Derivatives of 5-pyridinyl-1-azabicyclo[3.2.1]octane, preparation method thereof and use of same in therapeutics

1. A compound of formula (I):

in which:

R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

2. The compound of formula (I) according to claim 1 , wherein

R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

3. The compound of formula (I) according to claim 1 , wherein

R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

4. The compound of formula (I) according to claim 1 , wherein

R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

5. The compound of formula (I) according to claim 1 , wherein

R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

6. The compound of formula (I) according to claim 1 , wherein

R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

7. The compound of formula (I) according to claim 1 , wherein

R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl groups; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

8. The compound of formula (I) according to claim 1 , which is chosen from the following compounds:

5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;

5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]-oct-3-ene;

5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene

5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo [3.2.1]oct-3-ene

5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo [3.2.1]octane

5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo [3.2.1]octane

5-[2-(1H-imidazol-2-yl)pyrid-5-yl]-1-azabicyclo [3.2.1]octane

5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(1H-1,2,4-triazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(thiazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane

5-[2-(pyrazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane

5-[2-(2-methylthiazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane

5-[2-(tetrazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

5-[2-(1-isobutyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane; and

5-[2-(1-n-propyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;

or an acid-addition salt thereof, a pure enantiomer or a mixture of enantiomers thereof.

9. A process for preparing a compound of formula (I) according to claim 1 , comprising

reacting a compound of formula (V) or (VI):

in which Z represents a bromine atom, with a boronic acid of formula R—B(OH) 2 in which R is as defined in claim 1 , in the presence of a palladium catalyst;

or with a compound of formula R—H in which R is as defined in claim 1 , in the presence of a strong base in a solvent;

or with a stannous derivative of formula R—Sn[(CH 2 ) 3 CH 3 )] 3 in which R is as defined in claim 1 , in the presence of a palladium catalyst;

or with a compound of formula R—H in which R is as defined in claim 1 , in the presence of n-butyllithium, zinc chloride and a palladium catalyst.

10. A process for preparing a compound of formula (I):

in which:

R represents a group chosen from triazolyl, oxadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein

the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond,

comprising

reacting a compound of formula (VI):

in which Z represents a bromine atom,

with potassium cyanide in the presence of tetrakis(triphenylphosphine)palladium in a solvent to obtain a compound of formula (VII):

and then

reacting the compound of formula (VII) with formic hydrazide in the presence of a strong base in a solvent when R represents a triazolyl group; or

converting the compound of formula (VII) into the N-hydroxycarboxamidine of formula (VIII) when R represents an oxadiazolyl group,

in the presence of hydroxylamine hydrochloride in basic medium, and then reacting compound of formula (VIII) with acetic anhydride in a solvent; or

reacting the compound of formula (VII) with sodium azide in the presence of ammonium chloride in a solvent when R represents a tetrazolyl group.

11. A compound of formula (VII):

12. A compound of formula (VIII):

13. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising a compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising a compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising a compound of formula (I) according to claim 6 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

19. A pharmaceutical composition comprising a compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.

20. A pharmaceutical composition comprising a compound of formula (I) according to claim 8 or a pharmaceutically acceptable salt thereof in combination with at least one pharmaceutically acceptable excipient.