Asymmetric phenylalkylamine

Abstract

This specification provides substituted phenylalkylamine analogs, such as asymmetrically substituted 2,5-dialkoxyphenethylamines (e.g., where the 2-alkoxy substituent and the 5-alkoxy substituent are different). Also provided are methods for preparing such compounds, pharmaceutical compositions thereof, and methods of use thereof in the treatment of mental health disorders, neurodegenerative conditions, pain disorders and inflammation, including as part of psychedelic support therapy. [Case 1] JPEG2026519532000061.jpg2940 Equation (I)

Claims

1. Compounds of formula (II) or their pharmaceutically acceptable salts, hydrates, solvates, or isotopic derivatives: 【Chemistry 1】 During the ceremony, X is Br, F, Cl, I, C １ ~C ６ Haloalkyl or C １ ~C ６ It is alkylthio; R ５ is n-propyl, n-butyl, n-pentyl, n-hexyl or C ３ ~C ６ It is Alkenil.

2. R ５ The compound according to claim 1, wherein the compound is n-propyl, n-butyl, n-pentyl, or n-hexyl.

3. R ５ The compound according to claim 2, wherein R is n-propyl.

4. The compound according to claim 1, wherein X is Br.

5. The compound is having the structure of formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof: 【Chemistry 2】 In the formula, X is Br, F, Cl, I, or CF ３ That is, The compound according to claim 1.

6. The compound according to claim 5, wherein X is Br.

7. A compound selected from TABLE1, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

8. Compounds having the following structures, or their pharmaceutically acceptable salts, hydrates, solvates, or isotopic derivatives: 【Transformation 3】 。

9. A compound selected from TABLE2, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

10. A compound according to any one of claims 1 to 9, for use in the treatment of a medical condition.

11. A compound according to any one of claims 1 to 10, or a compound having the structure of formula (1), or a pharmaceutically acceptable salt, hydrate, solvate, or isotope derivative thereof: 【Chemistry 4】 During the ceremony, R α is H or C １ ~C ６ It is alkyl; R β is H, OH, or C １ ~C ６ It is an alkoxy; X is Br, F, Cl, I, C １ ~C ６ Alkyl, C ２ ~C ８ Alkenil, C ２ ~C ８ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, cyano, nitro, or amino; where each C １ ~C ６ Alkyl, C ２ ~C ８ Alkenil, C ２ ~C ８ Alkinyl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxys, 3-6 membered cycloalkyls, 4-6 membered heterocycloalkyls, or aminos are independently deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH) ２ , -OC(O)H, -OSO ２ OH or -OC(O)NH ２ It is optionally replaced by; R ２ and R ５ One of them is methyl, and the other is C ３ ~C ６ Alkyl, C ３ ~C ６ Alkenil, C ２ ~C ８ Alkinyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkylene-3 to 6-membered cycloalkyl, C １ ~C ６ Alkylene-4 to 6-membered heterocycloalkyl, or C １ ~C ６ Alkylene-aryl, or C １ ~C ６ It is alkylene-heteroaryl; R ３ and R ６ Both are H; or, R ２ and R ３ It combines with the intervening atom to form a 4-6 member heterocycloalkyl or 4-6 member heteroaryl; R ５ C ３ ~C ６ Alkyl, C ３ ~C ６ Alkenil, C ２ ~C ８ Alkinyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkylene-3 to 6-membered cycloalkyl, C １ ~C ６ Alkylene-4 to 6-membered heterocycloalkyl, or C １ ~C ６ Alkylene-aryl, or C １ ~C ６ It is alkylene-heteroaryl; R ６ is H; or R ５ and R ６ together with an intervening atom form a 4- to 6-membered heterocycloalkyl or 4- to 6-membered heteroaryl; R ２ is C ３ to C ６ alkyl, C ３ to C ６ alkenyl, C ２ to C ８ alkynyl, C １ to C ６ haloalkyl, C １ to C ６ alkylene-3- to 6-membered cycloalkyl, C １ to C ６ alkylene-4- to 6-membered heterocycloalkyl, or C １ to C ６ alkylene-aryl, or C １ to C ６ alkylene-heteroaryl; R ３ is H.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

13. The pharmaceutical composition according to claim 12, suitable for oral, buccal, sublingual, intranasal, injection, subcutaneous, intravenous, intraocular, topical, or transdermal administration.

14. The pharmaceutical composition according to claim 12, wherein the composition is provided in a unit dosage form.

15. The pharmaceutical composition according to claim 14, comprising the compound in a total amount of 1 to 200 mg or 5 to 100 mg.

16. The pharmaceutical composition according to claim 15, comprising the compound in a total amount of 10 to 75 mg or 20 to 50 mg.

17. The pharmaceutical composition according to claim 14, wherein the unit dosage form is an immediate-release, controlled-release, sustained-release, extended-release, or modified-release formulation.

18. The pharmaceutical composition according to claim 12, further comprising a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

19. The pharmaceutical composition according to claim 18, wherein the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic agents and anti-nociceptors, anti-migraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociative agents, cannabinoids, immunostimulants, anticancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, antihypertensive agents, anticonvulsants, antiepileptic agents, bronchodilators, neuroprotective agents, nootropics, empathogens, hallucinogens, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins.

20. The pharmaceutical composition according to claim 18, wherein the additional active compound acts to increase the therapeutic effect, provide additional therapeutic effects, reduce undesirable effects, increase stability or shelf life, improve bioavailability, induce synergistic effects, or alter pharmacokinetics or pharmacodynamics.

21. The pharmaceutical composition according to claim 20, wherein the additional therapeutic effects are antioxidant, anti-inflammatory, analgesic, antineuropathic, anti-nociceptive, anti-migraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anticancer, antiemetic, appetite-stimulating, anti-ulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilating, neuroprotective, empathogenic, psychedelic, sedative, or stimulating effects.

22. A method for treating a medical condition of a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

23. The method according to claim 22, wherein the medical condition is a disorder related to dysregulation or insufficient function of neurotransmission.

24. The method according to claim 23, wherein the impairment related to dysregulation or insufficient function of neurotransmission is an impairment of monoaminergic neurotransmission.

25. The method according to claim 24, wherein the impairment related to dysregulation or insufficient function of monoaminergic neurotransmission is an impairment of serotonergic, dopaminergic, or noradrenergic neurotransmission.

26. The method according to claim 22, wherein the medical condition is a mental health disorder.

27. The method according to claim 26, wherein the mental health disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety disorder, phobic disorder, bulimia disorder, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance use disorder, substance-induced mood disorder, mood disorder associated with another health condition, destructive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, and dissociative disorder.

28. The method according to claim 27, wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).

29. The method according to claim 27, wherein the anxiety disorder is generalized anxiety disorder (GAD).

30. The method according to claim 27, wherein the mental health disorder is PTSD.

31. The method according to claim 27, wherein the substance use disorder is alcohol use disorder (AUD), nicotine dependence or tobacco use disorder, opioid use disorder (OUD), stimulant use disorder, or sedative, hypnotic or anxiolytic use disorder.

32. The method according to claim 22, wherein the medical condition is a neurodegenerative disorder, pain or pain disorder, or inflammation or inflammatory disorder.

33. The method according to claim 22, wherein the medical condition is ischemic injury.

34. The method according to claim 33, wherein the ischemic injury is a stroke or ischemia-reperfusion injury.

35. The method according to claim 22, wherein the compound is administered in conjunction with one or more sessions of psychotherapy or psychological support.

36. A method for modulating neurotransmission in a subject, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

37. The method according to claim 36, wherein regulating neurotransmission includes activating monoamine neurotransmitter receptors and / or regulating the uptake activity of monoamine transporters.

38. The method according to claim 37, wherein the monoamine neurotransmitter receptor may be any of serotonin receptors, dopamine receptors, and norepinephrine receptors.

39. The serotonin receptor mentioned above is 5-HT ２Ａ The method according to claim 38, wherein the receptor is...

40. The method according to claim 37, wherein the monoamine transporter is a serotonin transporter (SERT).

41. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, for the manufacture of a pharmaceutical for treating a medical condition.

42. A method for treating a medical condition of a subject requiring treatment, comprising administering the pharmaceutical composition described in claim 12 to the subject.

43. A method for regulating neurotransmission in a subject, comprising administering the pharmaceutical composition described in claim 12 to the subject.

44. A pharmaceutical composition according to claim 12, for use in treating a medical condition.

45. Use of the pharmaceutical composition according to claim 12 for manufacturing a pharmaceutical for treating a medical condition.

46. A method for treating a medical condition of a subject requiring treatment, comprising administering to the subject a compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

47. A method for modulating neurotransmission in a subject, comprising administering to the subject a compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof.

48. A compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, for use in the treatment of a medical condition.

49. Use of the compound described in claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, or isotopic derivative thereof, for the manufacture of a pharmaceutical for treating a medical condition.

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