

in which

- R ₆ represents a hydrogen or halogen atom, or an alkyl group (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆₎ linear or branched, amino, alkylamino (C ₁ -C ₆ ) linear or branched, or dialkylamino (C ₁ -C ₆ ) linear or branched,

X represents an oxygen atom or an N-OR _{7 group} in which R ₇ represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl, aryl or aryl (C ₁ -C ₆₎ alkyl group; ) linear or branched,

or R ₃ represents a hydrogen atom and R ₁ and R ₂ form together with the 2 adjacent carbon atoms which carry them a ring of formula (II) as defined above,

> R ₄ and R _5, 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, amino linear or branched alkyl (C ₁ -C ₆ ) alkyl or linear or branched (C ₁ -C ₆ ) dialkylamino,

> 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 ₃ (where R ₃ 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 (M):

-R ₈

(BDO R ₉

in which R ₈ represents a group -COOR and R ₉ 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 = N-OR ₇ may 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 ₂ (wherein R _b and R ₀ , 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,

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, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, and the like. An advantageous variant relates to the compounds of formula (I) for which R ₄ , R ₅ and R ₆ represent a hydrogen atom.

Another particular aspect of the invention relates to the compounds of formula (I) for which X represents an N-OR _{7 group} such as, for example, the hydroxyimino or methoxyimino groups.

A advantageously represents an ethyleneoxy group.

One variant of the invention relates to the compounds of formula (I) for which the R ₈ group is the COOH or COOEt group.

Another variant of the invention relates to the compounds of formula (I) for which the group R ₉ is the group OEt or OCH ₂ CF ₃ .

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

* 3- {4- [2- (2,9-dioxo-2H-fluoreno [3,2-rf] [1,3] thiazol-3 (9H) -yl) ethyl] phenyl} -2-ethoxypropanoate of ethyl,

3- {4- [2- (2,6-dioxo-2H-fluoreno [3,4-b] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} -2-ethoxypropanoate of ethyl, 3- {4- [2- (2,6-dioxo-2H-fluoreno [3,4-b [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} 2-Ethoxy-3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4-tri] [1,3] thiazol-3 (6H) -2-ethoxy-3- {4- [2- (6-hydroxyimino) -2-oxo} ) -yl) ethoxy] phenyl} propanoate, * 2-ethoxy-3- {4- [2 - ((6Z) -6- (hydroxyimino) -2-oxo-2H ^"-fluoréno [3,4- -c (| [l, 3] thiazol

Ethyl 3 (6H) -yi) ethoxy] phenyl} propanoate,

2-Ethoxy-3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-c] [1,3] thiazol-3 (6H) -yl) ethyl ethoxy] phenyl} propanoate, _ _

* The 2-ethoxy-3- {4- [2- (6- (hydroxyimino) -2-oxo-2H ^"-fluoréno [3.4-4] [l, 3] thiazol-3 (6H) - yl) ethoxy] phenyl} propanoic acid,

2-Ethoxy-3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-b] [1,3] thiazol-3 (6H) -yl ) ethoxy] phenyl} propanoic acid, 3- {4- [2- (2,9-dioxo-2H-fluoreno [3,2-b] [1,3] thiazol-3 (9H) -yl) ethoxy] ethyl phenyl} -2- (2,2,2-trifluoroethoxy) propanoate,

* 3- {4- [2- (2 ₃ 9-dioxo-2H-fluoréno [3,2 - ^ [l, 3] thiazol-3 (9H) -yl) ethoxy] phenyl} -2- ( 2,2,2-trifluoroethoxy) propanoic

3- {4- [2- (2,6-Dioxo-2H-fluoreno [3,4-b] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} -2- (2) Ethyl 2,2-trifluoroethoxypropanoate,

* 3- {4- [2- (2,6-dioxo-2H-fluoreno [3,4-O [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} -2- ( 2,2,2-trifluoroethoxy) propanoic

3- {4- [2- (6- (Hydroxyimino) -2-oxo-2H-fluoreno [3,4-c] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} - Ethyl 2- (2,2,2-trifluoroethoxy) propanoate, 3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-J] [ ethyl 1,3-thiazol-3 (6H) -yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoate,

* 3- {4- [2- (6- (Hydroxyimino) -2-oxo-2H-fluoreno [3,4-b] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} } -2- (2,2,2-trifluoroethoxy) propanoic acid,

3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-i]] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl) -2- (2,2,2-trifluoroethoxy) propanoic 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 the preparation of the compounds of formula (I), characterized in that a compound of formula (IV) is used as starting material: - -

in which R ₆ is as defined in formula (I), on which a compound of formula (V) is condensed in basic medium

in which A, R ₄ and R ₅ are as defined in formula (I), B 'represents a group B as defined in formula (I) in which R ₈ is different from a COOH group, and Ha represents a halogen atom, to yield the compound of formula (VI):

wherein R ₄ , R ₅ , R ₆ , A and B 'are as previously defined, which are subjected to a cyclization reaction in the presence of potassium acetate and palladium acetate, to give the compounds of formulas (I / a) and (ITb), particular cases of the compounds of formula (I): - -

in which R ₄ , R ₅ , R ₆ , A and B 'are as defined above, which are subjected to a saponification reaction to yield compounds of formulas

(I / c) and (I / d), particular cases of the compounds of formula (I):

in which R ₄ , R ₅ , R ₆ and A are as defined above, and B "represents a group of formula B as defined in formula (I) in which R ₈ represents a COOH group, composed of formulas (Va ), (Vb), (Vc) and (Fd) which is subjected to the action of a compound of formula NH ₂ OR ₇₅ HCl in which R ₇ is as defined in formula (I), to conduct to the compounds of formulas (17e) and (Vf), particular cases of the compounds of formula (I): - -

in which R ₄ , R ₅ , R ₆ , R ₇ , A and B are as defined above,

the compounds of formulas (Fa) to (Vf) forming all of the compounds of formula (I), which can be purified according to a conventional separation technique, which, if desired, are converted into their 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 compounds of formula (T), characterized in that a compound of formula (IV) is used as starting material:

in which R ₆ is as defined in formula (T), which is subjected to a cyclization reaction in the presence of potassium acetate and palladium acetate, to yield compounds of formulas (VII) and ( VIII):

in which R ₆ is as defined in formula (I), which is subjected to the action of a compound of formula NH ₂ OR ₇₅ HCl in which R ₇ is as defined in formula (I), to yield compounds of formulas (DC) and (X):

in which R ₆ and R ₇ are as defined above, compounds of formulas (VII), (VIII), (DC) and (X) on which a compound of formula (XI) is condensed:

in which A, R ₄ , R ₅ and B are 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.

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

The compounds of the present invention possess very valuable pharmacological properties.

These compounds show in particular an excellent activity in the reduction of blood glucose levels. These properties justify their therapeutic application in the treatment and / or prophylaxis of hyperglycemia, dyslipidemia and more particularly in the treatment of non-insulin-dependent diabetes type II, glucose intolerance, disorders related to syndrome X (including hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia), coronary artery disease and other cardiovascular diseases (including high blood pressure, heart failure, venous 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, inflammatory bowel diseases, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma. The activity of these compounds is also recommended for the treatment and / or prophylaxis of other diseases including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, dyslipidemia in 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 for prevention or for the treatment of hypercholesterolemia, obesity with beneficial effects on hyperlipidemia, hyperglycemia, osteoporosis, glucose intolerance, insulin resistance 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 may be used in combination with HMG CoA reductase inhibitors, fibrin, 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 (T) as defined above and an antioxidant agent for obtaining pharmaceutical compositions that are useful in the treatment and / or prevention 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 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4-d] [1,3] thiazol-3 ( 6H) -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 (BVIC> 30) and overweight (25 <BMI <30) can have several origins: they can occur as a result of deregulation of food intake, hormonal dysregulation, or as a result administration of treatment: Type II anti-diabetic therapy with sulfonylureas results in weight gain in patients. Similarly 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; Annals of Internal Medicine, 1998, 128, 165-175).

Obesity and overweight are well-established risk factors for cardiovascular disease: they are associated with a significant increase in the risk of stroke, 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 which, even when moderated, significantly reduces all the risk factors associated with obesity (Int, J. Obes, 1997, 21, 55-9, Int. Obes., 1992, 21, S5-9). The combination according to the invention thus finds its utility in the treatment and / or prevention of obesity and weight overload characterized by a body index greater than 25. The invention therefore relates to the use of the association between a compound of formula (I) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity and weight overload 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 The invention therefore relates to the use of the combination between a compound of formula (I) and an antioxidant agent for obtaining pharmaceutical compositions intended for the treatment and / or prevention of obesity. and 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) 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) 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 illustrate the invention and do not limit it in any way.

EXAMPLE 1 3- {4- [2- (2,9-Dioxo-2H-fluoréno [3 _s 2-4] [l, 3] thiazol-3 (9 ^) - yl) ethoxy] phenyl} -2 ethyl ethoxypropanoate

Step A: Ethyl 3- {4- [2- (6- (2-Bromobenzoyl) -2-oxo-1,3-benzothiazol-3 (2H) -yl) ethoxy] phenyl} -2-ethoxypropanoate

2.99 mmol of 6- (2-bromobenzoyl) -l, 3-benzothiazol-2 (3i- ⁷⁾ -one are dissolved in 150 ml of dimethylformamide and 8.98 mmol of potassium carbonate are added. The mixture is stirred for 1 hour at 100 ° C., then 3.59 mmol of ethyl 3- [4- (2-chloroethoxy) phenyl] -2-ethoxypropanoate are added and the reaction medium is stirred for 15 hours at reflux of ΛζN- dimethylformamide. The solution is filtered and the filtrate is hydrolyzed then - Io -

extracted with ethyl acetate. After washing with a saturated solution of sodium hydrogencarbonate, the organic phases are combined, dried and evaporated. The residue obtained is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate 7/3) to yield the title product in the form of a pale yellow oil.

Step B: 3- {4- [2- (2,9-Dioxo-2H-fluoreno [3,2-d] [1,3] thiazol-3 (9H) -yl) ethoxy] phenyl} -2-ethoxypropanoate ethyl

Under a nitrogen atmosphere in a sealed tube, 0.84 mmol of the compound obtained in Step A are dissolved in 10 ml of N-dimethylacetamide and 0.25 mmol of palladium acetate and 2.52 mmol of potassium acetate are successively added. The tube is closed and heated for 5 hours at 120 ^° C.

The reaction mixture is filtered through Celite ^® and the filtrate is hydrolyzed and then extracted with ethyl acetate. The organic phases are combined, dried and evaporated. The residue obtained is purified by HPLC chromatography (eluent: toluene / ethyl acetate 98/2) to yield the 2 cyclized products possible. The product of the title is obtained in the form of a solid. Melting point: 140-144 ^° C.

EXAMPLE 2 3- {4- [2- (2 ₅ 6-Dioxo-2fl-flιioréno [3,4 ^ I [l, 3] thiazol-3 (6fl) -yl) ethoxy] phenyl} -2-êthαxyprQpanoate ethyl

Process of Example 1, purification of the second cyclization adduct corresponding to the title product.

Melting point: 157-161 ^° C

EXAMPLE 3: 3- {4- [2- (2 ₎ 6-dioxo-2 H] -fluoreno [3,4- (fH], 3-thiazol-3 (6H) -yl) ethoxylphenyl} -2-ethoxypropanoic acid The compound obtained in Example 2 (0.39 mmol) is dissolved in a mixture of 12 ml of tetrahydrofuran and 8 ml of water, and 0.46 mmol of lithium hydroxide are added and the reaction mixture is then stirred. hours at room temperature. The solvent is evaporated and then the residue is hydrolyzed with 6N hydrochloric acid solution and extracted with dichloromethane. The organic phases are combined, dried and evaporated. After purification by chromatography on silica gel (eluent: 95/5 dichloromethane / methanol), the title compound is obtained in the form of a yellow solid. Melting point: 135-139 ° C

EXAMPLE 4: 2-Ethoxy-3- {4- [2 - ((6Z) -6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4-di] [1,3] thiazol-3 (6H) -yl ) ethoxy] phenyl} propanoate ethyl

The compound obtained in Example 2 (0.97 mmol) is dissolved in 50 ml of pyridine and 3.88 mmol of hydroxylamine hydrochloride are added. The reaction medium is stirred for 4 hours under reflux of the pyridine. The solvent is evaporated and the residue is acidified with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phases are combined, dried and evaporated. The residue obtained is purified on silica gel (eluent: petroleum ether / ethyl acetate 8/2) to yield the title product in the form of a white solid. Melting point: 174-178 ° C

EXAMPLE 5 2-Ethoxy-3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-di [1,3] thiazol-3 (6H) -yl) Ethyl] phenyl} propanoate of ethyl

The compound obtained in Example 2 (0.97 mmol) is dissolved in 50 ml of pyridine and 3.88 mmol of O-methylhydroxylamine hydrochloride are added. The reaction medium is stirred for 4 hours under reflux of the pyridine. The solvent is evaporated and the residue is acidified with 1N hydrochloric acid solution and extracted with dichloromethane. The organic phases are combined, dried and evaporated. The residue obtained is purified on silica gel (eluent: petroleum ether / ethyl acetate 7/3) to yield the title product in the form of a yellow solid. _{. o}

- 18 -

Melting point: 116-12O ⁰ C

EXAMPLE 6 2-Ethoxy-3- {4- [2- (6 "(hydroxyimino) -2-oxo-2H-fluoreno [3,4-trifluorazol-3 (6H-yl)] éthαxy] phenyl} propanGïque

Process of Example 3 starting from the compound obtained in Example 4. The title product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 98/2) and obtained in the form of a white solid. Melting point: 120-124 ^° C.

EXAMPLE 7 2-ethoxy-3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluorénop _"4-FIFÍ [l, 3] thiazol-3 (6ii) -yl) ethoxy] phenyl} propanoic

Process of Example 3 from the compound obtained in Example 5. The title product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 98/2) and obtained in the form of a yellow solid. Melting point: 79-83 ^° C.

EXAMPLE 8 3- {4- [2- (2,9-Dioxo-2H-fluoréno [3,2 _'qil} 3] thiazol-3 (9 _J S) -yi) ethoxy] phenyl} -2- (2,2 Ethyl 2-trifluoroethoxypropanoate

Process of Example 1, replacing in Step A ethyl 3- [4- (2-chloroethoxy) phenyl] -2-ethoxypropanoate with 3- [4- (2-chloroethoxy) phenyl] -2- (2 Ethyl 2,2-trifluoroethoxy) propanoate. The purification is carried out by chromatography on silica gel (eluent: petroleum ether / ethyl acetate 7/3). The title product is obtained in the form of a yellow solid.

Melting point: 92-96 ° C EXAMPLE 9 3- {4- [2- (2,9-Dioxo-2H-fluoreno [3,2-di [1,3] triazol-3 (9] 2-yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoiique

Process of Example 3 starting from the compound obtained in Example 8. The title product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 98/2) and obtained in the form of an orange solid. Melting point: 92-96 ° C

EXAMPLE 10 3- {4- [2- (2 _s 6-Dioxo-2 ^ -fluoréno [3 _s 4- <q [l, 3] thiazol-3 (62i) -yl) êtlιoxy] phenyl} -2 Ethyl (2,2,2-trifluoroethoxy) propanoate

Process of Example 1, replacing in Step A ethyl 3- [4- (2-chloroethoxy) phenyl] -2-ethoxypropanoate with 3- [4- (2-chloroethoxy) phenyl] -2- (2 Ethyl 2,2-trifluoroethoxy) propanoate. The purification is carried out by chromatography on silica gel (eluent: petroleum ether / ethyl acetate 7/3). The title product is the second cyclization adduct and is obtained as a yellow solid. Melting point: 135-139 ° C

EXAMPLE 11 3- {4- [2- (2,6-dioxo-2fl ~ fluoréno [3,4 - </ Hl ₅ 31thiazol-3 (6fl) -yl) ethoxy] phenyl} -2- (2, 2,2-trifluoroétlιoxy) propanoic

Process of Example 3 from the compound obtained in Example 10. The title product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 98/2) and obtained in the form of a yellow solid. Melting point: 133-137 ° C

EXAMPLE 12 3- {4- [2- (6- (Hydroxyimino) -2-oxo-2H-fluoreno [3,4-di] [1,3] thiazol-3

(6fl) -yl) éthoxylphényl} -2 (2.2 2-trifluoroethoxy) propanoate _^d; "ethyl Process of Example 4 from the compound obtained in Example 10. The title product is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate 75/25) and obtained in the form of a white solid. Melting point: 182-186 ° C

EXAMPLE 13 3- {4- [2- (6- (methoxyimino) -2-oxo-2fl-fluoréno [3 _s 4- <q [l, 3] thiazol-3

(6ii) -yl) ethoxy] phenyl} -2- _(2? 2,2-trifluoroethoxy) ethyl prQpanoate

Process of Example 5 from the compound obtained in Example 10. The title product is obtained as a yellow solid. Melting point: 92-96 ° C

EXAMPLE 14 3- {4- [2- êtlιαxy] phenyl (6- (hydroxyimmo) -2-oxo-2i -fluoréno [3.4- <fl [1.31 thiazol-3 ^(r 6H) -yl?)} -2- (2 _s 2 ^ -trifluoroéthoxy) propanoic

Process of Example 3 from the compound obtained in Example 12. The title product is obtained as a yellow solid. Melting point: 212-216 ° C

EXAMPLE 15: 3- {4- [2- (6- (Inoxylimino) -2-fluoro-2'-fluoreno [3.4 - [[1, 1H] thiazol-Cβ1-yl-ethoxy-1-phenyl] -alkyl-trifluoroethoxy) -propanoic acid

Process of Example 3 starting from the compound obtained in Example 13. The title product is purified by chromatography on silica gel (eluent: dichloromethane / methanol 98/2) and obtained in the form of a yellow solid. Melting point: 162-166 ^° C . -

PHARMACOLOGICAL STUDY

Example A: Acute Toxicity Study

Acute toxicity was assessed after oral administration to batches of 8 mice (26 + 2 g). The animals were observed at regular intervals during the first day and daily for two weeks following treatment. The LD _50, killing 50% of the animals, was evaluated and demonstrated 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. The animals are kept under a light-dark cycle of 12 hours at 25 ⁰ C. This mouse has a basal hyperglycaemia of 2 g / 1. 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. The activity of the products is evaluated by measuring blood glucose 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. In addition, no side effects were observed during the in vivo tests.

Example C: Pharmaceutical Composition

1000 tablets dosed with 5 mg of 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4 - [[1,3] thiazol-3 (6H)] - yl) Etb.oxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoic acid

(Example 14) 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 various combinations to be tested, between a compound of formula (I) and an antioxidant, 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) 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 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fmoreno [3,4 - [[1,3] thiazol-3 (6H)] - yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoic acid (Example 14) and 10 mg of coenzyme Q ₁₀

3- {4- [2- (6- (Hydroxyimmo) -2-oxo-2H-fluoreno [3,4-i]] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} - 2- (2,2,2-trifluoroethoxy) propanoic acid (Example 14) 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 :

> R ₁ represents a hydrogen atom and R ₂ and R ₃ together with the 2 adjacent carbon atoms which carry them a ring of formula (II):

in which

- R ₆ represents a hydrogen or halogen atom, or an alkyl (Ci-C ₆₎ linear or branched alkoxy (Ci-C ₆₎ linear or branched, amino, alkylamino (C ₁ -C ₆₎ linear or branched, or dialkylamino (Ci-C ₆ ) linear or branched,

- X represents an oxygen atom or a group N-OR ₇ wherein R ₇ represents a hydrogen atom or an alkyl (Ci-C ₆₎ linear or branched, aryl, or aryl- (Ci-C ₆₎ linear or branched, or R ₃ represents a hydrogen atom and R ₁ and R ₂ form together with the 2 adjacent carbon atoms which carry them a ring of formula (II) as defined above,

> 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 (III):

Being heard that :

the oxime = N-OR ₇ may be of Z or E configuration,

aryl means a phenyl, naphthyl or biphenyl group, these groups being able to be partially hydrogenated,

with heteroaryl is meant any aromatic mono- or bicyclic group containing 5 to 10 members, which may be partially hydrogenated on one of the rings in the case 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 ₀ (in which R _b and R ₀ , which are 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 ₄ , R ₅ and R ₆ represent a hydrogen atom, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.

3. Compounds of formula (I) according to claim 1 wherein X represents a group N-OR ₇ , their enantiomers and diastereoisomers and their addition salts 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 R ₈ represents a COOH or COOEt group, their enantiomers and diastereoisomers and addition salts with a pharmaceutically acceptable acid or base.

6. Compounds of formula (I) according to claim 1 wherein R ₉ represents a group OEt or OCH ₂ CF ₃ , their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. - -

A compound of formula (I) according to claim 1 which is 2-ethoxy-3- {4- [2- (6- (methoxyimino) -2-oxo-2H-fluoreno [3,4-cr]] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} propanoic acid, its enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base.

A compound of formula (I) according to claim 1 which is 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4-ύ (]] 1, 3] thiazol-3 (6H) -yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoic acid, its enantiomers and diastereoisomers and addition salts thereof with an acid or a pharmaceutically acceptable base acceptable., Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (IV) is used as starting material:

wherein R _4, R _5, R _6, A and B 'are as defined hereinbefore, which is subjected to cyclization reaction in the presence of potassium acetate and palladium acetate to give the compounds of formulas (I / a) and (I / b), particular cases of the compounds of formula (I):

wherein R _4, R _5, R _6, A and B 'are as defined hereinbefore, which is subjected to a saponification reaction to give the compounds of formulas (Vc) and (JID), particular cases of compounds of formula (I):

in which R ₄ , R ₅ , R ₆ and A are as defined above, and B "represents a group of formula B as defined in formula (T) in which R ₈ represents a COOH group, compounds of formulas (I (a), (I / b), (I / c) and (Vd) which is subjected to the action of a compound of formula NH ₂ OR ₇₅ HCl wherein R ₇ is as defined in the formula (I), to give compounds of formulas (Ve) and (Vf), particular cases of compounds of formula (I):

in which R ₄ , R ₅ , R ₆ , R ₇ , A and B are as defined above, the compounds of formulas (JJa) to (I / f) forming all of the compounds of formula (I), which can be purified according to a conventional separation technique, which are converted, if desired, into their salts; addition to a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique.

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

in which R ₆ is as defined in formula (I), which is subjected to a cyclization reaction in the presence of potassium acetate and palladium acetate, to yield compounds of formulas (VII) and ( VIII):

in which R ₆ is as defined in formula (I), which is subjected to the action of a compound of formula NH ₂ OR ₇₅ HCl in which R ₇ is as defined in formula (I), to yield compounds of formulas (IX) and (X):

in which R ₆ and R ₇ are as defined above, compounds of formulas (VII), (VIII), (IX) and (X) on which a compound of formula (XI) is condensed:

in which A, R ₄ , R ₅ and B are as defined in formula (I), to yield the compound of formula (I),

11. Pharmaceutical compositions containing as active ingredient at least one compound of formula (T) according to any one of claims 1 to 8 or a pharmaceutically acceptable acid or base addition salt thereof, alone or in combination with one or more pharmaceutically acceptable excipients.

12. Pharmaceutical compositions according to claim 11, useful 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, insulin resistance, glucose intolerance, syndrome X-related disorders, coronary artery disease and other cardiovascular diseases, kidney disease, retinopathies, disorders related to activation of endothelial cells, 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, and cancerous pathologies, including hormone-dependent cancers such as breast cancer and colon cancer, and as inhibitors of angiogenesis.

"Association containing a compound of formula (I) according to one of claims 1 to 8 and an antioxidant.

14. The combination of claim 13 wherein the compound of formula (I) is 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H ^" -fluoreno [3,4-cr] [1,3] thiazol-3 (6H) -yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoic acid, its enantiomers and diastereoisomers, and its addition salts with an acid or a base pharmaceutically acceptable.

15, Association according to claim 13 or 14 wherein the antioxidant is coenzyme Q ₁₀ .

16. A combination according to claim 13 which is 3- {4- [2- (6- (hydroxyimino) -2-oxo-2H-fluoreno [3,4-b] [1,3] thiazol- 3 (6H) -yl) ethoxy] phenyl} -2- (2,2,2-trifluoroethoxy) propanoic acid and coenzyme Q ₁₀ .

17, Pharmaceutical compositions containing as active ingredient a combination according to any one of claims 13 to 16 alone or in combination with one or more pharmaceutically acceptable excipients.

18. Pharmaceutical compositions according to claim 17 useful for the manufacture of a medicament for the treatment and / or prevention of obesity. - -

Pharmaceutical compositions according to claim 17, useful for the manufacture of a medicament for the treatment and / or prevention of overweight characterized by a body weight index greater than 25 and less than 30.

20. Use of an association according to any one of claims 13 to 16 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity.

21. Use of an association according to any one of claims 13 to 16 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by a therapeutic treatment.

22. Use of an association according to any one of claims 13 to 16 for obtaining pharmaceutical compositions for the treatment and / or prevention of obesity induced by treatment of type I diabetes or IL

23. Use of a combination according to any one of claims 13 to 16 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. .

24. Use of an association according to any one of claims 13 to 16 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.

25. Use of a combination according to any one of claims 13 to 16 for obtaining pharmaceutical compositions for the treatment and / or prevention of weight overload characterized by a body weight index greater than 25 and less than 30. induced by treatment of type I or II diabetes.