Morphan and morphinan analogues, and methods of use
View Patent ↗The present application relates to analogues 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 II:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, cycloalkyl, heterocyclyl, hydroxyalkyl, or alkoxyalkyl;
R 2 and R 3 are each C 1 -C 4 alkyl, or alternatively, R 2 and R 3 , together with the carbon atoms to which they are attached, form a 6-membered carbocyclic ring which is optionally substituted with a ketone, a hydroxyl, or a NR 5 R 6 group wherein R 5 and R 6 are each independently H, alkyl, or substituted acyl group;
when is a single bond, R 4 is H; and
when is a double bond, R 4 is O.
2. The compound of claim 1 , wherein R 1 is C 2 -C 6 alkenyl or cycloalkyl.
3. The compound of claim 1 , wherein R 2 and R 3 are each methyl.
4. The compound of claim 1 , wherein is a single bond, and R 4 is H.
5. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
6. 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.
7. The compound of claim 6 , wherein the Emax is 15% to 35% in a GTPγS binding assay.
8. The compound of claim 6 , wherein the agonist has a low risk of opioid dependence, opioid addiction, and/or symptoms of opioid withdrawal.
9. The compound of claim 1 , having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over baseline in a rat.
10. The compound of claim 9 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.
11. 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.
12. The compound of claim 11 , 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.
13. The compound of claim 11 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 .
15. 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 μ opioid receptor agonist having an Emax of 5% to 45% in a GTPγS binding assay.
16. 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 has a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.
17. 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 does not attenuate thermal pain in a rodent hot plate model when administered at a dose of at least 1 mg/kg.
18. 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.
19. The method of claim 18 , wherein the depressive symptom is selected from the group consisting of depressed mood, loss of pleasure, post-partum depression, adjustment disorders with depressed mood, bereavement, bipolar I disorder, bipolar II disorder, cyclothymia, dysthymia, depression, dysthymic disorder, mixed mania, post-traumatic stress disorder, and seasonal affective disorder.
20. The method of claim 18 , wherein the depressive symptom is acute stress disorder, anxiety disorder, Asperger syndrome, attention deficit, borderline personality disorder, fatigue, hyperactivity disorder, impulse control disorder, loss of appetite, 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.
21. The method of claim 20 , wherein the depressive symptom is an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, panic, agoraphobia, acute stress, or post-traumatic stress disorder.
22. The method of claim 18 , wherein the depressive symptom is depression.
23. The method of claim 18 , wherein the subject is a human.
24. The method of claim 22 , wherein the depression is major depressive disorder (MDD) or treatment-resistant disorder (TRD).