CN118284607A

CN118284607A - LSD derivatives, synthesis and methods for the treatment of diseases and disorders

Info

Publication number: CN118284607A
Application number: CN202280076638.6A
Authority: CN
Inventors: 胡施曼德·塞施巴拉达兰; 斯科特·鲁奇; 阿布迪·加法里; 斯特凡·索德曼; 佩塔尔·杜斯帕拉
Original assignee: Bilaifu Treatment Co
Current assignee: Bilaifu Treatment Co
Priority date: 2021-09-20
Filing date: 2022-09-20
Publication date: 2024-07-02

Abstract

Described herein are LSD derivative compounds having the structure of formula I, including pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof, and polymorphs thereof, methods of synthesizing, compositions, and methods of treating diseases and disorders; wherein: r ¹ to R ¹⁴ are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group, and X is selected from a halogen group,

Description

LSD derivatives, synthesis and methods for the treatment of diseases and disorders

Technical Field

The present application relates generally to novel LSD derivatives and polymorphs thereof, compositions thereof, methods of synthesis and therapeutic uses thereof.

Background

LSD, commonly known as acid, scientifically known as lysergic diacetic amide, is an effective semisynthetic illusive substance that causes uncontrolled sensory distortion and intense ocular illusion to mental sensation and multiple effects linked to everything. LSDs can cause a state of separation in the user and sometimes send them into full panic attacks.

LSDs are classified by regulatory authorities as tightly controlled substances and are therefore illegal in most parts of the world. However, LSD has advantages because it is not addictive and has been demonstrated to promote nerve cell growth.

It would be beneficial to provide a non-fanciful form of LSD that retains at least one beneficial property.

Disclosure of Invention

The present disclosure describes general lysergic acid diacetamide (LSD) derivatives and crystalline polymorphs thereof, and their use in medicine.

The present disclosure relates generally to compounds having the structure of formula I:

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof; wherein: r ¹ to R ¹⁴ are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group, and X is selected from a halogen group.

According to one aspect of the invention are novel compounds of formula I. In some aspects, these are substantially non-illusive and in another aspect unexpectedly do not induce tolerance as in LSD.

According to one aspect of the invention are novel polymorphic compounds of formula I. In some aspects, these compounds are substantially non-magic and, in another aspect, unexpectedly do not induce tolerance as LSD does.

LSD derivative compounds of formula I and polymorphs thereof include crystalline forms, optionally isolated crystalline forms. In some aspects, the invention includes polymorphs, optionally, isolated polymorphs. In some aspects, the invention consists essentially of a crystalline form. In some aspects, the invention consists essentially of a polymorph. In some aspects, the invention includes one or more polymorphs thereof that are substantially free of solvates. In a presently preferred embodiment, the polymorph is substantially free of water. In some aspects, the compound is (5 r,8 r) 2-bromo-LSD semi-D-tartrate.

In some aspects, the compound is an isolated polymorph of (5 r,8 r) 2-bromo-LSD semi-D-tartrate. In another aspect, the isolated polymorph of (5 r,8 r) 2-bromo-LSD semi-D-tartrate (E559) is formulated as a composition or formulation.

Another embodiment of the invention includes a pharmaceutical composition comprising a compound of formula I substantially free of solvates and a pharmaceutically acceptable carrier, diluent or excipient thereof. In other embodiments, the pharmaceutical compositions contemplated herein further comprise other forms of formula I in crystalline, solvate or amorphous form.

According to another aspect, compositions and formulations of non-fanciful LSD derivatives, including polymorphs thereof, are provided.

Compositions and formulations comprise compounds of formula I; formula I'; formula Ia, formula Ib, formula Ic, formula Id; formula Ia ', formula Ib', formula Ic ', formula Id'; formula Ia ", formula Ib", formula Ic ", formula Id"; formula IA, formula IB, formula Ic, formula Id; formula IAA, formula IBB, formula ICC, formula IDD; formula IAA ', formula IBB', formula ICC ', formula IDD'; formula IAA ", formula IBB", formula ICC ", formula IDD"; LSD derivatives represented by formula IAA '", formula IBB'", formula ICC '", formula IDD'" and polymorphs thereof; and any mixtures thereof.

According to another aspect, the LSD derivatives and polymorphic compounds/compositions/formulations disclosed herein are useful for treating one or more of the following diseases: depression; bipolar disorders and related disorders; schizophrenia lineages and other psychotic disorders; personality disorder; anxiety disorders; trauma and stress related disorders; obsessive compulsive disorder and related disorders; destructive disorders, impulse control behavioral disorders; ingestion and eating disorders; a separation disorder; somatic symptoms and related disorders; a neurological disorder; sleep-wake disorders; substance-related and addictive disorders; headache disorder; pain disorders; spasticity; a nerve injury disorder; fatigue; neurodegenerative disorders; sexual dysfunction and sex anxiety disorders; a neurocognitive disorder; neuro-viral infection; against side effects of other drugs; and overall well-being.

In embodiments, the novel LSD derivatives and polymorph compounds/compositions/formulations disclosed herein are useful for reducing one or more signs or symptoms of any one or more of: depression; bipolar disorders and related disorders; schizophrenia lineages and other psychotic disorders; personality disorder; anxiety disorders; trauma and stress related disorders; obsessive compulsive disorder and related disorders; destructive disorders, impulse control behavioral disorders; ingestion and eating disorders; a separation disorder; somatic symptoms and related disorders; a neurological disorder; sleep-wake disorders; substance-related and addictive disorders; headache disorder; pain disorders; spasticity; a nerve injury disorder; fatigue; neurodegenerative disorders; sexual dysfunction and sex anxiety disorders; a neurocognitive disorder; neuro-viral infections.

In some aspects, the compounds of the invention may alternatively not be used in the treatment of recurrent cluster headache disorder, wherein the subject suffers from recurrent cluster headache disorder in terms of one or more prophylactic treatment afflictions. In some aspects, the compounds of the invention may alternatively not be used in the treatment of trigeminal autonomic headache, enteral, sublingual, or parenteral administration conditions.

The compounds of the present disclosure may be described as embodiments in any of the following enumerated clauses. It should be understood that any of the embodiments described herein may be used in combination with any other embodiment described herein, provided that the embodiments are not inconsistent with each other.

Aspects disclosed herein include:

1. a compound having the structure of formula I:

2. The compound of claim 1, wherein the compound is crystalline.

3. The compound of claim 1 or 2, wherein the compound is in an isolated crystalline form.

4. A compound according to any one of claims 1 to 3, wherein the compound comprises its polymorph.

5. The compound according to any one of claims 1 to 4, wherein the compound comprises a single polymorph thereof.

6. The compound of any one of claims 1 to 5, wherein the compound comprises an isolated polymorph thereof.

7. A compound according to any one of claims 1 to 6, wherein:

(i) The compound is one or more polymorphs thereof;

(ii) The compounds include one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s;

(iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s, 8r;

(iv) The compounds include one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8 r;

V) the compound has two stereocenters of 5r,8 r;

vi) the compound has two stereocenters of 5r,8 s; and

Vii) any one or more of (i) to (vi).

8. The compound of claim 1 or 2, wherein the compound has a stereocenter 5s,8r;5R,8R;5R,8S; or 5s,8s.

9. The compound of claim 8, wherein the compound has a stereocenter 5s,8r;5R,8R; or 5r,8s.

10. The compound of claim 9, wherein the compound has a stereocenter selected from 5r,8s or 5r,8 r.

11. The compound according to any one of claims 1 to 10, wherein the compound is a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

12. The compound according to any one of claims 1 to 5, wherein the compound is an acid salt.

13. The compound of claim 12, wherein the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid (ERYTHRARIC ACID)), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid), or a combination thereof.

14. The compound of claim 13, wherein the acid salt acid is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

15. The compound of claim 14, wherein the acid of the acid salt is selected from tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

16. The compound according to any one of claims 1 to 15, wherein R ¹ to R ¹⁴ are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

17. The compound of claim 16, wherein R ¹ to R ¹⁴ are each independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or substituted or unsubstituted C ₂-C₆ alkynyl.

18. The compound of claim 17, wherein R ¹ to R ¹⁴ are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl.

19. The compound of claim 18, wherein R ¹ to R ¹⁴ are each independently selected from H, methyl or ethyl.

20. The compound according to any one of claims 1 to 19, wherein R ¹ and R ² are each independently selected from H, methyl or ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H, and R ⁵ is methyl.

21. The compound according to any one of claims 1 to 20, wherein R ¹ and R ² are each independently selected from methyl or ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H; and R ⁵ is methyl.

22. The compound of any one of claims 1 to 21, wherein R ¹ and R ² are each ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H; and R ⁵ is methyl.

23. A compound according to any one of claims 1 to 22, wherein X is selected from bromine, chlorine, fluorine or iodine.

24. The compound of claim 23, wherein X is selected from bromine, chlorine, or fluorine.

25. The compound of claim 24, wherein X is selected from bromine or chlorine.

26. The compound of claim 23, wherein X is bromine.

27. The compound of claim 1, wherein the compound has the structure of formula I':

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof; wherein: r ¹ and R ² are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group.

28. The compound of claim 27, wherein the compound is crystalline.

29. The compound of claim 27 or 28, wherein the compound is in an isolated crystalline form.

30. A compound according to any one of claims 27 to 29, wherein the compound comprises a polymorph thereof.

31. The compound of any one of claims 27 to 30, wherein the compound comprises a single polymorph thereof.

32. The compound of any one of claims 27 to 31, wherein the compound comprises an isolated polymorph thereof.

33. The compound of any one of claims 27 to 32, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

34. The compound of claim 27 or 28, wherein the compound has a moiety selected from 5s,8r;5R,8R;5R,8S; or 5s,8 s.

35. The compound of claim 34, wherein the compound has a moiety selected from the group consisting of 5s,8r;5R,8R; or the stereocenter of 5r,8 s.

36. The compound of claim 35, wherein the compound has a stereocenter selected from 5r,8s or 5r,8 r.

37. The compound of any one of claims 27 to 36, wherein the compound is a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.

38. The compound of any one of claims 27 to 37, wherein the compound is an acid salt.

39. The compound of claim 38, wherein the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid, or a combination thereof.

40. The compound of claim 39, wherein the acid salt is an acid selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

41. The compound of claim 40, wherein the acid salt acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythorbic acid), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

42. The compound of any one of claims 27 to 41, wherein R ¹ and R ² are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

43. A compound of claim 42, wherein R ¹ and R ² are each independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or substituted or unsubstituted C ₂-C₆ alkynyl.

44. The compound of claim 43, wherein R ¹ and R ² are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl.

45. The compound of claim 44, wherein R ¹ and R ² are each independently selected from H, methyl, or ethyl.

46. The compound of claim 45, wherein R ¹ and R ² are each independently selected from methyl or ethyl.

47. The compound of claim 46, wherein each of R ¹ and R ² is ethyl.

48. The compound of claim 27, wherein the compound has a structure of formula I' selected from the group consisting of:

49. The compound of claim 48, wherein the compound is crystalline.

50. The compound of claim 48 or 49, wherein the compound is in an isolated crystalline form.

51. The compound of any one of claims 48 to 50, wherein the compound comprises a polymorph thereof.

52. The compound of any one of claims 48 to 51, wherein the compound comprises a single polymorph thereof.

53. The compound of any one of claims 48 to 52, wherein the compound comprises an isolated polymorph thereof.

54. The compound of any one of claims 48 to 53, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

55. The compound of claim 48 or 49, wherein formula I' is selected from formula Ia; formula 1b; or formula Id.

56. The compound of claim 55, wherein formula I' is formula Ib or formula Id.

57. The compound of any one of claims 48 to 56, wherein the compound is a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.

58. The compound of any one of claims 48 to 57, wherein the compound is an acid salt.

59. The compound of claim 58, wherein the acid salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid, methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

60. The compound of claim 59, wherein the acid salt acid is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

61. The compound of claim 60, wherein the acid salt acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

62. The compound of any one of claims 48 to 61, wherein R ¹ and R ² are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

63. The compound of claim 62, wherein R ¹ and R ² are each independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or substituted or unsubstituted C ₂-C₆ alkynyl.

64. The compound of claim 63, wherein R ¹ and R ² are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl.

65. The compound of claim 64, wherein R ¹ and R ² are each independently selected from H, methyl, or ethyl.

66. The compound of claim 65, wherein R ¹ and R ² are each independently selected from methyl or ethyl.

67. The compound of claim 66, wherein each of R ¹ and R ² is ethyl.

68. The compound of claim 27, wherein the compound has a structure of formula I' selected from the group consisting of:

pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs or combinations thereof.

69. The compound of claim 68, wherein the compound is crystalline.

70. The compound of claim 68 or 69, wherein the compound is in an isolated crystalline form.

71. The compound of any one of claims 68 to 70, wherein the compound comprises a polymorph thereof.

72. The compound of any one of claims 68 to 71, wherein the compound comprises a single polymorph thereof.

73. The compound of any one of claims 68 to 72, wherein the compound comprises an isolated polymorph thereof.

74. The compound of any one of claims 68 to 73, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

75. The compound of claim 73 or 74, wherein formula I 'is selected from formula Ia'; formula 1b'; or Id'.

76. The compound of claim 75, wherein formula I ' is formula Ib ' or formula Id '.

77. The compound according to any one of claims 68 to 76, wherein the compound is a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

78. The compound of any one of claims 68 to 77, wherein the compound is an acid salt.

79. The compound of claim 78, wherein the acid salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid, methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

80. The compound of claim 79, wherein the acid salt acid is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

81. The compound of claim 80, wherein the acid salt acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

82. The compound of claim 27, wherein the compound has a structure of formula I' selected from the group consisting of:

Or a combination thereof.

83. The compound of claim 82, wherein the compound is crystalline.

84. The compound of claim 82 or 83, wherein the compound is in an isolated crystalline form.

85. The compound of any one of claims 82 to 84, wherein the compound comprises a polymorph thereof.

86. The compound of any one of claims 82 to 85, wherein the compound comprises an isolated polymorph thereof.

87. The compound of any one of claims 82 to 86, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

88. The compound of claim 82 or 83, wherein formula I' is selected from formula Ia "; formula 1b "; or formula Id).

89. The compound of claim 88, wherein formula I ' is formula Ib ' or formula Id '.

90. The compound of any one of claims 82 to 89, wherein the compound is a pharmaceutically acceptable salt, hydrate, and/or solvate thereof.

91. The compound of any one of claims 82 to 90, wherein the compound is an acid salt.

92. The compound of claim 91, wherein the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid, or a combination thereof.

93. The compound of claim 92, wherein the acid salt acid is selected from hydrochloric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

94. The compound of claim 93, wherein the acid salt acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythritol), glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof.

95. A compound according to any one of claims 1 to 94, wherein the compound is selected from the group consisting of:

Or a combination thereof.

96. The compound of claim 95, wherein the compound is crystalline.

97. The compound of claim 95 or 96, wherein the compound is in an isolated crystalline form.

98. The compound of any one of claims 95 to 97, wherein the compound comprises a polymorph thereof.

99. The compound of any one of claims 95 to 98, wherein the compound comprises a single polymorph thereof.

100. The compound of any one of claims 95 to 99, wherein the compound comprises an isolated polymorph thereof.

101. The compound of any one of claims 95 to 100, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

102. A compound according to any one of claims 95 to 101, wherein the compound comprises 2-bromolsd tartrate (about 1: about 0.5) and/or (about 1: about 1), i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

103. The compound of any one of claims 1 to 102, wherein the ratio of the compound of formula I, formula I ', formula Ia, formula Ib, formula Ic, formula Id, formula Ia ', formula Ib ', formula Ic ', or formula Id ' to the acid is from about 0.5:1 to about 2:1.

104. A compound according to any one of claims 1 to 103, wherein the compound is (5 r,8 r) 2-bromo-LSD hemi-D-tartrate.

105. A compound according to any one of claims 1 to 104, wherein the compound is an isolated polymorph of (5 r,8 r) 2-bromo-LSD semi-D-tartrate.

106. The compound of any one of claims 1 to 105, wherein the compound has a powder X-ray diffraction (PXRD) pattern comprising peaks at about 10.3 ° (2Θ).

107. The compound of any one of claims 1 to 105, wherein the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7 ° (2Θ), about 9.4 ° (2Θ), and about 10.3 ° (2Θ).

108. The compound of any one of claims 1 to 105, wherein the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7 ° (2Θ), about 9.4 ° (2Θ), about 10.3 ° (2Θ), and about 20.1 ° (2Θ).

109. The compound of any one of claims 1 to 105, wherein the compound has a peak comprising at about 10.3 ° (2Θ) and aboutPowder X-ray diffraction (PXRD) patterns of d values of (c).

110. The compound of any one of claims 1 to 105, wherein the compound has a peak comprising at about 4.7 ° (2Θ) and aboutD value of (2), peak at about 9.4 ° (2 theta) and aboutD-value of (2-theta) and peak at about 10.3 deg. (2-theta) and aboutX-ray powder diffraction (PXRD) patterns of d values of (c).

111. The compound of any one of claims 1 to 105, wherein the compound has a peak comprising at about 4.7 ° (2Θ) and aboutD value of (2), peak at about 9.4 ° (2 theta) and aboutD value of (2), peak at about 10.3 ° (2 theta) and aboutD value of (2), peak at about 20.1 ° (2 theta) and aboutX-ray powder diffraction (PXRD) patterns of d values of (c).

112. The compound of any one of claims 1 to 105, wherein the compound has a powder X-ray diffraction (PXRD) pattern comprising peaks at 10.3 ° ± 0.2 ° (2Θ).

113. The compound of any one of claims 1 to 105, wherein the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7 ° ± 0.2 ° (2Θ), 9.4 ° ± 0.2 ° (2Θ), and 10.3 ° ± 0.2 ° (2Θ).

114. The compound of any one of claims 1 to 105, wherein the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7 ° ± 0.2 ° (2Θ), 9.4 ° ± 0.2 ° (2Θ), 10.3 ° ± 0.2 ° (2Θ), and 20.1 ° ± 0.2 ° (2Θ).

115. The compound of any one of claims 1 to 105, wherein optical rotation is about 0.30 ° to about 0.40 °; optionally, about 0.30 ° to about 0.35 °.

116. The compound of any one of claims 1 to 115, wherein the compound or polymorph thereof is non-magic.

117. The compound of any one of claims 1 to 116, wherein the compound or polymorph thereof is substantially non-magic.

118. The compound of any one of claims 1 to 117, wherein the compound does not induce tolerance in an individual.

119. The compound of any one of claims 1 to 118, wherein the compound is a mild to potent pan-agonist for all 5-HT1 receptor subtypes.

120. A compound according to any one of claims 1 to 119, wherein said compound is a potent 5-HT6 receptor partial agonist.

121. A compound according to any one of claims 1 to 120, wherein the compound is a partial agonist of the 5-HT2A and 5-HT1A receptor subtypes.

122. The compound of any one of claims 1 to 121, wherein the compound exhibits agonism at D2-like receptors comprising D2 and D4.

123. The compound of claim 122, wherein the compound promotes neuroplasticity in neurons, such as cortical neurons.

124. A composition comprising a compound of any one of claims 1 to 123.

125. The composition of claim 124, further comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle.

126. The composition of claim 124 or 125, wherein the composition further comprises a second therapeutic agent.

127. The composition of any one of claims 124-126, wherein the composition is a pharmaceutical composition.

128. A formulation comprising the composition of any one of claims 124-126 and/or the pharmaceutical composition of claim 127.

129. The formulation of claim 128, wherein said formulation is a liquid or a solid, optionally wherein said solid is a powder, tablet or pill.

130. The formulation of claim 128 or 129, wherein said formulation comprises a defined amount of said compound, optionally wherein said formulation is for oral administration or parenteral administration.

131. The formulation of any one of claims 128 to 130, wherein said formation is used in the preparation of a medicament for the treatment of one or more of: depression; bipolar disorders and related disorders; schizophrenia lineages and other psychotic disorders; personality disorder; anxiety disorders; trauma and stress related disorders; obsessive compulsive disorder and related disorders; destructive disorders, impulse control behavioral disorders; ingestion and eating disorders; a separation disorder; somatic symptoms and related disorders; a neurological disorder; sleep-wake disorders; substance-related and addictive disorders; headache disorder; pain disorders; spasticity; a nerve injury disorder; fatigue; neurodegenerative disorders; sexual dysfunction and sex anxiety disorders; a neurocognitive disorder; neuro-viral infection; against side effects of other drugs; and overall well-being.

132. The formulation of any one of claims 128 to 130, wherein said formation is for use in treating one or more of: depression; bipolar disorders and related disorders; schizophrenia lineages and other psychotic disorders; personality disorder; anxiety disorders; trauma and stress related disorders; obsessive compulsive disorder and related disorders; destructive disorders, impulse control behavioral disorders; ingestion and eating disorders; a separation disorder; somatic symptoms and related disorders; a neurological disorder; sleep-wake disorders; substance-related and addictive disorders; headache disorder; pain disorders; spasticity; a nerve injury disorder; fatigue; neurodegenerative disorders; sexual dysfunction and sex anxiety disorders; a neurocognitive disorder; neuro-viral infection; against side effects of other drugs; and overall well-being.

133. The formulation of any one of claims 128 to 130, wherein said formation is for reducing one or more signs or symptoms of any one or more of: depression; bipolar disorders and related disorders; schizophrenia lineages and other psychotic disorders; personality disorder; anxiety disorders; trauma and stress related disorders; obsessive compulsive disorder and related disorders; destructive disorders, impulse control behavioral disorders; ingestion and eating disorders; a separation disorder; somatic symptoms and related disorders; a neurological disorder; sleep-wake disorders; substance-related and addictive disorders; headache disorder; pain disorders; spasticity; a nerve injury disorder; fatigue; neurodegenerative disorders; sexual dysfunction and sex anxiety disorders; a neurocognitive disorder; neuro-viral infections.

134. A method of preparing a compound of any one of claims 1 to 76, wherein the method comprises:

a) Hydrolyzing a compound of formula IA to form an intermediate of formula IB:

b) Reacting an intermediate of formula IB with R ¹-NH-R² to form a compound of formula IC

C) The compound of formula IC is converted into a salt or hydrate using an organic or inorganic acid,

Wherein R is selected from-OR ₁ OR-NR ₁R₂,R₁ and R ₂ are each independently selected from H, a halogen group, a hydroxyl group, an amino group, a substituted OR unsubstituted hydrocarbon group, a substituted OR unsubstituted hetero group, a substituted OR unsubstituted carbocyclic group, a substituted OR unsubstituted heterocyclic group, a substituted OR unsubstituted aromatic group, OR a substituted OR unsubstituted heteroaromatic group, optionally R ₁ and R ₂ are each independently selected from H, a substituted OR unsubstituted hydrocarbon group, a substituted OR unsubstituted hetero group, a substituted OR unsubstituted carbocyclic group, a substituted OR unsubstituted heterocyclic group, a substituted OR unsubstituted aromatic group, OR a substituted OR unsubstituted heteroaromatic group.

135. A method according to claim 134, wherein said method of preparation does not use LSD as substrate and/or other primary species (schedule I substance).

136. The method of claim 134 or 135, wherein the hydrolysis is an acid or base hydrolysis, optionally the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid and/or nitric acid, or the base is selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, barium hydroxide, lithium hydroxide and/or tetrabutylammonium hydroxide.

137. The method of claim 134, 135 or 136, wherein the method further comprises using a water miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, or a combination thereof.

138. The method of any one of claims 134 to 137, wherein the method comprises heating from about 50 ℃ to about 95 ℃ in a), b), and/or c).

139. The method according to any one of claims 134 to 137, wherein b) further comprises converting the hydroxyl group of the carboxylic acid into a better Leaving Group (LG), such as a halide (e.g. Cl, br, I), tosylate, mesylate or perfluoroalkylsulfonate, optionally using phosphoryl chloride or thionyl chloride to an acyl chloride.

140. The method of any of claims 134-139, wherein b) further comprises base-catalyzed amide bond formation, optionally using a base and a coupling agent.

141. The method according to claim 140, wherein the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP), uranium 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenyl aminooxy) dimethylaminomorpholino) ] hexafluorophosphate (COMU) 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tri-1-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tri-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), and, 6-chloro-benzotriazol-1-yloxy-tripyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxadec-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof.

142. The method of claim 141, wherein the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

143. The method according to any one of claims 134 to 142, wherein b) further comprises base-catalyzed amide bond formation, optionally using N-methylmorpholine (NMM) and 1,1' -Carbonyldiimidazole (CDI).

144. The method of any one of claims 134 to 143, wherein in a) and/or b), the acidity of the intermediates of formula IB and formula IC is adjusted to form a precipitate; optionally, the pH is adjusted from about 6 to about 8 with an acid.

145. The method of any of claims 134-144, wherein in c) the compound of formula IC is converted to a salt or hydrate thereof using an organic or inorganic acid, with (b) in situ or in a separate step.

146. The method of claim 145, wherein the acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid), or a combination thereof.

147. The method of any one of claims 134 to 146, wherein c) comprises heating the compound of formula IC with the organic or inorganic acid in a water-immiscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc., or a combination thereof.

148. The method of any of claims 134 to 147, wherein c) comprises heating at a temperature of about 60 ℃ to about 80 ℃, optionally about 60 ℃ to about 70 ℃.

149. The method of any of claims 134-148, wherein the water miscible solvent is selected from methanol, ethanol, isopropanol (IPA), or a combination thereof; optionally, wherein the water miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA).

150. The method of any of claims 134 to 149, wherein the compound of formula IC is heated with the organic or inorganic acid for about 30 minutes to about 1 hour.

151. The method of any of claims 134 to 150, wherein the compound is cooled in solution to about 0 ℃ to about 10 ℃, optionally about 3 ℃ to about 7 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

152. The method of any of claims 134-151, wherein the salt or hydrate of the compound of formula IC is recrystallized to form a crystalline compound.

153. The method of claim 152, wherein the salt or hydrate of the compound of formula IC is an isolated crystalline form.

154. The method of claim 153, wherein the salt or hydrate of the compound of formula IC comprises a polymorph thereof.

155. The method of claim 154, wherein the salt or hydrate of the compound of formula IC comprises a single polymorph thereof.

156. The method of claim 155 wherein the salt or hydrate of the compound of formula IC comprises an isolated polymorph thereof.

157. The process of any one of claims 134 to 156, wherein the salt or hydrate of the compound of formula IC is recrystallized using a water miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.), or a combination thereof.

158. The method of claim 157, wherein the water miscible solvent is selected from methanol, ethanol, isopropanol (IPA), or a combination thereof; optionally, wherein the water miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA).

159. The method of any of claims 134-158 wherein recrystallising comprises heating the salt or hydrate of the compound of formula IC in the solvent to a suitable temperature for a suitable period of time and cooling to form the compound of any of claims 27-123.

160. The method of any of claims 134-158 wherein recrystallising comprises heating the salt or hydrate of the compound of formula IC in the solvent from about 60 ℃ to about 80 ℃, optionally from about 60 ℃ to about 70 ℃.

161. The method of any of claims 134-158 wherein recrystallising comprises heating the salt or hydrate of the compound of formula IC in a solvent at about 60 ℃ to about 80 ℃, optionally about 60 ℃ to about 70 ℃ for about 1 hour to about 2 hours.

162. The method of any of claims 134 to 158 wherein recrystallising comprises heating the salt or hydrate of the compound of formula IC in a solvent at about 60 ℃ to about 80 ℃, optionally about 60 ℃ to about 70 ℃ for about 1 hour to about 2 hours, and cooling the compound in solution to about 0 ℃ to about 10 ℃, optionally about 3 ℃ to about 7 ℃, optionally about 5 ℃, optionally for about 1 hour to about 2 hours.

163. The method of any of claims 134 to 162 wherein the recrystallized compound has about 99% to about 99.9% purity, optionally about 99.5% to about 99.9% purity.

164. The method of any one of claims 134-163, wherein the method comprises:

a) Hydrolyzing a compound of formula IAA (5 s,8 r) to form an intermediate of formula IBB:

b) Reacting an intermediate of formula IBB with R ¹-NH-R² to form formula ICC

C) The compound of formula ICC is converted into a salt or hydrate using an organic or inorganic acid.

165. The method of any one of claims 134-163, wherein the method comprises:

a) Hydrolyzing a compound of formula IAA '(5 r,8 r) to form an intermediate of formula IBB':

b) Reacting the intermediate of formula IBB 'with R ¹-NH-R² to form formula ICC'

C) The compound of formula ICC' is converted into a salt or hydrate using an organic or inorganic acid.

166. The method of any one of claims 134-163, wherein the method comprises:

a) Hydrolyzing a compound of formula IAA "(5 r,8 s) to form an intermediate of formula IBB":

b) Reacting the intermediate of formula IBB "with R ¹-NH-R² to form ICC'

C) The compound of formula ICC "is converted to a salt or hydrate using an organic or inorganic acid.

167. The method of any one of claims 134-163, wherein the method comprises:

a) Hydrolyzing a compound of formula IAA '"(5 s,8 s) to form an intermediate of formula IBB'":

b) Reacting the intermediate of formula IBB '"with R ¹-NH-R² to form ICC'".

C) The compound of formula ICC' "is converted to a salt or hydrate using an organic or inorganic acid.

168. The method of any of claims 134 to 167, wherein the compound of formula IA, formula IAA ', formula IAA ", or formula IAA'" is a bromine-containing ergoline derivative, such as bromocriptine mesylate.

169. The method of any one of claims 134 to 167, wherein the compound of formula IA, formula IAA ', formula IAA ", or formula IAA'" is

170. A process as set forth in any of claims 134 to 169 wherein said process comprises heating 2-bromolysergic acid diamide and IPA, combining D-tartaric acid and IPA with 2-bromolysergic acid diamide and IPA wherein the combined solution becomes clear, heating said combined solution for a predetermined time, cooling the mixture to about room temperature, further cooling to provide a solid comprising a major amount of (5 r,8 r) 2-bromo-LSD semi-D-tartrate and a minor amount of (5 r,8 s) 2-bromo-LSD semi-D-tartrate.

171. A process as set forth in any of claims 134 to 170 wherein the process comprises heating 2-bromolysergic acid diamide and IPA to about 65 ℃, combining D-tartaric acid and IPA with 2-bromolysergic acid diamide and IPA wherein the combined solution becomes clear, heating the combined solution to about 65 ℃ for a predetermined time, cooling the mixture to about room temperature, cooling to about 5 ℃ to provide a solid comprising a major amount of (5 r,8 r) 2-bromo-LSD semi-D-tartrate salt and a minor amount of (5 r,8 s) 2-bromo-LSD semi-D-tartrate salt.

172. The method of claim 171, wherein the predetermined time is about 30 minutes.

173. A process according to any of claims 134-172, wherein the ratio of (5 r,8 r) 2-bromo-LSD hemi-D-tartrate to (5 r,8 s) 2-bromo-LSD hemi-D-tartrate is from about 87 to about 13.

174. A process of any one of claims 134 to 172, wherein the solid is recrystallized to obtain (5 r,8 r) 2-bromo-LSD semi-D-tartrate; ethanol is optionally used.

175. A process of any of claims 134-172 wherein the solid is recrystallized to obtain (5 r,8 r) 2-bromo-LSD semi-D-tartrate having about 99% to about 99.9% purity, optionally about 99.5% to about 99.9% purity.

176. The method of any one of claims 134 to 135, wherein the solid is a polymorph.

177. A method of treating depression, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

178. The method of claim 177, wherein the depression is: depression, major depressive disorder (including major depressive episode), devastating mood disorder, atypical depression, psychotic major depression, tension depression, postpartum depression, premenstrual anxiety, seasonal affective disorder, substance/drug induced depression, double depression, depressive personality disorder, persistent depression (hypo-affective disorder), recurrent transient depression, mild depression, depression due to medical conditions, depression not otherwise indicated, or depression resistant to treatment.

179. The method of claim 177 or 178, wherein the depression is major depression.

180. The method of claim 179, wherein the major depressive disorder is dysthymia.

181. The method of claim 178, wherein the depression is atypical depression.

182. The method of claim 178, wherein the depression is tension depression.

183. The method of claim 178, wherein the depression is due to a medical condition.

184. The method of claim 177, wherein the depressive disorder is postpartum depression.

185. The method of claim 177, wherein the depression is premenstrual dysphoric disorder.

186. The method of claim 177, wherein the depression is a seasonal affective disorder.

187. The method of any one of claims 177-186, wherein the amount of the compound for administration to the subject is selected from about 25-500 μg/kg/body weight/day; or about 50 to about 2000 μg/kg/body weight/day; or about 10 to about 500 μg/kg/body weight/day.

199. A method of treating bipolar disorders and related disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

200. The method of claim 199, wherein the bipolar disorder and related disorder is bipolar I disorder, bipolar II disorder, substance/drug induced bipolar disorder and related disorder, and bipolar disorder not otherwise indicated.

201. The method of claim 200, wherein the amount of the compound for administration to the individual is selected from about 25 to about 1000 μg/kg/body weight/day.

202. A method of treating schizophrenia lineages and other psychotic disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

203. The method of claim 202, wherein the schizophrenic lineage and other psychotic disorder is: delusional disorders, transient psychotic disorders, schizophrenia, schizophreniform disorders, schizoaffective disorders, substance/drug-induced psychotic disorders, schizophreniform (personality) disorders, psychotic disorders due to another medical condition, stress disorders associated with another psychotic disorder, and other indicated or unspecified schizophreniform and other psychotic disorders.

204. The method of claim 203, wherein the amount of the compound for administration to the individual is about 50 to about 2000 μg/kg/body weight/day.

205. A method of treating personality disorder by DSM-5 classification, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

206. The method of claim 205, wherein the personality disorder is: paranoid personality disorder; split-like personality disorder; split personality disorder; anti-social personality disorder; edge personality disorder; performance personality disorder; self-loving personality disorder; avoidance personality disorder; a dependent personality disorder; forced personality disorder; personality changes due to another medical condition; other indicated personality disorders and unspecified personality disorders.

207. A method of treating anxiety disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

208. The method of claim 207, wherein the anxiety disorder: generalized anxiety disorder, separation anxiety disorder, panic disorder, selective mutism, specific phobia (animal, natural environment, blood/injection/injury fear, context, others), social anxiety disorder, panic attack-specific disorder, agoraphobia, substance/drug-induced anxiety disorder, anxiety disorder due to other medical conditions, and other indicated or unspecified anxiety disorders.

209. The method of claim 208, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

210. A method of treating a wound and stress-related disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

211. The method of claim 210, wherein the trauma and stress-related disorder comprises an attachment disorder, a disinhibited social engagement disorder, a post-trauma stress disorder (PTSD), an acute stress disorder, an adaptation disorder, other indicated or unspecified trauma and stress-related disorders.

212. The method of claim 211, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

213. A method of treating obsessive-compulsive disorders and related disorder conditions, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

214. The method of claim 213, wherein the obsessive-compulsive disorder and related disorders comprises: obsessive Compulsive Disorder (OCD), somatic dysmorphism, stocking disorder, dehairing disorder (dehairing disorder), exfoliative (skin scratching) disorder, substance/drug induced obsessive compulsive disorder and related disorders, obsessive compulsive disorder and related disorders due to another medical condition, and other indicated and unspecified obsessive compulsive disorders and related disorders (e.g., body-centered repetitive behavioral disorders, compulsive jealogy).

215. The method of claim 214, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

216. A method of treating destructive, impulse control and behavioral disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

217. The method of claim 216, wherein the destructive, impulse control, and behavioral disorders comprise: oppositional defiant disorder, intermittent explosive disorder, behavioral disorder, antisocial personality disorder, pyromania, pilgrim, dehairing, and other destructive, impulse control and behavioral disorders both indicated and unspecified.

218. A method of treating ingestion and eating disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

219. The method of claim 218, wherein the ingestion and eating disorder comprises: pica, ruminant disorders, avoidance/restriction type food intake disorders, anorexia nervosa, binge eating disorders, bulimia nervosa, overeating or overeating disorders, diabetic hyperphagia, prader-willi syndrome and hypothalamic obesity, somatic dysmorphia, and other indicated and unspecified intake or eating disorders.

220. A method of treating a separation disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

221. The method of claim 220, wherein the separation disorder comprises separation identity disorder, separation forgetfulness, personality/reality dissociation disorder, and other designated and unspecified separation disorders.

222. A method of treating a neurodevelopmental disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

223. The method of claim 222, wherein the neurodevelopmental disorder comprises: mental disability (mental development disorder), general developmental retardation, communication (language, speech/sound, childhood fluency or stuttering, social, unspecified) disorders, autism spectrum disorders, attention Deficit Disorder (ADD), attention Deficit Hyperactivity Disorder (ADHD), specific learning disorders, movement disorders (developmental coordination, notch-plate movement, tourette's disorder, persistent/chronic movement or vocal tic disorders, transient tic disorders), and other neurological development disorders indicated or unspecified.

224. A method for treating a disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130, wherein the disorder comprises: epileptic seizures (including generalized seizures, focal seizures, seizures of unknown origin and focal to bilateral seizures) and seizures (including generalized seizures, focal seizures, generalized and focal seizures, dravet syndrome and seizures of unknown origin).

225. A method of treating a sleep-wake disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

226. The method of claim 225, wherein the sleep-wake disorder comprises: insomnia, excessive somnolence disorder, narcolepsy, respiratory-related sleep disorders (e.g., obstructive sleep apnea hypopnea, central sleep apnea, primary central sleep apnea, sleep-related hypoventilation), circadian rhythm-related sleep-wake disorders, non-rapid eye movement (NREM) sleep arousal disorders, nightmares, rapid Eye Movement (REM) sleep behavioral disorders, restless leg syndrome, substance/drug-induced sleep disorders, and other indicated and unspecified sleep-wake disorders.

227. A method of treating substance-related disorders (SRD) and addictive disorders, wherein the method comprises administering to an individual in need thereof a compound of any of claims 1-123, a composition of any of claims 124-127, or a formulation of any of claims 128-130.

226. The method of claim 227, wherein the substance-related disorders (SRD) and addictive disorders include, but are not limited to, the following drug categories: alcohol, nicotine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (amphetamine-type substances, cocaine, and other stimulants), and drugs, as well as other indicated or unspecified substance-induced disorders.

227. A method of treating a non-substance related disorder, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

228. The method of claim 227, wherein the non-substance related disorder is a gambling disorder.

229. A method of treating headache disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

230. The method of claim 229, wherein the headache disorder is classified by the international headache classification committee and comprising: primary headaches including migraine headaches (including non-premonitory migraine, premonitory migraine and chronic migraine), tension headaches (including sporadic headaches, frequent headaches and chronic tension headaches), trigeminal autonomic headaches (including cluster headaches, paroxysmal migraine, transient unilateral neuralgia-like headache attacks and persistent migraine), and other primary headaches.

231. The method of claim 229, wherein the headache disorder is trigeminal autonomic headache (TAC), including cluster headache (familial cluster headache, histamine headache, or vascular-derived facial pain), episodic cluster headache, recurrent or chronic cluster headache, transient unilateral neuralgia-like headache episodes (SUNHA), transient unilateral neuralgia-like headache episodes (SUNCT) and transient unilateral neuralgia-like headache episodes (SUNCT) with conjunctival congestion and lacrimation, and transient unilateral neuralgia-like headache with craniocerebral autonomic symptoms.

232. The method of claim 229, wherein the headache disorder is a secondary headache comprising headache due to head and/or neck trauma or injury, headache due to craniocerebral and/or cervical vascular disorders, headache due to non-vascular intracranial conditions, headache due to substance or withdrawal thereof, headache due to infection, headache due to imbalance disorders, headache or facial pain due to cranium, neck, eye, ear, nose, sinus, tooth, mouth or other facial or neck structural disorders, headache due to mental disorders, and headache category and other facial pain due to painful lesions of cranial nerves including pain due to injury or disease of trigeminal nerves.

233. A method of treating pain, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

234. The method of claim 233, wherein the pain is caused by conditions including inflammation (e.g., rheumatoid arthritis, lupus, behcet's disease), genetic factors (e.g., erythromelalgia), conditions such as diabetes including nerve damage resulting in pain, cancer and cancer treatments such as chemotherapy, neurological conditions such as Multiple Sclerosis (MS), neurodegenerative conditions such as parkinson's disease, stroke, shingles, HIV, leprosy, gill-barre syndrome, vascular disease, vascular malformations and autoimmune conditions, all neuropathies including peripheral neuropathy, autonomic neuropathy, focal neuropathy, proximal neuropathy, diabetic neuropathy and stress mononeuropathy, phantom limb pain, residual limb pain and Complex Regional Pain Syndrome (CRPS), trigeminal neuralgia, postherpetic neuralgia, radiculopathy, and all radiculopathy including chest or lumbar radiculopathy, nociceptive pain (e.g., pain resulting from injury), somatic or nociceptive pain (e.g., chronic pain, chronic fibromyalgia, chronic pain, chronic back pain, chronic pain of the jaw, chronic pain of the back, chronic pain of the lower jaw, chronic etiology, chronic pain of the underlying origin, chronic pain of the disease, chronic etiology syndrome, chronic pain of the disease, chronic etiology, chronic pain of the disease, and chronic pain of the disease, or the various causes.

235. The method of claim 233, wherein the pain is chronic pain comprising: chronic primary pain (which includes fibromyalgia, chronic pelvic pain, nonspecific back pain, and chronic primary pain not otherwise indicated); chronic cancer pain (which includes pain due to cancer and metastasis, pain due to chemotherapy, pain due to radiation therapy, pain due to cancer surgery, and other chronic pain associated with cancer); chronic postoperative and post-traumatic pain (which includes all postoperative and post-traumatic pain, as well as postoperative/post-traumatic pain not otherwise indicated); chronic neuropathic pain (which includes peripheral neuropathic pain, central neuropathic pain, and other neuropathic pain and neuropathic pain not otherwise indicated); chronic headache and orofacial pain (which includes chronic primary headache, chronic secondary headache, chronic orofacial pain, headache and orofacial pain not otherwise indicated); chronic visceral pain (which includes chronic visceral pain from persistent inflammation, and/or vascular mechanisms, and/or obstruction/expansion, and/or traction/compression, and/or combined mechanisms, or chronic visceral pain from other locations, from cancer, or chronic pain of unknown functional or causative origin); and chronic musculoskeletal pain (which includes chronic musculoskeletal pain from persistent inflammation and/or structural bone joint changes, and/or chronic musculoskeletal pain from neurological diseases (e.g., spasmodic pain), as well as chronic non-specific musculoskeletal pain and related pain syndromes).

236. The method of claim 233, wherein the pain is acute pain, including pain of a short duration, from hours or days or up to 3 months, regardless of the type of pain, and including inflammatory, nociceptive, neuropathic, plastic, and other types of pain, and including acute pain from tissue injuries including those caused by any type of surgery, dental work, labor, cutting, burns, fractures, and other accidents or wounds, acute pain caused by any disease state, acute pain caused by any type of wound, and acute pain caused by uncertain reasons.

237. A method of treating spasticity, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

238. The method of claim 237, wherein the spasticity is with or without neuropathic pain and comprises: cerebral palsy, stroke, multiple Sclerosis (MS), traumatic Brain Injury (TBI), amyotrophic Lateral Sclerosis (ALS), hereditary spastic paraplegia, adrenoleukodystrophy (ALD), phenylketonuria, keara, and spinal cord injury.

239. A method for treating disorders and diseases associated with nerve injury or trauma, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

240. The method of claim 239, wherein the disorders and diseases are associated with nerve injury or trauma from: peripheral nerve injury or trauma regardless of cause, and/or central nervous system (brain and spinal cord) nerve injury or trauma regardless of cause; disorders and diseases caused by external physical factors such as accidents, sports injuries, falls, gunshots or explosive impacts; or internal factors such as stroke, ruptured cerebral aneurysms, hypoxia, infection (viral, bacterial, prion or other), autoimmune disease; other nerve injuries or traumas caused directly or indirectly by external factors, and/or nerve injuries or traumas caused directly or indirectly by disease states.

241. A method of treating fatigue, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

242. The method of claim 241, wherein the fatigue is chronic fatigue (e.g., physical fatigue, mental fatigue, or mental fatigue) from Traumatic Brain Injury (TBI), chronic Fatigue Syndrome (CFS), and related disorders, as well as other diseases and/or disorders that cause chronic fatigue.

243. A method of treating a neurodegenerative disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

244. The method of claim 243, wherein the neurodegenerative disorder comprises: alzheimer's disease, amyotrophic Lateral Sclerosis (ALS), bay's disease, friedel Lai Xixing ataxia, huntington's disease, lewy body disease, motor neuron disease, multiple sclerosis, parkinson's disease, prion disease, spinal muscular atrophy, neurodegenerative conditions caused by viral (e.g., HIV) or bacterial infection, neurodegenerative conditions caused by substances/drugs, and other neurodegenerative conditions associated with aging and non-aging.

245. A method of treating a disease and/or disorder selected from the group consisting of delayed ejaculation due to sexual dysfunction, erectile dysfunction, female orgasmic disorder, female sexual interest/arousal disorder, reproductive pelvic pain/infiltration disorder, male hyposexuality disorder, premature ejaculation (premature ejaculation), substance/drug-induced sexual dysfunction, other indicated and unspecified sexual dysfunction, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

246. A method of treating gender anxiety, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

247. A method of treating a neurodegenerative disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

248. The method of claim 247, wherein the neurocognitive disorder (NCD) comprises delirium, NCD caused by alzheimer's disease, vascular NCD, NCD with lewy bodies, NCD caused by parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance/drug induced NCD; NCD caused by huntington's disease, NCD caused by prion disease; NCD caused by another medical condition, NCD caused by a variety of etiologies, and unspecified NCD.

249. The method in claim 247, wherein the neurocognitive disorder is a neurocognitive/learning disorder comprising memory problems, mental confusion, poor attention, and/or inattention due to infection (viral/bacterial/prion/other) or other indicated or unspecified disorder, disease or other unknown cause.

250. The method of claim 247, where the neurocognitive disorder is a decrease in memory, cognition, and/or learning with or without obvious signs of a neurodegenerative disorder or a neurodevelopmental disorder, and/or a decrease in memory, cognition, and/or learning with or without obvious signs of a neurodegenerative disorder or a neurodevelopmental disorder and independent of age.

251. The method in claim 247, where the neuro-cognitive disorder is a neurological and/or neuropsychiatric disorder and/or a condition associated with normal aging and/or luteal phase syndrome.

252. A method of treating a neurological disease caused by a viral infection, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130, wherein the neurological disease is caused by a viral infection that utilizes a neuronal cell surface receptor comprising a 5-hydroxytryptamine energy (5-HT) receptor (particularly a 5-HT2A receptor), such as Progressive Multifocal Leukoencephalopathy (PML) caused by JC virus.

253. A method of reducing and/or preventing the adverse effects of a hallucinogen, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

254. A method of maintaining or improving well-being, wherein the method comprises administering to an individual in need thereof the compound of any one of claims 1 to 123, the composition of any one of claims 124 to 127, or the formulation of any one of claims 128 to 130.

255. A method of treating a disease and/or disorder comprising agonism of one or more 5-HT1 receptor subtypes, such as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F, by a therapeutic mechanism associated with activation of the 5-HT1 receptor, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

256. A method of treating a disease and/or disorder associated with cognitive/learning/memory deficit or decline, wherein the therapeutic mechanism is associated with 5-HT6 receptor activation (agonism), wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

257. A method of treating a disease and/or disorder, wherein the therapeutic mechanism is associated with 5-HT2A receptor activation (agonism), wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

258. A method of treating a disease or disorder, wherein the therapeutic mechanism is associated with D2-like receptor activation (agonism) such as the D2 and D4 receptor subtypes, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

259. The method of any one of claims 177-258, wherein the treatment excludes the illusive effect and does not induce tolerance to the compound of any one of claims 1-123, the composition of any one of claims 124-127, or the formulation of any one of claims 128-130.

These and other features, embodiments, and advantages of the present disclosure are not intended to limit or define the disclosure, but rather to provide examples that aid in understanding the disclosure when read in conjunction with the following description and with reference to the accompanying drawings.

Drawings

Embodiments will now be described, by way of example only, with reference to the accompanying drawings.

FIGS. 1A and 1B show examples of ¹ H-NMR and ¹³ C-NMR spectra of 2-bromolysergic acid (B) in DMSO-d ₆, respectively;

FIGS. 2A and 2B show examples of electrospray ionization mass spectra of 2-bromo-LSDC-A;

FIGS. 3A and 3B show examples of the effect of pH on E405 purity and yield;

FIG. 4 shows an example of electrospray ionization mass spectrometry of 2-bromo-LSDC;

FIG. 5 shows an example of ¹ H-NMR spectrum of (5R, 8R) -2-bromo-LSD semi-D-tartrate in DMSO-D ₆;

Fig. 6A to 6D show examples of high resolution PXRD of (5 r,8 r) -2-bromo-LSD semi-D-tartrate: (6A) shows small scale crystallization from ethanol; (6B) shows crystallization from IPA; (6C) Showing the overlap of crystals from ethanol (black) and IPA (red); and (6D) shows crystallization from ethanol performed at a scale of about 350 g;

Fig. 7A to 7C show examples of mass spectra of (5 r,8 r) -2-bromo-LSD semi-D-tartrate and SEM images of (5 r,8 r) -2-bromo-LSD semi-D-tartrate;

fig. 8 shows an example of high resolution PXRD of (5 r,8 r) -2-bromo-LSD semi-L-tartrate recrystallized from ethanol;

FIG. 9 shows examples of FTIR spectra of (5R, 8R) -2-bromo-LSD-hemi-D-tartrate and (5R, 8R) -2-bromo-LSD-hemi-L-tartrate;

Fig. 10A/10B are graphs demonstrating the lack of magical activity of LSD polymorph E559 in rodents using Head Twitch Response (HTR). Polymorphic forms E559 were administered at 0.1, 0.3, 1,3 and 10mg/kg or LSD (0.1 mg/kg). Data are expressed as group mean ± standard deviation of the entire 60 minute test period (a) and individual data points (B) per 2 minute block;

Fig. 11A-11D are diagrams demonstrating that LSD polymorph E559 crosses the blood brain barrier. The plasma level of the "E559 polymorph" increased in a time-dependent and dose-dependent manner, and appeared in plasma rapidly (10 minutes) after administration in all the administration groups of male mice (a) and female mice (B). Brain tissue exposed to the compound increases proportionally in a time dependent manner (C) and a dose dependent manner (D);

Fig. 12 is a graph demonstrating that LSD polymorph E559 exhibits good oral bioavailability, which is not affected by fed status, as shown by the concentration of E559 polymorph measured in plasma samples between fasted dogs and fed dogs;

Fig. 13A and 13B show the illusive effect of LSD polymorph E559 blocking the illusive compound 2, 5-dimethoxy-4-iodoamphetamine (DOI) in a mouse HTR model. Pretreatment of mice with the "E559 polymorph" significantly attenuated the ability of DOI to induce HTR in mice (fig. 13A). Fig. 13B, pretreatment of mice with the "E559 polymorph" almost completely blocked DOI-induced HTR during the first 10 minutes, and the blocking gradually decreased until after 40-60 minutes, no blocking was detected any more;

Fig. 14A to 14D are graphs showing the binding and functional effects of LSD polymorph E559 on 5HT2B receptors. LSD in (a), (B) and (C) showed potent agonism of the 5-HT2B receptor, as seen in all three functional assessments, whereas E559 polymorph did not show agonism seen with LSD. In (D), the E559 multimer only produced a weak block of hERG channel activity at very high concentrations (ec50=31.6 μm), indicating that it shows a low risk of causing arrhythmia in humans;

fig. 15 is a graph demonstrating the presence of a receptor/target at the CNS: a graph of the activity of polymorph E559 at 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6 and 5-HT7A, and compared to the activity of serotonin (5-HT) and LSD.

FIGS. 16A/16B are graphs demonstrating the activity of polymorph E559 for a second messenger activity downstream of each of the target receptors 5-HT1A, 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT 7;

FIG. 17A is a graph showing that polymorph E559 antagonizes 5-HT2A receptor activation mediated by 5-HT as assessed by the Gq dissociation assay;

FIG. 17B is a graph showing activation of the BRET assay by polymorph E559 antagonizing 5-HT mediated beta-arrestin 2 recruitment to the 5-HT2A receptor;

fig. 18A shows images of rat cortical neurons stained with vehicle (no drug control) or MAP2 treated with E559 polymorph on day 6 in vitro (DIV 6);

fig. 18B shows a schematic diagram of Sholl analysis that yields a measure of neuron axis complexity by evaluating (a) the number of neuronal process crossings, (B) the total length of the neurons, and (C) the number of nodes and endpoints.

Fig. 19A-F: the E559 polymorph was shown to promote neuroplasticity: (A) Representative Sholl traces of neurons treated with vehicle (control) or increasing concentrations of E559 polymorph; (B) Showing the total number of Sholl radius crossings of MAP2 positive neurites after treatment with vehicle (control), E559 polymorph or ketamine; (C) Displaying the total number of dendrite axis lengths from neurons in fig. 19A and 19B; (D) Representative fluorescence images of dendritic spines were shown in cortical neurons treated with vehicle (control), E559 polymorph or ketamine; (E) Showing the total number of spines per 10 μm cross section (see fig. 18B) on the longest tip dendrite scored from the first branch point; and (F) shows the ratio of surviving to dead neuronal cells in a randomly selected 40X objective field of view in a cell viability assay. The horizontal lines in all figures represent mean ± standard error of mean (s.e.m);

FIGS. 20A-C demonstrate the E559 polymorph-mediated neuroplasticity acting via the 5-HT2A receptor: (A) The tracing of cortical neurons (DIV 3) treated with 0.1, 0.5 or 1mM flugliptin (Vol) followed by vehicle or E559 polymorph (1 μm) is shown. (B) Showing the total number of Sholl hybridizations of neurons processed in fig. 20A; (C) The total dendritic axis length of neurons processed in fig. 20A;

fig. 21A/21B show that repeated administration of the E559 polymorph did not induce tolerance in vitro. (A) Is a graph showing that the "E559 polymorph" is a weak recruitment of β -arrestin 2 compared to DOI and LSD activity using a BRET-based β -arrestin 2 recruitment assay (described in example 8) for 5-HT2A receptors; (B) Is a graph showing that the E559 polymorph shows only weak internalization of 5-HT2A receptors compared to effective internalization by LSD, DOI and 5-HT;

Figure 22 is a graph showing that repeated treatment with the E559 polymorph did not induce in vivo tolerance (HTR model used in mice) compared to significant tolerance induced by repeated dosing of DOI.

Figures 23A-D demonstrate that the E559 polymorph exhibits antidepressant/anxiolytic activity in a chronic stress-agonist model: (a) shows the study design of the self-combing splash test; (B) The distance traveled in the open field for female mice treated with the E559 polymorph is shown: (C) The time the mice in fig. 23B spent in the center of the open field; (D) The time spent self-grooming in the splatter test of female mice treated as described in fig. 23A is shown. The horizontal line represents the mean ± standard error of the mean (s.e.m.) and the asterisk represents statistical significance;

Fig. 24A-B: the long-term antidepressant and anxiolytic effects of the E559 polymorph after 28 days of the experiment depicted in fig. 23 are demonstrated: (A) The effect of CVS in decreasing time of OFT center remained reversed (at a level similar to the acute effect of E559 polymorph at 28 days post last E559 polymorph treatment, CVS-brine and CVS-E559 polymorph 4X 1mg/kg ^** p=0.0052, (B) represents the time it takes female mice to self-comb in the splatter test at 28 days post last E559 polymorph treatment as shown in fig. 23A;

Figures 25A-G demonstrate that the E559 polymorph exhibits antidepressant/anxiolytic activity in an acute stress-agonist model: (A) Study design is described in which female/male mice (n=10/group/sex) were treated by IP injection of E559 polymorph or vehicle (saline), followed by open field and forced swim tests 24 hours after treatment; (B) And (E) represents the total distance traveled in the open field 24 hours after vehicle or E559 polymorph in female and male mice, respectively; (C) And (F) represents the time of female and male mice, respectively, in the center of the open field; (D) And (G) represent the time of immobility during the last 4 minutes of the forced swim test of female and male mice, respectively. The horizontal line represents the mean ± standard error of the mean (s.e.m.) and the asterisk represents statistical significance;

Figures 26A-D demonstrate that the E559 polymorph exhibits antidepressant/anxiolytic effects involving in vivo 5-HT2A receptors using the assay of example 14: (A) The flugliptin pretreatment blocks the reduction of immobility induced by the E559 polymorph in FST in female mice; (B) The flugliptin pretreatment blocks the reduction of immobility induced by the E559 polymorph in FST in female mice; (C) And (D) flugliptin or a combination of flugliptin and E559 polymorph does not affect the movement of OFT in female or male mice;

Fig. 27 is a graph showing pain response assessment results after single dose treatment of E559 polymorph, vehicle or gabapentin on postoperative day 7 using von frey fiber filaments in a rat retained nerve injury (SNI) model. The E559 polymorph showed potent analgesic activity in a single administration neuropathic pain model; and

Fig. 28 is a graph showing the results of pain response assessment after multi-dose treatment of E559 polymorph, vehicle or gabapentin starting on day 7 post-surgery. The E559 polymorph shows potent analgesic activity in a model of neuropathic pain administered repeatedly.

Detailed Description

As used herein, the term "invention" or "invention (present invention)" is a non-limiting term and is not intended to refer to any single aspect of a particular invention, but encompasses all possible aspects as described in the specification and claims.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the application is not entitled to antedate such disclosure by virtue of prior application. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

In case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter herein belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

Reference to "one embodiment," "an embodiment," "a preferred embodiment," or any other phrase referring to the word "embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure, and also means that any particular feature, structure, or characteristic described in connection with an embodiment can be included in, or omitted from, any embodiment. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments necessarily mutually exclusive of other embodiments. Furthermore, various features described may be exhibited by some embodiments and not by others and may be omitted from any of the embodiments. Furthermore, any particular feature, structure, or characteristic described herein may be optional. Similarly, various requirements are described which may be requirements for some embodiments but not other embodiments. Any of the features discussed herein with respect to one aspect or embodiment of the invention may be applied to another aspect or embodiment of the invention where appropriate. Similarly, any features discussed herein with respect to one aspect or embodiment of the invention may optionally be and/or omitted from this aspect or embodiment of the invention or any other aspect or embodiment of the invention discussed or disclosed herein, where appropriate, with respect to this aspect or embodiment of the invention or any other aspect or embodiment of the invention discussed or disclosed herein.

Definition of the definition

Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to apply to all embodiments and aspects of the application described herein, as those skilled in the art will appreciate.

It is to be understood that all amounts are approximate and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below.

In understanding the scope of the present application, the articles "a," "an," and "the" are intended to mean that there are one or more of the elements. In addition, the term "comprising" and its derivatives, as used herein, are intended to be open ended terms that specify the presence of, for example, the stated features, elements, compounds, molecules, components, groups, integers, and/or steps, but do not exclude the presence of, for example, other unstated features, elements, compounds, molecules, components, groups, integers, and/or steps. The foregoing also applies to words having similar meanings such as the terms, "including", "having" and their derivatives.

It will be understood that any aspect described as "comprising" certain (e.g., features, elements, compounds/molecules, components, groups, integers and/or steps) may also "consist of … …" or "consist essentially of … …," where "consisting of … …" has a capped or limiting meaning and "consisting essentially of … …" is intended to include, for example, specified features, elements, compounds/molecules, components, groups, integers and/or steps, but not include other components that preclude the presence of materials as impurities, unavoidable materials that exist as a result of methods for providing, for example, the features, elements, compounds/molecules, components, groups, integers and/or steps, and components added for purposes other than achieving the technical effects of the present invention. For example, a composition defined using the phrase "consisting essentially of … …" includes any known acceptable additive, excipient, diluent, carrier, etc. Typically, a composition consisting essentially of a set of components will include less than 5 wt%, typically less than 3 wt%, more typically less than 1 wt%, and even more typically less than 0.1 wt% of unspecified components.

Terms of degree such as "substantially," "about," and "approximately" as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least 5% of the modified term if this deviation would not negate the meaning of the word it modifies.

The abbreviation "for example" derives from the latin example (exempli) and is used herein to represent a non-limiting example. Thus, the abbreviation "e.g. (e.g)" is synonymous with the term "e.g. (for example)".

The phrase "e.g., (suchs)" should be interpreted as "e.g., including".

The term "and/or" as used herein means that the listed items are present or used singly or in combination. In practice, the term means that "at least one" or "one" or more "of the listed items is used or exists.

The phrase "at least one" is understood to mean one (species) or a plurality of (species). The phrase "at least one (seed)" of the phrase ". And". Is understood to mean at least one (seed) of the listed elements or a combination thereof, if not explicitly listed. For example, "at least one of A, B and C" is understood to mean a alone or B alone or C alone or a combination of a and B or a combination of a and C or a combination of B and C or a combination of A, B and C. "at least one of A, B and C" is understood to mean at least one of A alone or B alone or C alone or combination of A and C or combination of B and C or combination of A and C.

All language, such as "up to", "at least", "greater than", "less than", etc., includes the recited numbers and refers to ranges that can be subsequently broken down into ranges and sub-ranges. The scope includes each individual member. Thus, for example, a group having 1-3 members refers to a group having 1,2, or 3 members. Similarly, a group having 6 members refers to a group having 1,2,3, 4, or 6 members, and so forth.

The pattern verb "may" means that one or more options or choices are preferred for use or selection of several of the described embodiments or features contained therein. Without disclosing options or choices regarding a particular embodiment or feature contained in a particular embodiment or feature, the pattern verb "may" refers to affirmative actions regarding how to proceed or use the described embodiment or feature and aspects of the described embodiment or feature contained in the described embodiment or feature, or to use a determined decision regarding the particular skill of the described embodiment or feature contained in the described embodiment or feature. In the latter case, the verb "can (make)" has the same meaning and connotation as the auxiliary verb "can" (can).

As used herein, the terms "reduce", "decrease", "lessening" and similar terms mean a reduction of at least about 10%, about 15%, about 20%, about 25%, about 35%, about 50%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97% or more.

As used herein, the terms "improve," "increase," "enhance," and similar terms mean an increase of at least about 10%, about 15%, about 20%, about 25%, about 50%, about 75%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more.

Diseases and disorders are defined as described in the mental disorder diagnosis and statistics handbook (DSM-5) published by the american psychiatric association or the International Classification of Diseases (ICD) published by the world health organization.

As used herein, the phrase "substantially non-fanciful" or "non-substantial fanciful" or similar statements means derivatives that exhibit reduced fanciful to a non-detectable level of fanciful, or significantly reduced fanciful intensity, or significantly reduced fanciful duration, as compared to LSD, and wherein significantly means that the fanciful activity of the derivative is reduced by ≡50% as compared to the fanciful activity or a surrogate measure thereof in an animal model observed with LSD. Hallucinations are the mental/psychosocial effects that a human individual experiences when administering psychotropic drugs. In the mouse model, the head twitch response in mice is considered the most reliable animal substitute for the hallucinogenic activity of the compound in humans (Halbertstad AL et al, neuropharmacology, volume 167, month 5, day 020, month 1, 107933;Adam L.Halberstadt and Mark a.german.psychropharmacology (Berl), 2013jun;227 (4)).

As used herein, the phrase "effective amount" or "therapeutically effective amount" (used interchangeably herein) refers to the amount of a composition or formulation described herein that will elicit the diagnostic, biological, or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

As used herein, the term "modulate" means reduce or inhibit and/or increase or enhance.

As used herein, "individual" is interchangeable with "patient" or "subject" and refers to an animal in need of treatment, which may be a human or non-human animal.

As used herein, the term "individual in need thereof" refers to a human or non-human individual that may be treated with any of the compounds or pharmaceutical compositions disclosed herein when the compounds or pharmaceutical compositions are used as therapeutic agents.

As used herein, "pharmaceutically acceptable" refers to materials and compositions that are physiologically tolerable and do not generally produce allergic or similar untoward reactions (e.g., gastric discomfort, dizziness, etc.) when administered to a human. Generally, as used herein, "pharmaceutically acceptable" refers to approval or approval by regulatory bodies of the federal or state government, or by inclusion in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The phrase "pharmaceutically acceptable salt" as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. The compounds contained in the composition of the present invention, which are basic in nature, are capable of forming various salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfuric acid, citric acid, maleic acid, acetic acid, oxalic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, hydrogen sulfate, phosphoric acid, acid-type phosphoric acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, acid-type citric acid, tartaric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphtalent) ] salts. In addition to the acids described above, the compounds comprising an amino moiety included in the compositions of the present invention may form pharmaceutically acceptable salts with various amino acids.

As used herein, the term "pharmaceutically acceptable carrier" may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is admixed with the finely divided active component. In tablets, one or more active ingredients are mixed with a carrier having the desired binding characteristics in suitable proportions and compacted in the shape and size desired. Liquid form preparations include solutions, suspensions and emulsions, for example, water or aqueous propylene glycol solutions. For parenteral injection, the liquid formulation may be formulated in solution in an aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

As used herein, a "therapeutic agent" may be any agent that is administered to an individual to treat the individual. A therapeutic agent may refer to an agent that modulates the biological activity of Ornithine Aminotransferase (OAT), for example, wherein the agent inhibits the biological activity of OAT to catalyze the synthesis of glutamate or glutamine. A therapeutic agent may refer to an agent that modulates the biological activity of gammA-Aminobutyric acid aminotransferase (GABA-AT), for example, wherein the agent inhibits the biological activity of GABA-AT to degrade GABA into Succinic Semialdehyde (SSA). Therapeutic agents may include, but are not limited to, small molecules or compounds disclosed herein. Therapeutic agents may include, but are not limited to, pharmaceutical compositions comprising small molecules or compounds disclosed herein.

As used herein, the term "binder" or "excipient" refers to an agent used to impart cohesive properties to a powdered material. Binders, or "granulating agents," as they are sometimes known, impart cohesiveness to the tablet formulation, which ensures that the tablet remains intact after compression, as well as improving free-flowing properties by formulating particles having a desired hardness and size. Materials commonly used as binders include starch; gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as acacia, sodium alginate, extracts of irish moss, panwar gums, indian gum (ghatti gum), mucilage of isapol hulls, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, magnesium aluminum silicate, microcrystalline cellulose, microcrystalline dextrose, amylose, and larch arabinogalactan and the like. By "excipient" is meant a substantially inert substance that acts as a diluent or imparts a form or consistency to the formulation. In general, excipients may be defined as ingredients in the form of drugs taken by or administered to a patient, rather than active substances; see, e.g., annex of Directive/2001/83/EC. Certain excipients may also be used as disintegrants, i.e. they aid in the dispersion of the solid pharmaceutical composition when exposed to body fluids.

As used herein, a "diluent" is an inert substance that is added to increase the volume of the formulation, thereby making the tablet the actual size for compression. Common diluents include calcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar, silicon dioxide and the like.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages, such as pills, tablets, caplets, hard or soft capsules, each unit containing a predetermined quantity of LSA derivative, including pharmaceutically acceptable salts thereof. By "hard capsule" is meant a capsule comprising a membrane that forms a two-part capsule-like container capable of carrying a solid or liquid payload of a drug and excipients. By "soft capsule" is meant a capsule molded in a single container that carries a liquid or semi-solid payload of the drug and excipients.

The terms "extended release", "controlled release" or "sustained release" as used interchangeably herein refer to a pattern of release of, for example, a derivative of lysergic acid diacetamide (LSD), including polymorphs thereof, from a formulation thereof such that it is absorbed by the body over a period of time, increasing t _1/2 and decreasing Cmax relative to that observed with administration of an immediate release formulation administered at the same dosage level. Prolonged release formulations of the active agent may be achieved, for example, by embedding the active agent in a network of substances in which the body is slowly dissolved, such that the active ingredient slowly and regularly exudes from the coating, or by swelling the active agent to form a gel having a nearly impermeable surface, wherein the drug slowly leaves the semipermeable layer.

As used herein, the term "dry weight" refers to a measurement of the mass of a sample after all or substantially all of the liquid has been removed from the sample. In one embodiment, removing the liquid includes dewatering, heating, stirring, filtering, and/or any other suitable method of liquid water. In one embodiment, dry weight is measured in pounds. In one embodiment, dry weight is measured in ounces. In one embodiment, dry weight is measured in grams, e.g., milligrams, kilograms, etc.

As used herein, the term "dry powder" refers to a substance that consists of fine particles and contains little or no liquid material.

As used herein, the terms "mass percent," "percent by mass," "mass%" and the like refer to the fraction of a compound that is 100 in amount relative to the entire mass of the sample. In one embodiment, for a compound of interest, the mass percentages are calculated using the formula: (mass of target compound in grams)/(total mass of composition in grams) ×100%.

The term "purified" refers to a compound having a purity of 80% to 100%, which means that the compound comprises 80% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity of 90% to 100%, meaning that the compound comprises 90% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity of 95% to 100%, meaning that the compound comprises 95% to 100% of the total mass of the composition. In one embodiment, the term "purified" refers to a compound having a purity of 99% to 100%, meaning that the compound comprises 99% to 100% of the total mass of the composition.

In one embodiment, the term "purified" refers to about 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% to 100% pure compound, meaning that the compound comprises 99.9% to 100% of the total mass of the composition.

As used herein and unless otherwise indicated, the term "substantially pure" when used to describe a polymorph, crystalline form, or solid form of a compound or complex described herein refers to a solid form of the compound or complex that comprises the particular polymorph and is substantially free of other polymorphs and/or amorphous forms of the compound.

As used herein, unless otherwise indicated, a composition that is "substantially free" of compounds means that the composition contains less than about 20% by weight, less than about 10% by weight, less than about 5% by weight, less than about 3% by weight, or less than about 1% by weight of compounds.

As used herein, and unless otherwise indicated, the term "stable" refers to a compound or composition that does not readily decompose or change chemical constitution or physical state. The stable compositions or formulations provided herein do not significantly decompose under normal manufacturing or storage conditions. In some embodiments, the term "stable," when used in conjunction with a formulation or dosage form, means that the active ingredient of the formulation or dosage form remains unchanged in the chemical composition or physical state for a specified period of time and does not significantly degrade or aggregate or otherwise change (e.g., as determined by, for example, HPLC, FTIR, or XRPD). In some embodiments, about 70% or greater, about 80% or greater, about 90% or greater, about 95% or greater, about 98% or greater, or about 99% or greater of the compound remains unchanged after a specified period of time. In one embodiment, the polymorphs provided herein are stable after long term storage (e.g., the polymorph forms do not change significantly after about 1,2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, 48, 54, 60 or more than about 60 months).

It is to be understood that any component defined herein as comprising can be explicitly excluded from the claimed invention by way of limitation or negative limitation.

Furthermore, all ranges given herein include the end of range as well as any intermediate range point, whether or not explicitly stated.

The definition of specific functional groups and chemical terms is described in more detail below. Chemical elements are identified according to the periodic Table of the elements (CAS version, handbook of CHEMISTRY AND PHYSICS, 75 th edition), the coverage and specific functional groups therein being generally defined as described herein. Furthermore, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in the Organic Chemistry,Thomas Sorrell,University Science Books,Sausalito,1999;Smith and March March's Advanced Organic Chemistry, fifth edition. John Wiley & Sons, inc, new york, 2001; larock, comprehensive Organic Transformations, VCH Publishers, inc., new York, 1989; and Carruthers, some Modern Methods of Organic Synthesis, third edition. Cambridge university Press, cambridge, 1987.

With respect to compound terminology, in general, reference to an element such as hydrogen or H means, if appropriate, all isotopes of that element are included.

The term "alkyl" when used alone or within other terms such as "haloalkyl" and "alkylamino" encompasses straight-chain or branched-chain carbon groups having, for example, from 1 to about 20 carbon atoms, or in particular embodiments, from 1 to about 12 carbon atoms. In other embodiments, alkyl is a "lower alkyl" having from 1 to about 6 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. In a more specific embodiment, the lower alkyl has 1 to 4 carbon atoms.

The term "alkenyl" includes straight or branched chain carbon groups having at least one carbon-carbon double bond. The term "alkenyl" may include conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. Alkenyl groups, for example and without limitation, may include 2 to about 20 carbon atoms, or in one particular embodiment, 2 to about 12 carbon atoms. In embodiments, alkenyl is "lower alkenyl" having 2 to about 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl" include groups having "cis" and "trans" orientations, or "E" and "Z" orientations.

The term "alkynyl" means a straight or branched carbon group having at least one carbon-carbon triple bond. The term "alkynyl" may include conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. Alkynyl groups, for example and without limitation, may include 2 to about 20 carbon atoms, or in one particular embodiment, 2 to about 12 carbon atoms. In embodiments, alkynyl is a "lower alkynyl" having 2 to about 10 carbon atoms. Some examples are lower alkynyl groups having 2 to about 4 carbon atoms. Examples of such groups include propargyl, butynyl, and the like.

The term "halo" means a halogen, such as a fluorine, chlorine, bromine or iodine atom.

The term "haloalkyl" includes groups in which any one or more of the alkyl carbon atoms are replaced by a halogen as defined above. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups, including perhaloalkyl. Monohaloalkyl, for example, may have iodine, bromine, chlorine or fluorine atoms in the group. Dihalo-and polyhaloalkyl groups may have two or more identical halogen atoms or a combination of different halogen groups. "lower haloalkyl" includes groups having 1 to 6 carbon atoms. In some embodiments, the lower haloalkyl has 1 to 3 carbon atoms. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term "hydroxyalkyl" includes straight or branched chain alkyl groups having, for example, but not limited to, from 1 to about 10 carbon atoms, any of which may be substituted with one or more hydroxyl groups. In embodiments, hydroxyalkyl is a "lower hydroxyalkyl" having 1 to 6 carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term "alkoxy" includes straight or branched chain oxygen containing groups each having an alkyl moiety such as, but not limited to, 1 to about 10 carbon atoms. In embodiments, alkoxy is "lower alkoxy" having 1 to 6 carbon atoms. Examples of such groups include: methoxy, ethoxy, propoxy, butoxy and t-butoxy. In certain embodiments, the lower alkoxy group has 1 to 3 carbon atoms. The "alkoxy" group may be further substituted with one or more halogen atoms, such as fluorine, chlorine or bromine, to provide a "haloalkoxy" group. In other embodiments, the lower haloalkoxy has from 1 to 3 carbon atoms. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term "aromatic group" or "aryl group" refers to an aromatic group having one or more rings, where such rings may be linked together in a pendent manner or may be fused together. In particular embodiments, the aromatic group is one, two or three rings. Monocyclic aromatic groups may contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 4 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups have two or three rings. Polycyclic aromatic groups having two or three rings typically have 8 to 16 carbon atoms, preferably 8 to 14 carbon atoms, in the ring. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthylenyl.

The term "heteroatom" refers to an atom other than carbon. Typically, the heteroatoms are selected from sulfur, phosphorus, nitrogen and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

The term "heteroaromatic group" or "heteroaryl group" refers to an aromatic group having one or more rings, where such rings may be linked together in a pendent manner or may be fused together, where the aromatic group has at least one heteroatom. The monocyclic heteroaromatic group may contain 4 to 10 member atoms, typically 4 to 7 member atoms, and more typically 4 to 6 member atoms in the ring. Typical polycyclic heteroaromatic groups have two or three rings. Polycyclic aromatic groups having two or three rings typically have 8 to 16 member atoms, more typically 8 to 14 member atoms, in the ring. Examples of heteroaromatic groups include, but are not limited to, pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, quinoline, isoquinoline, quinazoline, quinoxaline, and the like.

The term "carbocyclic group" means a saturated or unsaturated carbocyclic hydrocarbon ring. Carbocyclic groups are not aromatic. Carbocyclic groups are monocyclic or polycyclic. Polycyclic carbocycle groups may be fused, spiro or bridged ring systems. Monocyclic carbocyclic groups may contain 4 to 10 carbon atoms, typically 4 to 7 carbon atoms, and more typically 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups may contain 8 to 12 carbon atoms, typically 9 to 10 carbon atoms, in the ring.

The term "heterocyclic group" means a saturated or unsaturated ring structure containing carbon atoms and 1 or more heteroatoms in the ring. The heterocyclic group is not aromatic. Heterocyclic groups are monocyclic or polycyclic. The polycyclic heterocyclic groups may be fused, spiro or bridged ring systems. The monocyclic heterocyclic group may contain 4 to 10 member atoms (i.e., including both carbon atoms and at least 1 heteroatom) in the ring, typically 4 to 7, and more typically 5 to 6. Bicyclic heterocyclic groups may contain 8 to 18 member atoms, typically 9 or 10 member atoms, in the ring. Representative heterocyclic groups include, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1, 4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline, and the like.

The term "heterogroup" means a saturated or unsaturated chain comprising carbon atoms and at least one heteroatom. Heterogeneous groups typically have 1 to 25 member atoms. More typically, the chain contains 1 to 12 member atoms, 1 to 10, most typically 1 to 6. The chain may be straight or branched. Typical branched heterogroups have one or two branches, more typically one branch. Typically, the heterogeneous group is saturated. The unsaturated heterogeneous group may have one or more double bonds, one or more triple bonds, or both. Typical unsaturated heterogroups have one or two double bonds or one triple bond. More typically, the unsaturated heterogeneous group has one double bond.

The term "hydrocarbon group" or "hydrocarbon group" refers to a chain of carbon atoms. In certain aspects, the term includes from 1 to 25 carbon atoms, typically from 1 to 12 carbon atoms, more typically from 1 to 10 carbon atoms, and most typically from 1 to 8 carbon atoms. The hydrocarbon group may have a straight chain or branched structure. Typical hydrocarbyl groups have one or two branches, typically one branch. Hydrocarbyl groups include saturated, unsaturated, conjugated, unconjugated, and combinations thereof. The unsaturated hydrocarbon groups may have one or more double bonds, one or more triple bonds, or a combination thereof.

When the term "unsaturated" is used in connection with any group, the group may be fully unsaturated or partially unsaturated. However, when the term "unsaturated" is used in conjunction with a particular group as defined herein, the term maintains the limitations of that particular group. For example, unsaturated "carbocycle groups" do not include aromatic groups, based on the limitations of "carbocycle groups" as defined herein.

The term "carboxy" or "carboxyl group", whether used alone or in combination with other terms such as "carboxyalkyl", means- (c=o) -O-.

The term "carbonyl", whether used alone or in combination with other terms such as "aminocarbonyl", means- (c=o) -.

The term "alkylcarbonyl" refers to a carbonyl group substituted with an alkyl group. In certain embodiments, a "lower alkylcarbonyl" has a lower alkyl group as described above attached to the carbonyl group.

The term "aminoalkyl" includes straight or branched chain alkyl groups having from 1 to about 10 carbon atoms, any of which may be substituted with one or more amino groups. In some embodiments, aminoalkyl is a "lower amino" group having 1 to 6 carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

The term "alkylaminoalkyl" includes aminoalkyl groups having nitrogen atoms independently substituted with alkyl groups. In certain embodiments, an alkylaminoalkyl group is a "lower alkylaminoalkyl" group having an alkyl group of 1 to 6 carbon atoms. In other embodiments, the lower alkylaminoalkyl has an alkyl group of 1 to 3 carbon atoms. Suitable alkylaminoalkyl groups may be mono-or dialkyl-substituted, such as N-methylaminomethyl, N-dimethyl-aminoethyl, N-diethylaminomethyl, and the like.

The term "aralkyl" includes aryl substituted alkyl groups. In embodiments, an aralkyl is a "lower aralkyl" having an aryl group attached to an alkyl group having 1 to 6 carbon atoms. In other embodiments, the lower aralkylphenyl is attached to an alkyl moiety having 1 to 3 carbon atoms. Examples of such groups include benzyl, diphenylmethyl and phenylethyl. The aryl groups in the aralkyl groups may be additionally substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.

The term "arylalkenyl" includes aryl-substituted alkenyl. In embodiments, arylalkenyl is a "lower arylalkenyl" having an aryl group attached to an alkenyl group having 2 to 6 carbon atoms. Examples of such groups include phenylvinyl. The aryl groups in the arylalkenyl groups may additionally be substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy.

The term "arylalkynyl" includes aryl-substituted alkynyls. In embodiments, an arylalkynyl group is a "lower arylalkynyl group" having an aryl group attached to an alkynyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethynyl. The aryl groups in the aralkyl groups may be additionally substituted with halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.

The term "alkylthio" includes groups containing a straight or branched chain alkyl group of 1 to 10 carbon atoms attached to a divalent sulfur atom. In certain embodiments, the lower alkylthio group has 1 to 3 carbon atoms. An example of "alkylthio" is methylthio (CH ₃ S-).

The term "alkylamino" refers to an amino group substituted with one alkyl group and two alkyl groups, including the terms "N-alkylamino" and "N, N-dialkylamino". In embodiments, an alkylamino group is a "lower alkylamino" group having one or two alkyl groups of 1 to 6 carbon atoms attached to a nitrogen atom. In other embodiments, the lower alkylamino has 1 to 3 carbon atoms. Suitable "alkylamino" groups may be mono-or dialkylamino groups, such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, etc.

The term "arylamino" refers to an amino group substituted with one or two aryl groups, such as N-phenylamino. The "arylamino" group may be further substituted on the aryl ring portion of the group.

The term "heteroarylamino" means an amino group substituted with one or two heteroaryl groups, such as N-thienylamino. The "heteroarylamino" group may be further substituted on the heteroaryl ring portion of the group.

The term "aralkylamino" denotes an amino group substituted with one or two aralkyl groups. In other embodiments, phenyl-C ₁-C₃ -alkylamino, such as N-benzylamino, is present. The "aralkylamino" group may be further substituted on the aryl ring portion of the group.

The term "alkylaminoalkylamino" means an alkylamino group substituted with one or two alkylamino groups. In embodiments, a C ₁-C₃ -alkylamino-C ₁-C₃ -alkylamino group is present.

The term "arylthio" includes aryl groups of 6 to 10 carbon atoms attached to a divalent sulfur atom. An example of an "arylthio" group is phenylthio. The term "aralkylthio" includes aralkyl groups as described above attached to a divalent sulfur atom. In certain embodiments, phenyl-C ₁-C₃ -alkylthio is present. An example of an "aralkylthio" group is benzylthio.

The term "aryloxy" includes optionally substituted aryl groups as defined above attached to an oxygen atom. Examples of such groups include phenoxy.

The term "aralkoxy" includes an oxyalkyloxy group attached to another group through an oxygen atom. In certain embodiments, the aralkoxy group is a "lower aralkoxy" group as described above having an optionally substituted phenyl group attached to the lower alkoxy group.

The term "cycloalkyl" includes saturated carbocyclic groups. In certain embodiments, the cycloalkyl group comprises a C ₃-C₆ ring. In embodiments, compounds are present that include cyclopentyl, cyclopropyl, and cyclohexyl.

The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds; conjugated or unconjugated, or a combination thereof. The terms "cycloalkenyl" and "cycloalkyldienyl" compounds are included in the term "cycloalkenyl". In certain embodiments, cycloalkenyl includes a C ₃-C₆ ring. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl. "cycloalkenyl" may have 1 to 3 substituents such as lower alkyl, hydroxy, halogen, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like.

The term "suitable substituent", "substituent" or "substituted" as used in connection with the groups described herein refers to a chemically acceptable group, i.e., a moiety that retains the utility of the compounds of the present invention. It will be appreciated that substituents and substitution patterns on the compounds of this invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art and those methods set forth below. If the substituent itself is substituted with more than one group, it is understood that these multiple groups may be on the same carbon/member atom or on different carbon/member atoms, so long as a stable structure is obtained. Illustrative examples of some suitable substituents include cycloalkyl, heterocyclyl, hydroxyalkyl, benzyl, carbonyl, halogen, haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, aralkyl or heteroarylalkyl, aralkoxy or heteroarylalkoxy, HO- (c=o) - -, amido, amino, alkyl-and dialkylamino, cyano, nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl and arylsulfonyl. Typical substituents include aromatic groups, substituted aromatic groups, hydrocarbyl groups including alkyl groups (e.g., methyl groups), substituted hydrocarbyl groups such as benzyl groups, and heterogroups including alkoxy groups (e.g., methoxy groups).

The term "fused" means that two or more carbon/member atoms are common to two adjacent rings, e.g., the rings are "fused rings".

The term "leaving group" is well understood in the art and is a fragment of a molecule that separates from a pair of electrons in a heterolytic bond cleavage. The leaving group may be an anionic or neutral molecule and is capable of stabilizing the additional electron density resulting from bond isoschizomers.

The term "isotopic form" refers to variants of a particular chemical element. All isotopes of a given element share the same number of protons, and each isotope differs from the others in terms of the number of photons therein.

The term "solvate" refers to a solvated form of a compound described herein that is typically associated with a solvent by a solvolysis reaction. Such physical bonding may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "solvate" includes both solution phases and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "salt" includes salts of compounds prepared from suitable acids or bases, depending on the particular substituents on the compounds described herein. When the compounds described herein contain relatively basic functionalities, acid salts can be obtained by contacting the compounds in neutral form with a sufficient amount of the desired acid. Examples of inorganic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, combinations thereof, and the like. Examples of organic acid salts include those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluene sulfonic acid (e.g., monohydrate), p-toluene sulfonic acid (e.g., monohydrate), 10-camphor sulfonic acid (e.g., (-) -10-camphor sulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluene sulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythro diacid (ERYTHRARIC ACID)), methane sulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), isoascorbic acid (L-isoascorbic acid or D-isoascorbic acid), combinations thereof, and the like.

The term "half" means that the ratio of compound to acid (whether organic or inorganic) in the crystal structure of the salt of the compound (e.g. formula I) is 1:0.5 (or 2:1), respectively.

With respect to the formation of suitable salts, any suitable counterion may be formed. "counter-ions" or "anionic counter-ions" are negatively charged groups associated with, for example, cationic quaternary amino groups to maintain electroneutrality. Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃-、ClO₄-、OH-、H₂PO₄-、HSO₄-、-BF₄、-PF₆、 sulfonate ions and carboxylate ions).

Salts of the compounds described herein may be synthesized from the compounds described herein. Typically, salts of basic compounds are prepared by reacting the free base with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or combination of solvents.

Furthermore, the International Union of Pure and Applied Chemistry (IUPAC) nomenclature for the generation of 2-halo-LSD related compounds shows chiral centers at carbon 6 and 9. However, as demonstrated in the structures herein, a more common numbering system is employed herein, consistent with the halogen group bonded to the second carbon, placing both chiral carbons in the 5 and 8 positions. Furthermore, as used herein, the stereocenter nomenclature of "5ar,8r", "5ar,8s", "5as,8r" and "5as,8s" may be interchanged with "5r,8r", "5r,8s", "5s,8r" and "5s,8s", respectively.

The term "derivative" generally refers to a molecule that is modified and/or altered in any way relative to a reference molecule or starting molecule.

The term "polymorph" refers to a crystalline structure in which a compound (e.g., a salt or solvate thereof) can crystallize in a particular crystalline packing arrangement. Different polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and/or solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to a polymorph predominance. Polymorphs of a compound can be prepared by crystallization under different conditions.

It is to be understood that this specification includes any racemic, optically active, stereoisomeric and/or polymorphic form.

Recitation of a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or combination of groups listed. Recitation of embodiments of variables herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

Lysergic acid diacetamide (LSD) -derivatives and polymorphs thereof

Novel derivatives and polymorphs of LSD are provided. These are represented by formula I. These compounds proved to have the desired biological effect, be essentially non-illusive, and not induce tolerance. The novel derivatives and polymorphs of LSD of formula I include desirable properties (such as, but not limited to, mechanical, thermal, physical and chemical properties) to have desirable effects on bioavailability, hygroscopicity, stability and other performance characteristics. Thus, the compounds of the present invention are suitable for use in the development of therapeutic products.

I) Certain embodiments include compounds having the structure of formula I:

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof; wherein: r ¹ to R ¹⁴ are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group, and X is selected from a halogen group. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

In another embodiment, the compound comprises a polymorph of formula I. In another embodiment, the compound comprises a single polymorph thereof. In another embodiment, the compound is an isolated polymorph thereof. In other embodiments, wherein the i) compound is a diastereomer and/or enantiomer; and/or ii) is crystalline, optionally, its polymorph or a single polymorph thereof.

In a further embodiment, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S. In one or more of these embodiments, the compound is a pharmaceutically acceptable salt, hydrate, and/or solvate thereof. In embodiments, the compound is an acid salt. Salts may be formed from any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythorbic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid), or a combination thereof, and the like. In any salt embodiment, the salt may be a half salt.

Regarding the options of formula I, formula I may be any suitable embodiment listed above and combined in any manner as follows:

In an embodiment of formula I, R ¹ to R ¹⁴ are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In other embodiments, each of R ¹ to R ¹⁴ is independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or a substituted or unsubstituted C ₂-C₆ alkynyl. In further embodiments, R ¹ to R ¹⁴ are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl. In a further embodiment, R ¹ to R ¹⁴ are each independently selected from H, methyl or ethyl. In another embodiment, R ¹ and R ² are each independently selected from H, methyl or ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H, and R ⁵ is methyl. In another embodiment, R ¹ and R ² are each independently selected from methyl or ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H; And R ⁵ is methyl. In another embodiment, R ¹ and R ² are each ethyl; r ³、R⁴ and R ⁶ to R ¹⁴ are each H; And R ⁵ is methyl.

In a further embodiment of formula I, X is selected from bromine, chlorine, fluorine or iodine. In other embodiments, X is selected from bromine, chlorine, or fluorine. In another embodiment, X is selected from bromine or chlorine. In another embodiment, X is bromine.

II) other embodiments include compounds having the structure of formula II':

pharmaceutically acceptable salts, hydrates, solvates, tautomers, enantiomers, diastereomers, racemates, polymorphs, or combinations thereof; wherein: r ¹ and R ² are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

In another embodiment, the compound comprises its polymorph. In another embodiment, the compound comprises a single polymorph thereof. In another embodiment, the compound is an isolated polymorph thereof. In other embodiments, wherein the i) compound is a diastereomer and/or enantiomer; and/or ii) is crystalline, optionally, its polymorph or a single polymorph thereof.

In a further embodiment, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S. In one or more of these embodiments, the compound is a pharmaceutically acceptable salt, hydrate, and/or solvate thereof. In typical embodiments, the compound is an acid salt. Salts may be formed from any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythorbic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid), or a combination thereof, and the like. In any salt embodiment, the salt may be a half salt.

Regarding the options of formula I ', formula I' may be any suitable embodiment listed above and combined in any manner as follows:

In an embodiment of formula I', R ¹ and R ² are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In other embodiments, R ¹ and R ² are each independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or substituted or unsubstituted C ₂-C₆ alkynyl. In a further embodiment, R ¹ and R ² are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl. In a further embodiment, R ¹ and R ² are each independently selected from H, methyl or ethyl. In another embodiment, R ¹ and R ² are each independently selected from methyl or ethyl. In another embodiment, R ¹ and R ² are each ethyl.

Iii) In other embodiments, wherein the compound is selected from:

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, or combinations thereof; wherein: r ¹ and R ² are each independently selected from H, or a substituted or unsubstituted hydrocarbyl group. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

With respect to the options above, the compounds may be any suitable embodiment listed above and combined in any manner as follows:

In embodiments, R ¹ and R ² are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In other embodiments, R ¹ and R ² are each independently selected from H, substituted or unsubstituted C ₁-C₆ alkyl, substituted or unsubstituted C ₂-C₆ alkenyl, or substituted or unsubstituted C ₂-C₆ alkynyl. In a further embodiment, R ¹ and R ² are each independently selected from H, or substituted or unsubstituted C ₁-C₆ alkyl. In a further embodiment, R ¹ and R ² are each independently selected from H, methyl or ethyl. In another embodiment, R ¹ and R ² are each independently selected from methyl or ethyl. In another embodiment, R ¹ and R ² are each ethyl.

Iv) in other embodiments, wherein the compound is selected from:

Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs or combinations thereof. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

V) in other embodiments, wherein the compound is a 2-bromo-LSD acid salt selected from the group consisting of:

Or a combination thereof. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

In a further embodiment, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S. The acid may be any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or a combination thereof, and the like. In any salt embodiment, the salt may be a half salt.

Vi) in particular embodiments, the compound may be selected from 2-bromo-LSD acid salts:

Or a combination thereof. In other embodiments, wherein the compound is a polymorph thereof. In embodiments, the compound is crystalline. In a more specific embodiment, the compound is in an isolated crystalline form.

In a further embodiment, wherein i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S. In further embodiments, wherein the compound comprises 2-bromoLSD tartrate (about 1: about 0.5) and/or (about 1: about 1), i) the compound is one or more polymorphs thereof; and/or ii) the compound comprises one or more compounds each having a moiety independently selected from 5s,8r;5R,8R;5R,8S; or two stereo centers of 5s, 8s; iii) The compounds include one or more compounds each having a moiety independently selected from 5r,8s;5R,8R; or two stereogenic centers of 5s,8r; iv) the compound comprises one or more compounds each having two stereocenters independently selected from 5r,8s or 5r,8r; v) the compound has two stereocenters of 5r,8r; or vi) the compound has two stereocenters of 5R, 8S.

In any of the acid derivatives of LSD described above, the ratio of the 4-ring compound of formula I, I ', ia, ib, ic, id, ia', ib ', ic' or Id 'to the acid of formula I, I', ia, ib, ic, id, ia ', ib', ic 'or Id' may be any suitable ratio, for example and typically is a half salt (0.5:1 or 2:1). In embodiments, the ratio need not be a perfect balance of positive and negative charges. For example, the charge balance ratio of 2-bromolsd to tartrate may be 2:1, as 2-bromolsd is about +1 and tartrate is about-2. For L-tartrate, the salt formed may be about 1 to about 1, meaning that there is an excess of negative charge. This can be balanced by hydrogen. Phosphates may be present in ratios of 1:3, 1:2, 1:1 or 2:1, as well as above and below, wherein other bystander ions/counter ions may be used, such as hydrogen, hydroxide, sodium, chlorine, calcium and potassium may be used to balance the charge. In embodiments, the ratio depends on the total charge of the acid. In certain embodiments, the ratio is about 0.5:1 to about 2:1 (hemi-salt) (on a mol/mol basis) and any increment therebetween, e.g., about 0.6:1 to about 2:1; about 0.7:1 to about 2:1; about 0.8:1 to about 2:1; about 0.9:1 to about 2:1; about 1:1 to about 2:1; about 1.1:1 to about 2:1; about 1.2:1 to about 2:1; about 1.3:1 to about 2:1; about 1.4:1 to about 2:1; about 1.5:1 to about 2:1; about 1.6:1 to about 2:1; about 1.7:1 to about 2:1; about 1.8:1 to about 2:1; about 1.9:1 to about 2:1; about 0.5:1 to about 1.9:1; about 0.5:1 to about 1.8:1; about 0.5:1 to about 1.7:1; about 0.5:1 to about 1.6:1; about 0.5:1 to about 1.5:1; about 0.5:1 to about 1.4:1; about 0.5:1 to about 1.3:1; about 0.5:1 to about 1.2:1; about 0.5:1 to about 1.1:1; about 0.5:1 to about 1:1; about 0.5:1 to about 0.9:1; about 0.5:1 to about 0.8:1; about 0.5:1 to about 0.7:1; or about 0.5:1 to about 0.6:1.

In embodiments, the compounds of formula I, I ', ia, ib, ic, id, ia ', ib ', ic ', or Id ' have a powder X-ray diffraction (PXRD) pattern comprising peaks at about 10.3 ° (2θ). In other embodiments, the compounds have an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7 ° (2θ), about 9.4 ° (2θ) and about 10.3 ° (2θ). In other embodiments, the compounds have an X-ray powder diffraction (PXRD) pattern comprising peaks at about 4.7 ° (2θ), about 9.4 ° (2θ), about 10.3 ° (2θ), and about 20.1 ° (2θ).

In embodiments, the compound of formula I, I ', ia, ib, ic, id, ia ', ib ', ic ', or Id '74 has a peak contained at about 10.3 ° (2θ) and aboutPowder X-ray diffraction (PXRD) patterns of d values of (c). In other embodiments, the compounds have peaks including at about 4.7 ° (2θ) and aboutD value of (2), peak at about 9.4 ° (2 theta) and aboutD-value of (2-theta) and peak at about 10.3 deg. (2-theta) and aboutX-ray powder diffraction (PXRD) patterns of d values of (c). In other embodiments, the compounds have peaks including at about 4.7 ° (2θ) and aboutD value of (2), peak at about 9.4 ° (2 theta) and aboutD value of (2), peak at about 10.3 ° (2 theta) and aboutD value of (2), peak at about 20.1 ° (2 theta) and aboutX-ray powder diffraction (PXRD) patterns of d values of (c). In still further embodiments, the compound has a powder X-ray diffraction (PXRD) pattern comprising peaks at 10.3 ° ± 0.2 ° (2Θ). In other embodiments, the compounds have an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7 ° ± 0.2 ° (2Θ), 9.4 ° ± 0.2 ° (2Θ), and 10.3 ° ± 0.2 ° (2Θ). In another embodiment, the compound has an X-ray powder diffraction (PXRD) pattern comprising peaks at 4.7 ° ± 0.2 ° (2Θ), 9.4 ° ± 0.2 ° (2Θ), 10.3 ° ± 0.2 ° (2Θ), and 20.1 ° ± 0.2 ° (2Θ).

In embodiments, the compound of formula I, I ', ia, ib, ic, id, ia ', ib ', ic ', or Id ' has about 0.30 ° to about 0.40 °; optionally, an optical rotation of about 0.30 ° to about 0.35 °.

Process for preparing derivatives of LSD (including polymorphs thereof)

Described herein are methods of preparing derivatives and polymorphs of LSD. In general, the methods described herein for preparing derivatives of LSD, including polymorphs thereof, do not use lysergic acid diacetamide (LSD) as a substrate or intermediate. The absence of a planning substance as a starting material or in any step of the synthesis process is beneficial because it eliminates the need for special controlled substance treatment permits. The process produces derivatives and polymorphs of LSD intended for use in humans and therefore Good Manufacturing Practice (GMP) is applicable. The method controls the level of impurities to ensure that the compounds of the present invention are produced consistently to meet predetermined specifications. The process may be used on a commercial scale, i.e., in particular, safe, expandable, effective, economically viable, and/or have other desirable properties.

In embodiments of the methods for preparing the compounds described herein, the groups (R ¹-R¹⁴ and X) are as defined in the previous section and R is-NR ₁R₂ OR-OR ₁, wherein R ₁ and R ₂ are each independently selected from any suitable group that allows the CO (R) group to undergo hydrolysis. R ₁ and R ₂ are each independently selected from H, a halogen group, a hydroxyl group, an amino group, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterogroup, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group. In embodiments, R ₁ and R ₂ are each independently selected from H, a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterogroup, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted heteroaromatic group. In other embodiments, R ₁ and R ₂ are each independently selected from H, or a substituted or unsubstituted heteroaromatic group.

In embodiments of the method, the compound may be prepared as follows:

a) Hydrolyzing the compound of formula IA to form an intermediate of formula IB:

Wherein the hydrolysis is acid hydrolysis or alkaline hydrolysis. The substrates used in the first step of the synthesis of these compounds are commercially available or prepared using methods well known to those skilled in the art. Hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid and/or nitric acid may be used for acid hydrolysis; however, any suitable acid may be used. Potassium hydroxide, sodium hydroxide, potassium tert-butoxide, barium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide can be used for the base hydrolysis; however, any suitable base may be used. The reaction may be carried out in a water miscible solvent (e.g., alcohol (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.) and/or heated to a suitable reaction temperature. In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 50 ℃ to about 60 ℃.

B) The intermediate of formula IB is reacted with R ¹-NH-R² to form formula IC (e.g., the free base).

The hydroxyl group of the carboxylic acid can be converted to a better Leaving Group (LG). Any suitable leaving group may be used and may be selected, for example, from weak bases such as halides (e.g., cl, br, I), tosylate, mesylate and perfluoroalkylsulfonate. To convert the hydroxyl group to a better leaving group to facilitate reaction with the amine (R ¹-NH-R²), any suitable reactant may be used. For example, it can be converted to an acid chloride using phosphorus oxychloride or thionyl chloride. Alternatively, the reaction may be carried out with an amine (R ¹-NH-R²) under base-catalyzed amide bond formation. Any suitable base may be used. For example, N-methylmorpholine (NMM) and 1,1' -Carbonyldiimidazole (CDI) (e.g., coupling agent) are used. The reaction may be carried out in any suitable solvent (e.g., THF, 2-methyl-THF, etc.) for forming a solution of the reactants. The reaction is carried out at any suitable reaction temperature. In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 50 ℃ to about 60 ℃.

In embodiments, in the presence of a coupling agent, upon its reaction with an amine (R ¹-NH-R²), the reaction proceeds via base-catalyzed amide bond formation of formula IB. Any suitable coupling agent may be used. Coupling agents such as, but not limited to, those selected from the group consisting of Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP) uranium (COMU) 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenylaminooxy) dimethylamino morpholino) ] hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tris-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tris-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof. In specific embodiments, the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

In steps (a) and (b), the pH of the intermediates of formula IB and formula IC is adjusted to form a precipitate. The pH may be adjusted, for example, from about 4 to about 8 or from about 6 to about 8 (e.g., hydrochloric acid).

Any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or combinations thereof, and the like, may also be reacted in situ or alone with (b) to convert the formula (ID) to any suitable salt or hydrate of formula (ID). With respect to the formation of suitable salts, as outlined in the definition, the counterion may be any negatively charged group associated with, for example, an amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-、^-BF₄、^-PF₆、 sulfonate ions and carboxylate ions (e.g., acetate, ascorbate, acetate, isoascorbate, propionate, benzoate, glyceride, lactate, tartrate, glutamate, glycolate, etc.), the reaction can be carried out in any suitable solvent, such as, but not limited to, water miscible solvents (e.g., alcohols (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 60 ℃ to about 65 ℃. In embodiments, the compound of formula IC is heated with an organic or inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In other embodiments, cooling to about 0 to about 10 ℃, optionally about 3 to about 70 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

In another embodiment of the process for preparing the compounds described herein, the compounds can be prepared as follows and the groups (R, R ¹-R¹⁴ and X) are as defined in the preceding section:

a) Hydrolyzing a compound of formula IAA (5 r,8 r) to form an intermediate of formula IBB:

B) The intermediate of formula IBB is reacted with R ¹-NH-R² to form formula ICC (e.g., free base).

In embodiments, in the presence of a coupling agent, upon its reaction with an amine (R ¹-NH-R²), the reaction proceeds via base-catalyzed amide bond formation of formula IBB. Any suitable coupling agent may be used. Coupling agents such as, but not limited to, those selected from the group consisting of Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP) uranium (COMU) 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenylaminooxy) dimethylamino morpholino) ] hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tris-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tris-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof. In specific embodiments, the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

In steps (a) and (b), the acidity of the intermediates of formula IBB and formula ICC is adjusted to form a precipitate. The pH may be adjusted with an acid (e.g., hydrochloric acid), for example, from about 6 to about 8.

Any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphonic acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or combinations thereof, and the like, may also be reacted in situ or alone with (b) to convert any suitable salt of formula (D or a suitable salt of formula (D). With respect to the formation of suitable salts, as outlined in the definition, the counterion may be any negatively charged group associated with, for example, an amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-、^-BF₄、^-PF₆、 sulfonate ions and carboxylate ions (e.g., acetate, ascorbate, acetate, isoascorbate, propionate, benzoate, glyceride, lactate, tartrate, glutamate, glycolate, etc.), the reaction can be carried out in any suitable solvent, such as, but not limited to, water miscible solvents (e.g., alcohols (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 60 ℃ to about 65 ℃. In embodiments, the compound of formula ICC is heated with an organic acid or inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In other embodiments, cooling to about 0 to about 10 ℃, optionally about 3 to about 70 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

a) Hydrolyzing the compound of formula IAA '(5 s,8 r) to form an intermediate of formula IBB':

B) The intermediate of formula IBB 'is reacted with R ¹-NH-R² to form formula ICC' (e.g., free base).

In embodiments, in the presence of a coupling agent, upon its reaction with an amine (R ¹-NH-R²), the reaction proceeds via base-catalyzed amide bond formation of formula IBB'. Any suitable coupling agent may be used. Coupling agents such as, but not limited to, those selected from the group consisting of Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP) uranium (COMU) 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenylaminooxy) dimethylamino morpholino) ] hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tris-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tris-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) methyl salt) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof. In specific embodiments, the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

In steps (a) and (b), the acidity of the intermediates of formula IBB 'and formula ICC' is adjusted to form a precipitate. The pH may be adjusted with an acid (e.g., hydrochloric acid), for example, from about 6 to about 8.

Any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphonic acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or combinations thereof, and the like, may also be reacted in situ or alone with (b) to convert the formula (ICC) to a suitable salt of any suitable formula (D'). With respect to the formation of suitable salts, as outlined in the definition, the counterion may be any negatively charged group associated with, for example, an amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-、^-BF₄、^-PF₆、 sulfonate ions and carboxylate ions (e.g., acetate, ascorbate, acetate, isoascorbate, propionate, benzoate, glyceride, lactate, tartrate, glutamate, glycolate, etc.), the reaction can be carried out in any suitable solvent, such as, but not limited to, water miscible solvents (e.g., alcohols (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 60 ℃ to about 65 ℃. In embodiments, the compound of formula ICC' is heated with an organic acid or an inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In other embodiments, cooling to about 0 to about 10 ℃, optionally about 3 to about 70 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

In another embodiment of the process for preparing the compounds described herein, the compounds can be prepared as follows and the groups (R, R ¹-R¹⁵ and X) are as defined in the preceding section:

a) Hydrolysis of the compound of formula IAA "(5 s,8 s) to form an intermediate of formula IBB":

B) The intermediate of formula IBB "is reacted with R ¹-NH-R² to form formula ICC" (e.g., the free base).

In embodiments, in the presence of a coupling agent, upon its reaction with an amine (R ¹-NH-R²), the reaction proceeds via base-catalyzed amide bond formation of formula IBB ". Any suitable coupling agent may be used. Coupling agents such as, but not limited to, those selected from the group consisting of Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP) uranium (COMU) 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenylaminooxy) dimethylamino morpholino) ] hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tris-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tris-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof. In specific embodiments, the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

In steps (a) and (b), the acidity of the intermediates of formula IBB "and formula ICC" is adjusted to form a precipitate. The pH may be adjusted with an acid (e.g., hydrochloric acid), for example, from about 6 to about 8.

Any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphonic acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrose diacid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or combinations thereof, and the like, may also be reacted in situ or alone with (b) to convert the formula (i-c acid) to a suitable salt of any suitable "or a suitable salt of D"). With respect to the formation of suitable salts, as outlined in the definition, the counterion may be any negatively charged group associated with, for example, an amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-、^-BF₄、^-PF₆、 sulfonate ions and carboxylate ions (e.g., acetate, ascorbate, acetate, isoascorbate, propionate, benzoate, glyceride, lactate, tartrate, glutamate, glycolate, etc.), the reaction can be carried out in any suitable solvent, such as, but not limited to, water miscible solvents (e.g., alcohols (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 60 ℃ to about 65 ℃. In embodiments, the compound of formula icc″ is heated with an organic acid or an inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In other embodiments, cooling to about 0 to about 10 ℃, optionally about 3 to about 70 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

a) Hydrolyzing a compound of formula IAA '"(5 s,8 r) to form an intermediate of formula IBB'":

B) The intermediate of formula IBB '"is reacted with R ¹-NH-R² to form formula ICC'" (e.g., free base).

In embodiments, in the presence of the coupling agent, upon its reaction with the amine (R ¹-NH-R²), the reaction proceeds via base-catalyzed amide bond formation of formula IBB' ". Any suitable coupling agent may be used. Coupling agents such as, but not limited to, those selected from the group consisting of Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate (BOP) uranium (COMU) 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenylaminooxy) dimethylamino morpholino) ] hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tris-1-pyrrolidinyl-phosphonium hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tris-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim), and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof. In specific embodiments, the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), or a combination thereof.

Any suitable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid or phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrose diacid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid (L-erythorbic acid or D-erythorbic acid), or combinations thereof, and the like, may also be reacted in situ or alone with (b) to convert the formula (ICC) to a suitable salt of either of the formula (D)'. With respect to the formation of suitable salts, as outlined in the definition, the counterion may be any negatively charged group associated with, for example, an amide (e.g., formula IC). Exemplary counterions include halide ions (e.g., ,F-、Cl-、Br-、I-)、NO₃ ^-、ClO₄ ^-、OH^-、H₂PO₄ ^-、HSO₄ ^-、^-BF₄、^-PF₆、 sulfonate ions and carboxylate ions (e.g., acetate, ascorbate, acetate, isoascorbate, propionate, benzoate, glyceride, lactate, tartrate, glutamate, glycolate, etc.), the reaction can be carried out in any suitable solvent, such as, but not limited to, water miscible solvents (e.g., alcohols (methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.).

In embodiments, the temperature is from about 50 ℃ to about 95 ℃. In certain embodiments, the temperature is from about 50 ℃ to about 95 ℃, from about 60 ℃ to about 95 ℃, from about 70 ℃ to about 95 ℃, from about 80 ℃ to about 95 ℃, from about 90 ℃ to about 95 ℃, from about 50 ℃ to about 90 ℃, from about 50 ℃ to about 80 ℃, from about 50 ℃ to about 75 ℃, from about 50 ℃ to about 70 ℃, from about 50 ℃ to about 65 ℃, or from about 60 ℃ to about 65 ℃. In embodiments, the compound of formula ICC' "is heated with an organic acid or an inorganic acid for any suitable time (e.g., about 30 minutes to about 1 hour). It may then be cooled, for example, to about room temperature. In other embodiments, cooling to about 0 to about 10 ℃, optionally about 3 to about 70 ℃, optionally about 5 ℃, and optionally about 30 minutes to about 2 hours.

In the methods described herein, the products and intermediates can be purified by washing and recrystallization without any chromatography; however, chromatography may also be used. Recrystallization of the compound of formula ID, formula IDD ', formula IDD ", or formula IDD'" forms a crystalline compound, e.g., an isolated crystalline form, a polymorph thereof, a single polymorph thereof, or an isolated polymorph thereof. The compound of formula IC is recrystallized using a water miscible solvent, optionally an alcohol (e.g., methanol, ethanol, isopropyl alcohol (IPA), etc.), acetonitrile, acetone, isopropyl acetate, THF, 2-methyl-THF, etc.), or a combination thereof. The water miscible solvent may be selected from methanol, ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, wherein the water miscible solvent is selected from ethanol, isopropyl alcohol (IPA), or a combination thereof; optionally, ethanol or isopropyl alcohol (IPA). Recrystallization may include heating a salt or hydrate of the compound of formula 1D, formula IDD ', formula IDD ", or formula IDD'" in a solvent to a suitable temperature for a suitable period of time and cooling to form the compound. In embodiments, recrystallization includes heating a compound of formula 1D, formula IDD ', formula IDD ", or formula IDD'" (e.g., a salt or hydrate of a compound of formula IC, formula ICC ', formula ICC ", or formula ICC'") in a solvent of about 60 ℃ to about 80 ℃, optionally about 60 ℃ to about 70 ℃. In another embodiment, the recrystallization comprises heating a compound of formula 1D, formula IDD ', formula IDD ", or formula IDD'" in a solvent at about 60 ℃ to about 80 ℃, optionally about 60 ℃ to about 70 ℃ for about 1h to about 2h. In further embodiments, recrystallisation comprises heating the salt or hydrate of the compound of formula 1D, formula IDD ', formula IDD ", or formula IDD'" in a solvent of from about 60 ℃ to about 80 ℃, optionally from about 60 ℃ to about 70 ℃ for from about 1 hour to about 2 hours, and cooling the compound in solution to from about 0 ℃ to about 10 ℃, optionally from about 3 ℃ to about 7 ℃, optionally from about 5 ℃, and optionally from about 1 hour to about 2 hours. In embodiments, the recrystallized compound is about 99% to about 99.9% pure, optionally about 99.5% to about 99.9% pure.

In other embodiments, formula IA, formula IAA ', formula IAA ", or formula IAA'" is a bromocriptine derivative, such as bromocriptine mesylate. These substrates may be prepared by known methods and/or are commercially available.

With respect to the methods outlined above and in the embodiments, the methods provide polymorphs of formula 1D, formula IDD ', formula IDD ", or formula IDD'". In embodiments of the method, R is-NR ₁R₂ OR-OR ₁, where R ₁ and R ₂ are each independently selected from any suitable group that allows the CO (R) group to undergo hydrolysis; each R ³-R¹⁴ is independently selected from H or methyl; x is bromine; and R ¹ and R ² are each independently selected from H, methyl or ethyl.

It is to be understood that in any of the above-described methods of preparing acid derivatives of LSD, the ratio of the compound (e.g., formula I ', formula Ia, formula Ib, formula Ic, formula Id, formula Ia', formula Ib ', formula Ic') to the acid can be any suitable ratio, for example, and is typically a half salt (0.5:1 or 2:1). In embodiments, the ratio need not be a perfect balance of positive and negative charges. For example, the charge balance ratio of 2-bromolsd to tartrate can be 2 to 1, as 2-bromolsd is about +1 and tartrate is about-2. For L-tartrate, the salt formed may be about 1 to about 1, meaning that there is an excess of negative charge. This can be balanced by hydrogen. Phosphates may be present in ratios of 1:3, 1:2, 1:1 or 2:1, as well as above and below, wherein other bystander ions/counter ions may be used, such as hydrogen, hydroxide, sodium, chlorine, calcium and potassium may be used to balance the charge. In embodiments, the ratio depends on the total charge of the acid. In certain embodiments, the ratio is about 0.5:1 to about 2:1 (hemi-salt) (on a mol/mol basis) and any increment therebetween, e.g., about 0.6:1 to about 2:1; about 0.7:1 to about 2:1; about 0.8:1 to about 2:1; about 0.9:1 to about 2:1; about 1:1 to about 2:1; about 1.1:1 to about 2:1; about 1.2:1 to about 2:1; about 1.3:1 to about 2:1; about 1.4:1 to about 2:1; about 1.5:1 to about 2:1; about 1.6:1 to about 2:1; about 1.7:1 to about 2:1; about 1.8:1 to about 2:1; about 1.9:1 to about 2:1; about 0.5:1 to about 1.9:1; about 0.5:1 to about 1.8:1; about 0.5:1 to about 1.7:1; about 0.5:1 to about 1.6:1; about 0.5:1 to about 1.5:1; about 0.5:1 to about 1.4:1; about 0.5:1 to about 1.3:1; about 0.5:1 to about 1.2:1; about 0.5:1 to about 1.1:1; about 0.5:1 to about 1:1; about 0.5:1 to about 0.9:1; about 0.5:1 to about 0.8:1; about 0.5:1 to about 0.7:1; or about 0.5:1 to about 0.6:1.

Formulation LSD derivatives and polymorphs thereof

The LSD derivatives and polymorphs thereof disclosed herein may be provided as formulations suitable for administration to a mammal. In terms of use for human and/or veterinary purposes.

In some embodiments, the disclosed compounds can be formulated as pharmaceutical compositions comprising: (a) an amount of one or more compounds as disclosed herein, or (b) a therapeutically effective amount of one or more compounds as disclosed herein, and (c) one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition may include any desired range of compounds as understood by those skilled in the art. For example, the non-limiting range may be about 0.001-2000mg (preferably about 0.05-500mg, more preferably about 0.25-100 mg). The pharmaceutical composition may be administered at a daily dose of about 0.005 to about 1000mg/kg body weight (preferably about 0.01 to about 500mg/kg body weight, more preferably about 0.01 to about 100mg/kg body weight) to provide the compound. In some embodiments, after administration of the pharmaceutical composition to the subject (e.g., after about 1,2, 3, 4, 5, or 6 hours after administration), the concentration of the compound at the site of action may be in a concentration range defined by endpoints selected from 0.001 μm, 0.005 μm, 0.01 μm, 0.5 μm, 0.1 μm, 1.0 μm, 10 μm, and 100 μm (e.g., 0.1 μm-10.0 μm).

The disclosed compounds and pharmaceutical compositions comprising the disclosed compounds may be administered in methods/uses for treating individuals in need thereof. In some embodiments of the disclosed methods/uses, a dose of a compound as low as, for example, but not limited to 0.25mg、0.75mg、1.25mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、57.5mg、60mg、62.5mg、65mg、67.5mg、70mg、72.5mg、75mg、77.5mg、80mg、82.5mg、85mg、87.5mg、90mg、100mg、200mg、500mg、1000mg or 2000mg, can be administered to an individual once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times weekly to treat a disease or disorder in the individual. In some embodiments, a dose of up to 0.25mg、0.75mg、1.25mg、2.5mg、5mg、7.5mg、10mg、12.5mg、15mg、17.5mg、20mg、22.5mg、25mg、27.5mg、30mg、32.5mg、35mg、37.5mg、40mg、42.5mg、45mg、47.5mg、50mg、52.5mg、55mg、57.5mg、60mg、62.5mg、65mg、67.5mg、70mg、72.5mg、75mg、77.5mg、80mg、82.5mg、85mg、87.5mg、90mg、100mg、200mg、500mg、1000mg or 2000mg of the compound may be administered to an individual once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times weekly to treat a disease or disorder in the individual. The minimum and/or maximum dose of a compound may include doses falling within the dose range having any of these disclosed doses (e.g., 2.5mg-20 0 mg) as endpoints.

In some embodiments, the minimum dosage level of the compound for achieving treatment in the disclosed methods/uses of treatment may be at least about 10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1200、1400、1600、1800、1900、2000、3000、4000、5000、6000、7000、8000、9000、10000、15000 or 20000ng/kg of body weight of the individual. In some embodiments, the maximum dosage level of the compound for achieving treatment in the disclosed methods/uses of treatment may not exceed about 10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1200、1400、1600、1800、1900、2000、3000、4000、5000、6000、7000、8000、9000、10000、15000 or 20000 μg/kg body weight of the subject. The minimum and/or maximum dose levels of a compound for achieving treatment in the disclosed methods/uses of treatment may include dose levels falling within the range having any of these disclosed dose levels (e.g., 5-2000 μg/kg body weight of the subject) as endpoints.

The compounds used in the methods/uses disclosed herein may be formulated as pharmaceutical compositions in solid dosage form, although any pharmaceutically acceptable dosage form may be used. Exemplary solid dosage forms include, but are not limited to, tablets, capsules, sachets, troches, powders, pills, or granules, and the solid dosage forms may be, for example, fast-melt dosage forms, controlled release dosage forms, freeze-dried dosage forms, sustained release dosage forms, extended release dosage forms, pulsed release dosage forms, mixed immediate release and controlled release dosage forms, or combinations thereof.

The compounds used in the methods/uses disclosed herein may be formulated as pharmaceutical compositions comprising a carrier. For example, the carrier may be selected from the group consisting of proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste.

The compounds used in the methods/uses disclosed herein may be formulated as pharmaceutical compositions comprising one or more binders, fillers, lubricants, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, and effervescent agents. Fillers may include lactose monohydrate, anhydrous lactose, and various starches; examples of binders are various celluloses and crosslinked polyvinylpyrrolidone, microcrystalline cellulose (e.gPH101PH 102), microcrystalline cellulose and silicified microcrystalline cellulose (ProSolv)). Suitable lubricants, including agents that act on the flowability of the powder to be compressed, may include colloidal silica, e.gTalc, stearic acid, magnesium stearate, calcium stearate and silica gel. Examples of sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame potassium. Examples of flavoring agents are(MAFCO trademark), bubble gum flavoring and fruit flavoring, etc. Examples of preservatives may include potassium sorbate, methylparaben, propylparaben, benzoic acid and salts thereof, other esters of parahydroxybenzoic acid (e.g., butyl parahydroxybenzoate), alcohols (e.g., ethanol or benzyl alcohol), phenolic compounds (e.g., phenol), or quaternary ammonium compounds (e.g., benzalkonium chloride).

Suitable diluents may include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars, and mixtures of any of the foregoing. Examples of diluents include microcrystalline cellulose, e.gPH101PH102; lactose, e.g. lactose monohydrate, lactose anhydrous andDCL21; dibasic calcium phosphate, e.g.Mannitol; starch; sorbitol; sucrose; glucose.

Suitable disintegrants include lightly crosslinked polyvinylpyrrolidone, corn starch, potato starch, corn starch and modified starch, crosslinked sodium carboxymethylcellulose, crosslinked povidone, sodium starch glycolate, and mixtures thereof.

Examples of effervescent agents are effervescent agent pairs, such as organic acids with carbonates or bicarbonates. Suitable organic acids include, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and alginic acid, as well as anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Or only the sodium bicarbonate component of the effervescent couple may be present.

The crystalline LSD polymorphs described herein may be formulated into pharmaceutical compositions with one or more pharmaceutically acceptable carriers or excipients.

In some embodiments, the present disclosure provides pharmaceutical formulations comprising high purity LSD derivatives and polymorphs and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising crystalline LSDs and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising a crystalline LSD polymorph and one or more pharmaceutical carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising a high purity crystalline LSD polymorph and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising a high purity crystalline LSD polymorph and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides pharmaceutical formulations comprising a high purity crystalline LSD polymorph and one or more pharmaceutically acceptable carriers or excipients.

Preferred pharmaceutical excipients for oral formulations include: diluents, such as microcrystalline cellulose, starch, mannitol, anhydrous dibasic calcium phosphate or silicon dioxide, calcium carbonate, blends of microcrystalline cellulose and talc; disintegrants, for example sodium starch glycolate or croscarmellose sodium; binders, such as povidone, copovidone or hydroxypropyl cellulose; lubricants, such as magnesium stearate or sodium stearyl fumarate; glidants, such as colloidal silicon dioxide; and film coatings, such as Opadry II white or PVA-based brown Opadry II. Oral dosage forms also include disintegrants such as, but not limited to: starch glycolate, croscarmellose sodium, and/or mixtures thereof. In an oral dosage form aspect comprising 3% or less by weight of disintegrant, less than 3% by weight of disintegrant and greater than 0.001% by weight of disintegrant, about 2.5% or less by weight of disintegrant; 2% by weight or less of a disintegrant; 1.5% by weight or less of a disintegrant; 1% by weight or less of a disintegrant; 0.7% by weight or less of a disintegrant; 0.5% by weight or less of a disintegrant, or 0.3% by weight or less of a disintegrant. The disintegrant is sodium starch glycolate, which is present at less than 3% by weight, about 2% by weight or less, about 2% by weight; about 1% by weight or less, about 1% by weight; about 0.7% by weight or less, about 0.7% by weight; about 0.5% by weight or less, or about 0.5% by weight. In other embodiments, sodium starch glycolate is present at about 0.5% by weight to 1% by weight.

The compounds used in the methods/uses disclosed herein may be formulated into pharmaceutical compositions for delivery via any suitable route. For example, the pharmaceutical compositions may be administered by the oral, intravenous, intramuscular, subcutaneous, topical and pulmonary routes. Examples of pharmaceutical compositions for oral administration include capsules, syrups, concentrates, powders and granules. In some embodiments, the compounds are formulated as compositions for oral administration (e.g., in a solvent such as 5% dmso/oil (e.g., vegetable oil)).

The compounds used in the methods/uses disclosed herein may be administered according to conventional methods well known in the art in conventional dosage forms prepared by combining the active ingredient with standard pharmaceutical carriers or diluents. These methods may include mixing, granulating, and compressing or dissolving ingredients appropriate for the desired formulation.

Pharmaceutical compositions comprising the compounds may be adapted for administration by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the pharmaceutical arts, for example, by bringing the active ingredient into association with the carrier or excipient.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foam or whipping; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Suitable excipients for tablets or hard gelatine capsules include lactose, maize starch or derivatives thereof, stearic acid or salts thereof. Suitable excipients for use with soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols and the like.

In one embodiment of the invention, oral tablets may be prepared by direct compression of the compounds disclosed herein. It is generally known that the advantages of direct compression include the few manufacturing steps involved, physical stability and elimination of heat and moisture. The direct compressed tablet according to the present invention may additionally contain, for example, binders, disintegrants and colorants well known to those skilled in the art. In another embodiment, a preformed oral capsule contains a compound disclosed herein and an excipient. After compression of the tablets or closure of the capsules, a pharmaceutically acceptable coating may be applied to these formulations of the present invention in order to further modify the release profile of the active agent in the gastrointestinal tract. The selection of the optimal release site depends on the type of disease, the expected peak plasma concentration, the expected plasma time/concentration profile and the expected time/concentration profile of the target site.

In a further embodiment, the invention relates to a method for preparing a medicament based on a formulation of a compound disclosed herein suitable for oral administration, wherein the formulation is directly compressed into a tablet, optionally wherein the formulation is mixed with one or more excipients (pregelatinized starch, microcrystalline cellulose, colloidal silicon dioxide and stearic acid) and the mixture is filled in size 4, white opaque, hard gelatin, two-piece capsules to provide 5mg or 10mg of the compound disclosed herein per capsule, which can be used as an immediate release oral formulation in the digestive tract.

Pharmaceutical compositions suitable for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis.

Pharmaceutical compositions suitable for topical application may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain suitable conventional additives such as preservatives, solvents to aid in drug permeation and softeners in ointments and creams.

For application to the eye or other external tissues, such as the oral cavity and skin, the pharmaceutical composition is preferably applied as a topical ointment or cream. When formulated as ointments, the compounds may be used with paraffin or water-miscible ointment bases. Alternatively, the compounds may be formulated as creams with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions suitable for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions suitable for nasal administration in which the carrier is solid include coarse powders having a particle size (e.g., 20 to 500 microns) that are administered by nasal inhalation (i.e., by rapid inhalation through the nasal passage from a container of powder near the nose). Suitable formulations in which the carrier is a liquid for administration as a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.

Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

Tablets and capsules for oral administration may be in unit dosage presentation form and may contain conventional excipients, for example binding agents, such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, such as potato starch; or an acceptable wetting agent such as sodium lauryl sulfate. The tablets may be coated according to methods well known in conventional pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), such as almond oil, oily esters such as glycerol, propylene glycol or ethanol; preservatives, for example methyl or propyl parahydroxybenzoates or sorbic acid, and, if desired, conventional flavouring or colouring agents.

In some embodiments, the pharmaceutical compositions disclosed herein are modified release dosage forms that provide modified release characteristics. The modified release profile may exhibit immediate release, sustained release or extended release characteristics. Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions and suspensions typically release the drug into the mouth, stomach or intestine upon dissolution of the tablet, capsule shell or suppository, or in the case of syrups, solutions and suspensions, upon swallowing. The pattern of drug release from a Modified Release (MR) dosage form is intentionally different from the pattern of conventional dosage forms to achieve the desired therapeutic objectives and/or better patient compliance. Types of MR drug products include Orally Disintegrating Dosage Forms (ODDF) that provide immediate release, extended release dosage forms, sustained release dosage forms (e.g., enteric coatings), and pulsatile release dosage forms.

ODDF is a solid dosage form containing a drug or active ingredient that disintegrates rapidly, typically within a few seconds, when placed on the tongue. The disintegration time of ODDF is typically 1 or 2 seconds to about 1 minute. ODDF is designed to disintegrate or dissolve rapidly upon contact with saliva. Such a mode of administration may be beneficial to persons who may have problems swallowing tablets, whether or not the tablets are from an infirm or psychiatric nature. Some individuals with ocular disorders may exhibit this behavior. ODDF can provide rapid drug delivery to the blood stream through the mucosa, resulting in rapid onset of action. Examples of ODDF include orally disintegrating tablets, capsules, and fast dissolving films and wafers.

Prolonged release dosage forms (ERDFs) have prolonged release characteristics and are those that allow for a reduced frequency of administration compared to that exhibited by conventional dosage forms (e.g., solutions or unmodified release dosage forms). ERDF provides a sustained duration of drug action. Suitable formulations providing extended release properties are well known in the art. For example, coated sustained release beads or particles ("beads" and "particles" are used interchangeably herein), wherein any of the compounds described herein are applied to a bead, e.g., a confectionery noparel bead, and then coated with a conventional delayed release material such as wax, enteric coating, or the like. In embodiments, beads may be formed in which any of the compounds described herein are mixed with a material to provide a substance from which the compound leaches. In embodiments, the beads may be designed to provide different release rates by varying the properties of the coating or substance, such as thickness, porosity, use of different materials, and the like. Beads with different release rates may be combined into a single dosage form to provide variable or continuous release. The beads may be contained in capsules or compressed into tablets.

The treatment regimen may include: a monotherapy; adjuvant therapy (i.e., added to the standard of care drug therapy); in combination with other agents approved for the treatment of neurological and neurodegenerative disorders; in combination with other agents approved for the treatment of psychosis and related disorders; in combination with other agents approved for the treatment of different pain disorders; in combination with antidepressants and related agents (e.g., 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), selective 5-hydroxytryptamine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors, norepinephrine and specific 5-hydroxytryptamine antidepressants (NASSAs), ketamine, N-dimethyltryptamine and other tryptamine derivatives, 3, 4-methylenedioxymethamphetamine (MDMA) and related derivatives, nude and related derivatives, ibonurine and related derivatives) for the treatment of neuro-psychiatric disorders; in combination with other agents for the treatment of neuro-psychiatric disorders; in combination with standard of care agents for treating neurodegenerative disorders; in combination with standard of care agents for the treatment of different pain disorders; in combination with neuroprotective agents (e.g., dihydro and magnolol-B) for the treatment of neurodegenerative disorders (including alzheimer's disease, parkinson's disease, normal aging, and luteal syndrome); with anxiolytic and similar agents (including benzodiazepinesClass, cannabinoids and dihydropiperonyl alcohol-B) combinations for the treatment of neuro-psychiatric disorders; in combination with a hallucinogen to reduce side effects of the hallucinogen in the treatment of neuro-psychiatric disorders.

The schedule for treatment may include induction treatment and/or maintenance treatment, including short term maintenance, medium term maintenance, long term maintenance, and variations thereof.

LSD derivatives and polymorphs described herein may be provided in the following form: discrete dosage forms including capsules or tablets for sublingual or buccal administration; as for nasal sprays, metered dose inhalers or the like; as a patch for controlled release over a day or days; as a depot formulation for controlled release

In the context of the present disclosure, it is understood that a sample may include a small amount of liquid that is negligible in the final measurement of the sample. In one example, the compositions of the present disclosure may acceptably include, for example, up to about 7% water by mass percent.

An effective amount of a pharmaceutical composition or compound disclosed herein as described herein will provide a therapeutic benefit without causing substantial toxicity. Those of skill in the art will appreciate that toxicity of the pharmaceutical compositions or compounds disclosed herein may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose that is 50% lethal to the population) or the LD100 (the dose that is 100% lethal to the population). In some embodiments, the dose ratio between toxicity and efficacy is the therapeutic index. In some embodiments, the data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is non-toxic to human beings. In some embodiments, the dosage of a compound described herein is within a circulating concentration range that includes an effective dosage that is less or non-toxic. In some embodiments, the dosage may vary within this range depending upon the dosage form employed and the route of administration used. In some embodiments, the exact formulation, route of administration, and dosage may be selected by the individual physician according to the patient's condition. (see, e.g., fingl et al, 1996, 9 th edition Pharmacological Basis of Therapeutics, chapter 2, page 29, elliot M. Ross)

Examples of therapeutically effective dosages of the pharmaceutical compositions or compounds disclosed herein for various mental and/or emotional disorders are set forth below. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-1%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-2%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-2.5%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-5%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-10%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-15%. In some embodiments, the term "about" when used in reference to the amount of a pharmaceutical composition or compound disclosed herein means about +/-20%.

With respect to the pharmaceutical compositions disclosed herein, pharmaceutically acceptable carriers include diluents and excipients commonly used in pharmaceutical formulations, such as fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants, and the like. Non-limiting examples of suitable vectors are described herein.

Diluent agent

The diluent may be selected from, for example, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextran, dextrose, fructose, lactitol, anhydrous lactose, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose, maltodextrin, maltitol. In some embodiments, the diluent is selected from starch, lactose, cellulose derivatives, powdered sugar, and the like. Different grades of lactose include, but are not limited to lactose monohydrate, lactose DT (direct compression), lactose anhydrous and the like. Different starches include, but are not limited to, corn starch, potato starch, rice starch, wheat starch, pregelatinized starch, and the like. Different celluloses that may be used include crystalline celluloses, such as microcrystalline cellulose and powdered cellulose. Other useful diluents include, but are not limited to, carboxymethylcellulose, sugar alcohols such as mannitol, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic and tribasic calcium phosphate.

Adhesive agent

The binder may be selected from, for example, acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethylcellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl methylcellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low substituted hydroxypropyl cellulose, glucose, sorbitol.

Packing material

Suitable fillers may be selected, for example, from starch derivatives such as corn starch, potato starch or rice starch, polysaccharides such as dextrins, maltodextrins, dextrates, microcrystalline cellulose, powdered cellulose, mixtures of microcrystalline cellulose and guar gum, co-processed mixtures of microcrystalline cellulose; and polyols such as xylitol and sorbitol.

Disintegrating agent

The disintegrant may be selected from, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose.

Glidant

Glidants may be selected from, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide.

Lubricant

The lubricant may be selected from, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulfate, talc, polyethylene glycol and glyceryl behenate, glyceryl monostearate, palmitic acid, talc, carnauba wax, sodium calcium stearate, sodium or magnesium lauryl sulfate, lime soap, zinc stearate, polyoxyethylene monostearate, calcium silicate, silica, hydrogenated vegetable oils and fats, stearic acid and any combination thereof.

The pharmaceutical compositions of the present disclosure may be formulated into conventional pharmaceutical preparations such as tablets, fast-melt tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injections (liquids, suspensions, etc.), lozenges, intranasal spray transdermal patches, and the like.

Absorption enhancer

Absorption enhancers used according to certain embodiments of the present disclosure include, for example, gelucire 44/14; gelucire 50/13; tagat TO; tween 80; isopropyl myristate, polysorbate, sorbitol ester, poloxamer block copolymer, PEG-35 castor oil, PEG-40 hydrogenated castor oil, caproyl polyethylene glycol-8 glyceride, PEG-8 caprylic/capric glyceride, sodium lauryl sulfate, dioctyl sulfosuccinate, polyethylene dodecyl ether, ethoxydiglycol, propylene glycol mono-dicaprylate, glycerol monocaprylate, glycerol fatty acid (C8-C18) ethoxylation, oleic acid, linoleic acid, glycerol caprylate/caprate, glycerol monooleate, glycerol monolaurate, caprylic/capric triglyceride, ethoxylated nonylphenol, PEG- (8-50) stearate, olive oil PEG-6 ester, PEG-6 trioleate, lecithin, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, cyclodextrin, citric acid, sodium citrate, glyceryl triacetate, combinations thereof, and the like. In certain preferred embodiments, the absorption enhancer is glyceryl triacetate.

Sweetener/flavoring agent

Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; sodium cyclamate and salts thereof; saccharin and its salts; aspartame.

Flavoring agents may be incorporated into the composition, which may be selected from synthetic flavoring oils and flavoring aromatics, natural oils, plant extracts. Examples include cinnamon oil, oil of wintergreen, peppermint oil, clove oil, bay oil, fennel oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, or almond oil. Examples of flavoring agents include, but are not limited to, almonds, apples, bananas, berries, bubble gum, caramel, citrus, cherries, chocolate, coconut, grapes, green tea, honey, lemon, licorice, lime, mango, maple sugar, peppermint, orange, peach, pineapple, raisins, strawberries, vanilla, watermelon, and combinations thereof. The flavoring agent may be present in an amount of about 0.001% to about 5% by weight of the total formulation. In some embodiments, the flavoring agent may be selected from natural or synthetic flavoring agents, such as strawberry flavoring agent, wild cherry flavoring agent, green apple flavoring agent, spearmint flavoring agent, and peppermint flavoring agent. In some embodiments, the flavoring agent is selected from menthol, peppermint, wintergreen, orange, cherry and other fruits, vanilla, almond and other nuts, and the like.

In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of tablets, which may include one or more pharmaceutically acceptable carriers or excipients selected from lactose, sucrose, sodium chloride, glucose, urea, starch, xylitol, mannitol, erythritol, sorbitol, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, simple syrups, dextrose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose and other disintegrants; white sugar, stearin, cocoa butter, hydrogenated oil and other disintegration inhibitors; quaternary ammonium salts, sodium lauryl sulfate, and other absorption promoters; glycerin, starch, and other humectants; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents; refined talc, stearate, boric acid powder, polyethylene glycol, and other lubricants, and the like. Tablets may also be formulated with common coatings, such as sugar coated tablets, gelatin coated tablets, enteric coated tablets and film coated tablets, as well as bilayer and multilayer tablets.

In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of a pill, which may include one or more pharmaceutically acceptable carriers or excipients selected from glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, talc and other excipients; gum arabic powder, gum tragacanth powder, gelatin, ethanol and other binders; and laminarin, agar and other disintegrants, etc.

In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of capsules. According to a conventional method, capsules are prepared by mixing a carbostyril derivative such as anhydrous aripiprazole crystal as a first component and a 5-hydroxytryptamine reuptake inhibitor as a second component, together with the various carriers described above, and packaging them in hard gelatin capsules, soft capsule hydroxypropyl methylcellulose capsules (HPMC capsules), or the like.

In some embodiments, the pharmaceutical compositions of the present disclosure are in the form of suppositories, which may include one or more pharmaceutically acceptable carriers or excipients selected from polyethylene glycols, cocoa butter, higher alcohols, esters of higher alcohols, gelatin semisynthetic glycerides, and the like.

Route of administration and dosage form

The formulation according to the present disclosure may be administered to an individual via any common route, provided that the target tissue is available via that route. The formulations may conveniently be presented in dosage form units and may be prepared by any of the methods well known in the art of pharmacy. In some embodiments, the formulation is prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired dosage form. Of course, those skilled in the art will recognize that the active ingredients (e.g., compounds disclosed herein) are included in amounts sufficient to produce the desired pharmacological effect.

In some embodiments, the composition is administered according to the type of formulation and the age, sex, and other conditions of the patient (extent and condition of the disease, etc.). For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally. In the case of injectable formulations, they are administered intravenously, alone or in admixture with common auxiliary liquids (e.g. glucose or solutions of amino acids). Furthermore, the injectable formulation may be administered alone intradermally, subcutaneously, intramuscularly or intraperitoneally, if desired. In the case of suppositories, they are administered rectally.

In some embodiments, a pharmaceutical composition or compound disclosed herein is administered at least once a day at a dose such as described herein. In some embodiments, a pharmaceutical composition or compound disclosed herein is administered at a dose such as described herein at least twice a day. In some embodiments, a pharmaceutical composition or compound disclosed herein is administered at least three times a day at a dose such as described herein.

In other embodiments, the pharmaceutical compositions or compounds disclosed herein are administered at least once every other day at dosages such as described herein. In other embodiments, the pharmaceutical compositions or compounds disclosed herein are administered at least once every three days at dosages such as described herein. In further embodiments, the pharmaceutical compositions or compounds disclosed herein are administered at a dose such as described herein at least once every four days. In further embodiments, the pharmaceutical compositions or compounds disclosed herein are administered at dosages such as described herein, or at least once every five days.

In some embodiments, the methods and formulations may be practiced as a single, one-dose or long-term. Chronic refers to methods and compositions of the present disclosure that are practiced more than once for a given individual or individuals. For example, chronic administration may be multiple doses of the pharmaceutical composition administered to an individual daily, weekly, biweekly, monthly, or more or less frequently, as would be apparent to one of skill in the art. The long term administration may last for weeks, months or years, if appropriate, as judged by the person skilled in the art. Furthermore, if, at the discretion of the skilled artisan, certain doses exhibit a potentially unacceptable tolerability profile, the physician may reduce the dose to reduce such profile.

LSD derivatives and their polymorphs for therapeutic use

The novel LSD derivatives and polymorphs thereof as disclosed herein are suitable for formulation as therapeutic agents for treating an individual in need thereof. They have been shown to promote synaptic growth (promote neuroplasticity) and may lead to "rewiring" of the central and/or peripheral nervous system, producing sustained results without the illusion. They also proved to be non-fanciful and unexpectedly did not induce tolerance so that they could be used in multiple doses daily, weekly, monthly, etc. This advantageously avoids the need to have an intermittent dosing schedule where an individual may wait for several days (e.g., 3 days or more) before administering the next dose.

The applicant has synthesized a new polymorph of a LSD derivative characterized by having a mild to potent agonist for all 5-HT1 receptor subtypes, with a slight decrease in Emax (maximum efficacy) relative to LSD. Examples disclosed herein disclose E559 polymorphs [ (α (5 r,8 r) -2-Br-LSD semi-D-tartrate ], characterized by efficacy/activity at 5-HT1F and 5-HT1D receptors (known as anti-migraine and pain-sensing drug targets), (RamjrezRosas et al Activation of 5-hydroxytryptamine_1B/1D/1F receptors as a mechanism of action of antimigraine drugs,Expert Opinion on Pharmacotherapy,2013, 14:12, 1599-1610) and (Clemow, d.b. et al LASMIDITAN MECHANISM of action-review of A SELECTIVE-HT _1F agonist.j HEADACHE PAIN,2020, 21, 71) the description of E559 polymorphs as potent agonists of 5-HT1F and 1D receptor subtypes demonstrates therapeutic potential for alleviating symptoms such as headache, migraine and pain disorders.

The E559 polymorph has been characterized herein as a 5-HT6 partial agonist, similar to LSD.5-HT6 is an emerging target receptor for the treatment of cognitive deficits and disorders (Drop et al ,2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity.ACS Chemical Neuroscience 2021 12(7),1228-1240) and (Khoury et al ,The role of 5HT6-receptor antagonists in Alzheimer's disease:an update,Expert Opinion on Investigational Drugs,2018,27:6,523-533).) thus, the E559 polymorph, which is a potent partial agonist of the 5-HT6 receptor, has proven therapeutic utility in the treatment of cognition, learning and memory, and is thus useful, for example, in the treatment of cognitive disorders including cognitive decline associated with neurological and psychiatric disorders such as, but not limited to, alzheimer's disease, parkinson's disease, schizophrenia, down's syndrome and autism spectrum disorders.

Polymorphic forms E559 are characterized herein as partial agonists of the 5-HT2A and 5-HT1A receptor subtypes, which are known drug targets for the treatment of mood disorders such as depression and anxiety disorders (Celada et al, ,The therapeutic role of 5-HT_1A and 5-HT_2A receptors in depression.J Psychiatry Neurosci,2004, 7 months; 29 (4): 252-265), and thus have utility in the treatment of antidepressant or anxiolytic therapies.

The E559 polymorph demonstrated herein to have high potency (agonism) at D2-like receptors, including D2 and D4. As potent agonists of the D2/D4 dopamine receptor, it has therapeutic potential in D2/D4-linked neuropsychiatric disorders including but not limited to Parkinson's disease, schizophrenia, restless leg syndrome, psychosis, attention Deficit Hyperactivity Disorder (ADHD), substance use disorders, hyperprolactinemia and neuroparalytic malignancy (Bonifazi et al ,Novel and Potent Dopamine D₂ Receptor Go-Protein Biased Agonists.ACS Pharmacology&Translational Science 2019 2(1),52-65) and (Paul EKeck Jr&Susan L McElroy.Aripiprazole:a partial dopamine D2 receptor agonist antipsychotic,Expert Opinion on Investigational Drugs,2003,12:4,655-662) and (Woolley et al) ,Selective dopamine D4 receptor agonist(A-412997)improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat.Behavioural Pharmacology:December 2008-Volume 19-Issue 8-p765-776).

Depression symptoms

In some embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat a disease and/or disorder selected from the group consisting of: depression, major depressive disorder (including major depressive episode), devastating mood disorder, atypical depression, psychotic major depression, stress depression, postpartum depression, premenstrual anxiety, seasonal affective disorder, substance/drug induced depression, double depression, depressive personality disorder, persistent depression (hypo-affective disorder), recurrent transient depression, mild depression, depression due to medical conditions, depression not otherwise indicated. In some embodiments, the individual has depression that is resistant to treatment.

In some embodiments, suitable dosages for this group of depression are as follows:

The term "major depressive disorder" refers to a condition characterized by a period of time in which low mood occurs in most cases. Major depressive disorder is often accompanied by low self-esteem, loss of interest in normal pleasant activities, low energy and pain of no definite cause. In some cases, major depressive disorder is characterized by signs and symptoms that occur for two weeks, years, or almost always. Major depressive disorders can negatively affect a person's personal, work, or school life, as well as sleep, eating habits, and general health. Dysthymia is a subtype of major depression that consists of the same cognitive and physical problems as major depression, with less severe but longer lasting symptoms. Exemplary symptoms of major depressive disorder include, but are not limited to, sadness, crying, empty or undesirable sensations, anger, irritability or frustration, even minor things, loss of interest or pleasure in most or all normal activities, sleep disturbances including insomnia or too much sleep, fatigue and lack of energy, reduced appetite, weight loss or increase, anxiety, surprise or restlessness, thinking, speaking or physical bradykinesia, feeling of worthless or guilt, performing past failures or responsibilities, thinking, concentration, decision making and memory difficulties, frequent recall of death, suicide thoughts, suicide attempts or suicide, and physical problems of unspecified cause, such as back pain or headache.

By "atypical depression" is meant a condition in which an individual exhibits an emotional response (i.e., the emotion is pleasant due to an actual or potential positive event), significant weight gain, increased appetite, sleepiness, heaviness of the arms or legs, and/or a long-term pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment. Exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depression, loss of pleasure in what was once pleasant, severe changes in body weight (increase or decrease) or appetite, almost daily insomnia or excessive sleep, physical discomfort noticeable to a physical or other person, daily fatigue or loss of energy, undesired, worthless, or almost daily feeling of excessive guilt, almost daily problems of concentration or decision making, repeated thoughts of death or suicide, suicide plans, or suicide attempts.

"Stress depression" refers to a condition that causes an individual to remain nonverbal and motionless for a sustained period of time. Exemplary symptoms of stress depression include, but are not limited to, a feeling of sadness that may occur daily, lost interest in most activities, sudden weight gain or loss, altered appetite, difficulty falling asleep, difficulty getting up, restlessness, irritability, invasiveness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and/or suicide attempts.

"Depression due to a medical condition" refers to a condition in which an individual experiences symptoms of depression caused by another disease. Examples of medical conditions known to cause depression include, but are not limited to, HIV/AIDS, diabetes, arthritis, stroke, brain disorders such as parkinson's disease, huntington's disease, multiple sclerosis and alzheimer's disease, metabolic disorders (e.g., vitamin B12 deficiency), autoimmune disorders (e.g., lupus and rheumatoid arthritis), viral or other infections (hepatitis, mononucleosis, herpes).

"Postpartum depression" refers to a condition of mental regulation and/or fatigue to a human parent due to labor and hormonal changes. Postnatal depression is often associated with women, but men may also suffer from postnatal depression. Exemplary symptoms of post partum depression include, but are not limited to, sadness, unwillingness, emptiness, or an overwhelmed sensation; crying more frequently or for an unknown reason than usual; anxiety or feel of excessive anxiety; feeling happy, irritable or restless; excessive sleep, even when the infant falls asleep, cannot fall asleep; it is difficult to concentrate on, remember details, and make decisions; experience anger or furiousness; loss of interest in activities that are pleasant at ordinary times; suffering from physical pain and pain, including frequent headache, stomach illness, and muscle pain; too little or too much to eat; exit or avoid friends and family; difficulty establishing or forming emotional attachment with infants; permanently doubt his or her ability to care for the infant; and ideas about injuring oneself or infants.

"Premenstrual dysphoric disorder" refers to a condition in which an individual expresses mood swings, irritability, pathological dysphoria, and anxiety symptoms that recur during the premenstrual phase of the cycle and are relieved at or shortly after the onset of menstruation. Exemplary symptoms of premenstrual anxiety disorders include, but are not limited to, instability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, reduced interest in normal activities, difficulty concentrating, sleepiness and lack of energy, altered appetite (e.g., excessive eating or specific food craving), sleepiness or insomnia, feeling of overwhelmed or uncontrolled, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, feeling of "bloating" and weight gain), self-detracting ideas, anxiety or dysphoria, reduced interest in normal activities (e.g., work, school, friends, hobbies), subjectively difficulty concentrating, and tiredness.

"Seasonal affective disorder" refers to a condition in which an individual experiences a change in mood over a period of one year. In some cases, the individual experiences low mood, low energy, or other symptoms of depression in autumn and/or winter. In some cases, the individual experiences low mood, low energy, or other symptoms of depression in the spring and/or summer.

In some embodiments, the methods of the present disclosure reduce at least one sign or symptom of depression. In some embodiments, the sign or symptom of depression is depressed mood, reduced activity interest, weight loss or increase, reduced or increased appetite, insomnia or somnolence, psychomotor agitation or dullness, fatigue or energy loss, no value, or excessive or inappropriate feelings of guilt, reduced ability to concentrate or hesitate, or suicidal ideation or behavior.

In some embodiments, the methods described herein are provided to an individual with newly diagnosed depression. In some embodiments, the individual has been treated with one or more other antidepressants, but does not obtain adequate control of depressive symptoms or obtains adequate control of depressive symptoms, but is adversely affected by the side effects of the treatment. In some embodiments, the methods described herein are provided to an individual with treatment-resistant depression. In some embodiments, an individual has been diagnosed with "treatment-resistant depression," which refers to a depression that is unresponsive or resistant to at least one or more appropriate doses and durations of treatment attempts.

In some embodiments, the methods provided herein reduce at least one sign or symptom of depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of depression by about 5% to about 100% as compared to prior to treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of major depressive disorder by about 5% to about 100% as compared to prior to treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of atypical depression by about 5% to about 100% as compared to prior to treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of stress depression by about 5% to about 100% as compared to before treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of depression due to a medical condition by about 5% to about 100% as compared to before treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of post-partum depression or premenstrual anxiety by about 5% to about 100% as compared to pre-treatment.

In some embodiments, no additional therapeutic agent is administered to the individual to reduce signs or symptoms of depression after administration of the LSD derivatives or polymorphs disclosed herein.

In some embodiments, the methods of the present disclosure further comprise administering at least one additional therapeutic agent to the individual to reduce signs or symptoms of depression. In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine reuptake inhibitor, 5-HT1A receptor antagonist, 5-HT2 receptor antagonist, 5-HT3 receptor antagonist, monoamine oxidase inhibitor, or norepinephrine antagonist. In some embodiments, the at least one additional therapeutic agent is administered prior to administration of the LSD derivative or polymorph disclosed herein, on the same day as administration of the LSD derivative or polymorph disclosed herein, or after administration of the LSD derivative or polymorph disclosed herein. In some embodiments, at least one additional therapeutic agent is administered in the same regimen as the LSD derivative or polymorph disclosed herein (e.g., once every other day or twice weekly or once weekly). In some embodiments, at least one additional therapeutic agent is administered in a different regimen than the LSD derivatives or polymorphs disclosed herein. In some embodiments, the duration of treatment with the LSD derivative or polymorph may be the same as, or shorter than, or longer than the duration of treatment with the additional therapeutic agent.

Bipolar disorder

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used for the treatment of bipolar disorders, including bipolar I disorder, bipolar II disorder, cyclothymic disorder, substance/drug induced bipolar disorder, and bipolar disorder not otherwise indicated.

In some embodiments, the dosages for the set of disorders are as shown in the following table:

"bipolar disorder" refers to a condition that causes an individual to experience abnormal changes in emotion, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorders experience periods of abnormally strong mood, sleep patterns, and changes in activity levels, and abnormal behavior. These different periods are called "mood episodes". Mood episodes differ significantly from the mood and behavior typical for this person. Exemplary symptoms of manic, excessive behavior include, but are not limited to, abnormal optimistic, jumping or excited behavior; increased activity, energy or agitation, exaggerated well-being and self-confidence, reduced sleep need, unusual speech loving, thinking rushing, distraction and poor decision making.

Bipolar disorders include bipolar I disorder, bipolar II disorder and cyclothymic disorder. Bipolar I disorder is defined as a manic episode lasting at least 7 days or a severe manic symptom requiring hospitalization. Individuals with bipolar I affective disorders may also experience depressive episodes that typically last for at least 2 weeks. Depressive episodes with mixed features (i.e., simultaneous depressive and manic symptoms) are also possible. Bipolar II mood disorders are characterized by patterns of depression and manic episodes, but are not severe manic episodes of typical bipolar I mood disorders. Circulatory affective disorders (also known as environmental mood) are characterized by periods of hypomanic symptoms (elevated mood and euphoria) and depressive symptoms that last for at least 2 years.

In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder. In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar disorder by about 5% to about 100% as compared to prior to treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar I disorder by about 5% to about 100% as compared to prior to treatment.

In some embodiments, the methods provided herein reduce at least one sign or symptom of bipolar II affective disorder by about 5% to about 100% as compared to prior to treatment.

Schizophrenia pedigree and other psychotic disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for the treatment of schizophrenic lineages and other psychotic disorders, including delusional disorders, transient psychotic disorders, schizophrenia, schizoaffective disorders, substance/drug-induced psychotic disorders, schizophrenic (personality) disorders, psychotic disorders due to another medical condition, stress disorders associated with another psychotic disorder, and other indicated or unspecified schizophrenic lineages and other psychotic disorders.

Personality disorder

In further embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat personality disorders, such as those classified in the manual for diagnosis and statistics of mental disorders, 5 th edition (DSM-5); the disclosure of the american psychiatry association, 2013, is incorporated herein by reference in its entirety. Briefly, DSM-5 classifies personality disorders into 10 specific disorders: paranoid personality disorder (distrust and suspicious patterns such that others' motivations are interpreted as malicious); split-like personality disorder (pattern of departure from social relationships and limited range of emotional expression); schizophrenic personality disorder (a pattern of severe discomfort, cognitive or perceptual distortion, and behavioral mania in close relationship); antisocial personality disorder (a pattern of neglect and violation of others' rights); edge personality disorder (instability of interpersonal relationship, self-image and impact, and significant impulse); personality disorder of performance (excessive emotion and pattern of attention sought); self-loving personality disorder (exaggerated, required praise, lack of concentric patterns); avoidance personality disorder (pattern of social depression, spell, and oversensitivity to negative assessment); dependent personality disorders (patterns of compliance and adherence related to excessive need to be attended to); forced personality disorder (a pattern focused on order, perfection, and control); personality changes caused by another medical condition (judged as persistent personality disorder due to direct physiological effects of the medical condition); as well as other indicated personality disorders and unspecified personality disorders.

Anxiety disorders

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of anxiety disorders, such as those classified in the handbook of diagnosis and statistics of mental disorders, 5 th edition (DSM-5); the disclosure of the american psychiatry association, 2013, is incorporated herein by reference in its entirety. Briefly, anxiety disorders are classified by DSM-5 as: generalized anxiety disorder, separation anxiety disorder, panic disorder, selective mutism, specific phobia (animal, natural environment, blood/injection/injury fear, context, others), social anxiety disorder, panic attack-specific disorder, agoraphobia, substance/drug-induced anxiety disorder, anxiety disorder due to other medical conditions, and other indicated or unspecified anxiety disorders.

In some embodiments, the dosages for the above disorders are as shown in the following table:

Wound and stress related disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating trauma and stress related disorders, including attaching disorders, disinhibiting social participation disorders, post-traumatic stress disorder (PTSD), acute stress disorder, adaptation disorders, other indicated or unspecified trauma and stress related disorders.

Obsessive compulsive disorder and related disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating obsessive-compulsive disorder (OCD), somatic dysmorphism, stocking disorders, dehairing disorders (dehairing disorders), exfoliative (skin scratching) disorders, substance/drug-induced obsessive-compulsive disorder and related disorders, obsessive-compulsive disorder and related disorders due to another medical condition, and other indicated and unspecified obsessive-compulsive disorders and related disorders (e.g., body-centered repetitive behavioral disorders, compulsive jealousy).

Destructive impulse control and behavioral disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for the treatment of destructive, impulse control and behavioral disorders, including oppositional defiant disorder, intermittent explosive disorder, behavioral disorder, antisocial personality disorder, pyromania, kleptomania, dehairing, and other destructive, impulse control and behavioral disorders both indicated and unspecified.

Disorders of ingestion and eating

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of ingestion and eating disorders comprising: pica, ruminant disorders, avoidance/restriction type food intake disorders, anorexia nervosa, binge eating disorders, bulimia nervosa, overeating or overeating disorders, diabetic hyperphagia, prader-willi syndrome and hypothalamic obesity, somatic dysmorphia, and other indicated and unspecified intake or eating disorders.

Separation disorder

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating separation disorders, including separation identity disorders, dissociative forgetfulness, personality/reality separation disorders, and other indicated and unspecified separation disorders.

Somatic symptoms and related disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating somatic symptoms and related disorders, including somatic symptom disorders, disease anxiety disorders, conversion disorders (functional neurological symptom disorders OCDs), sexual disorders (imposed on itself and another person), and other designated and unspecified somatic symptoms and related disorders.

Disorders of neurodevelopment

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: neurological disorders including mental disability (mental developmental disorder), general developmental retardation, communication (language, speech/sound, childhood fluency or stuttering, social, unspecified) disorders, autism spectrum disorders, attention Deficit Disorder (ADD), attention Deficit Hyperactivity Disorder (ADHD), specific learning disorders, movement disorders (developmental coordination, notch board type movement, tourette's disorder, persistent/chronic movement or vocal tic disorders, transient tic disorders), and other neurological developmental disorders, either indicated or unspecified.

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: seizures (including generalized seizures, focal seizures, unknown onset seizures, and focal to bilateral seizures) and seizures (including generalized seizures, focal seizures, generalized and focal seizures, dravet syndrome, and seizures of unknown onset seizures).

Sleep-wake disorders

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: insomnia, excessive somnolence disorder, narcolepsy, respiratory-related sleep disorders (e.g., obstructive sleep apnea hypopnea, central sleep apnea, primary central sleep apnea, sleep-related hypoventilation), circadian rhythm-related sleep-wake disorders, non-rapid eye movement (NREM) sleep arousal disorders, nightmares, rapid Eye Movement (REM) sleep behavioral disorders, restless leg syndrome, substance/drug-induced sleep disorders, and other indicated and unspecified sleep-wake disorders.

Substance-related and addictive disorders

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: substance-related disorders (SRD) and addiction disorders, including but not limited to the following drug classes: alcohol, nicotine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (amphetamine-type substances, cocaine, and other stimulants), and solvent abuse, drugs, and other indicated or unspecified substance-induced disorders.

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used to treat non-substance related disorders, including but not limited to gambling disorders.

SRD (also known as substance-dependent disorder or drug use disorder or substance abuse disorder) is a condition in which the use of one or more substances results in significant injury, dysfunction or affliction. Addiction and dependency are components of SRD, where addiction represents a more severe form of disorder.

Headache disorder

In other embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat headaches classified as in the headache classification committee (The International Classification of Headache Disorders, 3 rd edition, CEPHALALGIA,2018, 38 (1), 1-211) of the international headache Institute (IHS), the disclosure of which is incorporated herein by reference in its entirety. Briefly, IHS groups headaches into three general categories: primary headache, secondary headache, or other headache disorders.

In some embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat and/or prevent and/or reduce the onset/duration of headaches classified by HIS as "primary headaches," including migraine headaches (including non-premonitory migraine, premonitory migraine and chronic migraine), tension headaches (including rare onset, frequent onset and chronic tension headaches), trigeminal autonomic headaches (including cluster headaches, paroxysmal migraine, transient unilateral neuralgia-like headache onset and persistent migraine) and other primary headache disorders.

Trigeminal autonomic headaches (TAC) include cluster headaches (sometimes referred to as familial cluster headaches, histamine headaches, or vascular-derived facial pain), including all subtypes thereof, such as narcotic cluster headaches and recurrent or chronic cluster headaches; transient unilateral neuralgia-like headache attacks (SUNHA) and subtypes thereof are accompanied by conjunctival congestion and tear (SUNCT) and transient unilateral neuralgia-like headache attacks are accompanied by cranium autonomic Symptoms (SUNA). The main subcategories of TAC are defined by IHS as follows:

trigeminal autonomic headache (TACs)

1. Cluster headache

1.1. Cluster headache

1.2. Chronic cluster headache

2. Paroxysmal migraine

2.1. Paroxysmal migraine

2.2. Chronic paroxysmal migraine

3. Transient unilateral neuralgia-like headache attacks

3.1. Transient unilateral neuralgia-like headache attacks are accompanied by conjunctival congestion and lacrimation (SUNCT)

3.1.1. Paroxysmal SUNCT

3.1.2. Chronic SUNCT

3.2. Transient unilateral neuralgia-like headache is accompanied by cranial autonomic Symptoms (SUNA)

3.2.1. Paroxysmal SUNA

3.2.2. Chronic SUNA

4. Persistent migraine

4.1. Persistent migraine, relief of subtype

4.2. Persistent migraine, uninterrupted subtype

5. Possible trigeminal autonomic headache

5.1. Possible cluster headache

5.2. Possible paroxysmal migraine

5.3. Possible transient unilateral neuralgia-like headache attacks

5.4. Possible persistent migraine

In some embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat and/or prevent and/or reduce the onset/duration of headaches classified by IHS as "secondary headaches," including headaches due to head and/or neck trauma or injury, headaches due to craniocerebral and cervical vascular disease, headaches due to non-vascular intracranial hematomas, headaches due to substance or withdrawal thereof, headaches due to infection, headaches due to disturbed homeostasis, headaches due to cranium, neck, eye, ear, nose, sinus, tooth, mouth, or facial pain or other facial or neck structural disorder, headaches due to psychotic disorder, and headache categories and other facial pain due to painful injury of the cranial nerve, including pain due to injury or disease of the trigeminal nerve.

Trigeminal Neuralgia (TN) has been defined by IHS as "disorder characterized by recurrent unilateral transient shock-like pain, bursts and ceases, localized to the distribution of one or more branches of the trigeminal nerve and triggered by innocuous stimuli" [ x ], and includes classical TN associated with TN caused by neurovascular compression alone (previously known as idiopathic trigeminal neuralgia), and is divided into two sub-forms: 1) Classical TN, pure paroxysmal and 2) classical TN with persistent facial pain; and secondary TN, which relates to trigeminal neuralgia-like pain associated with underlying diseases including tumors, wounds, viral infections, and multiple sclerosis, wherein the secondary TN has a clinical manifestation similar to classical TN, but may also exhibit some additional and/or different characteristics (e.g., TN due to multiple sclerosis, which may have bilateral manifestations and TN associated with tumors that often show abnormalities in electrophysiological tests, such as trigeminal brainstem reflex).

In some embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat and/or prevent and/or reduce the onset/duration of headaches classified by IHSs as "other headache disorders," including those not classified elsewhere and those not specified.

Pain and pain

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used for the treatment of pain caused by a disorder, such conditions include inflammation (e.g., rheumatoid arthritis, lupus, behcet's disease), genetic factors (e.g., erythromelalgia), neurological factors including nerve damage leading to pain (e.g., diabetes), cancer and cancer treatment (e.g., chemotherapy), neurological disorders (e.g., multiple Sclerosis (MS)), neurodegenerative disorders (e.g., parkinson's disease), stroke, shingles, HIV, leprosy, gilan-barre syndrome, vascular disease, vascular malformations and autoimmune disorders, all neuropathies including peripheral neuropathy, autonomic neuropathy, focal neuropathy, proximal neuropathy, diabetic neuropathy and stress mononeuropathy, phantom limb pain, residual limb pain and Complex Regional Pain Syndrome (CRPS), trigeminal neuralgia, postherpetic neuralgia, radiculopathy and all radiculopathy including chest or lumbar radiculopathy, nociceptive pain (e.g., pain due to injury, cancer), chemical or nociceptive pain (e.g., chronic extensive pain, fibromyalgia, chronic temporomandibular joint disorder, chronic pain, unknown back pain, chronic pain in the back, chronic primary pain, chronic disease, chronic primary pain (chronic disease, chronic disease pattern of the disease, chronic pain of the primary cause, chronic disease pattern, chronic pain, chronic disease pattern of the respective disease, chronic pain, chronic disease pattern of the back-causing syndrome).

In further embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat chronic PAIN (PAIN: 2015, 6 th to 156 th to 1003-1007 pages) of the International PAIN research Association (IASP) working group classification, the disclosure of which is incorporated herein by reference in its entirety. Briefly, chronic pain is defined as persistent or recurrent pain lasting for more than 3 months, and is classified into the following seven categories: chronic primary pain (which includes fibromyalgia, chronic pelvic pain, nonspecific back pain, and chronic primary pain not otherwise indicated); chronic cancer pain (which includes pain due to cancer and metastasis, pain due to chemotherapy, pain due to radiation therapy, pain due to cancer surgery, and other chronic pain associated with cancer); chronic postoperative and post-traumatic pain (which includes all postoperative and post-traumatic pain, as well as postoperative/post-traumatic pain not otherwise indicated); chronic neuropathic pain (which includes peripheral neuropathic pain, central neuropathic pain, and other neuropathic pain and neuropathic pain not otherwise indicated); chronic headache and orofacial pain (which includes chronic primary headache, chronic secondary headache, chronic orofacial pain, headache and orofacial pain not otherwise indicated); chronic visceral pain (which includes chronic visceral pain from persistent inflammation, and/or vascular mechanisms, and/or obstruction/expansion, and/or traction/compression, and/or combined mechanisms, or chronic visceral pain from other locations, from cancer, or chronic pain of unknown functional or causative origin); and chronic musculoskeletal pain (which includes chronic musculoskeletal pain from persistent inflammation and/or structural bone joint changes, and/or chronic musculoskeletal pain from neurological diseases (e.g., spasmodic pain), as well as chronic non-specific musculoskeletal pain and related pain syndromes).

In further embodiments, the pharmaceutical compositions or compounds disclosed herein may be used to treat acute pain and/or prevent or reduce the onset/duration of acute pain, defined as pain that lasts for hours or days or short periods of up to 3 months, regardless of the type of pain, and including inflammatory, nociceptive, neuropathic, plastic and other types of pain, and which includes acute pain from tissue injuries including those caused by any type of surgery, dental work, labor and delivery, cutting, burns, fractures and other accidents or wounds, acute pain caused by any disease state, acute pain caused by any type of wound, and acute pain caused by uncertain causes.

Cramps and cramps

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating conditions associated with spasticity with or without neuropathic pain, including, but not limited to, cerebral palsy, stroke, multiple Sclerosis (MS), traumatic Brain Injury (TBI), amyotrophic Lateral Sclerosis (ALS), hereditary spastic paraplegia, adrenoleukodystrophy (ALD), phenylketonuria, kerabdosia, and spinal cord injury.

Nerve injury

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating disorders and diseases associated with nerve damage or trauma from: peripheral nerve injury or trauma regardless of cause, and/or central nervous system (brain and spinal cord) nerve injury or trauma regardless of cause. These include disorders and diseases caused by external physical factors (e.g., accidents, sports injuries, falls, gunshots, or explosive impacts); or internal factors such as stroke, ruptured cerebral aneurysms, hypoxia, infection (viral, bacterial, prion or otherwise), and autoimmune disease; and they include other nerve injuries or traumas caused directly or indirectly by external factors, and/or nerve injuries or traumas caused directly or indirectly by disease states.

Fatigue of

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating chronic fatigue (e.g., physical, psychological or mental fatigue) from Traumatic Brain Injury (TBI), chronic Fatigue Syndrome (CFS), and related conditions, as well as other diseases and/or disorders that cause chronic fatigue.

Neurodegeneration

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: neurodegenerative disorders such as Alzheimer's disease, amyotrophic Lateral Sclerosis (ALS), barbat disease, friedel Lai Xixing ataxia, huntington's disease, lewy body disease, motor neuron disease, multiple sclerosis, parkinson's disease, prion disease, spinal muscular atrophy, neurodegenerative disorders caused by viral (e.g., HIV) or bacterial infection, neurodegenerative disorders caused by substances/drugs, and other neurodegenerative disorders related to aging and non-aging.

Sexual dysfunction and sexual anxiety disorder

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: sexual dysfunction including ejaculatory delays, erectile dysfunction, female orgasmic dysfunction, female sexual interest/arousal dysfunction, reproductive pelvic pain/infiltration dysfunction, male hyposexuality dysfunction, premature ejaculation (early), substance/drug-induced sexual dysfunction, other indicated and unspecified sexual dysfunction.

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating diseases and/or disorders selected from the group consisting of pediatric, adolescent, adult sexual anxiety, and other indicated and unspecified sexual anxiety.

Neurocognitive disorders

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: neurocognitive disorders (NCDs) including delirium, NCD caused by alzheimer's disease, vascular NCD, NCD with lewy bodies, NCD caused by parkinson's disease, frontotemporal NCD, NCD caused by craniocerebral injury, NCD caused by HIV infection, substance/drug induced NCD; NCD caused by huntington's disease, NCD caused by prion disease; NCD caused by another medical condition, NCD caused by a variety of etiologies, and unspecified NCD.

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are useful for treating neurocognitive/learning dysfunction, including memory problems, mental confusion, poor attention, and/or inattention due to infection (viral/bacterial/prion/other) or other indicated or unspecified disorders, diseases, or other unknown causes.

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a decrease in memory, cognition and/or learning with or without a significant sign of a neurodegenerative disorder or neurodevelopmental disorder, and/or a decrease in memory, cognition and/or learning with or without a significant sign of a neurodegenerative disorder or neurodevelopmental disorder and independent of age.

According to another embodiment, the pharmaceutical composition or compound disclosed herein is used for treating a decrease in memory, cognition and/or learning with or without the obvious signs of a neurodegenerative disorder associated with normal aging.

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: neurological and/or neuropsychiatric disorders and/or conditions associated with normal aging and/or luteal phase syndrome.

Neuro-viral infection

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: neurological diseases caused by viral infection that utilize neuronal cell surface receptor access, including 5-hydroxytryptamine energy (5-HT) receptors (particularly 5-HT2A receptors), such as Progressive Multifocal Leukoencephalopathy (PML) caused by JC virus.

Adverse effects of other drugs

According to another embodiment, the pharmaceutical composition or compound disclosed herein is for use in the treatment of a disease and/or disorder selected from the group consisting of: reducing and/or preventing side effects (e.g., hallucinations, terrorist hallucinations) of hallucinogens (e.g., nudity and LSD).

Health care

In other embodiments, the pharmaceutical compositions or compounds disclosed herein may be used for self-administration to provide an overall health sensation.

Therapeutic effects of 5-HT1 receptor mediated headache and pain disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used for the treatment of diseases and/or disorders, such as headache and pain disorders, wherein the therapeutic mechanism is associated with 5-HT1 receptor activation (agonism at one or more 5-HT1 receptor subtypes, such as 5-HT1A, 1B, 1D, 1E and 1F).

Therapeutic effects of 5-HT6 receptor mediated cognition, learning and memory

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used for the treatment of diseases and/or disorders associated with cognitive/learning/memory deficits or decline, such as alzheimer's disease, parkinson's disease, schizophrenia, down's syndrome and autism spectrum disorders, wherein the therapeutic mechanism is associated with 5-HT6 receptor activation (agonism).

Therapeutic effects of 5-HT2A receptor mediated depression and anxiety-related disorders

According to another embodiment, the pharmaceutical compositions or compounds disclosed herein are used for the treatment of diseases and/or disorders, such as depression and anxiety-related disorders, wherein the therapeutic mechanism is associated with 5-HT2A receptor activation (agonism).

Therapeutic effects of D2-like receptor mediated various neuropsychiatric disorders

According to another embodiment, the pharmaceutical composition or compound disclosed herein is used for the treatment of diseases and/or disorders, such as depressive disorders, parkinson's disease, schizophrenia, restless leg syndrome, psychosis, attention deficit hyperactivity disorder ADHD), substance use disorders, hyperprolactinemia and neuropathic paralytic malignancy, wherein the treatment mechanism is associated with D2-like receptor (e.g. D2 and D4 receptor subtypes) activation (agonism).

Non-fantasy and neural function remodelling factors and receptors

Hallucinations caused by LSD or other 5-hydroxytryptamine-enabled psychotropic compounds are thought to be driven by agonism of the 5HT2A receptor (Halberttadt A.L. Behaviora Brain research.2015,15; 277:99-120). LSD derivatives of 5HT2A agonists are therefore expected to be hallucinogens, i.e., to cause hallucinations. Thus, LSD derivatives with 5HT2A agonism are also substantially non-fanciful, which is unexpected and novel.

Several subtypes of 5-HT receptors identified so far in mammals include: 5HT-1A, 1B, 1D, 1E, 1F, 2A, 2B, 2C, 3, 4, 5A, 5B, 6 and 7. LSD is also known to exhibit 5HT-2B receptor agonism. This agonism of the 5HT-2B receptor is undesirable because it is believed to lead to fibrosis and subsequent cardiovascular side effects such as heart valve disease caused by LSD (Cavero and Guillon, journal of Pharmacological and Toxicological Methods,2014, 69:150-161). LSD derivatives that have 5HT2A agonism and are not 5HT-2B agonists would be novel and unexpected.

A nerve function remodeling factor is any compound that induces/promotes nerve plasticity. Neural plasticity may be defined as structural and functional changes in the nervous system, including neurogenesis, regulation of neuronal or astrocyte body or neurite size, shape and length, or synaptic plasticity (including synaptogenesis, synaptic reinforcement, acanthogenesis, synaptic spine loss, "pruning", changes in synaptic spine volume, changes in synaptic density) or changes in specific synaptic proteins and pathways. Promotion of neuroplasticity is considered an important therapeutic mechanism for the treatment of most neuropsychiatric and neurological diseases and/or disorders.

Thus, in some embodiments, the LSD derivatives disclosed herein, or polymorphs thereof, are substantially non-magic and exhibit a degree of agonism at the 5HT2A receptor.

In further embodiments, the LSD derivatives disclosed herein or polymorphs thereof are substantially non-pseudogenic and exhibit a neural function remodeling factor property with or without some agonism at the 5HT2A receptor.

In further embodiments, the LSD derivatives disclosed herein or polymorphs thereof are substantially non-pseudogenic, exhibit poor agonism or antagonism or inverse agonism at the 5HT2B receptor, and exhibit a neural function remodeling factor property with or without some degree of agonism at the 5HT2A receptor.

In further embodiments, the LSD derivatives and polymorphs thereof disclosed herein do not impart significant fantasy effects and are therefore suitable as "neuromorphic remodeling factor drugs" or "neuromorphic remodeling factors" having the potential to modulate neuromorphic plasticity, and are formulated as "neuromorphic remodeling factor agents".

In a further embodiment, the LSD derivatives and polymorphs thereof disclosed herein are administered in safe and well-tolerated doses capable of exerting a neurological remodeling factor effect for inducing/improving neuroplasticity that contributes to the treatment: mental diseases/disorders; for treating and/or preventing/reducing cognitive, learning and memory decline in all age groups, in particular in normal age groups; for treating and/or preventing/reducing cognitive, learning and memory decline in neurological diseases/disorders, regardless of age; and/or for treating and/or preventing/reducing cognitive, learning and memory decline in mental diseases/disorders, regardless of age.

In further therapeutic embodiments, the LSD derivatives and polymorphs thereof disclosed herein may be used for modulation of a neuro-receptor, which is agonism, antagonism or a partial change of any one, wherein modulation of the neuro-receptor aids in the treatment of a disease or disorder. As a non-limiting example, LSD derivatives and polymorphs disclosed herein may modulate 5-HT receptors, such as the 5-HT2A subtype, thereby affecting 5-HT type-affected neurological and psychiatric disorders, which will include depression, anxiety, PTSD and various forms of pain.

In further embodiments, the transport proteins referred to as solute carriers (SLCs) may be modulated by the novel LSD derivatives and polymorphs of the present disclosure, which modulation is agonism, antagonism, or a partial change of any one, and wherein modulation of the transport proteins facilitates treatment of a disease or disorder.

In a further embodiment, the LSD derivatives and polymorphs thereof disclosed herein are administered at safe and well-tolerated doses to exert a neurological remodeling factor effect for inducing/improving neuroplasticity that contributes to treatment: mental diseases/disorders; for aiding cognition, learning and memory in all age groups, particularly in normal age groups; for aiding cognition, learning and memory in neurological diseases/disorders, regardless of age; and/or to aid cognition, learning and memory in mental diseases/disorders, regardless of age.

The foregoing disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific examples. These examples are described for illustrative purposes only and are not intended to limit the scope of the present invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Examples

Nomenclature of

The names, structures and composite codes are shown in table I:

TABLE I

It should be noted that the International Union of Pure and Applied Chemistry (IUPAC) names generated for many 2-bromo-LSD related compounds show chiral centers at carbon 6 and carbon 9. However, numbering has been used, i.e., placing two chiral carbons at the 5 and 8 positions, consistent with bromine bonding to the second carbon, as demonstrated in the above structure.

Example 1: synthesis of 2-bromolysergic acid

(I) Preparation of 2-bromolysergic acid (B) via alkaline hydrolysis of bromocriptine mesylate (A)

The reaction is carried out by alkaline hydrolysis of bromocriptine mesylate (A) to 2-bromolysergic acid (B).

The general reaction:

An aqueous solution of potassium hydroxide (KOH) was added to bromocriptine mesylate at about room temperature, and the resulting mixture was heated at various temperatures. Different water miscible solvents such as ethanol, THF, 2-methyl-THF and isopropyl alcohol (IPA) were prepared to reduce caking of the solids. The resulting mixture was heated at different temperatures. A short reaction time and a relatively smooth filtration of the product are achieved. The reaction mixture was cooled to about 5 ℃ and neutralized to pH about 6.0 with about 2.5 equivalents HCl. The solid formed is filtered, dried and washed with ether such as MTBE. To completely remove the residual water, THF was added to the MTBE/water mixture to conduct azeotropic distillation. Further purification of the water can be achieved by dissolving the product in THF and evaporating or filtering one or more times.

Chemical:

All chemicals and solvents were purchased from commercial sources and used without further purification (e.g., bromocriptine mesylate (CAS 22260-51-1) from Tawa pharmaceutical industries, inc. (Teva Pharmaceutical Industries Ltd), IPA, water, methyl tert-butyl ether (MTBE) and Tetrahydrofuran (THF) from Caliden laboratories, inc. (Caledon Laboratories Ltd), and concentrated HCl from Siemens Feister technologies, inc. (FISHER SCIENTIFIC Company)).

Reaction equipment and conditions:

A high vacuum (0.02 mbar) was created by using an oil pump (Vacuubrand Model RZ).

Unless otherwise indicated, the reaction was stirred with a magnetic stirrer.

A potassium permanganate (KMnO ₄) solution used as a stain for TLC detection was prepared as follows: potassium permanganate KMnO ₄ (about 1.5 g) and potassium carbonate K ₂CO₃ (about 10 g) were dissolved in distilled water (about 150 mL) at room temperature.

The reaction:

A5L three-necked flask equipped with a condenser, thermometer, overhead stirrer, and nitrogen inlet was charged with bromocriptine mesylate (about 250g,0.333mol,1.0 eq.), IPA (about 500mL,2 volumes) and water (about 1500mL,6 volumes). 45% w/w KOH solution (about 390 mL,1.6 vol.) was added in one portion at a temperature of about 25deg.C, and the reaction mixture was adjusted to gentle reflux (about 85deg.C) for about 2-3 hours. The mixture slowly dissolved when heated to a dark brown solution at gentle reflux. The reaction solution was cooled to about 22 ℃. Ultra-high performance liquid chromatography UPLC) analysis showed complete conversion of the starting material.

After scale up, about 23.4kg bromocriptine was added to a 400L glass-lined reactor under a nitrogen purge, followed by about 36.8kg isopropanol (2 volumes). After mixing, about 140.4kg deionized water (6 volumes) was added to the reactor. The temperature of the mixture was adjusted to about 22±3 ℃, and the mixture was further stirred for about 30 minutes. After stirring, about 13.8 equivalents of potassium hydroxide was added to the reactor in the form of about 53.6kg of a 45% w/w aqueous solution. To ensure that all potassium hydroxide was added to the reactor, the addition line was flushed with approximately 9.4kg deionized water. The temperature of the mixture was raised to about 81 ℃ to reflux the mixture for about 2 hours. The reactor was maintained under nitrogen throughout the process. After refluxing, the mixture was cooled to about 25 ℃. UPLC analysis showed less than about 0.05% bromocriptine remaining after the reaction.

Post-treatment: the solution was distilled under reduced pressure to about 8.0-9.0 volumes (about 2.0-2.3L) at an internal temperature of about 45 ℃. The residual solution was then cooled to a temperature of about 25 ℃ and water (about 500ml,2.0 volumes) was added. The reaction flask was then adjusted to an internal temperature of about 3 ℃ (about 0-6 ℃). About 2.5M HCl solution (about 1125mL,4.5 volumes) was added to the reaction flask, the internal temperature was maintained at about 10deg.C, and stirring was performed for about 15 minutes to adjust the pH to about 5.8-6.2. The mixture was then warmed to room temperature and stirred for about 1-2 hours. The precipitate was filtered under vacuum through a buchner funnel prepared with filter paper and polyester filter cloth under nitrogen flow, washed with water (2×about 500 mL), MTBE (2×about 25 mL), and dried under vacuum under nitrogen flow for about 18 hours.

On scale up, the mixture is cooled to about 10 ℃ and distilled under vacuum at about-12.8 psig. After reaching vacuum, the mixture was heated to about 24 ℃ and the reaction mixture volume was reduced to about 200L. An additional about 46.8kg deionized water (2 volumes) was added to the reactor and the temperature was reduced to about 4.0 ℃. About 4.5 volumes of about 2.5MHcl were added to the reactor over a period of about 1 hour while cooling to maintain the reaction mixture temperature at about 5.0 ℃ to about 5.8 ℃. The pH was adjusted from about 13.3 to about 5.75 by adding about 43.3L of additional 2.5M HCl. The temperature of the mixture was raised to about 22 ℃ and stirred for about 1.5 hours. The precipitate was collected from the resulting slurry by filtration under nitrogen over a double cotton/polyester filter cloth and protected from light. The reactor was rinsed twice with about 2 volumes of deionized water each time, warmed to about room temperature, and then used to wash the filter cake. The reactor and filter cake were then washed twice with about one volume of MTBE at a time. The product was dried at about 45 ℃ for about 116 hours with a nitrogen stream passing through the solid. UPLC analysis showed the purity of (5R, 8R) 2-bromo-lysergic acid to be about 93.5%. The main impurity is the stereoisomer (5R, 8S) 2-bromo-lysergic acid, about 4.6%.

Purification and azeotropic drying: THF (about 1250ml,5 volumes) was added to the isolated wet product in a 5L three-neck reaction flask equipped with a distillation apparatus and thermometer. The suspension was stirred at about room temperature for about 30 minutes and concentrated under reduced pressure, and the internal temperature was raised to about 40 ℃ to reach a final volume of about 1.5-2.0 volumes (about 375-500 mL). This process was repeated about three times. The precipitate was filtered under vacuum through a buchner funnel prepared with filter paper and polyester filter cloth under nitrogen flow, washed with THF (2 x about 125 mL), and dried under vacuum under nitrogen flow for about 18 hours. The product is stored in the dark at about 2-8 ℃.

After scaling up, about 9kg of dry (5R, 8R) 2-bromo-lysergic acid was added to the reactor along with about 104kg of tetrahydrofuran (about 5 volumes) and mixed for about 15 minutes. The reactor temperature was adjusted to about 7 ℃ and vacuum was applied to about-13.3 psig vacuum. The temperature was raised to about 10 ℃ and the volume was reduced to about 45L under nitrogen. About 104kg tetrahydrofuran (about 5 volumes) was added and distillation was repeated, this time at about-13.8 psig and about 15 ℃. About 104kg of tetrahydrofuran of the third fraction was added and finally the distillation was repeated. The temperature was adjusted to about 21 ℃ and the product was stirred for about 1 hour. The precipitate was recovered by filtration over a double cotton/polyester filter cloth. The reactor was flushed and the filter cake was washed with 3 x about 0.5 volumes of wash solution. The filter cake was dried under vacuum and nitrogen at about 40 ℃ for about 106 hours. UPLC analysis showed that the purity of (5R, 8R) 2-bromo-lysergic acid was 95.3%. The main impurity is 2.4% of the stereoisomer (5R, 8S) 2-bromo-lysergic acid.

Final analysis for small-scale batches: KF: about 0.93%, HPLC: about 98.55% and yield: about 86g,74%.

The chemical formula: c ₁₆H₁₅BrN₂O₂

Accurate quality: 346.03

Molecular weight: 347.21

¹³ C and ¹ H Nuclear magnetic resonance Spectrometry

(B) 500MHz ¹ H-NMR and 125MHz ¹³ C-NMR spectra in DMSO-d ₆ are as follows (see also FIGS. 1A and 1B):

¹³C NMR(75MHz,DMSO)δ173.6,173.2,134.6,134.3,134.2,134.2,126.8,126.4,125.9,125.8,122.9,122.9,1197,112.0,109.4,109.2,109.1,103.9,103.8,61.7,61.6,54.4,53.3,43.1,42.8,41.6,406,25.9,

¹H NMR(300MHz,DMSO-d₆)δ11.52(s,1H),7.36-6.99(m,3H),650(t,J＝2.6Hz,1H),3.54(ddt,J＝11.0,5.6,3.0Hz,1H),3.35-2.99(m,3H),2.70-2.53[m,,1H),2.50(s,3H),2.46-2.34(m,1H).

high resolution mass spectrometry

(B) Electrospray ionization mass spectra of (2) are shown in fig. 2A and 2B.

(Ii) Preparation of 2-bromo-LSD (C) via 2-bromolysergic acid (B) and diethylamine

In the presence of a coupling agent, the reaction proceeds via base-catalyzed amide bond formation of 2-bromolysergic acid (B) upon reaction of 2-bromolysergic acid (B) with diethylamine. The 2-bromo-LSD free base (C) is recovered by precipitation.

The general reaction:

The sequence of different coupling agents, solvents, temperatures, rates and mixing reactants, and reaction times have been completed. Although the 5r,8s isomer is also formed, the reaction is generally complete and specific for the 5r,8r isomer. After coupling, the reaction mixture is cooled to about 5 ℃, water is added, and then the pH is reduced with a different acid, such as aqueous HCl, to a different pH value in the range of about 6 to about 8. The precipitate was collected by filtration. Further purification was provided by dissolving the product in THF and then concentrating and filtering.

Chemical:

all chemicals and solvents were purchased from commercial sources as described above and used without further purification.

Reaction equipment and conditions:

Unless otherwise indicated, the reaction was stirred with a magnetic stirrer.

The reaction:

A mixture of 2-bromo-lysergic acid (B) (about 5.20 g) and N-methylmorpholine (NMM) (about 3 equivalents or 4.56 g) in THF (about 3 volumes or 15.6 mL) was stirred at about room temperature for about 1 hour and treated with a solution of Carbonyldiimidazole (CDI) (about 2 equivalents or 14.6 g) in THF (about 5 volumes or 26 mL). The solution was stirred at about room temperature for about 2 hours and cooled to about 0 ℃. Diethylamine (DEA) (2.2 equivalents or 7.25 g) was added at about 0 ℃, the reaction solution was warmed to about room temperature, and stirred at that temperature. The mixture was monitored by HPLC, which confirmed complete consumption of starting material after about 18 hours.

Post-treatment: the solution was cooled to about 5 ℃, diluted with about 5 volumes of water, and slowly treated with HCl (about 1m,7 equivalents, 1.7 volumes/volumes) for about 3 hours to adjust the pH to about 5.9. An additional 18.3 volumes of water were added. The precipitated product was filtered and washed with 3 x2 volumes of water.

Final analysis: KF:0.93%, HPLC:98.55%

High resolution mass spectrometry

(C) Electrospray ionization mass spectrum of (2) is shown in figure 4.

The chemical formula: c ₂₀H₂₄BrN₃ O

Accurate quality: 401.11

Molecular weight: 402.34

^13C And ¹ H Nuclear magnetic resonance Spectrometry

(C) The 125MHz ¹³ C-NMR spectrum in DMSO-d ₆ is as follows:

¹³C NMR(75MHz,CDCl₃)δ171.57,135.37,134.30,126.92,126.43,123.37,120.21,113.26,110.71,109.11,103.51,77.48,67.98,62.68,55.99,43.89,42.13,40.40,39.76,26.77,25.62,14.91,13.18.

Selection of coupling agent

The component of the reaction of step 2 is a coupling agent. Any suitable coupling agent may be used. Coupling agents such as Carbonyldiimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethyluronium (HATU), propylphosphonic anhydride (T3P) and phosphoryl chloride (POCl ₃) have been evaluated. The results of the coupling agent screening are shown in table II below:

Table II

Isomerization improvements

When amidation of 2-bromolysergic acid (B) was performed, it was found that a similar racemic mixture of (5 r,8 r) -2-bromo-LSD and (5 r,8 s) -2-bromo-iso-LSD was formed, irrespective of the mass (input ratio) of the starting materials as shown in table III:

Table III

It was found that (5R, 8S) -2-bromo-iso-LSD was formed by basic conditions, whereas the (5R, 8R) -2-bromo-LSD isomer was formed by acidic conditions. In addition, the addition of N-methylmorpholine (NMM) to the THF slurry also preferably forms (5R, 8R) -2-bromo-LSD. Subsequently, it was found that isomers can interconvert over time, favoring (5R, 8R) -2-bromo-LSD over (5R, 8S) -2-bromo-LSD. As shown below, both yield and purity can be increased when the stirring time after the addition of the acid is increased from about 30 minutes to about 6 hours:

At 5 ℃, the yield increased from about 44% to about 48% at approximately 99% isomer purity over about 6 hours (table IV).

Table IV

Unexpectedly, the concentration of hydrochloric acid used, the final pH objective, and the volumes of water and hydrochloric acid used can affect yield and isomeric purity. Table V illustrates the effect of various combinations of these parameters on yield and isomeric purity: table V

The effect of pH on yield and purity appears to be inversely affected by each other. The pH does not appear to affect the yield of E405 (see fig. 3A and 3B).

Detection of secondary factors such as the concentration of HCl and the amount of water added was found to yield experimental advantages as described above.

(Iii) Preparation of 2-bromo-LSD acid salt (D) by combining 2-bromo-LSD (C) with an organic acid

The 2-bromo-LSD acid salt (D) is prepared by heating 2-bromo-LSD (C) with the corresponding acid in a suitable solvent such as isopropyl alcohol (IPA).

The product was purified by recrystallisation from solvent. Purification by chromatography is not required.

Hemitartrate salt

(A) 2-bromo-LSD-D-tartrate: (5R, 8R) 2-bromo-LSD semi-D-tartrate

Salt formation: 2-bromo-serine diamide (C) (about 3.0 g) in IPA (about 7 volumes or about 21 mL) was heated to about 65 ℃ for about 30 minutes. To this solution was added D-tartaric acid (about 1 equivalent) in IPA (about 8 volumes) and the combined solution became clear and was further heated at about 65 ℃. After about 30 minutes, the mixture was warmed to about room temperature and cooled to about 5 ℃ over about 30 minutes. The solid (about 2.77 g) was collected by filtration and dried over about 18 hours. HPLC showed product (5 r,8 r): the ratio of isomers (5R, 8S) was about 87:13.

And (5) recrystallizing: (D) (6 g) was suspended in EtOH (8 volumes) and heated to about 65℃for about 1h, cooled to about room temperature, and then cooled to about 5℃over about 1 h. The solid was filtered and dried to obtain about 3.54g of the objective product (D).

Final analysis: HPLC [5r,8r ]:99.67%, yield: about 64%

Any impurities are mainly (5 r,8 s) -2-bromo-LSD semi-D-tartrate, 2-bromo-lysergic acid and LSD.

In another method, D-tartaric acid (about 1 equivalent) is dissolved in about 3.3 volumes of ethanol and adjusted to about 40 ℃, and E405 (about 1 equivalent) is dissolved in about 6.7 volumes of ethanol. The E405 solution was added to the D-tartaric acid solution and the temperature was raised to about 50 ℃ and stirred for at least about 30 minutes. The temperature was then adjusted to about 22 ℃ and stirred for about 30-60 minutes over about 2-3 hours. The temperature is then raised to about 50 ℃ over about 1-2 hours, stirred for about 1-2 hours, and then lowered again to about 22 ℃ over about 2-3 hours, and stirred for about 1-2 hours. The crystalline slurry is then filtered and dried under vacuum at less than about 55 ℃ for at least about 14 hours. The resulting purity of E559 is about 99.85% with a yield of about 61%. The result is the hemi-D-tartrate salt of 5R, 8R-2-bromo-LSD.

After further optimization, E559 crystallization was performed on a scale of about 15 grams and about 200 grams. Crystallization to E559 gave a chiral purity of about 99.71% (15 g scale) and about 99.85% (200 g scale). The result is the semi-D-tartrate salt of 5r,8 r-2-bromo-LSD, which is less hygroscopic (about 3.4% weight gain versus about 6.3% at 75% relative humidity), and has a higher melting point (about 193 ℃ versus about 169 ℃) indicating better long term stability than the L-tartrate salt (method described below).

In another example, 2-bromo-LSD is crystallized from ethanol and recrystallized. The 2-bromo-LSD free base was dissolved in about 6.7 volume equivalents of ethanol and heated to about 50 ℃. About 1 equivalent of D-tartaric acid was added to about 3.3 additional volumes of ethanol and stirred. The two solutions were combined and then the combined solution was cooled to about 28 ℃ over about 2 hours. The solution was reheated to about 50 ℃ and stirred, and finally cooled again to room temperature within about 1.5 hours. Finally, the resulting crystal slurry was filtered, washed, and dried under vacuum with a nitrogen sweep and packaged. Four batches prepared by this method produced comparable results on four different scales as shown in table VI:

table VI

E404 to E559

The amounts of residual LSD found were about 27ppm and about 18ppm on a scale of about 26g and about 350g, respectively. These are very low levels of residual LSD and approach the quantitative limits of mass spectrometry-based assays. As table VII shows, all other specifications of the active pharmaceutical ingredient are met.

Table VII

And (5) recrystallizing: (D) (about 5.99 g) was suspended in IPA (about 20 volumes) and heated to about 65℃for about 1h, cooled to about room temperature, and then allowed to reach about 5℃within about 1 h. The solid was filtered and dried to obtain about 2.52g of the objective product (D).

Final analysis: HPLC (5R, 8R): 99.52%, yield: about 56%

¹ H Nuclear magnetic resonance Spectrometry of D-tartrate (E559)

500MHz ¹ H-NMR in DMSO-d ₆ is shown in FIG. 5.

High resolution PXRD of D-tartrate (E559)

The PXRD data for D-tartrate (E559) is shown in fig. 6A-6D and table VIII. Recrystallization from IPA and ethanol in different proportions gives the same (5 r,8 r) half-D-tartrate salt of 2-bromo-LSD and has the same crystal structure. Fig. 6A shows small scale crystallization from ethanol and fig. 6B shows crystallization from IPA. Fig. 6C shows an overlay of crystallization from ethanol (black) and IPA (red), and fig. 6D shows crystallization from ethanol performed at a scale of about 350 g.

Table VIII

Peak list

High resolution mass spectrometry

(D) The MS spectrum of- (D-tartrate) E559 was consistent with the expected form (see figure 7A).

Scanning electron microscope image

SEM images of (D) - (D-tartrate) E559 from ethanol (see fig. 7B (crude salt) and 7C (recrystallized salt)). SEM images showed a similar morphology of D-tartrate E559 from IPA (data not shown). SEM images showed a comparable morphology of L-tartrate E560 (data not shown).

(B) 2-bromo-lsd.l-tartrate: (5R, 8R) 2-bromo-LSD semi-L-tartrate

Salt formation: 2-bromo-serine diamide (C) (about 6.0 g) in IPA (about 7 volumes) was heated to about 65 ℃ for about 30 minutes. L-tartaric acid (about 1 equivalent) in IPA (about 8 volumes) was added to the solution, and the combined solution became clear and further heated at about 65 ℃. After about 30 minutes, the mixture was warmed to about room temperature and cooled to about 5 ℃ over about 30 minutes. The solid (about 4.77 g) was collected by filtration and dried over about 18 hours. HPLC showed product (5 r,8 r): the ratio of isomers (5R, 8S) was about 87:13.

And (5) recrystallizing: (D) (5.99 g) was suspended in IPA (20 volumes) and heated to about 65℃for about 1h, cooled to about room temperature, and then allowed to reach about 5℃within about 1 h. The solid was filtered and dried to obtain about 2.52g of the objective product (D).

Final analysis: HPLC:99.52%, yield: about 56%

High resolution PXRD of L-tartaric acid (E560)

The PXRD data for L-tartrate (E560) is shown in figure 8.

(D) Characterization of the semi-tartrate salt (E559 and E560)

The FTIR spectrum is shown in fig. 9.

(D) Comparison data of the semi- (D, L) -tartrate salt (E559 and E560)

Table IX shows additional comparison data.

Table IX

Screening was performed on various acids and solvents to determine if other crystalline forms are possible for 2-bromo-LSD. The solvents and acids used are shown in table X.

Table X

Screening was performed on a small scale in 96-well plates and after crystallization, the resulting crystals were analyzed by in situ x-ray diffraction. The results of the x-ray diffraction are shown in table XI:

Table XI

These results show other routes to crystalline salts of 2-bromo-LSD. Table XII shows examples of combinations of solvents and acids showing crystallization of 2-bromo-LSD:

Table XII

Example 2: polymorphic forms of LSD derivatives lack the activity of illusion

Hallucinogens such as LSD induce Head Twitch Response (HTR) in rodents (e.g., rats and mice), described as rapid side-to-side rotational head movements. HTR mouse models are widely used as proxy behavioral assays for magic activity in humans [ Halbertstad et al, neuropharmacology,2020, V167:107933; halberstadt et al Psychopharmacology (Berl). 2013,227 (4):727-39].

The (5 r,8 r) 2-bromo-LSD semi-D-tartrate polymorph compound from example 1 (referred to herein as the "E559 polymorph") showed negative in HTR at all doses tested in the HTR mouse model (fig. 10A and 10B). Briefly, seven groups of male C57BL/6J mice with magnet implants (n=5 per group) were intraperitoneally injected with vehicle (negative control), 0.1, 0.3, 1, 3, and 10mg/kg of "E559 polymorph" or LSD (0.1 mg/kg), and then 60 minutes of behavior was recorded in the magnetometer compartment. Magnet implant installation and magnetometer evaluation were performed as described previously (Halberstadt et al Psychopharmacology (Berl). 2013 227 (4): 727-739). Data are expressed as group mean ± standard deviation of the entire 60 minute test period (fig. 10A) and individual data points per 2 minute block (fig. 10B). Asterisks indicate statistical significance compared to the control (0 mg/kg).

In contrast to LSDs that induced strong HTR at 0.1mg/kg, the "E559 polymorph" did not induce HTR above baseline at any of the test doses, including the highest dose of 10mg/kg (FIG. 10A). Based on this HTR surrogate mouse model, the "E559 polymorph" was predicted to lack magic activity in humans.

Example 3: polymorphs of LSD derivatives are bioavailable and cross the blood brain barrier

Pharmacokinetic (PK) studies of the "E559 polymorph" were performed following a single Intraperitoneal (IP) injection in CD-1 mice. PK analysis of the "E559 polymorph" was performed in plasma samples and in brain tissue collected at different time points after injection. Three groups of male mice and three groups of female mice (n=24 per group) were administered "E559" at time zero by IP injection at different doses (0.75, 2.25 or 6.75 mg/kg). In each dose group, three mice/sex were sacrificed 0.17, 0.5, 1, 2, 4,8 and 24 hours before and after dosing to collect plasma and brain samples. The level of "E559 polymorph" in plasma and brain tissue was assessed by LC-MS/MS method. Briefly, to extract plasma samples, 200. Mu.L of acetonitrile containing 10ng/mL LSD-d3 was added to 50. Mu.L of plasma. The mixture was vortexed vigorously, centrifuged (13,000 rpm) at 4℃for 2 minutes, and then 50. Mu.L of supernatant was combined with 200. Mu.L of methanol/water (1:1, v/v) for LC-MS/MS analysis. The brain tissue was weighed and homogenized in cold acetonitrile at a ratio of brain tissue to extraction solvent of 1:1.5 (w/v) for about 1 minute. The brain samples were then centrifuged at 13,000rpm for 2 minutes at 4℃and the supernatants were collected for LC-MS/MS analysis. In the LC-MS/MS procedure, isocratic elution was performed on an ACE Excel 5SuperC TM column at 25℃with a run time of 6.5min. The mobile phase consisted of methanol-water (8:2, v/v) plus 0.1% NH ₄ OH at a flow rate of 0.8 mL/min. The injection volume was 10. Mu.L/sample. For MS/MS analysis, electrospray ionization (gas temperature 350 ℃, gas flow 13L/min; atomizer 60psi, capillary voltage 4 kV) was used in positive ion mode.

"E559 polymorph" was quantified by selective reaction monitoring of the following mass transitions (2-Br-LSD m/z 403.3, 302, LSD-d3 internal standard m/z 327.2.226.1). Quantification of the concentration of the "E559 polymorph" in the sample was achieved by using appropriate calibration standards. The calibration curve was fitted linearly using a weighting factor (1/x ²). Pharmacokinetic parameters were validated by non-compartmental analysis usingWinNonlin version 8.2 software (CERTARA INC).

PK analysis of the "E559 polymorph" in plasma samples showed that the plasma levels of the "E559 polymorph" increased in a time-dependent and dose-dependent manner and appeared in plasma rapidly (10 minutes) after dosing in all dosing groups of male and female mice (fig. 11A and 11B; the "E559 polymorph" concentration in plasma samples is shown as ng/mL plasma).

PK analysis of the "E559 polymorph" level in brain samples showed a proportional increase in the brain tissue exposed to the compound in a time-dependent and dose-dependent manner (fig. 11C and 11D; the test "polymorph HT compound" concentration in brain samples is shown as ng/g brain tissue), reflecting the PK profile observed in the plasma of the same animal (compare fig. 11A and 11B). The brain PK data also demonstrated that the "E559 polymorph" can readily cross the blood brain barrier in male and female mice.

Example 4: polymorphs of LSD derivatives exhibit good oral bioavailability, which is not affected by fed state

Single dose comparative Pharmacokinetic (PK) studies were performed in beagle dogs to assess oral bioavailability and the effect of food on the "E559 polymorph" (fig. 12). In the crossover design, 4 male dogs were used in 3 test groups with a clearance time of at least 3 days between each test group (group 1, group 2 and group 3). In group 1, four male dogs received a single Intravenous (IV) dose of 0.0324mg/kg of "polymorph E559". In group 2, the same four dogs received a single oral dose of 0.324mg/kg of "polymorph E559" in a fasted state. In group 3, the same four dogs received a single oral dose of 0.324mg/kg of the "E559 polymorph" (same oral dose as in group 2) in the fed state. Blood samples were collected from all dogs before and 0.08, 0.25, 0.5, 1,2, 4,8 and 24 hours post-dose to measure "E559 polymorph" levels by LC-MS/MS methods performed as described in example 3.

As shown in fig. 12, the "E559 polymorph" exhibited good oral bioavailability, whereas there was no difference in mean absolute and relative oral bioavailability between fasted and fed dogs (concentration in plasma samples was shown as ng/mL plasma). Data are expressed as group mean ± standard deviation.

Example 5: polymorphs of LSD derivatives block the illusion of illusive compounds

The effect of the "E559 polymorph" was studied to block the magic (HTR) response of magic 2, 5-dimethoxy-4-iodoamphetamine (DOI) in the mouse HTR model. DOI is a 5-hydroxytryptamine-induced compound commonly used as a positive control in HTR models [ Halberttadt et al Psychopharmacology (Berl).2013 Jun;227 727-39] HTR studies were performed as described in example 2 below: five groups of mice (n=6-7 per group, 31 total) were treated with vehicle (saline) or with 0.1, 0.3, 1 or 3mg/kg of the "E559 polymorph". After 10 minutes, all mice were injected with DOI (1 mg/kg), and then HTR activity was evaluated for 30 minutes. As shown in fig. 13A, pretreatment of mice with the "E559 polymorph" significantly attenuated the ability of DOI to induce HTR in the mice. All doses of the "E559 polymorph" effectively blocked the response to DOI in a dose-dependent manner. Data are expressed as group mean ± standard deviation, asterisks indicate statistical significance (< 0.0001) compared to vehicle (saline) control (0 mg/kg in fig. 13A).

The time course of DOI-induced HTR blockade by the "E559 polymorph" was examined. HTR studies were performed as described in example 2 below: two groups of mice were treated with vehicle or with 1mg/kg of the "E559 polymorph" (n=6 per group). After 10 minutes, all mice were injected with DOI (1 mg/kg), and then HTR activity was evaluated for 30 minutes. As shown in fig. 13B, pretreatment of mice with the "E559 polymorph" almost completely blocked DOI-induced HTR during the first 10 minutes, and this blocking gradually decreased until no more blocking was detected after 40-60 minutes. Data are expressed as group mean ± standard deviation, asterisks indicate statistical significance (< 0.0001) compared to vehicle (saline) control (0 mg/kg in fig. 13B). The time course of DOI-induced HTR blockade by the "E559 polymorph" reflects the time course of pharmacokinetics of the "E559 polymorph" in mouse brain tissue (as shown in example 3).

Example 6: polymorphs of LSD derivatives are 5HT2A agonists

The neuroreceptor binding and functional role of the "E559 polymorph" was examined by analyzing binding affinity [ Ki (nM) ] for a set of key receptors in neurophysiologic disorders, functional agonist activity [ EC50 (nM) ] and functional antagonist activity [ IC50 (nM) ]. Binding and functional assays were performed at "E559 polymorph" concentrations of 0.0003, 0.003, 0.01, 0.03, 0.1, 0.3, 1 and 10 μm. In the binding assay, cell membrane homogenates expressing each receptor target are incubated with the corresponding radioligand in the absence or presence of several concentrations of the "E559 polymorph" compound. Measurement of binding affinity for the "E559 polymorph" is indicated in table XIII by Ki (nM), calculated as the percent inhibition of binding of the radiolabeled reference ligand at each receptor. In a functional assay, HEK-293 cells expressing each receptor target were suspended in buffer and distributed in microplates and incubated for 30 minutes at room temperature or 37 ℃ in the presence of buffer alone (basal control), reference agonist or antagonist or "E559 polymorph". After incubation, the cells were lysed and the appropriate fluorescent probes (ca2+ flux, cAMP or IP 1) were added for 60 minutes to measure fluorescence transfer at the appropriate wavelength using a microplate reader. The cell agonist effect (EC 50) was calculated as a percentage of the control response to the known reference agonist and the cell antagonist effect (IC 50) was calculated as a percentage of inhibition of the control reference agonist response to each receptor.

As shown in Table XIII, the "E559 polymorph" is a 5-HT2A receptor agonist, which is novel and unexpected, because the "E559 polymorph" is non-fanciful (see example 2), and the hallucinations of 5-hydroxytryptamine compounds are believed to be mediated by 5-HT2A agonism (Halberstadt et al Behav Brain Res.2015,277: 99-120).

In this screen (Table XIII), the "E559 polymorph" showed potent agonist activity at 5-HT1B and α1A receptors in addition to 5-HT 2A. The "E559 polymorph" exhibits antagonist activity against 5-HT2B receptors. The "E559 polymorph" receptor functional properties are evaluated in more detail in examples 7 and 8. These results reveal that the "E559 polymorph" is a CNS active drug with pharmacological and therapeutic potential in various neuropsychiatric/neurological disorders.

Table XIII

Example 7LSD derivative polymorphs are not 5-HT2B agonists and have safer cardiovascular properties compared to LSD

When viewed with drugs, 5-HT2B receptor agonism is a cardiac safety possibility, as it has been reported to cause heart valve disease in humans (Cavero et al, journal of Pharmacological and Toxicological Methods, 2014, p 150-16). LSD is known to be a 5-HT2B agonist (Horvath et al, mov. Disord.,2004, 19:656-662). The "E559 polymorph" was examined to determine its binding and functional effect on the 5HT2B receptor. Unexpectedly and in significant contrast to LSD, which is a 5-HT2B agonist, the "E559 polymorph" was found to bind to the 5-HT2B receptor (table XIII-Ki column), but lacks agonist activity at the 5-HT2B receptor (table XIII-functional agonist column), and in fact was found to be a 5-HT2B antagonist (table XIII-functional antagonist column).

The activity of the "E559 polymorph" on the 5-HT2B receptor was further assessed by 5-HT2B mediated Gq dissociation (FIG. 14A), 5-HT2B mediated beta-arrestin 2 recruitment (FIG. 14B) and 5-HT2B Gq-mediated calcium flux assessment (FIG. 14C) using Bioluminescence Resonance Energy Transfer (BRET) assay in HEK293T cells. These assays were performed as described in example 8. In the 5-HT2B antagonist assay, the "E559 polymorph" antagonism is measured by its ability to block 5-HT activation of 5-HT2B receptors.

As shown in fig. 14A, 14B and 14C, LSD showed potent agonism of the 5-HT2B receptor, as seen in all three functional assessments, whereas "E559 polymorph" did not show agonism seen by LSD. In all three assays, an "E559 polymorph" antagonism was observed in blocking 5-HT mediated activation of the 5-HT2B receptor (comparison of 5-HT versus 2-Br-LSD+5-HT curves in FIGS. 14A, 14B and 14C, respectively).

The human Ether-related-des-Lai (hERG) channel is a potassium channel that inhibits the involvement of cardiac arrhythmias (Abbott et al, cell,1999, V97 (2); p 175-187). The effect of the "E559 polymorph" on hERG channels was performed in a cell-based hERG antagonist assay. Briefly, CHO-K1 cells were stably transfected with human hERG cDNA and allowed to achieve a whole cell configuration in culture. The cells were kept at-80 mV and 500ms pulses were delivered to-40 mV to measure leakage current, which was subtracted from tail current on-line. The cells were then depolarized to +40mV for 500ms, then to-80 mV on a 100ms ramp to induce hERG tail current. This example is transmitted every 8 seconds to monitor the current amplitude. The measurement was performed at room temperature. The "E559 polymorph" was then applied to the cells sequentially for 5 minutes from low to high concentrations (0.0003, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 10, 30 and 100 μm). Atemizole was used as a reference compound at various concentrations to calculate the percent inhibition of hERG channel by "polymorph E559".

As shown in fig. 14D, the "E559 polymorph" produced only a weak blockage of channel activity at very high concentrations (ec50=31.6 μm), indicating that the "E559 polymorph" exhibited a low risk of causing arrhythmias in humans.

Together, the data presented in this example predicts that, unexpectedly, the "E559 polymorph" has significantly safer cardiovascular toxicity profile compared to LSD.

Example 8: LSD derivative polymorphs exhibit activity towards key CNS receptors/targets

The data shown in this example illustrates the deep pharmacological profile of the "E559 polymorph" which spans 12 human 5-hydroxytryptamine (5-HT) receptors and 21 non-5-HT aminergic GPCR members (including D1-D5 dopamine α1A/1B, α A, B, C and β1/2 adrenergic, H1-H4 histamine and M1-M5 muscarinic subtypes) parallel to LSD using BRET-based G protein dissociation assays (FIG. 15, FIG. 17A and Table XIV.) furthermore, second messenger assays were performed on selected 5-HT or dopamine receptors, including G protein-mediated cAMP inhibition (G1/o) and accumulation (Gs), gq-calcium flux (FIG. 16A/B) and β -inhibitor 2 recruitment BRET (FIG. 17B). The assays in this example were performed as described previously (Cameron et al, nature,2021,589, p 474-479). Briefly, 48 hours prior to assay, target receptors were used in a 1:1:1:1 ratio using a reverse transfection method: gα -Rluc8. Beta. GFP ² -gamma. Constructs were transfected into HEK293T or Gq-KO or Gs-KO HEK293T cells. Human isoforms of 5-HT receptors are expressed in mammalian cell systems by using the receptor constructs in pCDNA vectors. A Flp-In 293T-Rex tetracycline induction system stably expressing the 5-HT2A/2B/2C receptor was used for calcium flux assays. HEK293T cells were co-transfected with the codon-optimized library of Tango pcDNA3.1 deleted of the V2tail/TEV/tTA coding region at a 1:1 ratio in a cAMP accumulation/suppression assay, yielding a "de-Tango" construct. For the beta-arrestin 2 recruitment assay, cells were transfected with 5-HT-Rluc8:GFP2 fused human beta-arrestin 2 at a 1:15 ratio. On the day of the assay, drug dilutions of all test compounds were performed in McCorvy buffer [1× HBSS,20mM HEPES,pH7.4, supplemented with 0.3% bsa fatty acid free (GoldBio), and 0.03% ascorbic acid ], and the treated cells were incubated in humidified incubator at 37 ℃ for 60 min or at the indicated time points. 5. Mu.M coelenterazine was added to the plates prior to reading the plates in FLIPR TETRA system (Molecular Devices). Immediately thereafter, the plates were read using PheraStarFSX (BMB Lab Tech) under 400nm Rluc8 and 510nm GFP2 emission filters for 0.8 seconds per well. The BRET ratio of 510/400 luminescence was calculated per well and GRAPHPAD PRISM or 9 (Graphpad Software inc., san Diego, CA) was used. Nonlinear regression "log (agonist) versus response" was used to analyze the data to generate Emax and EC ₅₀ parameter estimates. Data were normalized to positive control (reference ligand per receptor) stimulus, concentration-response curves were present on each plate. Data are shown as a percentage of the maximum response induced by the reference ligand and as group mean ± standard deviation.

A.5-HT1 receptor family

The detailed functional activity profile of the "E559 polymorph" was compared to LSD for the following 5-HT1 receptor subtypes: 5-HT1A, 5-HT 1B, 5-HT 1D, 5-HT 1E, and 5-HT 1F.

As shown in fig. 15 and 16A/B, the "E559 polymorph" is a mild to potent agonist of all 5-HT1 receptor subtypes, with a slight decrease in Emax (maximum drug effect) relative to LSD. The "E559 polymorph" showed the greatest efficacy (agonism) for the 5-HT1F and 5-HT1D receptors (FIGS. 15 and 16A/B).

B.5-HT2 receptor family

The detailed functional activity profile of the "E559 polymorph" was compared to LSD for the following 5-HT2 receptor subtypes: 5-HT2A, 5-HT2B and 5-HT2C. Agonism at the 5-HT2A receptor is understood to be the primary pathway for the illusion of hydroxytryptamine can hallucinogens and many potential therapeutic consequences of this compound (Preller et al, current Biology,2017,27 (3), p 451-457).

As shown in FIGS. 15 and 16A/B, the "E559 polymorph" is a potent partial agonist of 5-HT2A, while LSD is a potent almost complete 5-HT2A agonist. The binding of the "E559 polymorph" to the ligand pocket of 5-HT2A is very similar to that of the parent ligand 5-HT, as demonstrated by competition (antagonist) experiments in which the "E559 polymorph" antagonizes 5-HT activation as assessed by Gq dissociation (fig. 17A) and β -arestin 2 recruitment (fig. 17B) assays. As also illustrated in examples 2 and 6, the "E559 polymorph" is unexpectedly a 5-HT2A agonist, and does not exhibit hallucination. The "E559 polymorph" is further distinguished from LSD to the extent of 5-HT2A agonism (FIGS. 15 and 16).

The detailed functional profile for the 5-HT2B receptor demonstrates the conclusion drawn in example 7 that, in contrast to LSD which is a 5-HT2B agonist, the "E559 polymorph" is inactive as an agonist at the 5-HT2B receptor (FIGS. 15 and 16A/B) and therefore does not carry the cardiac safety problems associated with 5-HT2B agonist compounds (Cavero et al, journal of Pharmacological and Toxicological Methods, 2014, p 150-161).

A detailed functional profile for the 5-HT2C receptor shows that the "E559 polymorph" is moderately different in its effect on 5-HT2C compared to LSD. As shown in FIGS. 15 and 16A/B, LSD is almost completely agonist at 5-HT2C, whereas "E559 polymorph" shows partial agonist at 5-HT 2C.

C. Other 5-HT receptors

For the following other 5-HT receptors, the detailed functional activity profile of the "E559 polymorph" was compared to LSD: 5-HT4, 5-HT5a, 5-HT6 and 5-HT7A.

For the 5-HT4 receptor, the "E559 polymorph" is similar to LSD in that both lack potent agonist activity at the 5-HT4 receptor in a G protein dissociation assay (FIG. 15).

For the 5-HT5A receptor, LSD acts as a partial agonist, whereas in sharp contrast, the "E559 polymorph" antagonizes this receptor subtype (FIG. 15).

For the 5-HT6 receptor, the "E559 polymorph" similar to LSD acts as a very potent partial agonist in both the G protein dissociation (FIG. 15) and cAMP accumulation second messenger (FIG. 16A/B) assays.

For the 5-HT7 receptor, the "E559 polymorph" and LSD are similar and both act as potent antagonists and inverse agonists, as demonstrated by G protein dissociation (fig. 15) and cAMP accumulation second messenger assay (fig. 16A/B), although the "E559 polymorph" exhibits significantly greater inverse agonism at this receptor than LSD.

D. Alpha receptor family

The detailed functional activity profile of the "E559 polymorph" was compared to the LSD of the following adrenergic receptor: α1a, α1b, α2a, α2b, α2c, β1, and β2.

For α1a, α1b, β1, and β2 adrenergic receptors, "E559 polymorphs" such as LSD are antagonists, but the "E559 polymorphs" antagonize to a greater extent than seen for LSD (table XIV).

For the α2c adrenergic receptor, the "E559 polymorph" such as LSD is a partial agonist, but LSD is a more potent partial agonist than the "E559 polymorph" (table XIV).

For the alpha 2A and alpha 2B adrenergic receptors, the "E559 polymorph" activity unexpectedly differs significantly from that of LSD. For both receptors, LSD acts as a partial agonist, while the "E559 polymorph" acts as an antagonist of both receptors (table XIV).

E. dopamine receptor family

For the following other dopamine receptors, the detailed functional activity profile of the "E559 polymorph" was compared to LSD: d1, D2, D3, D4 and D5 receptors.

For the D1 receptor, the "E559 polymorph" activity was unexpectedly significantly different from that of LSD. LSD acts as a partial agonist, while "polymorph HT compound" acts as an antagonist of this receptor (table XIV).

For D2 receptors, the "E559 polymorph" like LSD is a potent agonist, but the "E559 polymorph" agonism is slightly more potent than that seen for LSD (fig. 16A/B and table XIV).

For D3 receptors, "E559 polymorphs" such as LSD are partial agonists, but the degree of partial agonism of "polymorph HT compounds" is significantly lower than seen for LSD (table XIV).

For the D4 receptor, the "E559 polymorph" has potent agonistic activity similar to LSD (fig. 16A/B and table XIV).

For the D5 receptor, the "E559 polymorph" is an agonist with higher activity than LSD based on EC50 values (table XIV).

F. Muscarinic acetylcholine receptor family

The detailed functional activity profile of the "E559 polymorph" was compared to LSD at the following other muscarinic acetylcholine receptors: m1, M2, M3, M4 and M5 receptors. Of all the muscarinic receptors tested, LSD and "E559 polymorphs" exhibited either weak or no activity in both agonist and antagonist modes of action. (Table XIV).

G. Histamine receptor family

The detailed functional activity profile of the "E559 polymorph" was compared to LSD at the following other histamine receptors: h1, H2, H3 and H4 receptors. At H1, H3 and H4 receptors, the "E559 polymorph" like LSD shows weak or no agonism (table XIV). At the H2 receptor, the "E559 polymorph" shows slightly different from LSD, a partial agonistic activity slightly greater than that of LSD (table XIV).

Table XIV

Example 9: polymorphic activity of LSD derivatives on CNS receptors is stereochemically dependent

The functional agonist activity [ EC50 (nM), emax ] and functional antagonist activity [ IC50 (nM) ] of the 5R:8S stereoisomer of the "E559 polymorph" (5 R:8S E558) was compared with the "E559 polymorph" (5 R:8R stereoisomer) at the selected 5-hydroxytryptamine receptor. The assay was performed as described in example 6.

As shown in table XV, 5r:8s E558 showed significantly reduced 5-hydroxytryptamine receptor functional activity (based on EC50 and Emax) at the 5-hydroxytryptamine receptor tested (agonist and antagonist modes) compared to the "E559 polymorph". These new results reveal that the stereochemistry of the "E559 polymorph" plays a key role in its 5-hydroxytryptamine receptor activity, and that different stereoisomers are expected to exhibit different pharmacological properties and activities. Different pharmacological properties may be selected for each treatment.

Table XV

Example 10: polymorphs of LSD derivatives are potent promoters of neuroplasticity

The "E559 polymorph" was evaluated for its ability to induce neuroplasticity in vitro. In vitro dendritic generation and dendritic generation assays were performed using primary rat embryonic cortical neurons. Briefly, cultured primary cortical neurons (rats) were treated with increasing concentrations (1, 10 and 100nm,1 and 10 mM) of the "E559 polymorph" for 3 hours in vitro (DIV) 3 days, and morphological changes in dendrite complexity (treetop) were assessed at DIV6 by immunofluorescent staining of the immobilized neurons with microtubule-associated protein 2 (MAP 2, microtubule markers), F-actin (cytoskeletal markers) and podophyllotoxin (actin filament markers), followed by fluorescence microscopy and Sholl analysis of neuronal images. Fig. 18B shows a schematic diagram of Sholl analysis. The spine density assessment (dendritic spine occurrence) was performed on DIV 18. Cell viability was assessed for DIV6 by using Neurite Outgrowth STAINING KIT including fluorescent probes for dead and living neuronal cells. Ketamine was used as a comparator and positive control. Ketamine is known to induce dendritic formation, and its effect on synaptic plasticity is thought to mediate its antidepressant effect (Aguilar-Valles et al, nature,2021,590, p 315-319). Representative images of MAP 2-stained rat cortical neurons treated with vehicle (no drug control) or with the "E559 polymorph" are shown in fig. 18A.

Fig. 19A shows a representative Sholl trace of neurons treated with vehicle (control) or increasing concentrations of the "E559 polymorph". Figure 19B shows the total number of Sholl radius crossings of MAP2 positive neurites after treatment with vehicle (control), "E559 polymorph" or ketamine. Fig. 19C shows the total number of dendrite lengths from neurons in fig. 19A and 19B. Fig. 19D shows representative fluorescence images of dendritic spines in cortical neurons treated with vehicle (control), "E559 polymorph" or ketamine. Fig. 19E shows the total number of spines per 10 μm cross section (see fig. 18B) on the longest tip dendrite scored from the first branch point. Fig. 19F shows the ratio of live neuronal cells to dead neuronal cells in a randomly selected 40X objective field of view in a cell viability assay. The horizontal lines in all figures represent the mean ± standard error of the mean (s.e.m).

Of all parameters of neuronal plasticity assessed, the "E559 polymorph" significantly induced neuronal plasticity in a dose-dependent manner in vitro, and an increase in neuronal plasticity was detectable at compound concentrations as low as 1nM, and reached statistical significance at concentrations as low as 1 μm (fig. 19B, 19C and 19E). In most parameters of neuronal plasticity, the compound showed significantly better than the positive control drug ketamine (tested at very high 10mM concentration). Briefly, the "E559 polymorph" significantly increased the number of total dendrites across Sholl radii, reaching maximum effect at the top two concentrations (1 and 10 mM) (fig. 19B; control and 1 μΜ 2-B-LSD ^* p=0.0113, control and 10 μΜ 2-Br-LSD ^* p=0.0193, and control and ketamine ^** p=0.0096). The total length of dendrites was also increased in neurons treated with the "E559 polymorph" compared to the 1 and 10 μm controls (fig. 19C; control and 1 μm 2-Br-LSD ^** p=0.0019, control and 10 μm 2-Br-LSD ^** p=0.003, and control and ketamine ^** p=0.0096). The "E559 polymorph" also increased spine density after incubation for 3 hours at 1 and 10 μm concentrations (fig. 19D and 19E, control with 1 μm 2-Br-LSD ^* p= 0.0322, control with 10 μm 2-Br-LSD ^*** p <0.0001, and control with ketamine ^*** p < 0.0001). The effect of the "E559 polymorph" on the viability of cultured primary rat neurons was tested, and no cytotoxic activity was observed at all concentrations tested (fig. 19F).

Example 11: polymorph-induced neuroplasticity of LSD derivatives is related to the 5-HT2A receptor (in vitro)

The 5-HT2A receptor plays a key role in the function of 5-hydroxytryptamine energy psychiatry and its derivatives (Jaster et al, psychopharmacology,2022,239, p 1665-1677.). We have demonstrated that the "E559 polymorph" induces neuroplasticity in both the dendritic and dendritic spinogenesis assays (see example 10). In vitro tree bursting assays were repeated in the presence or absence of the selective 5-HT2A antagonist, flugliptin. Briefly, FIG. 20A shows the tracing of cortical neurons (DIV 3) treated with 0.1, 0.5, or 1mM of Florixarene (Vol), followed by cortical neurons (DIV 3) treated with vehicle or "E559 polymorph" (1. Mu.M). Sholl radius intervals of 10 μm. Fig. 20B shows the total number of Sholl crossings of neurons processed in fig. 20A. Fig. 20C shows the total dendrite length of neurons processed in fig. 20A. In fig. 20B and 20C, the violin graph represents the distribution of individual cells (n=15/treatment), and the dot represents the average value of each independent experiment (n=5/treatment). In this study, primary cortical neurons (rats) were treated with the selected 5-HT2A receptor antagonist flugliptin (0.1-1. Mu.M) prior to administration of the "polymorph HT compound" (1. Mu.M 2-Br-LSD).

As shown in fig. 20, flugliptin alone (labeled as vehicle) did not alter any parameters related to dendrite complexity (marker of neuroplasticity). However, pretreatment with each concentration tested for flugliptin blocked the effect of the "E559 polymorph" (1 μM) on dendrite complexity to the level seen in control neurons as observed by Sholl crossover analysis (FIG. 20B; control-no volume, no 2-Br-LSD-, relative to volume and 2-Br-LSD ^*** p < 0.0001). Florixaline also blocked the increase in total dendritic length induced by the "E559 polymorph" (FIG. 20C; control-no volume, no "E559 polymorph" -, and volume and "E559 polymorph" ^*** p < 0.0001).

The data in this example demonstrate that 5-HT2A receptors play a role in the "E559 polymorph" neuroplasticity promoting activity.

Example 12: repeated administration of LSD derivative polymorphs does not induce tolerance

Tolerance (also known as fast tolerance) or cross tolerance, which is commonly observed with psychotropic drugs or 5-HT receptor agonists, can limit the efficacy of repeated drug administration or combination therapies with other CNS active drugs (Douglas et al Journal of Pharmacology and Experimental Therapeutics,2014,351 (3) p 485-491). As with most other psychotropic drugs, repeated administration of LSD results in decreased responsiveness or tolerance. Studies have shown that cutting LSD for 3 days is sufficient to fully restore patient tolerance from somatic and mental (Buchborn et al, neuropathology of Drug Addictions and Substance Misuse, chapter 79,Academic Press,2016,p846-858). Beta-arrestin recruitment via 5-HT receptors is responsible for receptor internalization and downregulation, both mechanisms involving induction of tolerance (Reiter et al Annu Rev Pharmacol Toxicol.2012;52: p 179-97). Thus, evaluation of β -arrestin recruitment via 5-HT receptors is a good alternative to predictive tolerance induction.

As shown in fig. 21A, the "E559 polymorph" is a weak recruitment of β -arrestin 2 at the 5-HT2A receptor using a BRET-based β -arrestin 2 recruitment assay (described in example 8). The comparisons tested were LSD, DOI and parent ligand 5-HT. In contrast to the "E559 polymorph", LSD, DOI and 5-HT are strong recruits of beta-arrestin 2. The data are shown as a percentage of the maximum response induced by 5-HT and as group mean.+ -. Standard deviation.

To assess the ability of the "E559 polymorph" to induce β -arrestin-mediated 5-HT2A receptor internalization in vitro, loss of surface expression of 5-HT2A receptor was measured using a NanoBit N-terminal inhibition fusion 5-HT2A construct cloned in HEK293T cells (1:15 ratio of 5-HT2A: β -arrestin 2). Briefly, cells were treated with serial dilutions of test compounds for 1 hour or at designated time points. About 15 minutes prior to reading, lgBit and coelenterazine (5 μm) were added to the cell plates and read at 485nm at 37 ℃ on a PHERASTAR FSX or Mithras Lb940 plate reader for time capture quantification of receptor internalization or loss of surface expression. Luminescence was plotted as a function of drug concentration using GRAPHPAD PRISM or 9 (Graphpad Software inc., san Diego, CA). As shown in figure 21B, treatment with the "E559 polymorph" for 1 hour showed only weak internalization of the 5-HT2A receptor, in contrast to the effective internalization seen with LSD, DOI and 5-HT. The data are shown as a percentage of the maximum response induced by 5-HT and as group mean.+ -. Standard deviation.

To determine whether repeated administration of the "E559 polymorph" can induce tolerance in vivo, the HTR experiments described in example 2 and example 5 were repeated, wherein mice received vehicle, DOI (10 mg/kg/day) or "E559 polymorph" (3 mg/kg/day; once daily, for 7 consecutive days) and then tested with DOI (1 mg/kg) after 24 hours. The data shown in figure 22 are group mean ± standard deviation of the entire 60 minute test period. Asterisks indicate statistical significance compared to vehicle control (vehicle is saline). As shown in figure 22, although repeated treatment with DOI induced a significant degree of rapid tolerance/tolerance as shown by the reduced HTR count (figure 22, vehicle vs DOI ^* p < 0.001), no tolerance was observed in mice repeated treatment with the "E559 polymorph". Repeated administration of the "E559 polymorph" does not induce tolerance to the known occurrence of LSD, which is an unexpected result. This should allow for administration of "polymorph HT compounds" at short intervals, including once a day or even multiple times a day, at a frequency that would not be possible with other tolerance-inducing 5-HT receptor agonists such as LSD.

EXAMPLE 13 LSD derivative polymorphs exhibit antidepressant/anxiolytic Activity in a model of chronic stress-agonist

The antidepressant/anxiolytic activity of "polymorph HT compounds" (from example 1) was tested in a Chronic Variable Stress (CVS) mouse model, such as by the self-combing splash test and Open Field Test (OFT) assessment, [ Strekalova et al, psychopharmacology (Berl), 2022,239 (3): 663-693; willner, P.neurobiol Stress,2017,6:78-93]. Briefly, C57BL/6J mice were subjected to a CVS regimen consisting of 2 stressors per day for 35 days. Untreated mice (not exposed to CVS) were used as controls for CVS-induced depressive activity. After 35 days of CVS, mice were treated with "E559 polymorph" (fig. 23) via intraperitoneal Injection (IP) as follows: 4 doses (1 mg/kg) were administered at a single dose after the last day of CVS (3 mg/kg) or every 48 hours starting on day 28 of CVS. Saline was used as vehicle control. Splash testing and OFT were performed as previously described in (Aguilar-Valles et al, nature,2021, 590, p 315-319). Briefly, fig. 23A shows a study design as described above. Figure 23B shows the distance traveled by female mice treated with the E559 polymorph in the open field. Fig. 23C shows the time taken in the center of the open field of the mouse in fig. 23B. Fig. 23D shows the time spent self-grooming in the splash test of treated female mice as described in fig. 23A. The horizontal line represents the mean ± standard error of the mean (s.e.m.) and the asterisk represents statistical significance.

As shown in fig. 23C, CVS induced a decrease of 55.95 ±19.3 seconds in the time it took for the mice to explore the open field center (untreated-saline versus CVS saline ^* p=0.0069) without changing the total distance travelled (fig. 23B). In the CVS group treated with 1mg/kg of the "E559 polymorph" repeat dose, this CVS-induced time reduction in exploring the open field center was completely reversed to the level observed in the control (untreated-saline) group (FIG. 23C; CVS-saline versus CVS-E559 polymorph 4X 1mg/kg ^** p=0.0044) without affecting movement (FIG. 23B). The effect of CVS was partially restored with a single dose of 3mg/kg of the "E559 polymorph" because this group spent a period of time in the center of the open field intermediate between CVS-saline and untreated-saline groups (FIG. 25C). As shown in fig. 23D, CVS mice spent significantly less time to comb in the splatter test (untreated-saline versus CVS-saline ^* p=0.0282), which is a measure of self-care behavior and depression-like behavior. The "E559 polymorph" partially reversed this effect of CVS induction by increasing the combing time in "E559 polymorph" treated CVS mice to an intermediate level between untreated-brine and CVS-brine (fig. 23D).

The same group of CVS mice was tested 28 days after the last "E559 polymorph" treatment. The effect of CVS in the time to decrease OFT centers remained reversed 28 days after the last treatment of the "E559 polymorph" (at a level similar to the acute effects of the "E559 polymorph"), supporting the long-term antidepressant and anxiolytic effects of the "E559 polymorph" (FIG. 24A; CVS-saline vs. CVS-E559 polymorph 4X 1mg/kg ^** p=0.0052). Figure 24B shows the self-grooming time spent in the splash test of female mice 28 days after the last "E559 polymorph" treatment shown in figure 23A.

Example 14: LSD derivative polymorphs exhibiting antidepressant/anxiolytic activity in acute stress-agonist models

The "E559 polymorph" exhibited antidepressant and anxiolytic activity in a non-stressed mouse model, which was assessed by two behavioral tests for screening antidepressant and anxiolytic treatments: forced Swim Tests (FST) and Open Field Tests (OFT) (Strekalova et al, psychopharmacology (Berl). 2022,39 (3): 663-693). Briefly, untreated mice were stressed with saline (control) or a single dose of "E559 polymorph" at a dose level of 0.3, 1 or 3mg/kg (IP injection) and evaluated 24 hours (OFT) and 25 hours (FST) after treatment. OFT is described in example 13. FST was performed as previously described in (Aguilar-Valles et al, nature,2021, 590, p 315-319). Briefly, FST was performed 24 hours after treatment by placing mice (one after the other) in a 4 liter wide mouth flask with 35℃water. Mice were recorded for 6 minutes of activity and animals were assessed for total time to stay motionless, i.e. signs of depression-like behaviour. Fig. 25A depicts a study design in which female/male mice (n=10/group/sex) were treated by IP injection with "E559 polymorph" or vehicle (saline) followed by open field and forced swim tests 24 hours after treatment. Figures 25B and 25E show the total distance traveled in the open field test for female and male mice after 24 hours of vehicle or "E559 polymorph" treatment, respectively. Fig. 25C and 25F show the time of female and male mice, respectively, in the center of the open field. Figures 25D and 25G show the time of immobility during the last 4 minutes of the forced swim test in female and male mice, respectively. The horizontal line represents the mean ± standard error of the mean (s.e.m.) and the asterisk represents statistical significance.

In OFT, female mice showed increased exploration of open field center after treatment with 1mg/kg and 3mg/kg of the "E559 polymorph" (FIG. 25C; vehicle (0 mg/kg) versus 1mg/kg of 2-Br-LSD ^*** p=0.0001, vehicle versus 3mg/kg of 2-Br-LSD ^* p=0.0459), with maximal effect at 1mg/kg dose (88.18.+ -. 18.89 seconds increase). In male mice, the search for an increase in the stress source region of the open field by the "E559 polymorph" was not apparent (fig. 25F).

The observed immobility in females was reduced by 35.18.+ -. 10.03 seconds at the dose of 1mg/kg "E559 polymorph" in FST (FIG. 25D; vehicle vs. 1mg/kg E559 polymorph ^** p=0.0069). At all concentrations measured, similar effects were observed in males (fig. 25G; vehicle pair 0.3mg/kg E559 polymorph ^* p=0.0464, vehicle pair 1mg/kg E559 polymorph ^** p=0.0056, vehicle pair 3mg/kg E559 polymorph ^** p=0.0014). The immobility reduction in males at doses of 0.3, 1 and 3mg/kg (20.89.+ -. 8.249; 27.27.+ -. 8.226; 31.36.+ -. 8.226s, respectively) was comparable to that induced in females at doses of 1mg/kg of the "E559 polymorph".

After testing in FST, brains were collected for dendritic spine density analysis in the prefrontal cortex area (about 26 hours after treatment; FIG. 25H). In both sexes, a significant increase in average dendritic spine density was observed following treatment with the "E559 polymorph" compared to the control (fig. 25I female mice: vehicle versus 1mg/kg E559 polymorph ^* p= 0.0447 and fig. 25I male mice: vehicle versus 1mg/kg E559 polymorph ^** p=0.0028).

The data in this example show that the "E559 polymorph" can reduce depression and anxiety-like behavior in mice in an acute stress environment, and that this effect is associated with promoting neuroplasticity in the prefrontal cortex region of the brain.

Example 15: polymorphs of LSD derivatives having antidepressant/anxiolytic effect on 5-HT2A receptor (in vivo)

The 5-HT2A receptor plays a key role in the function of many 5-hydroxytryptamine-able psychiatry and its derivatives (Jaster et al, psychopharmacology,2022,239, p 1665-1677.). We have demonstrated the antidepressant and anxiolytic properties of the "E559 polymorph" in a mouse depressive/anxiety model body (see example 13 and example 14). To further investigate the role of the 5-HT2A receptor in the "E559 polymorph" effect in these in vivo models, the open field and forced swim tests in mice were repeated as described in example 14, with and without treatment with flugliptin (a selective 5-HT2A antagonist). Briefly, flugliptin (0.125 mg/kg) was administered (IP injected) 1 hour before the administration of the "E559 polymorph" (1 mg/kg, IP) to stress untreated mice, and a forced swim test was performed after 24 hours as described in example 14. Briefly, fig. 26A shows the time of immobility in a forced swim test of female mice (n=12/group) pretreated with vehicle or flugliptin, followed by vehicle (saline) or "E559 polymorph" (1 mg/kg). Fig. 26B shows male mice treated as in fig. 26A, and the immobility in FST (n=12/group) was measured. Fig. 26C shows the distance traveled in the open field measured 24 hours (as in fig. 26A) after treatment in female mice (n=12). Fig. 26D shows the distance traveled in the open field measured 24 hours (as in fig. 26C) after treatment in male mice (n=12). The horizontal line in fig. 26 represents the mean ± standard error of the mean (s.e.m.) and the asterisk represents statistical significance.

As shown in fig. 26, the flugliptin pretreatment blocked the decrease in immobility induced by the "E559 polymorph" in FST of female mice (fig. 26A; vehicle and E559 polymorph pair Vol and E559 polymorph ^*** p=0.0006) and male mice (fig. 26B; vehicle and E559 polymorph ^* p=0.0187) relative to Vol and E559 polymorph ^* p. Neither flugliptin nor the combination of flugliptin and the "E559 polymorph" affected the movement of female or male mice in OFT (fig. 26C and 26D). These data indicate that 5-HT2A receptors play a role in the antidepressant and anxiolytic effects of the "E559 polymorph" in vivo.

Example 16: LSD derivative polymorphs reduce neuropathic pain in a model of reserved nerve injury

To evaluate the function of the "E559 polymorph" in neuropathic pain, mechanical allodynia tests were evaluated in a rat retained nerve injury (SNI) model by von frey filaments before and after treatment with the "E559 polymorph". SNI model and von Frey fiber yarn tests were performed as described previously (Decosterd & Woolf. Paint, 2000, v87, p 149-158). Briefly, animals with pain threshold <15g assessed using the von frey mechanical allodynia test were randomly placed in the experimental group. Each rat group consisted of 10 male rats. Treatment was started on day 7 post-surgery. Treatment was performed with the "E559 polymorph", vehicle alone (saline) as negative control or gabapentin as positive control.

Fig. 27 shows the pain response assessment results after a single dose treatment of the "E559 polymorph" on day 7 post-surgery. Pain response was assessed 2,4, 6 and 24 hours after preoperative day 0 (labeled baseline in fig. 27), postoperative day 6 (labeled day 6 pre-group in fig. 27) and 2,4, 6 and 24 hours after single oral doses of vehicle or 0.3, 1,3 or 10mg/kg of "E559 polymorph" (labeled BETR-001 in fig. 27) or 150mg/kg of gabapentin. Data are expressed as group mean ± standard deviation and asterisks indicate statistical significance. Single dose treatment of the "E559 polymorph" showed significant dose dependent inhibition of neuropathic pain at 2 and 4 hours post-administration compared to baseline and vehicle (figure 27; vehicle and 3mg/kg BETR-001 ^* p <0.05, vehicle and 10mg/kg BETR-001 4 hours ^** p <0.01, vehicle and 10mg/kg BETR-001 2 hours ^*** p <0.001, vehicle and gabapentin ^**** p < 0.0001).

Fig. 28 shows the results of pain response assessment after "E559 polymorph" multi-dose treatment starting on day 7 post-surgery. The rat group was treated (by oral administration) with vehicle or 20mg/kg of the "E559 polymorph" (labeled BETR-001 in FIG. 28) or 150mg/kg of gabapentin. Treatment was performed on days 7, 9, 11, 13 and 15 post-surgery. Pain response was assessed 2 hours after treatment administration on day 0 pre-surgery (labeled baseline in fig. 28), day 6 post-surgery (labeled day 6 pre-grouping in fig. 28) and days 7, 11 and 15 post-surgery (von frey test). Repeated dosing of the "E559 polymorph" enhanced the inhibition of mechanical allodynia to levels comparable to the gabapentin Ding Yangxing control (fig. 28, vehicle to BETR-001 days 7, 11 and 15 and vehicle to gabapentin Ding Di, 11 and 15 days ^**** p < 0.0001). Data are expressed as group mean ± standard deviation and asterisks indicate statistical significance.

These findings indicate that the "E559 polymorph" shows potent analgesic activity in both single and repeated administrations in the neuropathic pain model.

The foregoing disclosure generally describes the present invention. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Patent applications, patents and publications are cited herein to aid in the understanding of the embodiments. All such references cited herein are incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material.

Although specific embodiments of the invention have been described in detail herein, it will be appreciated by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

It should be understood that some of the above-described structures, functions, and operations of the above-described embodiments are not necessary to practice the present invention and are included in the description merely for completeness of an exemplary embodiment or embodiments. Furthermore, it should be understood that the specific structures, functions, and operations set forth in the above-described referenced patents and publications can be practiced in conjunction with the present invention, but they are not essential to its practice. It is therefore to be understood that the invention may be practiced otherwise than as specifically described without actually departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A compound having the structure of formula I:

2. The compound of claim 1, wherein the compound is crystalline.

7. A compound according to any one of claims 1 to 6, wherein:

(i) The compound is one or more polymorphs thereof;

v) the compound has two stereocenters of 5r,8 r;

vi) the compound has two stereocenters of 5r,8 s; and

Vii) any one or more of (i) to (vi).

13. The compound of claim 12, wherein the acid of the acid salt is selected from hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, ethanedisulfonic acid, phosphorous acid, acetic acid, propionic acid, isobutyric acid, butyric acid, maleic acid, mandelic acid (D or L), ethane-1, 2-disulfonic acid (dihydrate), toluenesulfonic acid (e.g., monohydrate), p-toluenesulfonic acid (e.g., monohydrate), 10-camphorsulfonic acid (e.g., (-) -10-camphorsulfonic acid), malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid (L-tartaric acid or D-tartaric acid), meso-tartaric acid (or erythrodicarboxylic acid), methanesulfonic acid, glutamic acid (L-glutamic acid or D-glutamic acid), ascorbic acid (L-ascorbic acid or D-ascorbic acid), erythorbic acid, or a combination thereof.

25. The compound of claim 24, wherein X is selected from bromine or chlorine.

26. The compound of claim 23, wherein X is bromine.

28. The compound of claim 27, wherein the compound is crystalline.

47. The compound of claim 46, wherein each of R ¹ and R ² is ethyl.

49. The compound of claim 48, wherein the compound is crystalline.

56. The compound of claim 55, wherein formula I' is formula Ib or formula Id.

67. The compound of claim 66, wherein each of R ¹ and R ² is ethyl.

69. The compound of claim 68, wherein the compound is crystalline.

Or a combination thereof.

83. The compound of claim 82, wherein the compound is crystalline.

Or a combination thereof.

96. The compound of claim 95, wherein the compound is crystalline.

124. A composition comprising a compound of any one of claims 1 to 123.

a) Hydrolyzing a compound of formula IA to form an intermediate of formula IB:

135. A method according to claim 134, wherein said method of preparation does not use LSD as a substrate and/or other primary species.

136. The method of claim 134 or 135, wherein the hydrolysis is acid hydrolysis or base hydrolysis, optionally the acid is selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrofluoric acid and/or nitric acid, or the base is selected from potassium hydroxide, sodium hydroxide, potassium t-butoxide, barium hydroxide, lithium hydroxide and/or tetrabutylammonium hydroxide.

141. The method according to claim 140, wherein the coupling agent is selected from Carbonyl Diimidazole (CDI), 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine (CDMT), 1-hydroxybenzotriazole (HOBt), hexafluorophosphate Azabenzotriazole Tetramethylurea (HATU), propylphosphonic anhydride (T3P), phosphoryl chloride (POCl ₃), ethyl 2-cyano-2- (hydroxyamino) acetate (OxymaPure), benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP), uranium 1- [ (1- (cyano-2-ethoxy-2-oxoethyl indenyl aminooxy) dimethylaminomorpholino) ] hexafluorophosphate (COMU) 2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HBTU), O- (1H-6-chlorobenzotriazol-1-yl) -1, 3-tetramethyluronium Hexafluorophosphate (HCTU), (3-hydroxy-3H-1, 2, 3-triazolo [4,5-b ] pyridinyl-O) tri-1-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP), (1H-benzotriazol-1-yloxy) (tri-1-pyrrolidinyl) phosphonium hexafluorophosphate (PyBOP), and, 6-chloro-benzotriazol-1-yloxy-tripyrrolidinylphosphonium hexafluorophosphate (PyClock), (E) - (ethylcyano ({ [ tris (pyrrolidin-1-yl) phosphine ] oxy } imino) formate) (PyOxim) and (5E) -6-cyano-N, 2-trimethyl-7-oxo-4, 8-dioxa-2, 5-diazadec-5-en-3-iminium tetrafluoroborate (TOTU), or a combination thereof.

164. The method of any one of claims 134-163, wherein the method comprises:

b) Reacting an intermediate of formula IBB with R ¹-NH-R² to form formula ICC

165. The method of any one of claims 134-163, wherein the method comprises:

166. The method of any one of claims 134-163, wherein the method comprises:

b) Reacting the intermediate of formula IBB "with R ¹-NH-R² to form ICC'

167. The method of any one of claims 134-163, wherein the method comprises:

b) Reacting the intermediate of formula IBB '"with R ¹-NH-R² to form ICC'".

181. The method of claim 178, wherein the depression is atypical depression.

182. The method of claim 178, wherein the depression is tension depression.

188. A method of treating bipolar disorders and related disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

189. The method of claim 199, wherein the bipolar disorder and related disorder is bipolar I disorder, bipolar II disorder, substance/drug induced bipolar disorder and related disorder, and bipolar disorder not otherwise indicated.

190. The method of claim 200, wherein the amount of the compound for administration to the individual is selected from about 25 to about 1000 μg/kg/body weight/day.

191. A method of treating schizophrenia lineages and other psychotic disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

192. The method of claim 202, wherein the schizophrenic lineage and other psychotic disorder is: delusional disorders, transient psychotic disorders, schizophrenia, schizophreniform disorders, schizoaffective disorders, substance/drug-induced psychotic disorders, schizophreniform (personality) disorders, psychotic disorders due to another medical condition, stress disorders associated with another psychotic disorder, and other indicated or unspecified schizophreniform and other psychotic disorders.

193. The method of claim 203, wherein the amount of the compound for administration to the individual is about 50 to about 2000 μg/kg/body weight/day.

194. A method of treating personality disorder by DSM-5 classification, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

195. The method of claim 205, wherein the personality disorder is: paranoid personality disorder; split-like personality disorder; split personality disorder; anti-social personality disorder; edge personality disorder; performance personality disorder; self-loving personality disorder; avoidance personality disorder; a dependent personality disorder; forced personality disorder; personality changes due to another medical condition; other indicated personality disorders and unspecified personality disorders.

196. A method of treating anxiety disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

197. The method of claim 207, wherein the anxiety disorder: generalized anxiety disorder, separation anxiety disorder, panic disorder, selective mutism, specific phobia (animal, natural environment, blood/injection/injury fear, context, others), social anxiety disorder, panic attack-specific disorder, agoraphobia, substance/drug-induced anxiety disorder, anxiety disorder due to other medical conditions, and other indicated or unspecified anxiety disorders.

198. The method of claim 208, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

199. A method of treating a wound and stress-related disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

200. The method of claim 210, wherein the trauma and stress-related disorder comprises an attachment disorder, a disinhibited social engagement disorder, a post-trauma stress disorder (PTSD), an acute stress disorder, an adaptation disorder, other indicated or unspecified trauma and stress-related disorders.

201. The method of claim 211, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

202. A method of treating obsessive-compulsive disorders and related disorder conditions, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

203. The method of claim 213, wherein the obsessive-compulsive disorder and related disorders comprises: obsessive Compulsive Disorder (OCD), somatic dysmorphism, stocking disorder, dehairing disorder (dehairing disorder), exfoliative (skin scratching) disorder, substance/drug induced obsessive compulsive disorder and related disorders, obsessive compulsive disorder and related disorders due to another medical condition, and other indicated and unspecified obsessive compulsive disorders and related disorders (e.g., body-centered repetitive behavioral disorders, compulsive jealogy).

204. The method of claim 214, wherein the amount of the compound for administration to the individual is about 10 to about 1000 μg/kg/body weight/day.

205. A method of treating destructive, impulse control and behavioral disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

206. The method of claim 216, wherein the destructive, impulse control, and behavioral disorders comprise: oppositional defiant disorder, intermittent explosive disorder, behavioral disorder, antisocial personality disorder, pyromania, pilgrim, dehairing, and other destructive, impulse control and behavioral disorders both indicated and unspecified.

207. A method of treating ingestion and eating disorders, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

208. The method of claim 218, wherein the ingestion and eating disorder comprises: pica, ruminant disorders, avoidance/restriction type food intake disorders, anorexia nervosa, binge eating disorders, bulimia nervosa, overeating or overeating disorders, diabetic hyperphagia, prader-willi syndrome and hypothalamic obesity, somatic dysmorphia, and other indicated and unspecified intake or eating disorders.

209. A method of treating a separation disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

210. The method of claim 220, wherein the separation disorder comprises separation identity disorder, separation forgetfulness, personality/reality dissociation disorder, and other designated and unspecified separation disorders.

211. A method of treating a neurodevelopmental disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

212. The method of claim 222, wherein the neurodevelopmental disorder comprises: mental disability (mental development disorder), general developmental retardation, communication (language, speech/sound, childhood fluency or stuttering, social, unspecified) disorders, autism spectrum disorders, attention Deficit Disorder (ADD), attention Deficit Hyperactivity Disorder (ADHD), specific learning disorders, movement disorders (developmental coordination, notch-plate movement, tourette's disorder, persistent/chronic movement or vocal tic disorders, transient tic disorders), and other neurological development disorders indicated or unspecified.

213. A method for treating a disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130, wherein the disorder comprises: epileptic seizures (including generalized seizures, focal seizures, seizures of unknown origin and focal to bilateral seizures) and seizures (including generalized seizures, focal seizures, generalized and focal seizures, dravet syndrome and seizures of unknown origin).

214. A method of treating a sleep-wake disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

215. The method of claim 225, wherein the sleep-wake disorder comprises: insomnia, excessive somnolence disorder, narcolepsy, respiratory-related sleep disorders (e.g., obstructive sleep apnea hypopnea, central sleep apnea, primary central sleep apnea, sleep-related hypoventilation), circadian rhythm-related sleep-wake disorders, non-rapid eye movement (NREM) sleep arousal disorders, nightmares, rapid Eye Movement (REM) sleep behavioral disorders, restless leg syndrome, substance/drug-induced sleep disorders, and other indicated and unspecified sleep-wake disorders.

216. A method of treating substance-related disorders (SRD) and addictive disorders, wherein the method comprises administering to an individual in need thereof a compound of any of claims 1-123, a composition of any of claims 124-127, or a formulation of any of claims 128-130.

217. The method of claim 227, wherein the substance-related disorders (SRD) and addictive disorders include, but are not limited to, the following drug categories: alcohol, nicotine, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants (amphetamine-type substances, cocaine, and other stimulants), and drugs, as well as other indicated or unspecified substance-induced disorders.

218. A method of treating a non-substance related disorder, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

219. The method of claim 227, wherein the non-substance related disorder is a gambling disorder.

220. A method of treating headache disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

221. The method of claim 229, wherein the headache disorder is classified by the international headache classification committee and comprising: primary headaches including migraine headaches (including non-premonitory migraine, premonitory migraine and chronic migraine), tension headaches (including sporadic headaches, frequent headaches and chronic tension headaches), trigeminal autonomic headaches (including cluster headaches, paroxysmal migraine, transient unilateral neuralgia-like headache attacks and persistent migraine), and other primary headaches.

222. The method of claim 229, wherein the headache disorder is trigeminal autonomic headache (TAC), including cluster headache (familial cluster headache, histamine headache, or vascular-derived facial pain), episodic cluster headache, recurrent or chronic cluster headache, transient unilateral neuralgia-like headache episodes (SUNHA), transient unilateral neuralgia-like headache episodes (SUNCT) and transient unilateral neuralgia-like headache episodes (SUNCT) with conjunctival congestion and lacrimation, and transient unilateral neuralgia-like headache with craniocerebral autonomic symptoms.

223. The method of claim 229, wherein the headache disorder is a secondary headache comprising headache due to head and/or neck trauma or injury, headache due to craniocerebral and/or cervical vascular disorders, headache due to non-vascular intracranial conditions, headache due to substance or withdrawal thereof, headache due to infection, headache due to imbalance disorders, headache or facial pain due to cranium, neck, eye, ear, nose, sinus, tooth, mouth or other facial or neck structural disorders, headache due to mental disorders, and headache category and other facial pain due to painful lesions of cranial nerves including pain due to injury or disease of trigeminal nerves.

224. A method of treating pain, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

225. The method of claim 233, wherein the pain is caused by conditions including inflammation (e.g., rheumatoid arthritis, lupus, behcet's disease), genetic factors (e.g., erythromelalgia), conditions such as diabetes including nerve damage resulting in pain, cancer and cancer treatments such as chemotherapy, neurological conditions such as Multiple Sclerosis (MS), neurodegenerative conditions such as parkinson's disease, stroke, shingles, HIV, leprosy, gill-barre syndrome, vascular disease, vascular malformations and autoimmune conditions, all neuropathies including peripheral neuropathy, autonomic neuropathy, focal neuropathy, proximal neuropathy, diabetic neuropathy and stress mononeuropathy, phantom limb pain, residual limb pain and Complex Regional Pain Syndrome (CRPS), trigeminal neuralgia, postherpetic neuralgia, radiculopathy, and all radiculopathy including chest or lumbar radiculopathy, nociceptive pain (e.g., pain resulting from injury), somatic or nociceptive pain (e.g., chronic pain, chronic fibromyalgia, chronic pain, chronic back pain, chronic pain of the jaw, chronic pain of the back, chronic pain of the lower jaw, chronic etiology, chronic pain of the underlying origin, chronic pain of the disease, chronic etiology syndrome, chronic pain of the disease, chronic etiology, chronic pain of the disease, and chronic pain of the disease, or the various causes.

226. The method of claim 233, wherein the pain is chronic pain comprising: chronic primary pain (which includes fibromyalgia, chronic pelvic pain, nonspecific back pain, and chronic primary pain not otherwise indicated); chronic cancer pain (which includes pain due to cancer and metastasis, pain due to chemotherapy, pain due to radiation therapy, pain due to cancer surgery, and other chronic pain associated with cancer); chronic postoperative and post-traumatic pain (which includes all postoperative and post-traumatic pain, as well as postoperative/post-traumatic pain not otherwise indicated); chronic neuropathic pain (which includes peripheral neuropathic pain, central neuropathic pain, and other neuropathic pain and neuropathic pain not otherwise indicated); chronic headache and orofacial pain (which includes chronic primary headache, chronic secondary headache, chronic orofacial pain, headache and orofacial pain not otherwise indicated); chronic visceral pain (which includes chronic visceral pain from persistent inflammation, and/or vascular mechanisms, and/or obstruction/expansion, and/or traction/compression, and/or combined mechanisms, or chronic visceral pain from other locations, from cancer, or chronic pain of unknown functional or causative origin); and chronic musculoskeletal pain (which includes chronic musculoskeletal pain from persistent inflammation and/or structural bone joint changes, and/or chronic musculoskeletal pain from neurological diseases (e.g., spasmodic pain), as well as chronic non-specific musculoskeletal pain and related pain syndromes).

227. The method of claim 233, wherein the pain is acute pain, including pain of a short duration, from hours or days or up to 3 months, regardless of the type of pain, and including inflammatory, nociceptive, neuropathic, plastic, and other types of pain, and including acute pain from tissue injuries including those caused by any type of surgery, dental work, labor, cutting, burns, fractures, and other accidents or wounds, acute pain caused by any disease state, acute pain caused by any type of wound, and acute pain caused by uncertain reasons.

228. A method of treating spasticity, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

229. The method of claim 237, wherein the spasticity is with or without neuropathic pain and comprises: cerebral palsy, stroke, multiple Sclerosis (MS), traumatic Brain Injury (TBI), amyotrophic Lateral Sclerosis (ALS), hereditary spastic paraplegia, adrenoleukodystrophy (ALD), phenylketonuria, keara, and spinal cord injury.

230. A method for treating disorders and diseases associated with nerve injury or trauma, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

231. The method of claim 239, wherein the disorders and diseases are associated with nerve injury or trauma from: peripheral nerve injury or trauma regardless of cause, and/or central nervous system (brain and spinal cord) nerve injury or trauma regardless of cause; disorders and diseases caused by external physical factors such as accidents, sports injuries, falls, gunshots or explosive impacts; or internal factors such as stroke, ruptured cerebral aneurysms, hypoxia, infection (viral, bacterial, prion or other), autoimmune disease; other nerve injuries or traumas caused directly or indirectly by external factors, and/or nerve injuries or traumas caused directly or indirectly by disease states.

232. A method of treating fatigue, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

233. The method of claim 241, wherein the fatigue is chronic fatigue (e.g., physical fatigue, mental fatigue, or mental fatigue) from Traumatic Brain Injury (TBI), chronic Fatigue Syndrome (CFS), and related disorders, as well as other diseases and/or disorders that cause chronic fatigue.

234. A method of treating a neurodegenerative disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

235. The method of claim 243, wherein the neurodegenerative disorder comprises: alzheimer's disease, amyotrophic Lateral Sclerosis (ALS), bay's disease, friedel Lai Xixing ataxia, huntington's disease, lewy body disease, motor neuron disease, multiple sclerosis, parkinson's disease, prion disease, spinal muscular atrophy, neurodegenerative conditions caused by viral (e.g., HIV) or bacterial infection, neurodegenerative conditions caused by substances/drugs, and other neurodegenerative conditions associated with aging and non-aging.

236. A method of treating a disease and/or disorder selected from the group consisting of delayed ejaculation due to sexual dysfunction, erectile dysfunction, female orgasmic disorder, female sexual interest/arousal disorder, reproductive pelvic pain/infiltration disorder, male hyposexuality disorder, premature ejaculation (premature ejaculation), substance/drug-induced sexual dysfunction, other indicated and unspecified sexual dysfunction, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

237. A method of treating gender anxiety, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

238. A method of treating a neurodegenerative disorder, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

239. The method of claim 247, wherein the neurocognitive disorder (NCD) comprises delirium, NCD caused by alzheimer's disease, vascular NCD, NCD with lewy bodies, NCD caused by parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance/drug induced NCD; NCD caused by huntington's disease, NCD caused by prion disease; NCD caused by another medical condition, NCD caused by a variety of etiologies, and unspecified NCD.

240. The method in claim 247, wherein the neurocognitive disorder is a neurocognitive/learning disorder comprising memory problems, mental confusion, poor attention, and/or inattention due to infection (viral/bacterial/prion/other) or other indicated or unspecified disorder, disease or other unknown cause.

241. The method of claim 247, where the neurocognitive disorder is a decrease in memory, cognition, and/or learning with or without obvious signs of a neurodegenerative disorder or a neurodevelopmental disorder, and/or a decrease in memory, cognition, and/or learning with or without obvious signs of a neurodegenerative disorder or a neurodevelopmental disorder and independent of age.

242. The method in claim 247, where the neuro-cognitive disorder is a neurological and/or neuropsychiatric disorder and/or a condition associated with normal aging and/or luteal phase syndrome.

243. A method of treating a neurological disease caused by a viral infection, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130, wherein the neurological disease is caused by a viral infection that utilizes a neuronal cell surface receptor comprising a 5-hydroxytryptamine energy (5-HT) receptor (particularly a 5-HT2A receptor), such as Progressive Multifocal Leukoencephalopathy (PML) caused by JC virus.

244. A method of reducing and/or preventing the adverse effects of a hallucinogen, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1-123, a composition of any one of claims 124-127, or a formulation of any one of claims 128-130.

245. A method of maintaining or improving well-being, wherein the method comprises administering to an individual in need thereof the compound of any one of claims 1 to 123, the composition of any one of claims 124 to 127, or the formulation of any one of claims 128 to 130.

246. A method of treating a disease and/or disorder comprising agonism of one or more 5-HT1 receptor subtypes, such as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F, by a therapeutic mechanism associated with activation of the 5-HT1 receptor, wherein the method comprises administering to an individual in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

247. A method of treating a disease and/or disorder associated with cognitive/learning/memory deficit or decline, wherein the therapeutic mechanism is associated with 5-HT6 receptor activation (agonism), wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

248. A method of treating a disease and/or disorder, wherein the therapeutic mechanism is associated with 5-HT2A receptor activation (agonism), wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

249. A method of treating a disease or disorder, wherein the therapeutic mechanism is associated with D2-like receptor activation (agonism) such as the D2 and D4 receptor subtypes, wherein the method comprises administering to a subject in need thereof a compound of any one of claims 1 to 123, a composition of any one of claims 124 to 127, or a formulation of any one of claims 128 to 130.

250. The method of any one of claims 177-258, wherein the treatment excludes the illusive effect and does not induce tolerance to the compound of any one of claims 1-123, the composition of any one of claims 124-127, or the formulation of any one of claims 128-130.