63789-86-6Relevant articles and documents
Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)
Dutta,Ryan,Thomas,Singer,Compton,Martin,Razdan
, p. 1591 - 1600 (2007/10/03)
Several novel 4-alkyloxy-aminoalkyl indole derivatives 3 were synthesized from 4-benzyloxyindole (1). Alkylation of 1 with 4-(2-chloroethyl)morpholine (NaH/HMPA) formed 2. Deprotection using palladium hydroxide on carbon/hydrogen followed by alkylation with the appropriate alkyl bromide gave the target compounds 3b-3j, the appropriate alkyl bromides 13 and 17 were prepared from the commercially available 1-naphthylethyl bromide 9 using the chain lengthening sequences as shown in Scheme 3. In receptor binding assay and in vivo testing, the long chain alkoxy compounds 3g and 3h (K(i)=127 nM) showed affinity for the CB1 receptor which was approximately 16-35-fold less than that of WIN 55,225. However, the pharmacological profile of 3h mimics that of WIN 55,212. An examination of the SAR of these analogues shows that translocating the napthyl group in AAIs from the C-3 position to C-4 via an oxygen (ether linkage) decreases activity which is in contrast to previous findings that a naphthylcarbonyl at C-4 retains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeling work suggest that, although reasonable superposition of key structural features between Δ9-THC and AAIs can be made, the overlay is not straightforward. The present study also illustrates the difficulty in accommodating AAIs into the cannabinoid pharmacophore and it seems likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical cannabinoid pharmacophore be clearly delineated.
9-Hydroxydibenzo[b,d]pyrans and intermediates
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, (2008/06/13)
9-Hydroxydibenzo[b,d]pyrans useful as analgesics, hypotensives, immunosuppressants, tranquilizers; as anti-secretory and anti-anxiety drugs; intermediates therefor and derivatives thereof having the formulae STR1 wherein R is hydrogen or alkanoyl having from one to five carbon atoms; R1 is hydrogen, alkanoyl having from one to five carbon atoms or --CO--(CH2)P --NR2 R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; Each of R4 and R5 is hydrogen, methyl or ethyl; R0 is oxo or alkylenedioxy having from two to four carbon atoms; Z is (a) alkylene having from one to nine carbon atoms; (b) --(alk1)m --X--(alk2)n --wherein each of (alk1) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than 9; Each of m and n is 0 or 1; X is O, S, SO or SO2 ; and W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl; With the proviso that when W is methyl, Z is --(alk1)m --X---(alk2)n --.
