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 I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl or
R 2 is H or methoxy; and
R 3 and R 4 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, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 .
2. The compound of claim 1 , wherein R 1 is cyclobutyl.
3. The compound of claim 1 , wherein R 2 is H.
4. The compound of claim 1 , wherein one of R 3 or R 4 , but not both, is hydroxyl, or alternatively, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O.
5. 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.
6. The compound of claim 5 , wherein the Emax is 15% to 35% in a GTPγS binding assay.
7. The compound of claim 1 , having a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over baseline in a rat.
8. The compound of claim 7 , having a maximal dopamine efflux in the nucleus accumbens of 200% to 300% over baseline in a rat.
9. 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.
10. The compound of claim 9 , 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.
11. The compound of claim 9 , wherein the compound does not attenuate thermal pain in a rodent hot plate model when administered at a dose of 10 mg/kg.
12. 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 μ opioid receptor agonist of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl or
R 2 is H or methoxy; and
R 3 and R 4 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, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 ,
wherein the μ opioid receptor agonist exhibits an Emax of 5% to 45% in a GTPγS binding assay.
13. 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 Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl or
R 2 is H or methoxy; and
R 3 and R 4 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, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 ,
wherein the compound has a maximal dopamine efflux in the nucleus accumbens of 125% to 300% over base line in a rat.
14. 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 Formula I:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is cyclobutyl or
R 2 is H or methoxy; and
R 3 and R 4 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, R 3 and R 4 , together with the carbon atom to which they are attached, form C═O or C═CH 2 ,
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.
15. 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.
16. The method of claim 15 , wherein the depressive symptom is acute stress disorder, adjustment disorders with depressed mood, Asperger syndrome, attention deficit, bereavement, bipolar I disorder, bipolar II disorder, borderline and personality disorder, cyclothymia and dysthymia, depression such as major depressive disorder (MDD) and treatment-resistant disorder (TRD), Dysthymic disorder, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoid, post-traumatic stress disorder, seasonal affective disorder, self-injury separation, sleep disorder, substance-induced mood disorder, Tourette syndrome and tic disorder, and/or Trichotillomania.
17. The compound of claim 1 , wherein substituted acyl is
wherein R 11 is linear or branched C 1 -C 6 alkyl; R 12 is halo, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and R 13 is aryl or heteroaryl.