Showing papers by "Lawrence S. Melvin published in 1981"

Selective and potent analgetics derived from cannabinoids.

Abstract: Based on the hypothesis that analgetic activity is a dissociable feature of the cannabinoid molecule, we examined modifications of the side chain, the phenolic moiety, and, most significantly, structures that lack the benzopyran functionality present in THC and (--)-9-nor-9 beta-hydroxyhexahydrocannabinol (HHC). A new grouping, the 1-methyl-4-phenylbutyloxy C-3 side chain, elaborates a unique lipopholic region. Replacement of the phenol substituent produced several derivatives which retain analgetic activity in the codeine potency range. Introduction of a weakly basic nitrogen at C-5 and deletion of the axial methyl group in the B ring, two structural changes forbidden by traditional cannabinoid SAR, resulted in a unique family of benzoquinolines with potent analgetic activity. The prototype of this series, levonantradol, exhibits potent and stereospecific analgetic and antiemetic activity.

2-Hydroxy-4-(substituted) phenyl cycloalkanes and derivatives

Abstract: Compounds having the formula ##STR1## R 1 is hydrogen, benzyl or an ester moiety; Y is --CH(R 2 ")CH(R 2 )-- or--CH(R 3 )CH 2 --; R 2 " is hydrogen or methyl; R 2 is OH or X-substituted (C 1-6 )alkyl; R 3 is OH, cyano or X-substituted (C 1-3 ) alkyl; X is --OR 6 , --SR 6 , --S(O)R 6 , --S(O) 2 R 6 , --NR 6 R 7 , --COOR 7 , --CONR 7 R 8 or oxo; with the proviso that when X is --NR 6 R 7 , --COOR 7 or --CONR 7 R 8 , said group is located on the terminal carbon atom of R 2 or R 3 ; R 6 is hydrogen, (C 1-6 )alkyl or acetyl; each of R 7 and R 8 is hydrogen or (C 1-6 )alkyl; s is an integer of 1 or 2; with the proviso that when R 6 is acetyl, R 7 is hydrogen and X is other than S(O)R 6 or S(O) 2 R 6 ; Z--W is alkyl, phenylalkyl or pyridylalkyl which can have an oxygen atom as part of the alkyl chain, and their use as CNS agents, antidiarrheals and antiemetics. Processes for their preparation and intermediates therefor are described.

3-¬2-hydroxy-4-(substituted)phenyl|-cycloalkanone and cycloalkanol analgesic agents and intermediates therefor

Abstract: Cycloalkanones, cycloalkanols and unsaturated analogs thereof, each of which has at the 3-position a 2-hydroxy-4-substituted phenyl group wherein the 4-position substituent is alkyl which can have an oxygen atom as part of the chain, or aralkyl which can have an oxygen atom as part of the alkyl chain, their use for pharmacological and medicinal purposes, intermediates therefor and processes for their preparation.

Pharmacologically active 4-[2-hydroxy-4-(substituted)phenyl]naphthalen-2(1H)-ones and 2-ols, derivatives thereof and intermediates therefor

Abstract: Compounds having the formula wherein is = 0, , , , or ; is =0, , =CH2, , , , , or ; R1 is hydrogen, benzyl or alkanoyl, X is C2-4 alkylene; and Z-W is alkyl, phenylalkyl or pyridylalkyl which can have an oxygen atom as part of the alkyl chain and their use as CNS agents, antidiarrheals and anti-emetics. Processes for their preparation and inter-mediates therefor are described.

Potent analgetics derived from 9-nor-9 beta-hydroxyhexahydrocannabinol.

Abstract: Based on the report of morphine-like analgetic activity of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC), we undertook a study of structural modifications of the C-3 side chain of HHC to optimize the analgetic activity. We ultimately examined four distinct classes of side chains: (1) alkyl (la-lc), (2) arylalkyl (ld-lh), (3) alkoxy (li-lj) and (4) arylalkyloxy (lk-lo). Three of these derivatives (lb, lf, ll) possessed analgetic activity 10X morphine. These studies demonstrate that the C-3 side chain of HHC can be modified in a structure-dependent fashion to yield potent, nonopioid analgetics. In addition, the effect of the 1 methyl-4-phenylbutyloxy side chain is unique among the side chains examined.