Hashish: synthesis and central nervous system activity of some novel analogs of cannabidiol and oxepin derivatives of .DELTA.9-tetrahydrocannabinol

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Abstract
Several C-10 substituted cannabidiol (CBD) derivatives and novel oxepin derivatives of .DELTA.9-tetrahydrocannabinol (.delta.9-THC) were synthesized and evaluated for biological activity in mice and dogs. Treatment of 10-bromocannabidiol diaceteate (3) with various amines in Me2SO gave the corresponding 10-aminocannabidiol derivatives 4-6 [10-morpholinocannabidiol diacetate, 10-(d-isopropylamino)cannabidiol diacetate and 10-(methylpropargylamino)cannabicidol diacetate]. Treatment of 3 with NaN3 gave the azido compound 7, which with LiAlH4 afforded the 10-aminocannabidiol 9. Reduction of 7 with CrCl2 formed the amide, which on further reduction with LiAlH4 gave the N-ethyl analog 10 [10.alpha.-(ethylamino)cannabidiol]. The oxepin analog was synthesized from 3 by treatment with Na2CO3 in CH3OH/H2O at room temperature. The dimethylheptyl analogs was similarly prepared. Incorporation of N-ethyl, N-methyl-N-propargyl, and morpholino groups in CBD at positon 10 resulted in analogs that were more potent than CBD in producing hypoactivity in mice. These analogs had relatively little effect on rectal temperatures. Selected substitutions at C-10 also resulted in analogs that were partially effective in blocking .DELTA.9-THC antinociceptive activity. This blockade was observed particularly in compound 10, which also showed unusually toxic properties. Incorporation of a 7-membered oxepin in the .DELTA.9-THC structure eliminated cannabinoid activity although substitution of the pentyl side chain with a 1,2-dimethylheptyl in the oxepin resulted in CNS depression in mice.