Combination of a hypnotic agent and substituted bis aryl and heteroaryl compound and therapeutic application thereof

1. A combination comprising at least one short acting hypnotic agent selected from the group consisting of zolpidem, zopiclone, eszopiclone, zaleplon, ramelteon, triazolam, etizolam, brotizolam and indiplon, and a compound defined by formula I, an enantiomer, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein:

X═Y denotes either a single or double bond between X and Y;

X is CR, N, or O;

Y is CR, CHR, CO, or N;

Z is NR;

A, B and E are the same or different and independently from each other are CR;

D is CH 2 ;

Ar is substituted or unsubstituted phenyl or furan;

each R is independently chosen from hydrogen, halogen, CN, or C 1-4 alkyl C 1-4 alkoxy, C 1-4 alkenyl,

R 1 and R 2 are the same or different and selected independently of each other from substituted or unsubstituted phenyl, benzyl, benzoyl, pyrrolidinylmethyl, and diC 1-4 alkylaminoalkyl; or

R 1 and R 2 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted piperazine; and wherein

the substituents are selected from the group consisting of substituted or unsubstituted phenyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl of the formula C n H x F y , and fluoroalkoxy of the formula OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1.

2. The combination as set forth in claim 1 , wherein the short-acting hypnotic agent is present in a galenic form adapted for an immediate or delayed release, and a compound of formula (I) is present in a galenic form adapted for an immediate release.

3. The combination as set forth in claim 1 , wherein the short-acting hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, zaleplon, ramelteon, and indiplon.

4. The combination as set forth in claim 1 , wherein the short acting hypnotic agent is zolpidem or a pharmaceutically acceptable salt thereof which is in combination with a compound of formula (I).

5. A pharmaceutical composition comprising at least one short acting hypnotic agent from the group consisting of zolpidem, zopiclone, eszopiclone, zaleplon, ramelteon, triazolam, etizolam, brotizolam and indiplon, and a compound defined by formula I, an enantiomer, a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein:

X═Y denotes either a single or double bond between X and Y;

X is CR, N, or O;

Y is CR, CHR, CO, or N;

Z is NR;

A, B and E are the same or different and independently from each other are CR;

D is CH 2 ;

Ar is substituted or unsubstituted phenyl or furan;

each R is independently chosen from hydrogen, halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl;

R 1 and R 2 are the same or different and selected independently of each other from substituted or unsubstituted phenyl, benzyl, benzoyl, pyrrolidinylmethyl, and diC 1-4 alkylaminoalkyl; or

R 1 and R 2 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted piperazine; and wherein

the substituents are selected from the group consisting of substituted or unsubstituted phenyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 alkenyl, fluoroalkyl of the formula C n H x F y , and fluoroalkoxy of the formula OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1;

in combination with one or more pharmaceutically acceptable diluent, excipient or a carrier.

6. The composition as set forth in claim 5 , wherein the short-acting hypnotic agent is present in a galenic form adapted for an immediate or delayed release, and a compound of formula (I) is present in a galenic form adapted for an immediate release.

7. The composition as set forth in claim 5 , wherein the short-acting hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, zaleplon, ramelteon and indiplon.

8. The composition as set forth in claim 5 , wherein the short-acting hypnotic agent is zolpidem or a pharmaceutically acceptable salt thereof which is in combination with a compound of formula (I).

9. The composition as set forth in claim 5 , wherein the short-acting hypnotic agent and a compound of formula (I) are released immediately.

10. The composition as set forth in claim 5 , which is formulated a tablet containing immediate-release pellets of the short-acting hypnotic agent and a compound of formula (I).

11. The composition as set forth in claim 5 , which is formulated a delayed-release enteric coated tablet comprising immediate-release pellets of a compound of formula (I) and immediate-release pellets of the short-acting hypnotic agent.