PHENETHYLAMINES AND METHODS OF PREPARATION THEREOF
20250074871 ยท 2025-03-06
Inventors
Cpc classification
C07C215/52
CHEMISTRY; METALLURGY
C07C217/70
CHEMISTRY; METALLURGY
A61P25/18
HUMAN NECESSITIES
C07C323/32
CHEMISTRY; METALLURGY
C07C217/60
CHEMISTRY; METALLURGY
C07C255/59
CHEMISTRY; METALLURGY
International classification
C07C323/32
CHEMISTRY; METALLURGY
C07C215/52
CHEMISTRY; METALLURGY
C07C217/60
CHEMISTRY; METALLURGY
C07C217/70
CHEMISTRY; METALLURGY
C07C255/59
CHEMISTRY; METALLURGY
A61K31/137
HUMAN NECESSITIES
A61P25/18
HUMAN NECESSITIES
Abstract
The present disclosure relates to compounds of Formula I that exhibit 5-HT.sub.2A receptor agonist activity and low 5HT.sub.2B receptor agonist activity or deemed 5HT.sub.2B receptor agonist inactivity. In at least some cases, such compounds show selectivity for the 5-HT.sub.2A receptor over the 5-HT.sub.2C receptor. As contemplated herein, phenethylamines may be used for the treatment of neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders including depression, drug (e.g. tobacco, opiate, and cocaine) addiction, alcoholism, post-traumatic stress disorder (PTSD), and neuropathic pain syndromes including cluster headaches and chemotherapy induced peripheral neuropathy.
Claims
1. A chemical compound of Formula 1, or isotopologue or pharmaceutically acceptable salt thereof: ##STR00067## wherein: R.sup.1: (i) is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.2 and R.sup.3 is independently selected from H, CH.sub.3, or halogen; or (ii) together with R.sup.2 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; or (iii) together with b form an alkanediyl, alkenediyl, or heteroalkanediyl moiety; R.sup.2: (i) is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.1 and R.sup.3 is independently selected from H, CH.sub.3, or halogen; or (ii) together with R.sup.1 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; R.sup.3: (i) is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.1 and R.sup.2 is independently selected from H, CH.sub.3, or halogen; or (ii) together with Z form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; wherein: one of R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is selected from the group consisting of R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, S(O).sub.2R.sup.9, N(R.sup.9)C(O)R.sup.9, N(R.sup.9)C(O)OR.sup.9, N(R.sup.9)C(O)N(H)R.sup.9, N(R.sup.9)C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, N(R.sup.9)S(O).sub.2R.sup.9, CH.sub.2OR.sup.9, CH.sub.2SR.sup.9, CH.sub.2S(O)R.sup.9, CH.sub.2S(O).sub.2R.sup.9, CH.sub.2N(R.sup.9)C(O)R.sup.9, CH.sub.2N(R.sup.9)C(O)OR.sup.9, CH.sub.2N(R.sup.9)C(O)N(H)R.sup.9, CH.sub.2N(R.sup.9)C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CH.sub.2N(R.sup.9)S(O).sub.2R.sup.9, CHNOR.sup.9, C(C.sub.1-C.sub.6 alkyl)NOR.sup.9, C(O)OR.sup.9, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CH.sub.2C(O)OR.sup.9, CH.sub.2C(O)N(H)R.sup.9, CH.sub.2C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CN, and halogen, a second one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.8 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, and halogen, and the remainder of R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently H, CH.sub.3, or halogen; or if R.sup.4 and R.sup.5 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, then each of R.sup.6, R.sup.7, and R.sup.8 is independently selected from the group consisting of H, CH.sub.3, and halogen; or if R.sup.4 and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then one of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, and halogen, and the remainder of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of H, CH.sub.3, and halogen; or if R.sup.4 and together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then one of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, CN, and halogen, and the remainder of R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently selected from the group consisting of H, CH.sub.3, and halogen; wherein: X is selected from the group consisting of CN, C(O)NH.sub.2, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, C(O)(C.sub.4-C.sub.6 heterocyclyl), CHF.sub.2, CF.sub.3, OH, O(C.sub.1-C.sub.6 alkyl), OCHF.sub.2, OCF.sub.3, S(C.sub.1-C.sub.6 alkyl), SCF.sub.3, SCHF.sub.2, F, C, aryl, and heteroaryl generally; Y is selected from the group consisting of H, CH.sub.3, C(O)R.sup.9, CH.sub.2OC(O)R.sup.9, and C(O)OR.sup.9; Z: (i) is selected from the group consisting of H, C.sub.1-C.sub.10 alkyl, substituted C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 heteroalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 heteroalkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.3 alkyl), (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.3 heteroalkyl), C.sub.4-C.sub.6 heterocyclyl, (C.sub.4-C.sub.6 heterocyclyl)(C.sub.1-C.sub.3 alkyl), (C.sub.4-C.sub.6 heterocyclyl)(C.sub.1-C.sub.3 heteroalkyl), aryl(C.sub.1-C.sub.3 alkyl), aryl(C.sub.1-C.sub.3 heteroalkyl), heteroaryl(C.sub.1-C.sub.3 alkyl), heteroaryl(C.sub.1-C.sub.3 heteroalkyl), C(O)R.sup.9, C(O)OR.sup.9, CH.sub.2OC(O)R.sup.9, C(O)NH.sub.2, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, and C(O)(C.sub.4-C.sub.6 heterocyclyl); or (ii) together with R.sup.3 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; wherein two of a, b, and c are each independently selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, while the third of a, b, and c is H, but if c and R.sup.4 together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety then a and b are each independently selected from H or CH.sub.3; and wherein R.sup.9 is, independently for each occurrence, selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.6 alkyl), (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.6 heteroalkyl), C.sub.3-C.sub.6 heterocyclyl, (C.sub.3-C.sub.6 heterocyclyl)(C.sub.1-C.sub.6 alkyl), (C.sub.3-C.sub.6 heterocyclyl)(C.sub.1-C.sub.6 heteroalkyl), aryl, aryl(C.sub.1-C.sub.6 alkyl), aryl(C.sub.1-C.sub.6 heteroalkyl), heteroaryl, heteroaryl(C.sub.1-C.sub.6 alkyl), and heteroaryl(C.sub.1-C.sub.6 heteroalkyl).
2. The compound as claimed in claim 1, or isotopologue or pharmaceutically acceptable salt thereof, wherein: (i) X is selected from the group consisting of CN, OH, O(C.sub.1-C.sub.6 alkyl), OCHF.sub.2, OCF.sub.3, S(C.sub.1-C.sub.6 alkyl), SCF.sub.3, SCHF.sub.2, F, Cl, aryl, and heteroaryl; and (ii) Z is selected from the group consisting of H and C.sub.1-C.sub.10 alkyl.
3. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of CN, OH, OCH.sub.3, F, C, CF.sub.3, SCH.sub.3, an oxazole, a pyrimidine, and an isoxazole.
4. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.4 is selected from the group consisting of H, F, Cl, OH, OR.sup.9, and SCH.sub.3.
5. The compound as claimed in claim 4, or isotopologue or pharmaceutically acceptable salt thereof, wherein: (i) X is CN; (ii) Z is H or CH.sub.3; and (iii) R.sup.4 is SCH.sub.3.
6. The compound as claimed in claim 5, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, a, b, y, c, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are H.
7. The compound as claimed in claim 5, or isotopologue or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: ##STR00068##
8. The compound as claimed in claim 4, or isotopologue or pharmaceutically acceptable salt thereof, wherein: (i) X is CF.sub.3; (ii) Z is CH.sub.3; and (iii) R.sup.8 is OH.
9. The compound as claimed in claim 8, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, a, b, y, c, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are H.
10. The compound as claimed in claim 8, or isotopologue or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: ##STR00069##
11. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.4 and c together form a heteroalkanediyl moiety.
12. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.4 and R.sup.5 together form a heteroalkanediyl moiety.
13. The compound as claimed in claim 12, or isotopologue or pharmaceutically acceptable salt thereof, wherein the heteroalkanediyl moiety is selected from the group consisting of NHCH.sub.2CH.sub.2, NHCH.sub.2NH, and SCH.sub.2CH.sub.2.
14. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.5 is selected from the group consisting of OR.sup.9, and F, Cl.
15. (canceled)
16. (canceled)
17. (canceled)
18. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.6 is selected from the group consisting of H, F, Cl, and OR.sup.9.
19. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.8 is selected from the group consisting of H, F, Cl, OH, OR.sup.9, and SCH.sub.3.
20. (canceled)
21. (canceled)
22. (canceled)
23. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.8 and R.sup.7 together form a heteroalkanediyl moiety.
24. The compound as claimed in claim 23, or isotopologue or pharmaceutically acceptable salt thereof, wherein the heteroalkanediyl moiety is selected from the group consisting of NHCH.sub.2CH.sub.2, NHCH.sub.2NH, and SCH.sub.2CH.sub.2.
25. The compound as claimed in claim 2, or isotopologue or pharmaceutically acceptable salt thereof, wherein R.sup.7 is selected from the group consisting of OR.sup.9, and F, Cl.
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. (canceled)
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. A method comprising administering to a patient an effective amount of the compound as claimed in claim 1, for the treatment of one or more of: (i) neuropsychiatric, neurodegenerative, neuroinflammatory, and pain disorders; (ii) hypertension, hypotension, cardiovascular disease, stroke, and stroke recovery; (iii) gut motility; (iii) ureter contractions in animals; and (iv) compulsive disorders, anxiety disorders, fear disorders and aggressiveness in animals.
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
Description
BRIEF DESCRIPTION OF DRAWINGS
[0016] In the accompanying drawings, which illustrate one or more embodiments:
[0017]
[0018]
[0019]
[0020]
[0021]
[0022]
[0023]
[0024]
[0025]
[0026]
[0027]
[0028]
[0029]
[0030]
[0031]
[0032]
DETAILED DESCRIPTION
[0033] Directional terms such as top, bottom, upwards, downwards, vertically, and laterally are used in the following description for the purpose of providing relative reference only, and are not intended to suggest any limitations on how any article is to be positioned during use, or to be mounted in an assembly or relative to an environment. The use of the word a or an when used herein in conjunction with the term comprising may mean one, but it is also consistent with the meaning of one or more, at least one and one or more than one. Any element expressed in the singular form also encompasses its plural form. Any element expressed in the plural form also encompasses its singular form. The term plurality as used herein means more than one, for example, two or more, three or more, four or more, and the like.
[0034] As used herein and unless otherwise specified, the term about, when used to describe a recited value, means within 10% of the recited value.
[0035] As used herein and unless otherwise specified, the term alkanediyl, used alone or as part of a larger moiety, means a substituted or unsubstituted, linear, divalent hydrocarbon chain that can be attached by way of its terminal carbon atoms and that is completely saturated. Unless otherwise specified, an alkanediyl group contains 1 to 5 carbon atoms (C.sub.1-C.sub.5 alkanediyl). Non-limiting examples of alkanediyl groups include methylene, ethylene, trimethylene, tetramethylene, and pentamethylene. A substituted alkanediyl group is one having at least one but no more than five substituents, and no more substituents than the number of hydrogen atoms in the unsubstituted group. Non-limiting examples of substituted alkanediyl groups include difluoromethylene, hydroxyethylene, methoxyethylene, CH.sub.2CH.sub.2C(O), CH.sub.2C(CH.sub.3).sub.2CH.sub.2, CH.sub.2CH.sub.2CH(CF.sub.3)CH.sub.2, and the like.
[0036] As used herein and unless otherwise specified, the term alkenediyl, used alone or as part of a larger moiety, means a substituted or unsubstituted, linear, divalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon double bond, that can be attached by way of its terminal carbon atoms. Unless otherwise specified, an alkenediyl group contains 2 to 5 carbon atoms (C.sub.2-C.sub.5 alkenediyl). Non-limiting examples of alkenediyl groups include vinylene (CHCH), propene-1,3-diyl(CH.sub.2CHCH), 1-butene-1,4-diyl(CH.sub.2CH.sub.2CHCH), 2-butene-1,4-diyl(CH.sub.2CHCHCH.sub.2), and 1,3-butadiene-1,4-diyl(CHCHCHCH). For illustration purposes, if a first end of a 1,3-butadiene-1,4-diyl group is attached to a first carbon atom of a carbon-carbon (CC) double bond or an aromatic ring, and a second end of the 1,3-butadiene-1,4-diyl group is attached to a second carbon atom of the CC double bond or the aromatic ring, and the second carbon atom is adjacent to the first carbon atom, then said two adjacent carbon atoms and the 1,3-butadiene-1,4-diyl group together represent a benzene ring. For illustration purposes, if a first end of a vinylene group is attached to a first carbon atom of a CC double bond or an aromatic ring, and a second end of the vinylene group is attached to a heteroatom (selected from the group consisting of N, O, and S) that is adjacent to a second carbon atom of the CC double bond or the aromatic ring, and the second carbon atom is adjacent to the first carbon atom, then the vinylene group together with said two adjacent carbon atoms and said heteroatom attached to the second carbon atom represent a pyrrole, furan, or thiophene ring.
[0037] As used herein and unless otherwise specified, the term alkenyl refers to a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon double bond. Examples of alkenyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 1,3-butadien-2-yl, 2,4-pentadien-1-yl, 1,4-pentadien-3-yl, and the like.
[0038] As used herein and unless otherwise specified, the term alkoxy, used alone or as part of a larger moiety, refers to the groups O-alkyl and O-cycloalkyl. As used herein and unless otherwise specified, the term substituted alkoxy, used alone or as part of a larger moiety, refers to the groups -O-(substituted alkyl) and -O-(substituted cycloalkyl).
[0039] As used herein and unless otherwise specified, the term alkyl, used alone or as part of a larger moiety, means a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain that is completely saturated. Unless otherwise specified, an alkyl group contains 1 to 7 carbon atoms (C.sub.1-C.sub.7 alkyl). For example, in some embodiments, alkyl groups contain 1 to 6 carbon atoms (C.sub.1-C.sub.6 alkyl); in some embodiments, alkyl groups contain 1 to 5 carbon atoms (C.sub.1-C.sub.5 alkyl); in some embodiments, alkyl groups contain 1 to 4 carbon atoms (C.sub.1-C.sub.4 alkyl, alternatively lower alkyl); and in some embodiments, alkyl groups contain 3 to 7 carbon atoms (C.sub.3-C.sub.7 alkyl). Non-limiting examples of saturated alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl. A substituted alkyl group is one having at least one but no more than five substituents, and no more substituents than the number of hydrogen atoms in the unsubstituted group. In some embodiments, the substituents are fluorine atoms. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF.sub.2, CF.sub.3, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, 4-fluorobutyl, and the like.
[0040] As used herein and unless otherwise specified, the term alkylthio, used alone or as part of a larger moiety, refers to the groups S-alkyl and S-cycloalkyl. Substituted alkylthio, used alone or as part of a larger moiety, refers to the groups -S-(substituted alkyl) and -S-(substituted cycloalkyl).
[0041] As used herein and unless otherwise specified, the term alkynyl refers to a substituted or unsubstituted, linear or branched, univalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, 1and 3-propynyl, 3-butyn-1-yl, and the like.
[0042] As used herein and unless otherwise specified, the term aryl, used alone or as part of a larger moiety (for example, (aryl)alkyl) refers to a univalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, aryl groups contain 6 or 10 ring members. Non-limiting examples of aryl include phenyl, naphthyl, and the like. The term aryl also refers to aryl groups that may be unsubstituted or substituted. For example, aryl groups can be unsubstituted or can be substituted with one, two, or three groups selected independently from the group consisting of halogen, OH, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, substituted C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, substituted C.sub.3-C.sub.6 cycloalkyl, C(O)OH, C(O)(C.sub.1-C.sub.6 alkyl), C(N-OH)(C.sub.1-C.sub.6 alkyl), C(O)(C.sub.1-C.sub.6 alkoxy), C(O)NH.sub.2, C(O)NH(C.sub.1-C.sub.6 alkyl), C(O)N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), C(O)-heterocyclyl, NHC(O)(C.sub.1-C.sub.6 alkyl), N(CH.sub.3)C(O)(C.sub.1-C.sub.6 alkyl), and cyano.
[0043] As used herein and unless otherwise specified, the term chemical entity refers to a compound having the indicated structure, whether in its free form (e.g., free compound or free base or free acid form, as applicable), or in a salt form, particularly a pharmaceutically acceptable salt form, and furthermore whether in solid state form or otherwise. In some embodiments, a solid state form is an amorphous (i.e., non-crystalline) form; in some embodiments, a solid state form is a crystalline form (e.g., a polymorph, pseudohydrate, hydrate, or solvate). Similarly, the term encompasses the compound whether provided in solid form or otherwise. Unless otherwise specified, all statements made herein regarding compounds apply to the associated chemical entities, as defined.
[0044] As used herein and unless otherwise specified, the terms comprising, having, including, containing, and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, un-recited elements and/or method steps. For example, A includes 1, 2, and 3 means that A includes but is not limited to 1, 2, and 3.
[0045] As used herein and unless otherwise specified, the term consisting essentially of when used herein in connection with a composition, use, or method, denotes that additional elements, method steps or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method, or use functions.
[0046] As used herein and unless otherwise specified, the term consisting of when used herein in connection with a composition, use, or method, excludes the presence of additional elements and/or method steps.
[0047] As used herein, the term cpd is an abbreviation for the word compound.
[0048] As used herein and unless otherwise specified, the term cycloalkyl, used alone or as part of a larger moiety, for example (cycloalkyl)alkyl, refers to: (i) a substituted or unsubstituted, univalent monocyclic hydrocarbon radical that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic; or (ii) bicyclo[m.n.o]alkyl wherein each of m, n, and o is independently an integer ranging from zero to 5, and the sum m+n+o ranges from 2 to 6. In some embodiments, cycloalkyl groups contain 3 to 8 ring carbon atoms (C.sub.3-C.sub.8 cycloalkyl). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like, as well as bicyclo[2.2.1]heptyl (also called norbornyl) and bicyclo[1.1.1]pentyl. A substituted cycloalkyl group is one having at least one but no more than five substituents. In some embodiments, the substituents are fluorine atoms. Non-limiting examples of substituted cycloalkyl groups include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, 4,4-difluorocyclohexyl, and the like.
[0049] As used herein and unless otherwise specified, the term halogen or halo, used alone or as part of a larger moiety, refers to fluoro, chloro, bromo, or iodo.
[0050] As used herein and unless otherwise specified, the term hERG risk refers to the risk of a compound potentially inhibiting the human ether-a-go-go-related gene (hERG) K.sup.+ channel, thereby leading to QT prolongation.
[0051] As used herein and unless otherwise specified, the term heteroalkanediyl refers to a substituted or unsubstituted alkanediyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. Non-limiting examples for heteroalkanediyl groups include NH, O, S, CH.sub.2NH, CH.sub.2O, CH.sub.2S, CH.sub.2CH.sub.2NH, CH.sub.2CH.sub.2O, CH.sub.2CH.sub.2S, CH.sub.2NHCH.sub.2, CH.sub.2OCH.sub.2, CH.sub.2SCH.sub.2, OCH.sub.2O, OCH.sub.2S, SCH.sub.2S, CH.sub.2CH.sub.2CH.sub.2NH, CH.sub.2CH.sub.2NHCH.sub.2, CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2CH.sub.2S, and CH.sub.2CH.sub.2SCH.sub.2. For illustration purposes, if the points of attachment of a heteroalkanediyl group are non-equivalent (e.g., CH.sub.2CH.sub.2NHCH.sub.2), and the points are attached to non-equivalent positions of a chemical structure, then the attachment of the heteroalkanediyl group to the chemical structure can occur in either direction (e.g., CH.sub.2CH.sub.2NHCH.sub.2 or CH.sub.2NHCH.sub.2CH.sub.2).
[0052] As used herein and unless otherwise specified, the term heteroalkenediyl refers to a substituted or unsubstituted alkenediyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. Non-limiting examples for heteroalkenediyl groups include CHN, CHCHNH, CHCHO, CHCHS, CHNCH.sub.2, NN, CHNNH, CHNO, CHNS, NHCHN, OCHN, SCHN, HNNN, CHCHCH=N, CHCHNCH, CHCHNN, CHNCH=N, NCHCHN, CHNNCH, CHCHCH.sub.2NH, CHCHCH.sub.2O, and CHCHCH.sub.2S. For illustration purposes, if the points of attachment of a heteroalkenediyl group are non-equivalent (e.g., in CHCHS), and the points are attached to non-equivalent positions of a chemical structure, then the attachment of the heteroalkenediyl group to the chemical structure can occur in either direction (e.g., CHCHS or SCHCH). For illustration purposes, if a first point of attachment of a heteroalkenediyl group is attached to a first carbon atom of a CC double bond or an aromatic ring, and a second point of attachment of the heteroalkenediyl group is attached to a second carbon atom of the CC double bond or the aromatic ring, and the first carbon atom and the second carbon atom are adjacent to each other, then said two adjacent carbon atoms and the heteroalkenediyl group together represent a heteroaromatic ring; particularly, (i) if the formed heteroaromatic ring is five-membered, then the single saturated atom of the heteroalkenediyl group is selected from the group consisting of N, O, and S, and (ii) if the formed heteroaromatic ring is a six-membered, then the heteroalkenediyl group comprises only C and N atoms as a part of its backbone and contains two conjugated double bonds. For illustration purposes, if a first point of attachment of a heteroalkenediyl group represented by the formula X=Y, wherein X and Y are independently selected from the group consisting of C and N, is attached to a first carbon atom of a CC double bond or an aromatic ring, and a second point of attachment of the heteroalkenediyl group is attached to a heteroatom (selected from the group consisting of N, O, and S) that in turn is attached to a second carbon atom of the CC double bond or the aromatic ring, and the second carbon atom is adjacent to the first carbon atom, then the moiety X=Y together with said two adjacent carbon atoms and said heteroatom attached to one of them represent a five-membered heteroaromatic ring.
[0053] As used herein and unless otherwise specified, the term heteroalkenyl refers to a substituted or unsubstituted alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
[0054] As used herein and unless otherwise specified, the term heteroalkyl refers to a substituted or unsubstituted alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
[0055] As used herein and unless otherwise specified, the term heteroaryl, used alone or as part of a larger moiety, e.g., (heteroaryl)alkyl, refers to a univalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6 or 10 rr electrons shared in a cyclic array, and having, in addition to ring carbon atoms, from one to four ring heteroatoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, naphthyridinyl, pteridinyl, and the like.
[0056] Heteroaryl groups may be unsubstituted or may be substituted with one, two, or three groups selected independently from halogen, OH, C.sub.1-C.sub.6 alkoxy, substituted C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, substituted C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, substituted C.sub.3-C.sub.6 cycloalkyl, C(O)OH, C(O)(C.sub.1-C.sub.6 alkoxy), C(O)NH.sub.2, C(O)NH(C.sub.1-C.sub.6 alkyl), C(O)N(C.sub.1-C.sub.4 alkyl)(C.sub.1-C.sub.4 alkyl), C(O)-heterocyclyl, NHC(O)(C.sub.1-C.sub.6 alkyl), N(CH.sub.3)C(O)(C.sub.1-C.sub.6 alkyl), and cyano.
[0057] As used herein and unless otherwise specified, the term heterocyclyl, used alone or as part of a larger moiety (for example, (heterocyclyl)alkyl) refers to a univalent stable 4to 7-membered monocyclic or 7to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and has, in addition to ring carbon atoms, one to four heteroatoms. Non-limiting examples of heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like. Heterocyclyl groups can be unsubstituted or can be substituted. For example, heterocyclyl groups can be unsubstituted or can be substituted with one, two, or three groups selected independently from the group consisting of halogen, OH, O(C.sub.1-C.sub.6 alkyl), O(substituted C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl.
[0058] As used herein and unless otherwise specified, the term HTR refers to head-twitch response, which is a measurement of 5-HT.sub.2A activation in vivo.
[0059] As used herein and unless otherwise specified, the term inactive (and all related terms thereto including inactivity), when used the context of EC.sub.50 (nM) and Eff % as such terms would be understood by a person skilled in the art or equivalent skilled person, and when used in reference to the activity at the 5-HT.sub.2B receptor, means a concentration of greater than 10,000 nM (when used in the context of EC.sub.50 (nM)) or an efficacy of 30% or lower (when used in the context of Eff %).
[0060] As used herein and unless otherwise specified, the term isotopologue refers to a species that differs from a specific compound only in the isotopic composition thereof. For example, all hydrogen atoms in a compound are independently of natural isotopic composition or of any isotopic composition enriched or depleted in one or both of the heavy isotopes, .sup.2H (D, deuterium) and .sup.3H (T, tritium), ranging from a depletion to zero % to an enrichment to 100%.
[0061] As used herein and unless otherwise specified, the term low 2B activity refers to a situation where the 5-HT.sub.2A agonist activity (or 5-HT.sub.2A receptor sensitivity) of a compound, as measured in terms of EC.sub.50 (nm), is 500 times or more greater than the 5-HT.sub.2B agonist activity (or 5-HT.sub.2B receptor sensitivity) of said compound and the Eff % at each receptor is less than 90% at the measured EC.sub.50 for each receptor. For example, a compound is deemed to have low 2B activity if such compound possesses: (i) an EC.sub.50 and Eff % of 1.0 nm and 95% respectively at the 5-HT.sub.2A receptor; and (ii) an EC.sub.50 and Eff % of 700 nm and 95% respectively at the 5-HT.sub.2B receptor.
[0062] As used herein and unless otherwise specified, the term mice refers to male C57BL/6J mice (6-8 weeks old).
[0063] As used herein and unless otherwise specified, the term pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of the compounds provided in this disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include salts of compounds comprising an amino group that are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydriodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Other pharmaceutically acceptable salts include those that are derived from appropriate bases such as alkali metal, alkaline earth metal, ammonium, and N+(C.sub.1-4 alkyl).sub.4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
[0064] Further non-limiting examples of pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
[0065] As used herein and unless otherwise specified, the term subject includes a mammal (e.g., a human, and in some embodiments including prenatal human forms). In some embodiments, a subject suffers from a relevant disease, disorder, or condition. In some embodiments, a subject is susceptible to a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a mammal with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and/or therapy is and/or has been administered. In some embodiments, a subject is a fetus, an infant, a child, a teenager, an adult, or a senior citizen (i.e., the subject is of advanced age, such as older than 50). In some embodiments, a child refers to a human that is between two and 18 years of age. In some embodiments, an adult refers to a human that is eighteen years of age or older.
[0066] As used herein and unless otherwise specified, the phrase such as is intended to be open-ended. For example, the phrase A can be a halogen, such as chlorine or bromine means that A can be, but is not limited to, chlorine or bromine.
[0067] Reference to specific moieties, functional groups, or substituents contemplates (where applicable) tautomers thereof.
[0068] Unless otherwise stated, structures depicted herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure (e.g., the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers). Unless otherwise stated, the compounds disclosed, taught, or otherwise suggested in this disclosure contemplate all single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise stated, the compounds disclosed, taught, or suggested in this disclosure contemplate all tautomeric forms thereof. Additionally, unless otherwise stated, structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. Additionally, incorporation of heavier isotopes such as deuterium (.sup.2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life, or reduced dosage requirements.
[0069] Chemical entities described herein are further illustrated by the classes, subclasses, and species disclosed herein. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5.sup.th 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, 3.sup.rd Edition, Cambridge University Press, Cambridge, 1987. In this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
[0070] Referring to
##STR00003##
wherein: [0071] R.sup.1: (i) can be selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.2 and R.sup.3 is independently selected from H, CH.sub.3, or halogen; or (ii) together with R.sup.2 can form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which moiety can further be substituted with a first substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and, if such moiety contains at least one additional H atom, a second substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, if R.sup.3 is H, CH.sub.3, or halogen. For example, if R.sup.3 is H, CH.sub.3, or halogen, then R.sup.1 and R.sup.2 together can form CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2, (CH.sub.2).sub.5, CHCHCHCH, CH.sub.2CH.sub.2O, CH.sub.2OCH.sub.2, OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2OCH.sub.2CH.sub.2, OCH.sub.2CH.sub.2CH.sub.2, OCHCH, CHCHO, OCH.sub.2O, OCH.sub.2CH.sub.2O, CH.sub.2CH.sub.2S, CH.sub.2SCH.sub.2, SCH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2S, CH.sub.2CH.sub.2SCH.sub.2, CH.sub.2SCH.sub.2CH.sub.2, SCH.sub.2CH.sub.2CH.sub.2, SCHCH, CHCHS, ONCH, CHNO, OCHN, NCHO, SNCH, CHNS, SCHN, NCHS, NHCHCH, CHCHNH, NHNCH, CHNNH, NHCHN, NCHNH, CHCHCH=N, CHCHNCH, CHNCHCH, or NCHCHCH; or (iii) together with b can form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, which moiety can be substituted with a substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and, if such moiety contains at least one additional H atom, a second substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, if each of R.sup.2 and R.sup.3 is independently selected from H, CH.sub.3, or halogen. For example, if R.sup.2 and R.sup.3 are each independently H, CH.sub.3, or halogen, then R.sup.1 and b can form any one of the following non-limiting linkages: CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, CHCH, CH.sub.2CHCH, CHCHCH.sub.2, OCH.sub.2, OCH.sub.2CH.sub.2, CH.sub.2OCH.sub.2, SCH.sub.2, SCH.sub.2CH.sub.2, and CH.sub.2SCH.sub.2; [0072] R.sup.2: (i) is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.1 and R.sup.3 is independently selected from H, CH.sub.3, or halogen; or (ii) together with R.sup.1 can form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which moiety can be substituted with a first substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and, if such moiety contains at least one additional H atom, a second substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, if R.sup.3 is H, CH.sub.3, or halogen; [0073] R.sup.3: (i) is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, substituted C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, substituted C.sub.1-C.sub.4 alkylthio, and halogen, if each of R.sup.1 and R.sup.2 is independently selected from H, CH.sub.3, or halogen; or (ii) together with Z can form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which moiety can be substituted with one selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, if each of R.sup.1 and R.sup.2 is independently selected from the group consisting of H, CH.sub.3, and halogen;
[0074] wherein: [0075] one of R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.3 is selected from the group consisting of R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, S(O).sub.2R.sup.9, N(R.sup.9)C(O)R.sup.9, N(R.sup.9)C(O)OR.sup.9, N(R.sup.9)C(O)N(H)R.sup.9, N(R.sup.9)C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, N(R.sup.9)S(O).sub.2R.sup.9, CH.sub.2OR.sup.9, CH.sub.2SR.sup.9, CH.sub.2S(O)R.sup.9, CH.sub.2S(O).sub.2R.sup.9, CH.sub.2N(R.sup.9)C(O)R.sup.9, CH.sub.2N(R.sup.9)C(O)OR.sup.9, CH.sub.2N(R.sup.9)C(O)N(H)R.sup.9, CH.sub.2N(R.sup.9)C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CH.sub.2N(R.sup.9)S(O).sub.2R.sup.9, CHNOR.sup.9, C(C.sub.1-C.sub.6 alkyl)NOR.sup.9, C(O)OR.sup.9, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CH.sub.2C(O)OR.sup.9, CH.sub.2C(O)N(H)R.sup.9, CH.sub.2C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, CN, and halogen, a second one of R.sup.4, R.sup.5, R.sup.6, R.sup.7 or R.sup.3 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, and halogen, and the remainder of R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.3 are each independently H, CH.sub.3, or halogen; [0076] or if R.sup.4 and R.sup.5 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which moiety can be substituted with a group selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, OCF.sub.3, C.sub.1-C.sub.4 alkylthio, CN, and halogen, then each of R.sup.6, R.sup.7, and R.sup.3 is independently selected from the group consisting of H, CH.sub.3, and halogen. Non-limiting examples of alkanediyl moieties include CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2CH.sub.2. A non-limiting example of an alkenediyl moiety is CHCHCHCH. Non-limiting examples of heteroalkanediyl moieties include CH.sub.2CH.sub.2O, CH.sub.2OCH.sub.2, OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2O, CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2OCH.sub.2CH.sub.2, OCH.sub.2CH.sub.2CH.sub.2, OCH.sub.2O, OCH.sub.2CH.sub.2O, CH.sub.2CH.sub.2S, CH.sub.2SCH.sub.2, SCH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2S, CH.sub.2CH.sub.2SCH.sub.2, CH.sub.2SCH.sub.2CH.sub.2, SCH.sub.2CH.sub.2CH.sub.2, NHCH.sub.2CH.sub.2, and NHCH.sub.2NH. Non-limiting examples of heteroalkenediyl moieties include OCHCH, CHCHO, SCHCH, CHCHS, ONCH, CHNO, OCHN, NCHO, SNCH, CHNS, SCHN, NCHS, NHCHCH, CHCHNH, NHNCH, CHNNH, NHCHN, NCHNH, CHCHCH=N, CHCHNCH, CHNCHCH, and NCHCHCH; [0077] or if R.sup.4 and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, which moiety can be substituted with (a) a first group selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and (b) a second group selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, then one of R.sup.5, R.sup.6, R.sup.7, and R.sup.3 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, and halogen, and the remainder of R.sup.5, R.sup.6, R.sup.7, and R.sup.3 are each independently selected from the group consisting of H, CH.sub.3, and halogen. Non-limiting examples of alkanediyl moieties include CH.sub.2 and CH.sub.2CH.sub.2. A non-limiting example of an alkenediyl moiety is CHCH. Non-limiting examples of heteroalkanediyl moieties include OCH.sub.2 and SCH.sub.2; [0078] or if R.sup.4 and c together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then one of R.sup.5, R.sup.6, R.sup.7, and R.sup.3 is selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, CHF.sub.2, CF.sub.3, OH, OCH.sub.3, OC.sub.2H.sub.5, OCHF.sub.2, OCF.sub.3, CN, and halogen, and the remainder of R.sup.5, R.sup.6, R.sup.7, and R.sup.3 are each independently selected from the group consisting of H, CH.sub.3, and halogen. Non-limiting examples of alkanediyl moieties include CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2. Non-limiting examples of alkenediyl moieties include CHCH, CH.sub.2CHCH, and CHCHCH.sub.2. Non-limiting examples of heteroalkanediyl moieties include CH.sub.2OCH.sub.2, OCH.sub.2CH.sub.2, CH.sub.2SCH.sub.2, and SCH.sub.2CH.sub.2;
[0079] wherein: [0080] X is selected from the group consisting of CN, C(O)NH.sub.2, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, C(O)(C.sub.4-C.sub.6 heterocyclyl), CHF.sub.2, CF.sub.3, OH, O(C.sub.1-C.sub.6 alkyl), OCHF.sub.2, OCF.sub.3, S(C.sub.1-C.sub.6 alkyl), SCF.sub.3, SCHF.sub.2, F, Cl, aryl, and heteroaryl generally, but otherwise selected from the group consisting of CN, C(O)NH.sub.2, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, C(O)(C.sub.4-C.sub.6 heterocyclyl), CHF.sub.2, CF.sub.3, OH, O(C.sub.1-C.sub.6 alkyl), OCHF.sub.2, OCF.sub.3, S(C.sub.1-C.sub.6 alkyl), SCF.sub.3, SCHF.sub.2, aryl, and heteroaryl in other instances if Z is alkyl and R.sup.4 is hydroxy; [0081] Y is selected from the group consisting of H, CH.sub.3, C(O)R.sup.9, CH.sub.2OC(O)R.sup.9, and C(O)OR.sup.9; [0082] Z: (i) is selected from the group consisting of H, C.sub.1-C.sub.10 alkyl, substituted C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 heteroalkyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 heteroalkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.3 alkyl), (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.3 heteroalkyl), C.sub.4-C.sub.6 heterocyclyl, (C.sub.4-C.sub.6 heterocyclyl)(C.sub.1-C.sub.3 alkyl), (C.sub.4-C.sub.6 heterocyclyl)(C.sub.1-C.sub.8 heteroalkyl), aryl(C.sub.1C alkyl), aryl(C.sub.1C heteroalkyl), heteroaryl(C.sub.1-C.sub.3 alkyl), heteroaryl(C.sub.1-C.sub.3 heteroalkyl), C(O)R.sup.9, C(O)OR.sup.9, CH.sub.2OC(O)R.sup.9, C(O)NH.sub.2, C(O)N(H)R.sup.9, C(O)N(C.sub.1-C.sub.6 alkyl)R.sup.9, and C(O)(C.sub.4-C.sub.6 heterocyclyl); or (ii) together with R.sup.3 form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which moiety can further be substituted with one group selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, CN, and halogen. Examples of alkanediyl moieties include CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2; non-limiting examples of alkenediyl moieties include CHCH; non-limiting examples of heteroalkanediyl moieties include CH.sub.2O, CH.sub.2CH.sub.2O, CH.sub.2S, and CH.sub.2CH.sub.2S; and non-limiting examples of heteroalkenediyl moieties include CHN;
[0083] wherein: [0084] with regard to a, b, and c: (i) two of a, b, and c are each independently selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5, while the third of a, b, and c is H; or (ii) b and c together are CH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2, or CH.sub.2OCH.sub.2, while a is H or CH.sub.3; or (iii) if b and R.sup.1 together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, which moiety can be substituted with a first substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and, if the moiety contains at least one additional H atom, a second substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, then one of a and c is H, CH.sub.3, or C.sub.2H.sub.5, and the other of a and c is H. Non-limiting examples of alkanediyl moieties include CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2. Non-limiting examples of alkenediyl moieties include CHCH, CH.sub.2CHCH, and CHCHCH.sub.2. Non-limiting examples of heteroalkanediyl moieties include CH.sub.2O, CH.sub.2CH.sub.2O, CH.sub.2OCH.sub.2, CH.sub.2S, CH.sub.2CH.sub.2S, and CH.sub.2SCH.sub.2; or (iv) if b and R.sup.4 together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, which moiety can be substituted with a first substituent selected from the group consisting of H, C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylthio, OCF.sub.3, OCHF.sub.2, SCF.sub.3, SCHF.sub.2, CN, and halogen, and, if the moiety contains at least one additional H atom, a second substituent selected from the group consisting of C.sub.1-C.sub.4 alkyl, substituted C.sub.1-C.sub.4 alkyl, and halogen, then one of a and c is H, CH.sub.3, and C.sub.2H.sub.5, and the other of a and c is H. Non-limiting examples of alkanediyl moieties include CH.sub.2 and CH.sub.2CH.sub.2. A non-limiting example of an alkenediyl moiety is CHCH. Non-limiting examples of heteroalkanediyl moieties include CH.sub.2O and CH.sub.2S; or (v) if c and R.sup.4 together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, then a and b are each independently selected from H or CH.sub.3. Non-limiting examples of alkanediyl moieties include CH.sub.2, CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2. Non-limiting examples of alkenediyl moieties include CHCH, and CH.sub.2CHCH. Non-limiting examples of heteroalkyl moieties include CH.sub.2O, CH.sub.2OCH.sub.2, CH.sub.2CH.sub.2O, CH.sub.2S, CH.sub.2SCH.sub.2, and CH.sub.2CH.sub.2S;
[0085] and wherein: [0086] R.sup.9 is, independently for each occurrence, selected from the group consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 heteroalkyl, substituted C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 heteroalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 heteroalkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.6 cycloalkyl, (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.6 alkyl), (C.sub.3-C.sub.6 cycloalkyl)(C.sub.1-C.sub.6 heteroalkyl), C.sub.3-C.sub.6 heterocyclyl, (C.sub.3-C.sub.6 heterocyclyl)(C.sub.1-C.sub.6 alkyl), (C.sub.3-C.sub.6 heterocyclyl)(C.sub.1-C.sub.6 heteroalkyl), aryl, aryl(C.sub.1-C.sub.6 alkyl), aryl(C.sub.1-C.sub.6 heteroalkyl), heteroaryl, heteroaryl(C.sub.1-C.sub.6 alkyl), and heteroaryl(C.sub.1-C.sub.6 heteroalkyl).
Examples of Embodiments of Chemical Entities
[0087] Examples of chemical entities of Formula I are provided in Table 1 below.
TABLE-US-00001 TABLE 1 Examples of Compounds of Formula I * # X Y Z R.sup.3 R.sup.2 R.sup.1 a b c R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 1 CN H Me H H H H H H H H H H H 2 CN H Me H H F H H H H H H H H 3 CN H Me H F H H H H H H H H H 4 CN H Me H F H H H H OH H H H H 5 CN H Me F H F H H H H H H H H 6 CN H Me H H H H H H F H H H H 7 CN H Me H H H H H H H F H H H 8 CN H Me H H H H H H H H F H H 9 CN H Me H H Cl H H H H H H H H 10 CN H Me H Cl H H H H H H H H H 11 CN H Me Cl H H H H H H H H H H 12 CN H Me H H H H H H Cl H H H H 13 CN H Me H H H H H H H Cl H H H 14 CN H Me H H H H H H H H Cl H H 15 CN H Me H H Me H H H H H H H H 16 CN H Me H Me H H H H H H H H H 17 CN H Me Me H H H H H H H H H H 18 CN H Me H H H H H H Me H H H H 19 CN H Me H H H H H H H Me H H H 20 CN H Me H H H H H H H H Me H H 21 CN H Me H H CF.sub.3 H H H H H H H H 22 CN H Me H CF.sub.3 H H H H H H H H H 23 CN H Me CF.sub.3 H H H H H H H H H H 24 CN H Me H H OMe H H H H H H H H 25 CN H Me H OMe H H H H H H H H H 26 CN H Me OMe H H H H H H H H H H 27 CN H Me H H H H H H OMe H H H H 28 CN H Me H H H H H H H OMe H H H 29 CN H Me H H H H H H H H OMe H H 30 CN H Me H (CHCH).sub.2 H H H Cl H H H H 31 CN H Me H CH.sub.2CH.sub.2O H H H Cl H H H H 32 CN H Me H CHCHO H H H Cl H H H H 33 CN H Me H OCH.sub.2O H H H Cl H H H H 34 CN H Me H CHCHNH H H H Cl H H H H 35 CN H Me H CHNO H H H Cl H H H H 36 CN H Me CHF.sub.2 H H H H H H H H H H 37 CN H H H H H H H H Cl H H H H 38 CN H CHF.sub.2 H H H H H H Cl H H H H 39 CN H CF.sub.3 H H H H H H Cl H H H H 40 CN H Et H H H H H H Cl H H H H 41 CN H Bu H H H H H H Cl H H H H 42 CN H cpm H H H H H H Cl H H H H 43 CN H CH.sub.2CH.sub.2 H H H H H Cl H H H H 44 CN H CHCH H H H H H Cl H H H H 45 CN H CH.sub.2O H H H H H Cl H H H H 46 CN H CH.sub.2CH.sub.2O H H H H H Cl H H H H 47 CN H CHN H H H H H Cl H H H H 48 CN H NCH H H H H H Cl H H H H 49 CN H Me H H H H H CH.sub.2 H H H H 50 CN H Me H H H H H CH.sub.2CH.sub.2 H H H H 51 CN H Me H H H H H (CH.sub.2).sub.3 H H H H 52 CN H Me H H H H H CH.sub.2O H H H H 53 CN H Me H H H H H CH.sub.2OCH.sub.2 H H H H 54 CN H Me H H H H H CH.sub.2CH.sub.2O H H H H 55 CN H Me H H H H H H OH H H H H 56 CN H Me H H H H H H H OH H H H 57 CN H Me H H H H H H H H OH H H 58 CN H Me H H H H H H Cl H H H Cl 59 CN H Me H H H H H H F H F H H 60 CN H Me H H H H H H Cl H H H Cl 61 CN H Me H H H H H H d H H H H 62 CN H Me H H H H H H e H H H H 63 CN H Me H H H H H H CH.sub.2CH.sub.2O H H H 64 CN H Me H H H H H H CHCHO H H H 65 CN H Me H H H H H H OCH.sub.2O H H H 66 CN H Me H H H H H H CHCHNH H H H 67 CN H Me H H H H H H CHNO H H H 68 CN H Me H H H H H H OCH.sub.2CH.sub.2 H H H 69 CN H Me H H H H H H OCHCH H H H 70 CN H H H H H H H H SCHCH H H H 71 CN H H H H H H H H NHCHCH H H H 72 CN H Me H H H H H H NHC(F)N H H H 73 CN H Me H H H H H H N(Me)CHN H H H 74 CN H Me H H H H H H ONCH H H H 75 CN H Me H H H H H H NCHCHCH H H H 76 CN H Me H H H H H H NCHCHCH H F H 77 CN H Me H H H H H H Cl H OH H H 78 CN H Me H H H H H H CN H H H H 79 CN H Me H H H H H H H H H H H 80 CN H Me H H H Me H H Cl H H H H 81 CN H Me H H H H Me H Cl H H H H 82 CN H Me H H H H H Me Cl H H H H 83 CN H Me H H H H CH.sub.2 Cl H H H H 84 CN H Me H H H H CH.sub.2CH.sub.2 Cl H H H H 85 CN H Me H H H H CH.sub.2CH.sub.2 OH H H H H 86 CN H Me H H H H (CH.sub.2).sub.3 Cl H H H H 87 CN H Me H H H H CH.sub.2OCH.sub.2 Cl H H H H 88 CN Me Me H H H H H H Cl H H H H 89 CN Ac Me H H H H H H Cl H H H H 90 CN Bz Me H H H H H H Cl H H H H 91 CN f Me H H H H H H Cl H H H H 92 d H Me H H H H H H Cl H H H H 93 CF.sub.3 H Me H H H H H H OH H H H H 94 CHF.sub.2 H Me H H H H H H Cl H H H H 95 OH H Me H H H H H H Cl H H H H 96 OMe H Me H H H H H H OH H H H H 97 OCHF.sub.2 H Me H H H H H H Cl H H H H 98 OCF.sub.3 H Me H H H H H H Cl H H H H 99 SCF.sub.3 H Me H H H H H H Cl H H H H 100 g H Me H H H H H H Cl H H H H 101 4-isoxazolyl H Me H H H H H H Cl H H H H 102 2-oxazolyl H Me H H H H H H Cl H H H H 103 2-thiazolyl H Me H H H H H H Cl H H H H 104 2-pyrimidyl H Me H H H H H H Cl H H H H 105 5-pyrimidyl H Me H H H H H H Cl H H H H 106 3-pyridyl H Me H H H H H H Cl H H H H 107 4-pyridyl H Me H H H H H H Cl H H H H 108 CN H Me H H H H H H SMe H H H H 109 CN H H H H H H H H SMe H H H H # X Y Z R.sup.3 R.sup.2 R.sup.1 b a c R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 110 CN H Me H H CH.sub.2 H H OH H H H H # X Y Z R.sup.3 R.sup.2 R.sup.1 a c b R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 111 CN H Me H H H H H CH.sub.2O H H H H # X Y Z R.sup.3 R.sup.2 R.sup.1 a b c R.sup.4 R.sup.5 R.sup.6 R.sup.7 R.sup.8 112 OMe H Me H H H H H H H H H H OH 113 CN H Me H H H H H H H H H H OH 114 CN H H H H H H H H H H H H OH 115 CN H CF.sub.3 H H H H H H H H H H OH 116 CF.sub.3 H H H H H H H H OH H H H H 117 CN H Me H F H H H H H H H H OH 118 CN Me Me H H H H H H H H H H Cl 119 OMe H H H H H H H H H H H H SMe 120 OH H H H H H H H H H H H H SMe 121 SMe H H H H H H H H H H H H SMe 122 SMe H H H H H H H H H H H H OH 123 CHF.sub.2 H H H H H H H H H H H H SMe 124 CN H H H H H H H H OCF.sub.3 H H H H 125 hexyl H Me H H H H H H H H H H OH 126 Benzyl H Me H H H H H H H H H H OH 127 O-Phenyl H Me H H H H H H H H H H OH 128 CN H Me H F H H H H H H H H SMe 129 CN H Me H F H H H H H H H H OH 130 F H H H H H H H H H H H H OMe 131 Cl H H H H H H H H H H H H OH 132 H H H H F H H H H OCH.sub.2O H H H
[0088] Abbreviations used in the table above have the following meanings: Ac=acetyl; Bz=benzoyl; Eu=butyl; cpm=cyclopropylmethyl; d=C(O)N(CH.sub.3).sub.2; e=S(O).sub.2NH.sub.2; Et=ethyl; f=C(O)OMe; g=C(O)NHCH.sub.3; Me=methyl.
Pharmacology
Serotonin Receptor 5-HT.SUB.2 .Functional Assays
[0089] Non-limiting examples of methods of measuring serotonin receptor functional activation are described as follows.
[0090] To measure serotonin receptor functional activation, either Gq dissociation by bioluminescence resonance energy transfer (BRET) or Gq-dependent calcium flux was performed for selected compounds. To measure 5-HT.sub.2 receptor-mediated Gq activation via Gq/1 dissociation as measured by BRET (McCorvy J D, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo A R, Olsen R H J, Che T, Jin J, Roth B L. Structural determinants of 5-HT.sub.2B receptor activation and biased agonism. Nat Struct Mol Biol. 2018; 25(9): 787-96), HEK293T cells were sub-cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% dialyzed fetal bovine serum (FBS) and were co-transfected in a 1:1:1:1 ratio with RLuc8-fused human Gaq (Gaq-RLuc8), a GFP.sup.2-fused to the C-terminus of human Gy1(G1-GFP.sup.2), human G1, and 5-HT.sub.2 receptor using TransiT-2020. After at least 18-24 hours, transfected cells were plated in poly-lysine coated 96-well white clear bottom cell culture plates in DMEM containing 1% dialyzed FBS at a density of 25,000-40,000 cells in 200 L per well and incubated overnight. The following day, medium was decanted, and cells were washed with 60 L of drug buffer (1 HBSS, 20 mM HEPES, pH 7.4), then 60 L of drug buffer was added per well. Cells were pre-incubated at in a humidified atmosphere at 37 C. before receiving drug stimulation. Drug stimulation utilized 30 L addition of drug (3) diluted in McCorvy buffer (1 HBSS, 20 mM HEPES, pH 7.4, supplemented with 0.3% BSA fatty acid free, 0.03% ascorbic acid) and plates were incubated at for 1 hour at 37 C. Substrate addition occurred 15 minutes before reading and utilized 10 L of the RLuc substrate coelenterazine 400a for Gq dissociation BRET.sup.2 (Prolume/Nanolight, 5 M final concentration). Plates were read for luminescence at 400 nm and fluorescent GFP.sup.2 emission at 510 nm at 1 second per well using a Mithras L B940 multimode microplate reader (e.g. one provided by Berthold). The BRET ratios of fluorescence/luminescence were calculated per well and were plotted as a function of drug concentration using Graphpad Prism 8 (Graphpad Software Inc., San Diego, CA). Data were normalized to % 5-HT stimulation and analyzed using nonlinear regression log(agonist) vs. response to yield E.sub.max and EC.sub.50 parameter estimates.
[0091] Calcium flux was measured using stable-expressing 5-HT.sub.2 Flp-In 293 T-Rex Tetracycline inducible system by methods known in the art (e.g. Investigation of the Structure-Activity Relationships of Psilocybin Analogues, ACS Pharmacol. Transl. Sci. 2020, Publication Date: Dec. 14, 2020, https://doi.org/10.1021/acsptsci.0c00176). Cell lines were maintained in DMEM containing 10% FBS, 10 g/mL Blasticidin, and 100 g/mL hygromycin B. At least 20-24 hours before the assay, receptor expression was induced with tetracycline (2 g/mL), and cells were seeded into 384-well poly-L-lysine-coated black plates at a density of 7,500 cells/well in DMEM containing 1% dialyzed FBS. On the day of the assay, the cells were incubated for 1 hour at 37 C. with Fluo-4 Direct dye (Invitrogen, 20 L/well) reconstituted in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) containing 2.5 mM probenecid. Drug dilutions were prepared at 5 final concentration in McCorvy buffer (20 mM HEPES-buffered HBSS, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After dye load, cells were allowed to equilibrate to room temperature for 15 minutes, and then placed in a FLIPR.sup.TETRA fluorescence imaging plate reader (Molecular Devices). The FLIPR.sup.TETRA was programmed to read baseline fluorescence for 10 s (1 read/s), and afterward 5 L of drug per well was added, and fluorescence was read for a total of 5-10 min (1 read/s). Fluorescence in each well was normalized to the average of the first 10 reads for baseline fluorescence, and then either maximum-fold peak increase over baseline or area under the curve (AUC) was calculated. Either peak or AUC was plotted as a function of drug concentration, and data were normalized to percent 5-HT stimulation. Data were plotted, and non-linear regression was performed using log(agonist) vs. response in Graphpad Prism 8 to yield E.sub.max and EC.sub.50 parameter estimates.
[0092] The functional activity of various compounds disclosed herein at each of the 5-HT.sub.2A, 5-HT.sub.2B, and 5-HT.sub.2C receptors was measured against and relative to the functional activity of 4-hydroxytryptamine at those receptors. A comparison of the functional activities is provided in Table 2 as follows. At least three replicate trials were performed for each compound:
TABLE-US-00002 TABLE 2 5-HT.sub.2A BRET 5-HT.sub.2B BRET 5-HT.sub.2C BRET Compound Identification EC.sub.50 EC.sub.50 EC.sub.50 (nM) Eff % (nM) Eff % (nM) Eff %
[0093] Many of the compounds disclosed in this disclosure show activity in the range of up to 400 nM at the 5-HT.sub.2A receptor, while showing inactivity at the 5-HT.sub.2B receptor and possessing greater activity at the 5-HT.sub.2A receptor than at the 5-HT.sub.2C receptor. Many of the compounds disclosed in this disclosure selectively activate the 5-HT.sub.2A receptor and show inactivity or limited activity at the 5-HT.sub.2B receptor. For example, the compounds disclosed in this disclosure may show activity at the 5-HT.sub.2A receptor in the range of less than about 1 M to about 400 nM, about 1 M to about 300 nM, about 1 M to about 200 nM, about 1 M to about 100 nM, about 1 M to about 90 nM, about 1 M to about 80 nM, about 1 M to about 70 nM, about 1 M to about 60 nM, about 1 M to about 50 nM, about 5 nM to about 95 nM, about 5 nM to about 80 nM, about 5 nM to about 65 nM, about 5 nM to about 50 nM, about 10 nM to about 90 nM, about 10 nM to about 80 nM, about 10 nM to about 70 nM, or any specific percentage therebetween. For example, the compounds disclosed in this disclosure may show selectivity for the 5-HT.sub.2A receptor over the 5-HT.sub.2C receptor in the following ranges: about 1 to about 100 fold, about 10 to about 100 fold, about 10 to about 90 fold, about 10 to about 80 fold, about 10 to about 70 fold, about 10 to about 60 fold, about 10 to about 50 fold, about 20 to about 100 fold, about 20 to about 80 fold, about 20 to about 60 fold, about 30 to about 90 fold, about 30 to about 60 fold, or any specific range therebetween. In an embodiment, the compound disclosed in this disclosure shows a selectivity for the 5-HT.sub.2A receptor over the 5-HT.sub.2C receptor of 10 to 100 fold.
[0094] Table 3 below summarizes the 5-HT receptor activity of psilocin, compound 109, and compound 93:
TABLE-US-00003 TABLE 3 Psilocin Compound 109 Compound 93 EC.sub.50, nM Eff, % EC.sub.50, nM Eff, % EC.sub.50, nM Eff, % 5-HT.sub.1A 46.9 93 4269 3 Not active 5-HT.sub.1B 14.3 94 Not active Not active 5-HT.sub.1D 2.2 102 378.7 6 Not active 5-HT.sub.1E 10.4 90 813.8 12 70060 211 5-HT.sub.1F 9.3 93 582.0 12 8086 69 5-HT.sub.2A 14.3 80 4.8 99 0.3 96 5-HT.sub.2B 2.1 32 3094 84 64.2 50 5-HT.sub.2C 16.7 86 225.4 110 1.5 99 5-HT.sub.4 562.6 81 0.2 3 Not active 5-HT.sub.5A 349 48 12330 133 Not active 5-HT.sub.6 182.5 74 5394 18 0.6 12 5-HT.sub.7 524.5 86 Not active 0.5 12
[0095] Phenethylamines of Formula 1 are generally known to potentially possess hERG risk. As a result of, many compounds disclosed in Table 1 and Table 2 were screened for the potential of hERG risk using pharmacological assays (e.g. Eurofins hERG Qube APC Assay). Compounds that exhibited strong potency at the 5-HT.sub.2A receptor were further assessed on hERG risk based on comparative exposure/IC.sub.50. A hERG IC.sub.50 value that is 30-fold greater than therapeutic free plasma concentration is the threshold for deeming a compound to be of low hERG risk.
[0096] An important factor for hERG risk evaluation at early drug discovery stage is the hERG IC.sub.50/in vitro 5-HT.sub.2a ratio; compounds exhibiting a ratio of over 200 will exhibit a ratio of hERG IC.sub.50 over estimated therapeutic plasma C.sub.max of greater than 30 (which is generally indicative of low hERG risk potential at clinically relevant dose levels); compounds exhibiting a ratio between 150-200 are generally indicative of moderate hERG risk potential; compounds exhibiting a IC.sub.50 (hERG) /EC.sub.50 (5-HT.sub.2A) ratio of less than or equal to 150 are generally indicative of high hERG risk potential. Table 4 summarizes the assessed hERG risk of various compounds in Tables 1 and 2.
TABLE-US-00004 TABLE 4 Compound IC.sub.50, EC.sub.50 IC.sub.50 (hERG)/EC.sub.50 hERG risk # M BRET .sub.2A (5-HT.sub.2A) ratio potential 109 2.9 4.8 604 Low 108 1.78 2.4 742 Low 27 2 4.2 476 Low 117 0.9 3.8 237 Low 93 0.62 1.2 517 Low 112 6 2.3 2609 Low 12 1.72 102 17 High 65 2 19.7 102 High 28 1.6 84 19 High 63 1.6 135 12 High 64 0.9 29.8 30 High 131 1.31 2.1 624 Low 122 0.79 1.4 564 Low Ref 2.3 451 5 High Compound 1a
[0097] Various compounds disclosed herein were subjected to an in vitro SafetyScreen44 panel for identifying off-target activity. Compounds of interest that are identified in the panel are then tested in follow up functional assays to identify if such compounds have a significant off-target risk. As summarized below in Table 5, compound 109 does not possess significant off-target activity. It is predicted that other compounds share similar characteristics with compound 109 and also lack of the off-target activity.
TABLE-US-00005 TABLE 5 SafetyScreen44 Compound panel hits Follow up studies 109 1a No significant 2a off-target activity Kappa (KOP) (MOP) 5-HT transporter (SERT)
[0098] Additional experimentation was performed on compound 109. Table 6 summarizes, among other things, the anticipated hepatic clearance of compound 109 in various species, as specified in Table 6 and as determined by calculating the in vitro hepatocyte clearance over time and scaling such rate with such species' hepatocyte count and the anticipated liver blood flow rate in such species.
TABLE-US-00006 TABLE 6 In vitro Scale- Hepatic In vitro Cl.sub.int up Cl.sub.int Extraction Predicted T.sub.1/2 (L/min/ (mL/min/ Ratio hepatic CL Species (min) 10.sup.6 cells) kg) (E) (mL/min/kg) Human 2.28 608.72 1548.76 0.99 20.43 Monkey 2.78 499.05 1796.57 0.98 42.57 Dog 6.96 199.06 1369.52 0.98 30.22 Rat 5.93 233.71 1093.74 0.95 52.55 Mouse <2.26 >614.02 >7253.14 >0.99 >88.90
[0099] Table 7a and Table 7b summarize, among other things, the observed plasma and Brain P K properties in animals, and the observed plasma and Brain P K properties predicted in humans, for compound 109 in Table 7a and compound 93 for Table 7b:
TABLE-US-00007 TABLE 7a T.sub.1/2 IM Brain BW Cl.sub.tot Vz Vz f Plasma Species (kg) [mL/h/Kg] [mL/Kg] (h) (%) AUC Ratio mice 0.029 17170.2 14040 0.6 144.5 8.39 rat 0.207 3204 9370 2.1 92.8 2.18 Dog 8.240 2382 4330 1.3 120.0 No Data Provided Human 70.0 971.1 2775.3 2.0 100.0 2.14 (predicted)
TABLE-US-00008 TABLE 7b BW Cl.sub.tot Vz T.sub.1/2 Brain/plasma Species (kg) [mL/h/Kg] [mL/Kg] Vz(h) Ratio mice 0.0265 11795 15112 0.9 15.6 rat 0.232 7622 15192 1.38 19.6 Dog 9.22 3188 7703 1.66 No Data Provided Human 70 2271 6391.8 1.95 9.55 (predicted)
[0100] HTR was assessed using a head-mounted neodymium magnet and a magnetometer detection coil, as described in Halberstadt et al., Psychopharmacology (Berl.), 2013, 227(4): 727-739. Table 8 below summarizes the ED.sub.50 in head twitch in mice of various compounds disclosed herein as compared to psilocybin.
TABLE-US-00009 TABLE 8 Cpd # ED.sub.50 in Head Twitch Psilocybin 0.38 mg/kg 112 0.73 mg/kg 109 2.69 mg/kg 108 7.23 mg/kg 93 0.28 mg/kg 27 3.00 mg/kg 117 2.09 mg/kg 131 1.24 mg/kg
[0101] The experimental data summarized in Tables 6-8 demonstrate that compound 109 exhibits high brain penetration, but less central hallucinogenic (or psychedelic) effects than traditional psychedelic compounds such as psilocybin.
[0102] Referring to
[0103] Additional experimentation was also done on compound 109. Namely, an intraperitoneal dose of up to 30 mg/kg of compound 109 and various reference compounds were delivered into healthy rat subjects and surgery induced abnormal rat subjects (olfactory bulbectomized rats). With regard to compound 109, there is no suggestion that an intraperitoneal dose of up to 30 mg/kg of such compound affects the normal locomotor activity of healthy rat subjects. However, a single dose of such intraperitoneal dose showed significant and long lasting inhibition of abnormal behavioral activity in the surgery induced abnormal rat subjects, in contrast to its short plasma t.sub.1/2 of less than an hour in healthy rat subjects. Without being bound by theory, it is believed that these observations are a result of long lasting neuroplasticity effects of compound 109 on surgery induced abnormal rat subjects.
[0104] Compound 93 also exhibited high clearance in in vitro tests. The results of this experiment are summarized in Table 9 below:
TABLE-US-00010 TABLE 9 In vitro Scale- In vitro Cl.sub.int up Cl.sub.int Predicted T.sub.1/2 (L/min/ (mL/min/ hepatic CL Species (min) 10.sup.6 cells) kg) (mL/min/kg) Human 25.28 54.83 139.52 18.03 Monkey 2.97 466.96 1681.07 42.50 dog 4.11 337.46 2321.69 30.49 Rat >2.26 <614.02 <2873.63 <54.16 Mouse >2.26 <614.02 <7253.14 <88.90
Methods of Chemical Synthesis
[0105] Non-limiting examples of procedures for preparing the compounds described herein are provided below.
[0106] N-Benzylphenethylamines can be prepared by N-benzylation of phenethylamines or N-phenethylation of benzylamines. These reactions may be carried out in a manner that leads directly to products in the oxidation state of amines using, for example, halides or sulfonates as alkylating agents. The amine nitrogen may be present in free form; or to avoid the common side-reactions of dialkylation and quaternization, the amine nitrogen may carry a protecting group that is removed at a later stage of the synthesis. The reactions may also be carried out using electrophiles at a higher oxidation state to obtain products such as imines or carboxamides that need to be reduced in situ or in a subsequent step to arrive at the desired amines. For example, a commonly employed protocol to effect the reductive alkylation of a primary amine consists of treating the amine with an aldehyde in the presence of a mild reducing agent, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride. Dialkylation and direct reduction of the aldehyde prior to imine formation represent frequently observed side reactions. Amines also readily react with acylating agents, such as acyl halides, carboxylic acid anhydrides, or free carboxylic acids in the presence of condensating agents, of which numerous representatives are known from research in the field of peptide synthesis, to form carboxamides. Unlike the often hydrolytically sensitive imines, carboxamides are stable compounds that are isolated and then reduced to amines in a subsequent step. This reduction process requires either strong reducing agents, such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), or borane, which are usually incompatible with the nitrile function that is present in many of the target compounds; or the carboxamide needs to be activated by formation of a mixed imidic acid anhydride upon treatment with a strong electrophile. Employing triflic anhydride in that role, carboxamides are reduced to amines without affecting nitriles and a variety of other reducible functional groups by sodium borohydride (Huang, P.-Q.; Geng, H. Org. Chem. Front. 2015, 2, 150) or by the mild hydride donor, Hantzsch ester (Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817). For a=b=c=H, the general synthetic scheme for the present target compounds of Formula I is shown in
[0107] The building blocks for the benzyl portion of phenethylamine can, among other possible approaches, be prepared by standard functional group transformations as shown (without details in the scheme) in
[0108] The same and additional functional group transformations can be enlisted to obtain commercially unavailable patterns of the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8. Halogen substituents, including F, can be accessed by halodecarboxylation of carboxylic acids (Varenikov, A.; Shapiro, E.; Gandelman, M. Chem. Rev. 2021, 121, 412). Aromatic fluorides can also be obtained from numerous other aromatic starting materials (Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612), for example from aromatic amines through the Balz-Schiemann reaction, or from other halides by halogen exchange. Transition-metal-mediated halogen exchange is applicable to a variety of combinations of the leaving and incoming halogen (Evano, G.; Nitelet, A.; Thilmany, P.; Dewez, D. F. Front. Chem. 2018, 6, article No. 114). Aryl triflates, readily available derivatives of phenols, also participate in this type of reaction (Sather, A. C.; Lee, H. G.; De La Rosa, V. Y.; Yang, Y.; Mller, P.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 13433). Trifluoromethylated aromatics can be synthesized, for example, from carboxylic acids with SF.sub.4; from amines by Sandmeyer reaction with sodium trifluoromethanesulfonate (Hong, J.; Wang, G.; Huo, L.; Zheng, C. Chin. J. Chem. 2017, 35, 761) orTogni's reagent II (1-trifluoromethyl-1,2-benziodoxol-3(1H)-one; Hong, J.; Huo, L.; Yang, Y.; Wang, G.; Zheng, C. Chem. Select 2017, 2, 3716); or from aryl halides by transition-metal-catalyzed nucleophilic trifluoromethylation (Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S. Tetrahedron 2011, 67, 2161). Difluoromethyl substituents are frequently generated from aldehydes by deoxofluorination. The group of reagents capable of performing this transformation has recently been enlarged by the combination of Selectfluor and diphenyl sulfide (He, G.; Xiao, X.; Jin, H.-Z.; Lin, J.-H.; Zhong, T.; Zheng, X.; Xiao, J. C. Tetrahedron 2021, 83, article No. 131963). (Trifluoromethoxy) arenes can be obtained from phenols by reaction of their derived xanthates with the commercial fluorinating agent, XtalFluor-E (diethylaminodifluorosulfinium tetrafluoroborate (Yoritate, M.; Londregan, A. T.; Lian, Y.; Hartwig, J. F. J. Org. Chem. 2019, 84, 15767). Aromatic amines are transformed to (trifluoromethoxy) arenes through action of AgOCF.sub.3 on their derived diazonium salts (Org. Lett. 2019, 21, 8003). The trifluoromethylthio group can be introduced into aromatics by displacement of other heteroatoms with the SCF.sub.3 moiety, or by electrophilic substitution of hydrogen in electron-rich aromatics (Barata-Vallejo, S.; Bonesi, S.; Postigo, A. Org. Biomol. Chem. 2016, 14, 7150). (Trifluoromethylthio) arenes are also obtained from arylthiols by reaction with electrophilic or free-radical trifluoromethylating agents, such as S-(trifluoromethyl)sulfonium salts or CF.sub.3 halides (review together with other methods: Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731). (Difluoromethoxy)and (difluoromethylthio) arenes are obtained from phenols and arenethiols, respectively, and various sources of difluorocarbene, in a recent example, an S-(difluoromethyl)diarylsulfonium salt (Liu, G.-K.; Qin, W.-B.; Li, X.; Lin, L.-T.; Wong, H. N. C. J. Org. Chem. 2019, 84, 15948).
[0109] Building blocks for the phenethyl portion can, among other possible approaches, be prepared by standard functional group transformations as generally shown in the scheme depicted in
[0110] As an example for the synthetic methods of the preceding paragraphs, two syntheses of the compound 12 are depicted in
[0111] Various heterocycles annulated to either benzene ring are encountered in certain compounds of this disclosure, resulting from the presence of linkages between R.sup.1 and R.sup.2, R.sup.3 and Z, and/or R.sup.4 and R.sup.5. As examples, syntheses of the phenethylamine building block for compound 32 (with a linkage between R.sup.1 and R.sup.2) and of the benzylamine building block for compound 76 (with a linkage between R.sup.4 and R.sup.5) are depicted in
[0112]
[0113]
[0114] Deuterium may be incorporated into the present compounds in various ways, using deuterated versions of reagents and building blocks under the same or similar conditions as those employed for their counterparts with natural hydrogen isotope composition. The reduction of carboxamides with commercially available LiAID.sub.4 or BD.sub.3-THF complex results in amines deuterated on the methylene group that originates from the amides' carbonyl group. Similarly, reductive aminations/alkylations can be effected with NaBD.sub.4 and NaBD.sub.3CN. Aromatics and heteroaromatics can also be deuterated by reaction with an excess of D.sub.2O in the presence of a heterogeneous transition metal catalyst (Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. Chem. Pharm. Bull. 2018, 66, 21-28). Deuteration of specific positions in aromatic or heteroaromatic rings is achievable by halogen-metal exchange reactions on compounds that bear a halogen atom (typically Br or 1) at the position to be deuterated, followed by quenching of the (hetero-)arylmetal intermediate with a deuterating agent such as D.sub.2O or CH.sub.3OD; or by free-radical deuterodehalogenation of the same precursors with Bu.sub.3SnD and a radical starter such as azobis(isobutyronitrile) or dibenzoyl peroxide; or by reaction of the same precursors with a deuteride source such as Bu.sub.3SnD or formic acid-d.sub.2 and a transition metal catalyst.
Methods of Use
[0115] Compounds described herein are believed to be useful in the treatment of depression (including major depressive disorder), drug resistant depression, psychotic depression, and PTSD, as well as to serve as stimulants, anorectics, decongestants, bronchodilators, and as psychedelics. In addition, the compounds disclosed herein are also believed to be useful in the treatment of addiction including alcoholism, tobacco addiction, cocaine addiction, and opioid addiction, pain indications including neuropathic pain, pain from chemotherapy associated neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headaches, migraines, dementia including Alzheimer's dementia, Parkinson's disease dementia, and Lewy body dementia, emotional distress associated with cancer, Fragile-X syndrome, autism spectrum disorder, bipolar disease, obsessive compulsive disease, Rett syndrome, and other CNS disorders.
[0116] Substituted phenethylamines make up a group of phenethylamine derivatives that contain phenethylamine as a backbone; in other words, this chemical class includes derivatives that are formed by replacing one or more of the hydrogen atoms in the phenethylamine scaffolding with other substituents. The class of substituted phenethylamines includes all substituted amphetamines, and substituted methylenedioxyphenethylamines (e.g., MDMA), and contains many drugs which act as empathogens, stimulants, psychedelics, anorectics, bronchodilators, decongestants, and/or antidepressants, inter alia.
[0117] Another potential use of these analogs is in the treatment of seizure disorders, including but not limited to infantile seizure disorders such as Dravet syndrome (Sourbon, J. et al. Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model, ACS Chem. Neurosci. 2016, 7, 588-598).
[0118] Another potential use of these analogs is in the treatment of compulsive disorders, anxiety disorders, fear disorders and aggressiveness in animals; non-limiting examples of animals include dogs, cats, pigs, mice and rats. Another potential use of these analogs is in inducing contraction of the ureter in animals; non-limiting examples of animals include dogs, cats, pigs, mice and rats.
[0119] The compounds described herein are believed to be safer than psilocybin, given that they lack at least some of the undesirable characteristics of 5-HT.sub.2B-agonist related activities.
Methods for Administration
[0120] As contemplated herein, a therapeutically effective amount of a compound described herein is administered to a subject in need thereof. Whether such treatment is indicated depends on the subject case, and is further subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
[0121] As contemplated herein, a compound described herein may be administered by any suitable route known in the art. Such routes include, but are not limited to, oral, buccal, inhalation, topical, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, transdermal, and parenteral administration (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site). Parenteral administration may be accomplished using a needle and syringe or using a high pressure technique.
[0122] Pharmaceutical compositions include those wherein a compound described herein is present in a sufficient amount to be administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by a qualified medical practitioner in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a compound described herein that is sufficient to maintain the desired therapeutic effects. It is possible that the compound described herein may only require infrequent administration (e.g. monthly, as opposed to daily) to achieve the desired therapeutic effect.
[0123] As contemplated herein, a therapeutically effective amount of a compound described herein adapted for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the compound that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently may be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four, or more subdoses per day. Multiple doses often may be desired or required.
[0124] As contemplated herein, the compounds described herein may be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the compounds described herein are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the compounds described herein.
[0125] Water is a preferred carrier when a compound described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
[0126] These pharmaceutical compositions may be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of a compound described herein is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a compound described herein. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a compound described herein.
[0127] When a therapeutically effective amount of a compound described herein described herein is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains an isotonic vehicle. A compound described herein can be infused with other fluids over a 10-30 minute span or over several hours.
[0128] The compounds described herein may be readily combined with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
[0129] Pharmaceutical preparations for oral use can be obtained by adding a compound described herein to a solid excipient, with or without grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added.
[0130] A compound described herein may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.
[0131] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a compounds described herein can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
[0132] In some embodiments, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0133] A compound described herein also may be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, a compound described herein also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound described herein may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.
[0134] A compound described herein may be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. The compounds described herein also may be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compounds described herein may be best used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. At least in some embodiments, compounds described herein are psilocybin analogs.
General
[0135] It is contemplated that any part of any aspect or embodiment discussed in this specification may be implemented or combined with any part of any other aspect or embodiment discussed in this specification. While particular embodiments have been described in the foregoing, it is to be understood that other embodiments are possible and are intended to be included herein. It will be clear to any person skilled in the art that modification of and adjustment to the foregoing embodiments, not shown, is possible.
[0136] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the content of this disclosure belongs. In addition, any citation of references herein is not to be construed nor considered as an admission that such references are prior art that are relevant to the content of this disclosure.
[0137] The scope of the claims should not be limited by the example embodiments set forth herein, but should be given the broadest interpretation consistent with the description as a whole.