Morphan and morphinan analogues, and methods of use
View Patent ↗The present application relates to analogs of morphan and morphinan, compositions thereof, and methods for treating a disease or condition comprising administering an effective amount of the compounds or compositions to a subject in need thereof.
1. A compound of Formula IV:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclopropyl or cyclobutyl;
X is H, hydroxyl, or methoxy;
Y and Z are each, independently, H, hydroxyl, or NR 5 R 6 wherein R 5 and R 6 are each independently H, alkyl or substituted acyl, or alternatively, Y and Z, together with the carbon atom to which they are attached, form C═O or C═CH 2 ;
R 3 is H or hydroxyl; and
R 2 is —C(O)NH 2 , or —NH—CH 2 -phenyl, wherein the phenyl can be substituted.
2. The compound of claim 1 , wherein R 1 is cyclopropyl.
3. The compound of claim 1 , wherein X is H or hydroxyl.
4. The compound of claim 1 , wherein Y and Z are each, independently, H or hydroxyl, or alternatively, Y and Z, together with the carbon atom to which they are attached, form C═O.
5. The compound of claim 1 , wherein R 2 is —C(O)NH 2 .
6. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
8. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 , wherein the compound is a p opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.
9. The method of claim 8 , wherein said agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.
10. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.
11. A method of treating a depressive symptom in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of claim 1 that does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.
12. A method of treating a depressive symptom in a subject in need thereof, comprising administering to the subject the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 , wherein the depressive symptom is depressed mood, loss of pleasure, loss of appetite, sleep disturbance, psychomotor changes, fatigue, and/or post-partum depression.
14. The method of claim 12 , wherein the depressive symptom is acute stress disorder, anxiety disorder, Asperger syndrome, attention deficit, borderline personality disorder, major depressive disorder (MDD), treatment-resistant disorder (TRD), fatigue, hyperactivity disorder, impulse control disorder, loss of apetitie, obsessive-compulsive personality disorder (OCD), paranoid, psychomotor changes, self-injury separation, sleep disturbance, sleep disorder, substance-induced mood disorder, Tourette syndrome, tic disorder, or Trichotillomania.
15. The method of claim 14 , wherein the depressive symptom is an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, agoraphobia, acute stress, and/or post-traumatic stress disorder.
16. The method of claim 12 , wherein the depressive symptom is associated with chronic or recurrent depression.
17. The compound of claim 1 , wherein the compound is a μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.
18. The compound of claim 17 , wherein the Emax is 15% to 35% in a GTPγS binding assay.
19. The compound of claim 17 , wherein the agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.
20. The compound of claim 1 , having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over baseline in a rat.
21. The compound of claim 20 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.
22. The compound of claim 1 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.
23. The compound of claim 1 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 3 mg/kg.
24. The compound of claim 1 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.