Small-molecule agonists for type-2 orexin receptor

1. A method for promoting enhanced wakefulness of a person subject determined to be in need thereof, comprising the step of:

(a) orally administering to the subject a type-2 orexin receptor (OX2R) agonist of formula I:

in which:

R 1 is

substituted or unsubstituted alkyl;

substituted or unsubstituted cycloalkyl;

substituted or unsubstituted alkenyl;

adamantyl;

substituted or unsubstituted phenyl;

a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

substituted or unsubstituted benzyl;

a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or

CH 2 XR 5 , where X is oxygen, sulfur, —NH— or —CH 2 — and R 5 is substituted or unsubstituted alkyl; substituted or unsubstituted cycloalkyl; substituted or unsubstituted phenyl; substituted or unsubstituted benzyl; 2-carbamide-indolyl; or a 5 to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

R 2 is

substituted or unsubstituted alkyl;

substituted or unsubstituted cycloalkyl;

substituted or unsubstituted alkenyl;

substituted or unsubstituted alkoxyalkyl;

a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

—(CH 2 ) n R 3 , where R 3 is (i) a 5- to 9-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (ii) —NR 6 R 7 where R 6 and R 7 are independently selected from hydrogen, methyl, ethyl and benzyl; or (iii) COOR 8 where R 8 is alkyl; and n is 2 or 3;

substituted or unsubstituted phenyl;

substituted or unsubstituted benzyl;

a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; or

methylene-1-naphthyl; and

R 4 is

hydrogen;

(CH 2 ) m COOR 15 where R 15 is alkyl or substituted alkyl; and m is 0, 1 or 2;

CONR 16 R 17 , where R 16 and R 17 are independently (i) hydrogen; (ii) alkyl or substituted alkyl; (iii) cycloalkyl; (iv) alkoxyalkyl; (v) a 5- to 10-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur; (vi) a saturated or unsaturated fused ring carbocyclic group having from 8 to 10 ring atoms; (vii) substituted or unsubstituted phenyl; (viii) (CH 2 ) p R 18 where R 18 is a 5- or 6-membered optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and p is 1, 2 or 3; (ix) optionally substituted benzyl; or (x) an aralkyl group comprising a chain of from 1 to 4 methylene groups substituted by one or two phenyl groups;

C 1 -C 4 alkoxy;

optionally substituted phenoxy;

SO 2 NR 19 R 20 where R 19 and R 20 are independently hydrogen, optionally substituted alkyl or phenyl;

NR 21 R 22 , wherein R 21 and R 22 are independently hydrogen, alkyl, optionally substituted phenyl or optionally substituted benzyl;

COR 23 where R 23 is alkyl or is NR 21 R 22 ;

COOR 24 where R 24 is hydrogen, alkyl, or benzyl; or

SO 2 R 25 where R 25 is alkyl or NR 21 R 22 ;

or a pharmaceutically acceptable salt thereof, or prodrug thereof.

2. The method of claim 1 , wherein the agonist is of formula:

X is Cl and Y is Cl,

X is Cl and Y is H,

X is H and Y is H,

X is OMe and Y is H

X is H and Y is Br, or

X is H and Y is NO 2 .

3. The method of claim 1 wherein the agonist is of formula:

4. The method of claim 1 , further comprising detecting a resultant enhanced wakefulness.

5. The method of claim 2 , further comprising detecting a resultant enhanced wakefulness.

6. The method of claim 3 , further comprising detecting a resultant enhanced wakefulness.

7. The method of claim 1 comprising administering to the subject the OX2R agonist regularly and chronically.

8. The method of claim 1 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

9. The method of claim 2 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

10. The method of claim 3 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

11. The method of claim 4 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

12. The method of claim 5 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

13. The method of claim 6 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness.

14. The method of claim 1 comprising administering to the subject the OX2R agonist in unit dosage form, and comprising the antecedent step of removing a capsule or tablet comprising the unit dosage form from a multipack adapted for sequential use.

15. The method of claim 2 comprising administering to the subject the OX2R agonist in unit dosage form, and comprising the antecedent step of removing a capsule or tablet comprising the unit dosage form from a multipack adapted for sequential use.

16. The method of claim 3 comprising administering to the subject the OX2R agonist in unit dosage form, and comprising the antecedent step of removing a capsule or tablet comprising the unit dosage form from a multipack adapted for sequential use.

17. The method of claim 1 , wherein the agonist is of formula:

wherein:

X is Cl and Y is H.

18. The method of claim 1 , wherein the agonist is of formula:

wherein:

X is H and Y is H.

19. The method of claim 1 , wherein the agonist is of formula:

wherein:

X is OMe and Y is H.

20. The method of claim 1 , wherein the agonist is of formula:

wherein:

X is H and Y is Br.

21. The method of claim 1 , wherein the agonist is of formula:

wherein:

X is H and Y is NO 2 .

22. The method of claim 1 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness, wherein the compound is caffeine.

23. The method of claim 3 comprising administering to the subject the OX2R agonist in conjunction with an effective amount of a different compound which promotes wakefulness, wherein the compound is caffeine.

24. The method of claim 1 further comprising the antecedent step of determining that the person is in need of said enhanced wakefulness.

25. The method of claim 3 further comprising the antecedent step of determining that the person is in need of said enhanced wakefulness.

26. The method of claim 1 wherein said person subject is determined to afflicted with daytime sleepiness.

27. The method of claim 1 wherein said person subject is determined to afflicted with nighttime insomnia.

28. The method of claim 1 wherein said person subject is determined to afflicted with depression with hypersomnia.

29. The method of claim 3 wherein said person subject is determined to afflicted with daytime sleepiness.

30. The method of claim 3 wherein said person subject is determined to afflicted with nighttime insomnia.

31. The method of claim 3 wherein said person subject is determined to afflicted with depression with hypersomnia.