C-3 Amido-Indole cannabinoid receptor modulators

Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylic acid, key intermediate in the synthesis of novel 3-amidoindole and indolopyridone cannabinoid ligands

“…Proton NMR spectra were recorded with a Bruker DRX-400 spectrometer using CDCl 3 or DMSO-d 6 as solvent and TMS as an internal standard. Chemical shifts (δ) are given from TMS (0 ppm) as internal standard for proton NMR.…”

“…[2][3][4] In our search for novel cannabinoid receptor modulators, it was discovered that 7-methoxy-2-methyl-1-(2-morpholinoethyl)-N-((1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-indole-3-carboxamide 1 binds selectively to the CB2 receptor and displays excellent in vivo potency against LPS induced TNF-α release in murine models of cytokine production. 3 Further optimization led to a novel cannabinoid ligand 2 which shows high affinity for the CB2 receptor (K i = 1.0nM) and possesses anti-inflammatory properties when administered orally in an in vivo murine inflammation model. 4 This novel C-3 amido indole and its cyclized and conformationally constrained indolopyridone cannabinoid receptor modulators 1 and 2 are derivatives of indole-3-carboxylates.…”

“…Alternatively, the indole-3-carboxylate could be prepared by acylation of 7-methoxy-2-methyl-1H-indole 4 with trichloroacetyl chloride followed by alcoholysis. 3,5 An example of this preferred approach is the preparation of methyl indole-3-carboxylate 5b, which was obtained in 92% yield. 3 The introduction of the N-morpholinoethyl side chain onto the indole-3-carboxylate 5 was accomplished by treating 5 with 4-(2-chloroethyl)morpholine hydrochloride 6 in the presence of a large excess of base.…”

“…3,5 An example of this preferred approach is the preparation of methyl indole-3-carboxylate 5b, which was obtained in 92% yield. 3 The introduction of the N-morpholinoethyl side chain onto the indole-3-carboxylate 5 was accomplished by treating 5 with 4-(2-chloroethyl)morpholine hydrochloride 6 in the presence of a large excess of base. Thus, treatment of ethyl indole-3-carboxylate 5a with 4 equivalents of sodium hydride followed by addition of 6 gave ethyl 7-methoxy-2-methyl-1-(2-morpholinoethyl)-1H-indole-3-carboxylate 7 in 62% yield after purification by silica gel chromatography.…”

Functional Activity and Switching of Novel Cannabinergic Ligands

“…Thus, hydrogen or methyl groups are well tolerated with the C-2 H analogs (e.g., 136, Figure 4.11) (CB1 Ki = 245 nM; CB2 Ki = 11 nM) exhibiting slightly higher affinities for the CB2 than C-2 methyl analogs (137, Figure 4.11) (CB1 Ki = 8 nM; CB2 Ki = 29 nM). 282,291,292 Recently, researchers at BristolMyers-Squibb reported their discovery of indazole carboxamides (e.g., 138, Figure 4.11), replacing the C-2 carbon of 3-amido aminoalkylindoles (136) 3.1.3. C-3 substituents of aminoalkylindoles.…”