Pyrimido-benzimidazole derivatives and the use thereof in the form of agonists and antagonists of melanocortin receptors

1. A compound of formula (I)

in racemic or enantiomeric form or any combinations of thereof, wherein:

A is —CH 2 — or —C(O)—;

R 1 is a hydrogen atom; a (C 1 -C 8 ) alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C 2 -C 6 ) alkenyl; or a radical of formula —(CH 2 ) n —X 1 ;

R 2 is a (C 1 -C 8 ) alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals; (C 2 -C 6 ) alkenyl; or a radical of formula —(CH 2 ) n —X 1 ;

each X 1 is, independently, a (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl radical,

the (C 3 -C 7 ) cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents including —(CH 2 ) n —V 1 —Y 1 , halo, nitro, cyano or aryl;

V 1 is —O—, —S— or a covalent bond;

Y 1 represents is a (C 1 -C 6 ) alkyl radical optionally substituted by one or more identical or different halo radicals;

n is an integer from 0 to 6 and n′ an integer from 0 to 2 with the proviso that when n is equal to 0, X 1 is not an alkoxy radical;

or R 1 and R 2 form, together with the nitrogen atom to which they are attached,

a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different substituents including hydroxy, (C 1 -C 6 ) alkyl optionally substituted by hydroxy, (C 1 -C 6 ) alkoxy-carbonyl, heterocycloalkyl or —C(O)—NV 1 ′Y 1 ′ wherein V 1 ′ and Y 1 ′ are, independently, a hydrogen atom or a (C 1 -C 6 ) alkyl; or

a radical of formula:

R 3 is a radical of formula —(CH 2 ) s —R′ 3 ;

R′ 3 is a guanidino radical; a heterocycloalkyl comprising at least one nitrogen atom and optionally substituted by (C 1 -C 6 ) alkyl or aralkyl; a heteroaryl comprising at least one nitrogen atom and optionally substituted by (C 1 -C 6 ) alkyl; or a radical of formula —NW 3 W′ 3

W 3 is a hydrogen atom or (C 1 -C 8 ) alkyl;

W′ 3 is a radical of formula —(CH 2 ) s —Z 3 ;

Z 3 is a hydrogen atom, (C 1 -C 8 ) alkyl optionally substituted by one or more identical or different substituents including a (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) alkylthio; hydroxy; (C 2 -C 6 ) alkenyl; (C 3 -C 7 ) cycloalkyl optionally substituted by one or more identical or different (C 1 -C 6 ) alkyl substituents; cyclohexene; heteroaryl or aryl;

the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals including: a radical of formula —(CH 2 ) s″ —V 3 —Y 3 , hydroxy, halo, nitro or cyano;

V 3 is —O—, —S—, —NH—C(O)—, —NV′ 3 or a covalent bond;

Y 3 is a hydrogen atom or a (C 1 -C 6 ) alkyl radical optionally substituted by one or more identical or different halo radicals;

V 3 ′ is a hydrogen atom or a (C 1 -C 6 ) alkyl;

s″ is an integer from 0 to 4;

or Z 3 is a radical of formula

s and s′ are, independently, an integer from 0 to 6;

B is a condensed, unsaturated, aromatic or non-aromatic mono- or bi-cyclic radical, optionally comprising one or more identical or different heteroatoms including O, S and N, and optionally substituted by one or more radicals, identical or different, including halo, nitro, cyano, oxy, —X B —Y B , or aryl optionally substituted by one or more substituents including halo and (C 1 -C 6 ) alkyl optionally substituted by one or more identical or different halo radicals;

X B is a covalent bond, —O—, —S—, —C(O)—, —NR N C(O)—, —C(O)—NR N , —C(O)—O—, —SO 2 — or —SO 2 NH—;

Y B is a hydrogen atom or a (C 1 -C 6 ) alkyl radical optionally substituted by one or more identical or different halo radicals;

R N is a hydrogen atom or a (C 1 -C 6 )alkyl radical;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein A is —C(O)—; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 1 and R 2 are, independently, a (C 1 -C 8 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein R 1 and R 2 are, independently, a (C 1 -C 6 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein R 1 and R 2 are, independently, a butyl, pentyl or isopentyl radical; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein R′ 3 is a heterocycloalkyl comprising at least one nitrogen atom and optionally substituted by (C 1 -C 6 ) alkyl or benzyl; or a radical of formula —NW 3 W′ 3 wherein W 3 is a hydrogen atom or a (C 1 -C 8 ) alkyl radical, and W′ 3 is a Z 3 radical and Z 3 is a hydrogen atom or a (C 1 -C 8 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein B is a radical including phenyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzothienyl, thieno-pyridinyl, thieno-pyrazinyl, indolyl, benzofuryl, cyclopentenyl, cyclohexenyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridinyl, tetrahydrobenzo-thienyl or dihydrocyclopentathienyl.

8. The compound according to claim 7 , wherein B is optionally substituted by one or more radicals, identical or different, including: halo, nitro, cyano, oxy, —X B —Y B , or phenyl optionally substituted by one or more substituents including halo or (C 1 -C 6 ) alkyl optionally substituted by one or more identical or different halo radicals;

X B is a covalent bond, —O—, —S—, —C(O)—, —NR N —C(O)— or —C(O)—O—;

Y B is a hydrogen atom or a (C 1 -C 6 ) alkyl radical optionally substituted by one or more identical or different halo radicals;

R N is a hydrogen atom; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein B is a radical including phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, thiazolyl, pyrazinyl, benzothienyl, thieno-pyridinyl, thieno-pyrazinyl, indolyl, benzofuryl, cyclohexenyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrobenzothienyl or dihydrocyclopentathienyl.

10. The compound according to claim 9 , wherein B is optionally substituted by one or more radicals, identical or different, including halo, nitro, cyano, —X B —Y B , or phenyl optionally substituted by one or more substituents including halo or (C 1 -C 6 ) alkyl;

X B is a covalent bond, —O—, —S—, —C(O)—, or —C(O)—O—;

Y B is a hydrogen atom or a (C 1 -C 6 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein B is a radical including phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, benzothienyl, thieno-pyridinyl, indolyl, benzofuryl, cyclohexenyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrobenzothienyl or dihydrocyclopentathienyl.

12. The compound according to claim 11 , wherein B is optionally substituted by one or more radicals, identical or different, including halo, nitro or —X B —Y B ; X B is a covalent bond, —O—, —C(O)— or —C(O)—O—; Y B is a (C 1 -C 6 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 , wherein B is optionally substituted by one or more radicals, identical or different, including halo, nitro or —X B —Y B ; X B is a covalent bond or —O— and Y B is a (C 1 -C 6 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein R′ 3 is a heterocycloalkyl comprising at least one nitrogen atom and optionally substituted by (C 1 -C 6 ) alkyl; or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 , wherein R′ 3 is a piperidinyl or pyrrolidinyl radical; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein R′ 3 is a heterocycloalkyl with 5 to 6 members and comprising a single nitrogen atom and optionally an oxygen atom; or a radical of formula —NW 3 W′ 3 wherein W 3 is a hydrogen atom or a (C 1 -C 6 ) alkyl radical, W′ 3 is a Z 3 radical and Z 3 is a hydrogen atom or a (C 1 -C 6 ) alkyl radical; or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16 , wherein R′ 3 is a piperidinyl or pyrrolidinyl radical and s is an integer from 2 to 4; or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 , wherein B is a radical including: phenyl, thienyl, pyrrolyl, pyrazolyl, pyridyl, benzothienyl, thieno-pyridinyl, thieno-pyrazinyl, indolyl, benzofuryl, cyclohexenyl, 4,5,6,7-tetrahydro-thieno[2,3-c]pyridinyl or dihydrocyclopentathienyl.

19. A method for the preparation of a compound of formula (I) according to claim 1 , comprising treating a compound of general formula:

with an ortho-ester isothiocyanate of general formula:

wherein P is a protective group;

in the presence of a coupling agent or yellow mercury (II) oxide in the presence of sulphur, a protic or aprotic solvent, and optionally in the presence of a base.

20. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient.

21. The method according to claim 19 , wherein the protective group (P) is a methyl, ethyl, or tert-butyl group.