BRPI0713462A2 - derived from tropane urea, its preparation and its application in therapeutics - Google Patents

Abstract

TROPAN UREA DERIVATIVES, THEIR PREPARATION AND THE RESPECTIVE APPLICATION IN THERAPEUTICS. The present invention relates to compounds corresponding to formula (I): in which R ~ 1a ~, R ~ 1b ~, R ~ 1c ~, R ~ 1d ~, R ~ 2a ~, R ~ 2b ~, R ~ 3 ~, R ~ 4 ~, p, r and X are as defined in the description. Process of preparation and application in therapy.

Description

Report of the Invention Patent for "TROPAN UREA DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION".

The present invention relates to tropane urea derivatives, their preparation and their therapeutic application. These compounds modulate the activity of 11β-hydroxysteroid dehydrogenase type 1 (11pHSD1) and are useful for the treatment of conditions in which such modulation is beneficial, such as metabolic syndrome or non-insulin dependent type 2 diabetes. .

11β-hydroxysteroid dehydrogenase type 1 (11pHSD1) locally catalyzes the conversion of inactive glucocorticoids (cortisone in man) to active glucocorticoids (cortisol in man) in different tissues and organs, mainly in the liver and adipose tissue, but also in the muscles. - glasses, bones, pancreas, endothelium, eye tissue and certain parts of the central nervous system. 11pHSD1 acts as a regulator of glucocorticoid action on the tissues and organs where it is expressed (Toginson et al., Endocrine Reviews 25 (5), 831-866 (2004), Davani et al., J. Biol. Chem 275, 34841 (2000); Moisan et al., Endocrinology, 127, 1450 (1990).

The most important pathologies involving glucocorticoids and 113HSD1 inhibition are given below. A. Obesity, Type 2 Diabetes, and Metabolic Syndrome

The role of 11PHSD1 in obesity, type 2 diabetes and metabolic syndrome (also known as syndrome X or insulin resistance syndrome), where symptoms include visceral obesity, glucose intolerance, resistance to Insulin, hypertension, type 2 diabetes and hyperlipidemia (Reaven Ann. Rev. Med. 44, 121 (1993)) are described in numerous publications. In men, treatment with carboxolone (a non-specific inhibitor of 11PHSDI) improves insulin sensitivity in lean volunteer patients and type 2 diabetics (Andrews et al., J. Clin. Endocrinol. Metab. 88, 285 (2003)). In addition, rats whose 113HSD1 gene was extinguished are resistant to stress-induced hyperglycemia and obesity, attenuate hepatic enzyme induction of neuglycogenesis (PEPCK et G6P), and have increased insulin sensitivity in adipose tissue (Kotelevstev et al., Proc. Nat Acad. Sci. 94, 14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001)). On the other hand, transgenic mice in which the pHSD1 gene was overexpressed in adipose tissues have a phenotype similar to that of human metabolic syndrome (Masuzaki et al., Science 294, 2166 (2001)). It should be noted that the observed phenotype exists without an increase in total circulating glucocorticoids, but is induced by the specific increase of active glucocorticoids in adipose deposits.

On the other hand, new classes of 11PHSD1 specific inhibitors will appear recently:

- arylsulfonamidothiazoles have been shown to improve insulin sensitivity and to reduce the glucose level in rat blood with hyperglycemia (Barf et al., J. Med. Chem. 45, 3813 (2002)). Moreover, in a recent study, it was shown that this type of compound reduced food intake as well as weight measurement in obese rats (Wang et Coll. Diabetologia 49, 1333 (2006)).

- triazoles have been shown to improve metabolic syndrome and slow the progression of atherosclerosis in rats (Hermanowski-Vosatka et al., J. Exp. Med. 202, 517 (2005)).

B. Cognition and Dementia

Mild cognitive problems are common phenomena in older people and can eventually lead to the progression of dementia. For both animals and elderly humans, interindividual differences for general cognitive functions were linked to differences in long-term exposure to glucocorticoids (Lupien et al., Nat. Neurosci. 1, 69, (1998)). On the other hand, HPA (hypothalamus-pituitary-adrenal) deregulation) resulting in chronic glucocorticoid exposure of certain brain subregions has been proposed to contribute to the decline of cognitive functions (Mc Ewen et al., Curr Opin, Neurobiol 5, 205, 1995). 11βHSDI is abundant in the brain and is expressed in numerous subregions, including the hypothalamus, frontal cortex, and cerebellum (Sandeep et al., Proc. Natl. Acad. Sci. 101, 6734 (2004)). 11βHSD1-deficient mice are protected against glucocorticoid-associated hypothalamus dysfunctions that are old-age (Yau et al., Proc. Nat. Acad. Sci. 98, 4716, (2001)). In addition, studies in men have shown that carbenoxolone administration improves verbal fluidity and verbal memory in older people (Yau et al., Proc. Nat. Acad. Sci. 98, 4716, (2001), San- Deep et al., Proc. Natl. Acad. Sci. 101, 6734 (2004)). Finally, the use of selective triazole 11βHSDI inhibitors has been shown to prolong memory retention in older rats (Rocha et al., Abstract 231 ACS meeting, Atlanta, 26-30 March 2006).

C. Intraocular Pressure

Glucocorticoids may be used topically or systemically for a wide variety of clinical ophthalmic pathologies. A particular complication of these treatments is corticoid-induced glaucoma. This condition is characterized by increased intraocular pressure (IOP). In these more severe cases and for untreated forms, IOP can lead to a partial loss of field of vision and eventually to a total loss of vision. IOP is the result of an imbalance between aqueous humor production and drainage. Aqueous humor is produced in unpigmented epithelial cells and drainage is performed through trabecular network cells. 11PHSD1 is localized to unpigmented epithelial cells and its function is clearly to amplify glucocorticoid activity in cells (Stokes et al., Invest. Ophthalmol. Vis. Sci. 41, 1629 (2000)). This notion is confirmed by the observation that free concentration is very much in excess of cortisone in aqueous humor (ratio 14/1). The functional activity of 11βHSDI in the eyes was assessed by studying the action of carbenoxolone in healthy volunteers. After seven days of carbenoxolone treatment, the IOP is reduced by 18% (Rauz et al., Invest Ophtamol Vis. Sci. 42, 2037 (2001)). Inhibition of 11βHSD1 in eyes is therefore predicted as reducing the local concentration of glucocorticoids and IOP, producing a beneficial effect in the treatment of glaucoma and other vision disorders.

D. Hypertension

Hypertensive substances from adipocytes such as leptin and angiotensinogene have been proposed as key elements in obesity-related hypertension pathologies (Wajchenberg et al., Endocr. Rev. 21, 697 (200)). Leptin, which is over secreted in transgenic aP2-1 ^ HSDI (Masuzaki et al., J. Clinical Invest. 112, 83 (2003)), can activate different networks of sympathetic neuronal systems, including those regulating blood pressure (Matsuzawa et al., Acad. Sci. 892T, 46 (1999)). ^ ^ ^ ^ ^ Renin-angiotensin system (SARS) has been identified as a determining pathway in blood pressure variation. Angiotensinogene, which is produced in the liver and adipose tissue, is a key substrate for renin and is the trigger for SARS activation. Plasma level in angiotensiogene is significantly elevated in transgenic ap2-1ipHSD1 rats, as are those of angiotensin II and aldosterone (Masuzaki et al., J. Clinical Invest. 112, 83 (2003)); These elements lead to increased blood pressure. Treatment of these mice by small doses of an angiotensin II receptor antagonist abolishes this hypertension (Masuzaki et al., J. Clinical Invest. 112, 83 (2003)). This information illustrates the importance of local activation of glucocorticoids in adipose tissue and liver, and suggests that this hypertension may be caused or exacerbated by 1ipHSD1 activity in these tissues. Inhibition of 11PHSD1 and reduction of glucocorticoid level in adipose tissue and / or liver is therefore predicted to have a beneficial role in the treatment of hypertension and associated cardiovascular pathologies.

E. Osteoporosis

Skeletal development and bone functions are also regulated by the action of glucocorticoids. 1ipHSD1 is present in osteoclasts and osteoblasts. Carbenoxolone treatment of healthy volunteers has shown a decrease in bone resorption markers without change in bone formation markers (Cooper et al., Bone, 27, 375 (2000)). Inhibition of 1ipHSD1 and reduced level of bone glucocorticoids could therefore be used as a protective mechanism in the treatment of osteoporosis.

Deran uranium derivatives that modulate 11PHSDI activity were then discovered.

The present invention relates to compounds corresponding to formula (I):

<formula> formula see original document page 6 </formula>

a hydrogen or halogen atom; a (C1-C5) alkyl group; (C1 -C5) alkoxy; (C1 -C5) haloalkyl, hydroxy; hydroxy- (C1-C5) alkyl, (C1-C5) alkoxy- (C1-C5) alkyl; cyan; a group -COOR5; a group -NR6 R7; a - COOR5 - (C1-C5) alkyl group, a -NR6R7- (C1C5) alkyl group, a - CONR6R7 group, a -CONR6R7 group, - (C1-C5) alkyl group, a group - SO2NR6R7;

- (R2a) P or (R2b) r may also form with the carbon atom to which a group C = O is attached;

- R3 represents a hydrogen atom, a fluorine atom or a (C1-C5) alkyl group; (C1 -C5) alkoxy; C1 -C5 alkoxyalkyl; hydroxy; hydroxy (C1-C5) alkyl; (C1 -C5) alkyl halogen; cyan; a group -COOR5; a group -NR6 R7; a -COOR5- (C1-C5) alkyl group, a -NR6R7- (C1-C5) alkyl group, a -CONR6R7 group, a -CONR6R7- (C1C5) alkyl group.

- R4 represents:

* a hydrogen atom, a (C1-C5) alkyl group;

* a (C3 -C6) cycloalkyl group;

* a heterocyclyl; * a mono- or bicyclic aryl group having from 5 to 10 carbon atoms;

* a mono- or bicyclic heteroaryl group having from 2 to 9 carbon atoms;

- the aryl or heteroaryl group being optionally substituted by 1 to 4 substituents chosen from the halogen atoms, the (C1-C5) alkyl groups; (C1 -C5) alkoxy; (C1 -C5) alkyl halogen; hydroxy; hydroxy (C1-C5) alkyl, (C1-C5) alkoxy (C1-C5) alkyl; cyan; optionally substituted phenyl; optionally substituted benzyl;

-COOR5; -NR6R7; a -COOR5- (C1-C5) alkyl group, a - NR6R7- (C1-C5) alkyl group, a -CONR6R7 group, a -CONR6R7- (C1-C5) alkyl group, a -SO2NR6R7 group, a -NR6 group -COR5;

-per, identical or different, are integers equal to 1 or 2;

-R5 represents a hydrogen atom, a (C1-C5) alkyl group; a (C3 -C6) cycloalkyl group;

- R6 and R7 are identical or different, each representing a hydrogen atom, a (C1-C5) alkyl group; a (C3 -C6) cycloalkyl group; (C1 -C5) alkyl carbonyl; hydroxy (C1 -C5) methyl alkyl; (C1 -C5) alkoxy methyl (C1 -C5) alkyl; an aryl group, a -SO 2 -R 5 group or may form together with the nitrogen atom to which an optionally substituted heterocycle is attached.

The compounds of formula (I) may have one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers, as well as mixtures thereof comprising racemic mixtures, are part of the invention.

The compounds of formula (I) may exist as endo / exo stereoisomers. These endo / exo stereo isomers as well as mixtures thereof are part of the invention.

The compounds of formula (I) may exist as bases or salified by acids or bases, notably pharmaceutically acceptable acids or bases. Such addition salts are part of the invention.

Such salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for purifying or isolating the compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more water molecules or a solvent. Such hydrates and solvates are also part of the invention.

Within the scope of the present invention, and unless otherwise stated in the text:

halogen atom: a fluorine, chlorine, bromine or iodine;

- a (C1-C5) alkyl group: a straight or branched saturated aliphatic group having 1 to 5 successive carbon atoms. By way of example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc;

- a (C3 -C6) cycloalkyl group: a cyclic alkyl group having 3 to 6 carbon atoms. Examples include cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .;

- a (C1-C5) alkoxy group: a -0- (C1-C5) alkyl radical in which the (C1-C5) alkyl group is as defined above:

- an aryl group: a mono- or bicyclic aromatic group comprising from 5 to 10 carbon atoms. Examples of aryl groups include phenyl, thiophene group, furan group or naphthalene group;

- a heteroaryl group: a mono- or bicyclic aromatic group having from 5 to 9 carbon atoms and comprising from 1 to 3 hetero atoms, such as nitrogen, oxygen or sulfur. Examples of the heteroaryl group include:

- pyridine

- pyrazine

- pyrimidine - pyrazole

- oxadiazole

- thiazole

- imidazole

- benzo thiophene

- quinoline

- indol

- a (C1C5) alkyl halogen group: a (C1-C5) alkyl group as defined above substituted by 1 to 5 halogen atoms. For example, fluoro methyl, difluoro methyl, trifluoro methyl, trichloromethyl or pentafluoroethyl groups will be mentioned;

- a heterocycle: a mono- or bicyclic group which may be fused or punctured, having from 4 to 10 atoms, of which at least one is selected from oxygen, nitrogen or sulfur atoms. For example, 2,3-dihydrobenzofuran and 1,4-benzodioxane groups will be cited;

- an "optionally substituted phenyl", "optionally substituted benzyl", "optionally substituted heterocycle" group: a phenyl or benzyl group or a heterocycle which may be substituted by one or more of the following groups: atoms halogen, (C1 -C5) alkyl groups; (C1 -C5) alkoxy; (C1 -C5) alkyl halogen; hydroxy; hydroxy (C1-C5) alkyl, (C1-C5) alkoxy (C1-C5) alkyl; cyan; phenyl; benzyl; -COOR5; - NR6R7; a -COOR5- (C1-C5) alkyl group, a -NR6R7- (C1-C5) alkyl group, a -CONR6R7 group, a -CONR6R7- (C1-C5) alkyl group, a -SO2NR6R7 group;

R1a, b, c, d denotes groups R1a, R1b, R1c and R1d and R2a, b denotes groups R2a and R2b.

Among the compounds of formula (I) objects of the invention there may be cited a subgroup of particularly preferred compounds, wherein X is carbon or oxygen, R 1 to R 7, X, p, r, and the dotted bond being such. as defined above.

Among these latter compounds, particularly preferred compounds of the invention are compounds of formula (I) wherein:

P and r represent 1;

dotted bonds represent a single or double bond;

- R1a, b, c, d represent hydrogen, or one of the groups R1a, b, c, d is a halogen and the others are hydrogen;

R2a, b represents hydrogen or one of R2a groups, b is a (C1 -C5) alkyl group, preferably methyl and the other R2a group, b is hydrogen;

R3 represents hydrogen;

R4 in position 4 is chosen from the following aryls or heteroarils:

- pyridine

- phenyl

- pyrazole

Another particularly preferred group of compounds in the sense of the invention is the derivatives of formula (I), wherein X represents the carbon atom and the dotted bond represents a double bond, R4 is a phenyl or a pyridine, R1a, b, c, d, R2a, b, R3, R5 to R7, ρ and r are as defined above.

Another particularly preferred group of compounds in the sense of the invention is the derivatives of formula (I), wherein X represents the oxygen atom and the dotted bond represents a single bond, R 4 is a phenyl, or a pyridine, Ria, b , c, d, R2a, b, R3, R5 to R7, ρ and r being as defined above.

Another particularly preferred group of compounds in the sense of the invention is those derivatives of formula (I) wherein X represents the carbon atom and the dotted bond represents a single bond, R4 is a phenyl, or a pyridine, or a pyrazole Ria, b, c, d, R2a, b, R3. R5 to R7, ρ and r being as defined above.

Among the compounds of formula (I) according to the invention may be mentioned: (3,4-dihydro-2H-quinolin-1-yl) - ((1S, 3S, 5R) -3-pyridin -4-yl-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-3-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-4-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - ((1S, 5R) -3-pyridin-3-yl-8-aza-bicyclo [3.2.1] oct-8-yl) - methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-2-yl-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-2-yl-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-phenyl-8-aza-bicyclo [3.2.1] oct-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-fluoro-pyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-8-yl] - methanone

[3- (4-chloro-phenyl) -8-aza-bicyclo [3.2.1] oct-8-yl] - (3,4-dihydro-2H-quinolin-1-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-fluoro-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-ethyl-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

2- [8- (3,4-dihydro-2H-quinolin-1-yl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -benzonitrile

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-fluoro-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

[3- (2-chloro-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin-1-yl) - methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-trifluoromethyl-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

5- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -thiophene-2-carbonitrile ( 3-benzo [b] thiophen-2-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) - (3,4-dihydro-2H-quinolin-1-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-m-tolyl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-isopropyl-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

4- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -benzonitrile

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-methoxy-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

3- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -benzonitrile

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-methoxy-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

2- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -benzamide

[3- (2-chloro-thiophen-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin-1 -yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-ethylphenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

[3- (2,3-dihydro-benzo [1,4] dioxin-6-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4 -dihydro-2H-quinolin-1-yl) methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (1H-indol-4-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-one il] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-quinolin-5-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-methoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-methoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (3-fluoro-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone [3- (2,3-dihydro-benzofuran-5-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro- 2H-quinolin-1-yl) methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-trifluoromethyl-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-fluoro-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-p-tolyl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (4-hydroxymethyl-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - methanone

N- {4- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -phenyl)- acetamide

4- [8- (3,4-dihydro-2H-quinoline-1-carbonyl) -8-aza-bicyclo [3.2.1] oct-2-en-3-yl] -N, N-dimethyl- benzamide

(3,4-dihydro-2H-quinolin-1-yl) - [3- (1H-indol-6-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-one il] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-methoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-isoquinolin-4-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

[3- (2-chloro-pyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin-1 -yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-naphthalen-1-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-thiophen-3-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

[3- (4-amino-phenyl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin-1-yl) - methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-fluoro-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-fluoro-2-methyl-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2 -en-8-yl] methanone [3- (2-chloro-6-methyl-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - ( 3,4-dihydro-2H-quinolin-1-yl) methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2,6-dimethoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en -8-yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-isoquinolin-5-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (8-methyl-quinolin-5-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (6-ethoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2-ethoxy-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8 -yl] -methanone

[3- (2,6-difluoro-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin -1-yl) methanone

[3- (5-chloro-2-methoxy-pyridin-4-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H -quinolin-1-yl) methanone

[3- (2,5-dichloro-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H-quinolin -1-yl) methanone

(3-benzo [b] thiophen-5-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) - (3,4-dihydro-2H-quinolin-1-yl ) -methanone

(3-benzo [b] thiophen-7-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) - (3,4-dihydro-2H-quinolin-1-yl ) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (1-methyl-1H-indol-2-yl) -8-aza-bicyclo [3.2.1] oct-2- en-8-yl] methanone

[3- (6-chloro-4-methyl-pyridin-3-yl) -8-aza-bicyclo [3.2.1] oct-2-en-8-yl] - (3,4-dihydro-2H -quinolin-1-yl) methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-3-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - (3-pyridin-3-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl) -methanone

(3,4-dihydro-2H-quinolin-1-yl) - [3- (2H-pyrazol-3-yl) -8-aza-bicyclo [3.2.1] oct-8-yl] -methanone ( 3,4-dihydro-2H-quinolin-1-yl) - [3- (2H-pyrazol-3-yl) -8-aza-bicyclo [3.2.1] oct-8-yl] -methanone

In the following, a protecting group (Pg) is understood to mean a group which, on the one hand, protects a reagent function, such as a hydroxy or an amine during a synthesis and, on the other hand, regenerates the reagent function. intact at the end of synthesis. Examples of protecting groups as well as protecting and deprotecting methods are given in "Protective Groups in Organic Synthesis", Green et al., 3rd Edition (John Wiley & Sons, Inc., New York).

Starting group (Lg) is understood to mean a group which can be easily cleaved from a molecule by disruption of a heterolytic bond with the departure of an electronic pair. This group can thus easily be replaced by another group, for example in a substitution reaction. Such leaving groups are, for example, halogens or an activated hydroxy group, such as a mesyl, tosyl, triflate, acetyl, paranitrile phenyl, etc. Examples of starting groups as well as references for their preparation are given in "Advances in Organic Chemistry", J. Mareh, 3rd Edition, Wiley Interscienee, pages 310-316.

According to the invention, the compounds of formula (I) may be prepared by the following processes. In the case where X represents a nitrogen atom, it must be replaced by either a group R2a, b (other than H) or a protecting group Pg as defined above.

Scheme 1 (Method 1):

<formula> formula see original document page 15 </formula> In Scheme 1, compounds of formula (IV) may be prepared by reaction between the intermediates of formula (II) and a carbonyl of formula (III), having two leaving groups Lg (for example a chlorine atom, a trichloromethoxy group, a para-nitrophenyl group, an imidazol group, or methyl imidazolium) in the presence of a base such as triethyl amine or diisopropyl amine in a solvent , such as dichloromethane, tetrahydrofuran, at a temperature ranging from room temperature to 80 ° C. The compounds of formulas (I) are obtained by coupling the activated derivatives (IV) and the amines (V) in the presence or absence of a base such as triethyl amine or potassium carbonate in a solvent such as tetrahydro. furan, dichloromethane, acetonitrile or water at a temperature ranging from room temperature to 100 ° C.

Heterocycles of formula (II) are commercially available or may be prepared by methods described in the literature (Comprehensive heterocyclic chemistry, Katritzky et al., 2 d Edition (Pergamon press)).

Heterocycles of formula (V) are commercially available or may be prepared by methods described in the literature (Sikazwe et al. Biorg. Med. Chem. Lett 14, 5739 (2004); Gilbert et cot. Biorg. Med Chem. Lett 14, 515 (2004); Lu et al., Biorg. Med. Chem. Lett 13, 1817 (2003)).

Scheme 2 details a synthesis of the compounds of formula (VI), wherein the dotted bond is a double bond and R 4 represents an aryl or heteroaryl group as defined above.

Scheme 2:

<formula> formula see original document page 16 </formula>

In Scheme 2, heterocycles (VIII) whose amine function is protected by a protective group Pg (for example a Boc or Fmoc group) having a vinyl sulfonate-A group (for example A may be a trifluoro methyl group). (a nonafluoro butyl group) may be prepared by converting ketones (VII) with a sulfonating agent such as trifluoro sulfonic anhydride or N-phenyltrifluoromethanesulfonimide in the presence of a base such as lithium diisopropyl amide or lithium hexamethyl disilazane in a solvent, such as tetrahydrofuran or ethylene glycol dimethyl ether at a temperature ranging from -78 ° C to room temperature. Heterocycles (X) are obtained by organometallic coupling between a compound (VIII) and a compound (IX) in which Y is a boron derivative (e.g. a boronic acid or a boronic ester), tin (e.g. tri n-butyl tin group) or a halogen atom (eg bromine or iodine) in the presence of an appropriate metal derivative (e.g. palladium, zinc or copper derivatives) in the presence of a base or not, such as potassium carbonate, potassium fluoride or sodium phosphate in a solvent or mixture of solvents such as dioxane, ethylene glycol dimethyl ether, toluene or water at a temperature ranging from ambient at 120 ° C. In a last step, the amines of formula (VI) are obtained by deprotecting the amine function of the compounds of formula (X) by methods chosen from those known to the person skilled in the art. These include the use of trifluoro acetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran, diethyl ether in the case of a Boc group protection and piperidine for an Fmoc group, at temperatures ranging from -10 to 100 ° C.

Scheme 3 details a synthesis of the compounds of formula (XI) in which the dotted bond is a single bond and R 4 represents an aryl or heteroaryl group as defined above.

Scheme 3:

In Scheme 3, heterocycles (XII) are obtained by hydrogenating the double bond of heterocycles (X) with a suitable metal catalyst in methanol or ethanol. In the second step, the amines of formula (XI) are obtained by deprotecting the amine function of the compounds of formula (XII) by methods chosen from those known in the art. These include the use of trifluoro acetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection by a Boc1 group and piperidine by an Fmoc group at temperatures varying. from -10 to 100 ° C.

Optionally in Scheme 4, the mixture of the endo (XIII) and exo (XIV) stereoisomers may be separated by flash chromatography, high pressure liquid chromatography or recrystallization, in other words it is used as it is called a mixture. (XI).

Scheme 4:

<formula> formula see original document page 18 </formula>

Scheme 5 is an alternative preparation view of the compounds of formula (I), wherein the dotted bond is a single bond and FU represents an aryl or heteroaryl group as defined above, such compounds are hereinafter referred to as compounds of formula (XV). Where X represents a nitrogen atom, it must be replaced either by a group Ffea, b (other than H), or by a protective group Pg as defined above.

Scheme 5 (Method 2):

<formula> formula see original document page 18 </formula> In Scheme 5, amines (XVI) are obtained by deprotecting the amine function of the compounds of formula (VIII) by methods chosen from those known in the art. These include the use of trifluoroacetic acid or hydrochloric acid in dichloromethane, dioxane, tetrahydrofuran or diethyl ether in the case of protection by a Boc1 group and piperidine for an Fmoc group at temperatures range from -10 to 100 ° C. The compounds of formula (XVII) are obtained by coupling the activated derivatives (IV) and the amines (XVI) with or without a base such as triethylamine or potassium carbonate in a solvent such as tetrahydrofuran, dichloromethane, acetonitrile or water at a temperature ranging from room temperature to 100 ° C. In the next step, heterocycles (XVIII) are obtained by organo-metal coupling between a compound (XVII) and a compound (IX) in which Y is a boron derivative (for example a boronic acid or a boronic ester), (e.g. a tri n-butyl tin group) or a halogen atom (for example bromine or iodine) in the presence of a suitable metal derivative (for example a palladium, zinc or copper) in the presence of a base or not, such as potassium carbonate, potassium fluoride or sodium phosphate in a solvent or solvent mixture, such as dioxane, ethylene glycol dimethylether, toluene or water, a temperature ranging from room temperature to 120 ° C. In a last step, the double bond of the heterocycles (XVIII) is hydrogenated with a suitable metal in methanol or ethanol to lead to derivatives (XV).

Optionally, in Scheme 6, the mixture of the endo (XIX) and exo (XX) stereoisomers may be separated by means of flash chromatography, high pressure liquid chromatography or recrystallization, in other words it is used as it is called mixture. (XV). Scheme 6: <formula> formula see original document page 20 </formula>

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and merely illustrate the present invention. The exemplified compound numbers refer to those given in the following table, which illustrates the chemical structures and physical properties of some compounds according to the invention. Example 1: 1 - [(3-Pyridin-3-yl-8-azabicyclor3.2.noct-8-yl) carbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (Compound 4) 1.1: tert-butyl 3 - ([(trifluoro methyl) sulfonyloxy) -8-aza bicyclo [3.2.1] oct -2-en-8-carboxylate.

In a 500 ml triple neck under nitrogen, 10 ml of a 2.5 N solution of n-butyllithium in hexane are added dropwise to a solution of 3.73 ml of diisopropyl amine in 100 ml of tetrahydrofuran res. - cooled to -60 ° C. After a quarter hour of stirring, 5 g of N-tert-butyloxycarbonyl nortropinone is added in tetrahydrofuran (50 ml) at 0 ° C. Finally, always at 0 ° C, 8.32 g of N-phenyl trifluoromethane sulfonimide are added. After stirring for 24 hours at room temperature, tetrahydrofuran is evaporated and the product is purified by flash filtration over alumina using a 2/1 heptane / ethyl acetate mixture as a purifier. 6.13 g of tert-butyl 3 - {[(trifluoro methyl) sulfonyl] oxide} -8-aza bicyclo [3.2.1] oct -2-en-8-carboxylate are obtained. M + H + = 358

1.2: 8-Aza bicyclor3.2.11oct -2-en-3-trifluoro methyl sulfonate hydrochloride.

In a 100 ml flask 2.76 g of tert-butyl 3 - {[(trifluoromethyl) sulfonyl] oxide} -8-aza bicyclo [3.2.1] oct -2-en-8-carboxylate are placed in 13 ml dioxane. 12.8 ml of a 4N hydrochloric acid solution in dioxane are then added gently. The reaction mixture is stirred for 3 hours. The dioxane is evaporated to give 2.27 g of 8-azabicyclo [3.2.1] oct-2-en-3-yl trifluoromethyl sulfonate hydrochloride. M + H + = 258 1.3: 8- (3,4-dihydruinolin-1 (2H) -ylcarbonyl) -8-aza bicyclo [3.2.1] oct-2-en-3-yl trifluoro methane sulfonate.

In a 250 ml triple neck under a nitrogen atmosphere is placed 1.13 g 1,2,3,4-tetrahydro quinoline, 85 ml dichloromethane and 1.54 ml triethyl amine. 0.834 g of triphosgene is added at 0 ° C, then the reaction is allowed to stir at room temperature for 4 hours. Then 2.27 g of 8-aza bicyclo [3.2.1] oct -2-en-3-yl trifluoro methyl sulfonate hydrochloride as well as 1.19 ml of triethyl amine are added, then the reaction mixture is refluxed for 18 hours. 200 ml of a saturated aqueous sodium hydrogen carbonate solution are added, then the aqueous phase is extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on silica gel by an 8/2 heptane / ethyl acetate mixture. 3.21 g of 8- (3,4-dihydroquinolin-1 (2H) -ylcarbonyl) -8-aza bicyclo [3.2.1] oct-2-en-3-yl trifluoromethanesulfonate are obtained.

M + H + = 417

1.4: 1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-2-en-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline

0.5 g of dihydroquinolin-1 (2H) -ylcarbonyl) -8-aza bicyclo [3.2.1] oct -2-en-3-yl trifluoro methane sulfonate are introduced into a 10 ml glass tube. 0.419 g of 3- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) pyridine, 0.1 g lithium chloride, 0.765 g potassium phosphate, 0.067 g of 2 - (dimethyl amino) -2-biphenyl palladium (II) dinorbornyl phosphine chloride and 4.3 ml dioxane. The tube is anchored, then heated to 100 ° C under microwave irradiation for 50 minutes. Water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is chromatographed on silica gel by a 3/7 heptane / ethyl acetate mixture. 0.3 g of 1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct -2-en-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline is obtained

M + H + = 346 1.5: 1-Γ (3-pyridin-3-yl-8-aza bicyclo3.2.11oct-8-yl) carbonyl -1,2,3,4-tetrahydroquinoline

In a high pressure reactor under nitrogen 0.148 g of 5% palladium on carbon is added to 0.240 g of 1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct -2 - en-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline solubilized in 9 ml of ethanol. The reaction mixture is placed under a pressure of 3 atmospheres of hydrogen at 25 ° C. and mechanically stirred for 15 hours. Palladium is filtered on Whatman paper and is washed with methanol. The solvent is evaporated, then the residue is chromatographed on silica gel with a heptane / ethyl acetate (3/7) to hepta / ethyl acetate (2/8) scrubber gradient. 0.146 g of 1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline is obtained.

M + H + = 348.3

1.6: H (3-Pyridin-3-yl-8-aza bicyclof3.2.11oct-8-yl) carbonyl-1,2,3,4-tetrahydroquinoline hydrochloride

1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline is dissolved in 6 ml of dichloromethane and 4.2 ml of a 4N hydrochloric acid solution in dioxane are added.

After evaporation, the residue is taken up in ethyl acetate. The precipitate is filtered, then dried under vacuum. 0.122 g of 1 - [(3-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline hydrochloride is obtained.

Melting point: 218-220 0C

M + H + = 348.3

1H-NMR (DMSO, 200MHx), δ (ppm): 1.4-2 (m, 9H), 2.2-2.44 (m, 1H), 2.6-2.78 (t, 2H); 2.9-3.1 (m, 0.4H), 3.2-3.45 (m, 0.6H), 3.5-3.61 (m, 2H), 4.1 (sl, 2H ), 6.78-6.98 (m, 1H), 7-7.2 (m, 3H), 7.8-7.96 (m, 1H), 8.3-8.55 (m, 1H) ), 8.64-8.9 (m, 2H).

Example 2: 1- (β (3-endo) -3-pyridin-2-yl-aza bicyclo3.2.11oct-8-yl carbonyl) -1,2,3,4-tetrahydroquinoline hydrochloride (Compound 5)

2.1: H (3-pyridin-2-yl-8-aza bicyclor3.2.11oct-2-en-8-yl) carbonyl -1,2,3,4-tetrahydroquinoline In an 80 ml glass tube are 2.87 g of tri-butyl tin 2-pyridine, 0.6 g of lithium chloride, 0.5 g of dihydro-quinolin-1 (2H) -ylcarbonyl) -8-aza-bicyclo [3.2. 1] oct-2-en-3-trifluoro methane sulfonate, 0.249 g of diphenyl phosphine palladium dichloride (11) and 19 ml of tetrahydrofuran. The tube is anchored, then heated to 140 ° C under microwave irradiation for one hour. The reaction mixture is filtered, then ethyl acetate and 0.5N aqueous potassium chloride solution are added.

The mixture is then filtered, then the organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel by a heptane / ethyl acetate mixture. 0.73 g of 1 - [(3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct-2-en-8-yl) carbonyl] -1,2,3,4-tetra are obtained -hydroquinoline. M + H + = 346

2.2: 1-IR3-endo) -3-pyridin-2-yl-8-aza bicyclor3.2.11oct-8-carbonyl) -1,2,3,4-tetrahydroquinoline

In a high pressure reactor under nitrogen, 0.5 g of 5% palladium on charcoal is added to 0.81 g of 1 - [(3-pyridin-2-yl-8-aza bicyclo [3.2.1 ] oct-2-en-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline solubilized in 29 ml of ethanol. The reaction medium is placed under 3 atmospheric hydrogen pressure at 25 ° C and mechanically stirred for 7 hours. The palladium is filtered over Whatman paper and washed by methanol. The solvent is evaporated, then the residue is chromatographed on silica gel, heptane / ethyl acetate scrubber gradient. 0.221 g of 1 - {[(3-endo) -3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct -8-yl] carbonyl} -1,2,3,4-tetra are obtained - hydroquinoline and 0.141 g of 1 - {[(3-exo) -3-pyridin-2-yl-aza bicyclo [3.2.1] oct -8-yl] carbonyl} -1,2,3,4- tetrahydroquinoline M + H + = 348.3

2.3: 1- (f (3-endo) -3-pyridin-2-yl-8-aza bicyclor3.2.11oct-8-yl] carbonyl) -1,2,3,4-tetrahydroquinoline hydrochloride

0.221 g of 1 - {[(3-endo) -3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct -8-yl] carbonyl} -1,2,3 is dissolved, 4-tetrahydroquinoline in 5.3 ml of dichloromethane and 6.4 ml of a solution of 0.2 N hydrochloric acid in ether are added. The precipitate is filtered, then dried under vacuum. 0.161 g of 1 - {[(3-endo) -3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct-8-yl] carbonyl} -1,2,3,4 hydrochloride are obtained. - tetrahydroquinoline.

Melting point: 161-163 ° C;

M + H + = 348.3

1H-NMR (CDCl3, 200MHz), δ (ppm): 1.36-1.56 (m, 2H), 1.67-1.8 (m, 2H), 1.85-2.1 (m, 4H ), 2.24-2.4 (m, 2H), 2.7 (t, 2H), 3 (q, 1H), 3.62 (t, 2H), 4-4.12 (m, 2H) 6.82 (t, 1H), 6.93-7.09 (m, 3H), 7.15-7.3 (m, 2H), 7.43-7.59 (m, 1h), 8 4-8.5 (m, 1H).

Example 3: 1- (N (3-Exo) -3-pyridin-2-yl-8-aza bicyclor3.2.11oct-8-ylcarbonyl) -1,2,3,4-tetrahydroquinoline hydrochloride (Compound 6)

0.13 g of 1 - {[(3-exo) -3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct -8-yl] carbonyl} -1.2 is dissolved, 3,4-Tetrahydroquinoline obtained by Example 2 (part 2.2) in 3.1 ml of dichloromethane and 3.7 ml of a solution of 0.2 N hydrochloric acid in the ether are added. After evaporation, the residue is taken up in ethyl acetate. The precipitate is filtered, then dried under vacuum. 0.101 g of 1 - {[(3-exo) -3-pyridin-2-yl-8-aza bicyclo [3.2.1] oct -8-yl] carbonyl} -1,2,3,4 hydrochloride are obtained. - tetrahydroquinoline.

Melting point: 178-180 ° C

M + H + = 348.3

1H-NMR (CDCl3, 200MHz), δ (ppm): 1.65-2 (m, 10H), 2.7 (t, 2H), 3.09-3.3 (m, 1H), 3.2 ( t, 2H), 4-4.2 (t, 2H), 6.84 (t, 1H), 6.95-7.23 (m, 5H), 7.5-7.67 (m, 1H) , 8.45 (d, 1H).

Example 4: 1- (4-Pyridin-3-yl-8-aza bicyclo [3.2.11 oct-8-yl carbonyl] -1,2,3,4-tetrahydroquinoline hydrochloride (Compound 1)

4.1: tert-Butyl 3-pyridin-4-yl-8-aza bicyclor3.2.1 Ioct-2-en-8-carboxylate

1 g of tert-butyl 3 - {[(trifluoro methyl) sulfonyl] oxy} - 8-aza bicyclo [3.2.1] oct-2-ene-8-carboxylate, 0.975, is introduced into an 80 ml glass tube. 4- (4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl) pyridine, 0.24 g lithium chloride, 1.78 g potassium phosphate, 0.157 g 2 '- (dimethylamino) -2-biphenyl palladium (11) dinorbornyl phosphine chloride and 10 ml dioxane. The tube is anchored, then heated to 100 ° C under microwave irradiation for 30 minutes. Water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane / ethyl acetate mixture. 0.458 g of tert-butyl 3-pyridin-4-yl-8-aza bicyclo [3.2.1] oct -2-ene-8-carboxylate are obtained.

M + H + = 387

4.2: tert-butyl 3-pyridin-4-yl-8-aza bicyclo [3.2.1] octane-8-carboxylate

In a high pressure reactor under nitrogen 0.17 g of 5% palladium on charcoal is added to 0.46 g of tert-butyl 3-pyridin-4-yl-8-aza bicyclo [3.2.1 ] oct-2-ene carboxylate solubilized in 20 ml of methanol. The reaction mixture is placed under a pressure of 3 atmospheres of hydrogen at 25 ° C, and mechanically stirred for two and a half hours. Palladium is filtered on Whatman paper and washed with methanol. The solvent is evaporated and 0.46 g of tert-butyl 3-pyridin-4-yl-8-aza bicyclo [3.2.1] octane-8-carboxylate is obtained.

M + H + = 289

4.3: 3-Pyridin-4-yl-8-aza bicyclo3.2.11 octane dihydrochloride

In a 10 ml flask are placed 2.76 g of tert-butyl 3-pyridin-4-yl-8-aza bicyclo [3.2.1] octane-8-carboxylate and 4 ml of a 4N hydrochloric acid solution in dioxane. The reaction mixture is stirred for 1.5 hours. The dioxane is evaporated and 0.341 g of 3-pyridin-4-yl-aza bicyclo [3.2.1] octane dihydrochloride is obtained.

M + H + = 189

4.4: 1 - [(4-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3.4-tetrahydroquinoline

In a 50 ml flask under a nitrogen atmosphere, 0.241 g 1,2,3,4-tetrahydroquinoline, 20 ml dichloromethane and 0.24 ml triethyl amine are placed. 0.178 g of triphosphine is added at 0 ° C, then the reaction mixture is allowed to stir at room temperature for 3 hours. Then 0.34 g of 3-pyridin-4-yl-8-aza bicyclo [3.2.1] octane dihydrochloride as well as 1.19 ml of triethyl amine are added, then the reaction mixture is refluxed for 2 hours. three hours. 200 ml of a saturated aqueous sodium hydrogen carbonate solution are added, then the aqueous phase is extracted three times to dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel by a 9/1 dichloromethane / methanol mixture. 0.04 g of 1 - [(4-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline are obtained.

M + H + = 348

4.5: 1 - [(4-Pyridin-3-yl-8-aza bicyclo [3.2.1] oct -8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline hydrochloride

0.04 g of 1 - [(4-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline is dissolved in 1.15 ml of a solution of 0.2 N hydrochloric acid in ether. After evaporation, the residue is taken up in ethyl acetate. The precipitate is filtered, then dried under vacuum. 0.004 g of 1 - [(4-pyridin-3-yl-8-aza bicyclo [3.2.1] oct-8-yl) carbonyl] -1,2,3,4-tetrahydroquinoline hydrochloride is obtained.

Melting point: 216-222 ° C

M + H + = 348.2

1H-NMR (DMSO, 200MHz), δ (ppm): 1.65-1.95 (m, 10H), 2.65 (t, 2H), 3.2-3.4 (m, 1H), 3, 45 (t, 2H), 4.05 (sl, 1H), 6.75-6.9 (m, 1H), 6.95-7.2 (m, 2H), 7.78 (d, 2H) 8.64 (d, 2H).

The following table illustrates the chemical structures and physical properties of some examples of compounds according to the invention. In this table:

- in the "salt" column, "-" represents a compound in the free base form, while "HCl" represents a compound in the hydrochloride form. <table> table see original document page 27 </column> </row> <table> Continued

<table> table see original document page 28 </column> </row> <table> <table> table see original document page 29 </column> </row> <table> <table> table see original document page 30 < / column> </row> <table> <table> table see original document page 31 </column> </row> <table> <table> table see original document page 32 </column> </row> <table> <table> table see original document page 33 </column> </row> <table> Continued

<table> table see original document page 34 </column> </row> <table> <table> table see original document page 35 </column> </row> <table> <table> table see original document page 36 < / column> </row> <table> The compounds according to the invention have as their object pharmacological tests to determine their inhibitory effect on the enzyme 11beta-HSD1 which is an enzyme involved in lipid metabolism or metabolism. of glucose.

These tests consisted of measuring the in vitro inhibitory activity of the compounds of the invention by means of a 384-well format Scintillation Proximity Assay (SPA) test. Recombinant 11beta-HSD1 protein was produced in S. cerevisiae lipid. The reaction was performed by incubating the enzyme in the presence of 3H-Cortisone and NADPH in the absence or presence of increasing inhibitor concentration. SPA beads coupled with an anti-mouse antibody, preincubated with an anti-cortisol antibody, allowed to measure the amount of cortisol formed during the reaction.

The inhibitory activity against the enzyme Hbeta HSD1 is given by the concentration that inhibits 50% of the activity of 11beta-HSD1 (IC50).

The IC 50 of the compounds according to the invention are less than 1 μΜ. For example, the IC 50 of compounds n and 4, 7, 13, 28 and 55 are respectively 0.019 μΜ, 0.004 μΜ, 0.122 μΜ, 0.19 μΜ and 0.534 μΜ.

Therefore, it appears that the compounds according to the invention have an inhibitory activity of the 11 beta-HSD1 enzyme. The compounds according to the invention may therefore be used for the preparation of medicaments, in particular 11beta-HSD1 enzyme inhibitor medicaments.

Thus, in another aspect thereof, the invention relates to medicaments comprising a compound of formula (I), or a salt thereof in addition to a pharmaceutically acceptable acid, or a hydrate or solvate of the compound of formula (I). ).

These drugs find use in therapy, notably in the treatment of obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome, hypertension, atherosclerosis, and dementia, glaucomas, osteoporosis and certain infectious diseases, increasing the effectiveness of the immune system.

In another aspect, the present invention relates to pharmaceutical compositions comprising as active ingredient a compound according to the invention. Such pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, hydrate or solvate of such compound as well as at least one pharmaceutically acceptable excipient.

Such excipients are chosen according to the pharmaceutical form and desired mode of administration from the usual excipients known to the skilled artisan.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, solvate or hydrate It may, if appropriate, be administered in unit dosage form, in admixture with classical pharmaceutical excipients, in animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention may be used in creams, gels, ointments or lotions.

By way of example, a unit dosage form of a compound according to the invention in tablet form may comprise the following compounds:

Compound according to the invention 50.0 mg

Mannitol 223.75 mg

Croscaramelose Sodium 6.0 mg

Starchy Corn 15.0 mg

Hydroxy Propyl Methyl Cellulose 2.25 mg Magnesium Stearate 3.0 mg

The present invention, in another aspect, also relates to a method of treating the above conditions comprising administering to a patient an effective dose of a compound according to the invention or one of its salts. pharmaceutically acceptable hydrates or solvates.

Claims (10)

1. A compound corresponding to formula (I) <formula> formula see original document page 40 </formula> in which: - X represents either a carbon, oxygen, sulfur or nitrogen atom or SO2 group; the dotted bond is a single bond or a double bond; - Ria, b, c, d and R2a, b, identical or different, each represent a hydrogen or halogen atom; a (C1-C5) alkyl group; (C1 -C5) alkoxy; (C1 -C5) haloalkyl, hydroxy; hydroxy- (C1-C5) alkyl, (C1-C5) alkoxy- (C1-C5) alkyl; cyan; a group -COOR5; a group -NR6 R7; a -COOR5- (C1-C5) alkyl group, a -NR6Ry- (C1-C5) alkyl group, a -CONR6R7 group, a -CONR6R7- (C1-C5) alkyl group, a -SO2NR6R7 group; - (R2a) p or (R2b) r may also form with the carbon atom to which a group C = O is attached; - R3 represents a hydrogen atom, a fluorine atom or a (C1-C5) alkyl group; (C1 -C5) alkoxy; C1 -C5 alkoxyalkyl; hydroxy; hydroxy- (C1-C5) alkyl; (C1 -C5) alkyl halogen; cyan; a group -COOR5; a group -NR6 R7; a -COOR5- (C1-C5) alkyl group, a -NR6R7- (C1-C5) alkyl group, a -CONR6R7 group, a -CONR6R7- (C1 -C5) alkyl group. - R4 represents: * a hydrogen atom, a (C1-C5) alkyl group; * a (C3 -C6) cycloalkyl group; * a heterocyclyl; * a mono- or bicyclic aryl group having from 5 to 10 carbon atoms; * a mono- or bicyclic heteroaryl group having from 2 to 9 carbon atoms; the aryl or heteroaryl group being optionally substituted by -1 to 4 substituents chosen from the halogen atoms, the (C1-C5) alkyl groups; (C1 -C5) alkoxy; (C1 -C5) alkyl halogen; hydroxy; hydroxy (C1-C5) alkyl, (C1-C5) alkoxy (C1-C5) alkyl; cyan; optionally substituted phenyl; optionally substituted benzyl; -COOR5; -NR6R7; a -COOR5- (C1-C5) alkyl group, a -NR6R7- (C1-C5) alkyl group, a -CONR6R 'group, a -CONR6Ry- (C1-C5) alkyl group, a -SO2NR6R' group, a -NR6-COR5; -per, identical or different, are integers equal to 1 or 2; - R5 represents a hydrogen atom, a (C1 -C5) alkyl group; a (C3 -C6) cycloalkyl group; - R6 and R7, identical or different, each represent a hydrogen atom, a (C1-C5) alkyl group; a (C3 -C6) cycloalkyl group; (C1 -C5) alkyl carbonyl; hydroxy (C1 -C5) methyl alkyl; (C1-C5) alkoxymethyl (C1-C5) alkyl; an aryl group, a -SO 2 -R 5 group or may form together with the nitrogen atom to which an optionally substituted heterocycle is attached; their salts, solvates and hydrates, as well as their enantiomers and diastereomers, including racemic mixtures thereof. Compounds according to claim 1 wherein X is carbon or oxygen, R 1 to R 7, X, p, r and dotted bonding are as defined in claim 1. Compounds of formula (I) according to claim 2, wherein: ρ and r represent 1; the dotted bond represents a single or double bond; - R1a, b, c, d represent hydrogen, or one of the groups Ria, b, c, d is a halogen and the other groups R1a, b, c, d are hydrogen; R2a, b are hydrogen or one of R2a groups, b is a (C1-C5) alkyl group, preferably methyl and the other group is hydrogen; R3 represents hydrogen; R4 in position 4 is chosen from the following aryl or heteroaryl: - pyridine - phenyl - pyrazole Compounds of formula (I) according to claim 2, wherein X represents the carbon atom and the dotted bond represents a double bond, R4 is a phenyl or a pyridine, Ria, b, c, d, R2a, b, R3, R5 to R7, ρ er being as defined in claim 1. Compounds of formula (I) according to claim 2, wherein X represents the oxygen atom and the dotted bond represents a single bond, R 4 is a phenyl, or a pyridine, or a pyrazole. , Ria, b, c, a, R2a, b. R3, R5 to R7, ρ and r being as defined in claim 1. Compounds of formula (I) according to claim 2, wherein X represents the dotted carbon atom represents a single bond, R4 is a phenyl, or a pyridine, or a pyrazole, Ria, b, c, d, R2a, b, R3, R5 to R7, ρ er being as defined in claim 1. Process for preparing a compound of formula (I) according to any one of claims 1 to 6, characterized in that a compound of formula (IV) is reacted: <formula> formula see original document page Wherein: - R1a, b, c, d, R2a, b, P and r are as defined in claim 1 for the compounds of formula (I) and - Lg is a leaving group; with a compound of formula (V) wherein: - R 3 and R 4 are as defined in claim 1 for the compounds of formula (I); and eventually transforming the compound thus obtained into one of its salts. Medicament, characterized in that it comprises a compound of formula (I) as defined in any one of claims 1 to 6, or a salt of addition of such compound to a pharmaceutically acceptable acid, or a hydrate or solvate of the compound. of formula (I). Pharmaceutical composition, characterized in that it comprises a compound of formula (I) as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as well as by at least one pharmaceutically acceptable excipient. Use of a compound of formula (I) as defined in any one of claims 1 to 6 for the preparation of a medicament for the treatment of obesity, diabetes, insulin resistance, metabolic syndrome, Cushing's syndrome1 of hypertension, atheroselerosis, cognition and dementia disorders, glaucomas, osteoporosis and certain pathological conditions, requiring activation of the immune system.