Glennon: Oxygenated DOB analogues

[Lego]

beta-Oxygenated Analogues of the 5-HT_2A Serotonin Receptor Agonist 1-(4-Bromo-2,5-dimethoxyphenyl)-2-aminopropane
Richard A. Glennon, Mikhail L. Bondarev, Nantaka Khorana, Richard Young, Jesse A. May, Mark R. Hellberg, Marsha A. McLaughlin, and Najam A. Sharif
J. Med. Chem., 2004, ASAP Web Release Date: 16-Oct-2004
DOI:

10.1021/jm040082s

Abstract: Activation of 5-HT_2A serotonin receptors represents a novel approach to lowering intraocular pressure.  Because 5-HT_2A serotonin receptor agonists might also produce undesirable central effects should sufficient quantities enter the brain, attempts were made to identify 5-HT₂ serotonin receptor agonists with reduced propensity to penetrate the blood-brain barrier. 1-(4- Bromo-2,5-dimethoxyphenyl)-2-aminopropan-1-ol (6), an analogue of the 5-HT₂ serotonin receptor agonist 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB; 1a) bearing a benzylic hydroxyl group, was identified as a candidate structure. Of the four optical isomers of 6, the 1R,2R-isomer (6d; K_i = 0.5 nM) was found to bind at 5-HT_2A receptors with an affinity similar to that of R(-)DOB (K_i = 0.2 nM). Like R(-)DOB, 6d behaved as a partial agonist (efficacy ca. 50%) in a 5-HT₂-mediated calcium mobilization assay. However, in an in vivo test of central action (i.e., stimulus generalization with rats as subjects), 6d was >15 times less potent than R (-)DOB. O-Methylation of 6d (i.e., 7d; 5-HT_2A Ki = 0.3 nM) resulted in an agent that behaved as a full (93% efficacy) agonist. Intraocular administration of 300 µg of 6d and 7d to ocular hypertensive monkeys was shown to reduce intraocular pressure by 20-27%. Given the route of administration (i.e., topical), and concentrations necessary to reduce intraocular pressure, compounds such as 6d should demonstrate minimal central effects at potentially useful therapeutic doses and offer useful leads for further development.



Scheme 1 Reagents and conditions: (a) Br₂/CHCl₃, 5 °C to room temperature, 2 h; (b) (CH₂)₆N₄/CHCl₃, 50 °C, 1 h, then HCl/EtOH, 50 °C, 3 h; (c) NaBH₄/MeOH, 0 °C; (d) ClCH₂COCl/NaOH/H₂O/CH₂Cl₂, 0 °C to room temperature, 2 h; (e) KOH/EtOH, 12 h, room temperature; (f) BH₃-THF, reflux, 12 h.




Scheme 2 Reagents and conditions: (a) (COCl)₂/CH₂Cl₂, 1-bromo-2,5-dimethoxybenzene/TiCl₄, -50 C to room temperature, 60 h; (b) SiH(CH₃)2Ph/TFA, -5 °C, 2 h then K₂CO₃, reflux, 2 h; (c) Ac₂O, room temperature to 110 °C, 1 h, then 60% H₂SO₄, 110 °C, 1 h; (d) NaH/THF, 0 °C to room temperature 0.5 h, then MeI, reflux, 1 h.

[Captain_America]

1-Hydroxy-1-(4-bromo-2,5-dimethoxyphenyl)-2-aminoethane
Hydrochloride (3b).

Bromine (7.99 g, 50 mmol) in CHCl₃ (20 mL) was added in a dropwise manner to a stirred solution of 2,5-dimethoxy-4-bromoacetophenone (12.95 g, 50 mmol) in CHCl₃ (100 mL) at 5 °C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The mixture was poured onto crushed ice; the organic portion was separated and washed with H₂O (2 x 100 mL), saturated NaHCO3 solution (2 x 100 mL), and again with H₂O (2 x 100 mL). The solution was dried (MgSO₄) and evaporated to dryness under reduced pressure to give a crude brown/white product. The product was recrystallized from MeOH to yield 14.70 g (87%) of the desired bromoacetophenone product as a white solid: mp 122-123 °C.

A solution of the above 2,5-dimethoxy-4-bromo-alpha-bromoacetophenone (16.90 g, 50 mmol) and hexamethylenetetramine (7.00 g, 50 mmol) in CHCl₃ (200 mL) was allowed to stir at 50 °C for 1 h. The reaction mixture was allowed to cool to the room temperature, and the white precipitate was collected by filtration and washed with CHCl3 (3 x 25 mL). The resulting quaternary salt was suspended in a mixture of 95% EtOH (50 mL) and concentrated HCl (25 mL) and heated at 50 °C for 3 h. After 15 min, the reaction mixture was homogeneous and the aminophenone hydrochloride began to crystallize. The mixture was cooled to 0 °C and the white solid was collected by filtration. The solid was recrystallized from H₂O and dried in vacuo over CaCl₂ to afford 10.25 g (66%) of crude product as its HCl salt, which was used without further purification.

Sodium borohydride (12.48 g, 330 mmol) was added in small portions to a stirred solution of the aminoacetophenone (10.25 g, 33 mmol) in MeOH (250 mL) at 0 °C over 1.5 h. After the addition was complete, the reaction mixture was allowed to stir at 0 °C for an additional 2 h. Solvent was evaporated under reduced pressure, H₂O (150 mL) was added, and the resulting mixture was extracted with CH₂Cl₂ (3 x 75 mL). The combined CH₂Cl₂ portions were washed with H₂O (3 x 50 mL) and dried (MgSO4). Solvent was evaporated under reduced pressure to give the crude free base of 3b as a yellow-white solid which was purified by recrystallization from MeOH/Et₂O to give the free base of 3b as white crystals: mp 130-131 °C. The free base in MeOH (50 mL) was treated with ethereal HCl and solvent was evaporated under reduced pressure to give 8.56 g (83%) of 3b as off-white crystals following recrystallization from 2-PrOH: mp 204-207 °C

The reduction of aminoacetophenone to corresponding alcohol would prolly work w/ sodiumdithionite instead of sodiumborohydride... It is known to reduce benzylic ketones to alcohols in high yield;

Post 497065

(Ganesha: "dithionite aldehyde/ketone reductions part II", Novel Discourse)

For the mild removal of the -OH;

Post 504623

(Kinetic: "Another way to methaephetamine", Novel Discourse)

Overall the route is interesting becouse of Delephine. This step yields somewhat low even on primary bromoketones and it's not a very OTC route if you want to make 2C-X compounds, there is better route for that. But more importantly, someone should try to taste the aminoketone instead of reducing it, it might show some interesting activity. If so this route would bee preffered for possible "CAT Pihkality" IMO. All in all - a good post Lego!

[Dextrose]

SWIM has wondered about the activity of the non-alpha-methylated cathinone-analogue (compund #9) for quite some time.

Perhaps the beta-substitution of cathinone works likewise on PEA's, providing a smooth 2C-B analogue?

Just a thought...

Edit: NM, SWIM just found Rhodium's post about beta-Keto-PEA's - seems like he isn't the only one wondering!