Synthese von neuen (Phenylalkyl)aminen zur Untersuchung von Struktur–Aktivitätsbeziehungen. Mitteilung 2

Abstract

Synthesis of Novel (Phenylalkyl)amines for the Investigation of Structure ± Activity Relationships. Part 2 1 ).4-Thio-Substituted [2-(2,5-Dimethoxyphenyl)ethyl]amines ( 2,5-Dimethoxybenzeneethanamines)The 4-substituted [2-(2,5-dimethoxyphenyl)ethyl]amines ( 2,5-dimethoxybenzeneethanamines) and its amethyl analogs are known to act as potent 5-HT 2A/C ligands, which have, depending on their 4-substituent, agonistic or antagonistic character. Generally, compounds with a small lipophilic substituent typically are agonists and those with a larger lipophilic substituent predominantly antagonists or at least partial agonists.Since little is known about the transition and more information is needed about the structural requirements of the 4-substituent to control the functional activity, 12 novel 4-thio-substituted [2-(2,5-dimethoxyphenyl)ethyl]amines were synthesized and spectroscopically characterized. Thus 2,5-dimethoxybenzenethiol (7) was converted to the thioether derivatives 8a ± l with several alkyl, fluoroalkyl, alkenyl, and benzyl halides. Subsequent Vilsmeier-formylation afforded the benzaldehydes 9a ± l, condensation with MeNO 2 the nitroethenyl derivatives 10a ± l, and reduction with AlH 3 the desired (2-phenylethyl)amines 11a ± l.Einf¸hrung. ± Der Neurotransmitter Serotonin ( 5-Hydroxytryptamin; 5-HT; 1) ist f¸r die Regulierung vieler biologischer Prozesse in Tieren und im Menschen verantwortlich, unter anderem f¸r Funktionen wie Schlaf, Appetit und sexuelle Aktivit‰t, aber auch andere mentale Prozesse sind involviert [2]. Die Beeintr‰chtigung der serotonergen Neurotransmission im Zentralnervensystem wurde mit diversen Krankheiten wie Depression, Phobien, Schizophrenie und Migr‰ne in Verbindung gebracht [3]. Die Wirksamkeit der Medikamente, welche solche Dysfunktionen zumindest teilweise zu unterbinden vermˆgen, liegt in der Interaktion mit 5-HT-Rezeptoren oder in der Modulation der serotonergen Neurotransmission. Viele Medikamente weisen zwar einen gewissen Grad der erw¸nschten Wirkung auf, jedoch ist diese nicht zuletzt oft wegen der unselektiven Rezeptor-Interaktion von Nebenwirkungen begleitet. Diese Lage erfordert neue, selektive Liganden, welche die einzelnen Funktionen der Rezeptor-Subtypen besser zu verstehen geben, um schliesslich gezielter Medikamente entwickeln zu kˆnnen.

Fluorine in psychedelic phenethylamines

“…[3] An even more dramatic increase of human potency has been observed with a 4-O to 4-S substitution. [85] Among numerous modifications of the 4-position, [3,86] 4-fluoroalkoxy derivatives have been prepared and investigated ( Figure 5). [3] It seems that the 5-HT 2A receptor affinities do not increase sufficiently by these structural modifications to explain the increased human potency; the enhanced lipophilicity and receptor activation could also play an important role.…”

“…4-Thiomescaline (4-TM, 71) is one order of magnitude more potent than mescaline. [86] The smallest investigated fluoro analogs of mescaline (22: 180-360 mg, 10-12 h), namely difluoromescaline (72: 50-100 mg, 12-18 h) and trifluoromescaline (73: 15-40 mg, 14-24 h) proved to show psychedelic properties, with 73 being one of the most potent mescaline derivatives so far discovered. [85] Among numerous modifications of the 4-position, [3,86] 4-fluoroalkoxy derivatives have been prepared and investigated ( Figure 5).…”

“…[86] A fluorinated analog of proscaline (79) [3] was also investigated. [86] At the cloned [ 3 H]ketanserin-labelled serotonin h5-HT 2A receptor fluoroproscaline (80: K i = 8792nM) showed only low affinity and in humans, fluoroproscaline (80: 60-150 mg, 3-5 h) was distinctly less potent and of shorter duration than proscaline (79: 30-60 mg, 8-12 h). Similarly, limited trials suggest that trifluoroproscaline (81: 66 mg or more) might be less potent as well.…”

“…[5] A series of 4-fluoroalkoxy analogs of 3,4,5-trimethoxyamphetamine (TMA, 12: 100-200 mg, 6-8 h [3] ) has also been investigated ( Figure 6, A). [86] The influence of fluorine introduction could not yet fully be determined, as at present too little biological data of either the non-fluorinated derivatives (85 [3] and compounds described in Trachsel [86] ) or the fluoro analogs 84 and 86-89 is available. For some fluorinated 3,4,5-substituted compounds some volunteers reported skin itching during experiments.…”

4‐Aryl‐Substituted 2,5‐Dimethoxyphenethylamines: Synthesis and Serotonin 5‐HT2A Receptor Affinities

“…The Suzuki protocol described above was applied to 10 and worked as well for the preparation of compound 11. A Henry condensation using the catalyst system BuNH 2 /AcOH [29] yielded the nitrostyrene 12. Final reduction of 12 with AlH 3 in THF at 08 afforded amine 6 in 75% yield.…”