ROGERADAMS, S. LOEWE,C. M. SMITHAND W. D. MCPHEE
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brecht for the preparation of acetylated CY- and /3-phenylglycosides has been improved. 2. A method has been described for the rearrangement of tetraacetyl- 6-phenylglucoside to tetraacetyl-a-phenylglucoside. 3. A method has been described for the transformation of tetraacetyl-a-methylglucoside and
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other acetylated glycosides to the corresponding acetylated phenylglycosides. 4. a-Phenyl-D-xyloside, triacetyl-a-phenyl-Dxyloside and a-o-nitrophenyl-D-glucosidehave been described. New data are reported for a number of other phenylglycosides. f j r THESDA,
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[CONTRIBUTION FROM THE KOYESCHEMICAL LABORATORY, UNIVERSITYOF ILLINOIS, AND FROM THE DEPARTMENT OF PHARMACOLOGY, CORNELL UNIVERSITY MEDICALCOLLEGE, I N COLLABORATION WITH THE TREASURY DEPARTMENT: NARCOTICS LABORATORY, WASHINGTON, D. C. ]
Tetrahydrocannabinol Homologs and Analogs with Marihuana Activity. XIII' BY ROGERADAMS,S. LOEWE,C. M. SMITHAND W. D. MCPHEE The series of homologs of tetrahydrocannabinol (I), in which the 3-n-amyl group is replaced by other groups, has been found to exhibit a maximum activity in the n-hexyl compound.2 The corresponding hexahydrocannabinol and its homologs have been prepared and the marihuana potencies determined. This series also exhibits a. potency maximum in the 3-mhexyl compound and with the exception of the n-hexyl and the n-butyl derivatives the potencies are all lower than those of the corresponding tetrahydro compounds. The potencies of the homologs of tetrahydrocannabino! and the activities of other products are shown in Table I to allow comparison. The high potencies of the optically active tetrahydrocannabinols obtained by isomerization of cannabidiol con-
trast strikingly with the very low potencies of crude hemp extracts. Todd and co-workerszb have just published a description of the synthesis and physiological action b the Gayer test of a series of homologs of tetrahydrocannabinol (17 with the amyl group replaced by various alkyl groups. Many of this series had been synthesized previously by us and the marihuana action determined by the dogataxia test.2~ The difference between the ratio of our tests and those of Todd is large. In this connection reference may he made to the extensive results of Loewe described briefly in the Harvey Lecture (February 19, 1942). He has demonstrated t h a t even when applying the "Bioassay by Approximation" procedure with the Gayer test, the intra-individual a n d inter-individual variations in sensitivity of rabbits is enormous, so t h a t the values of potency by this method are not suitable for anything hut qualitative purposes. The Gayer potencies do not parallel the dog-ataxia potencies of the same preparations. On the other hand, the relative potencies of the various products as determined by the dog-ataxia tests parallel to a surprisin degree the potencies observed in human subjects. The relative cfoses of several of the compounds eliciting a similar action in individual dogs elicited the equivalent degree of response in humans. The equated doses administered to the same individual human gave the same intensity of effect, and this result was observed in a large number of subjects.
An attempt has been made in this Laboratory3 and by Ghosh, Todd and Wright4 to synthesize an optically active isomer of the tetrahydroTABLE I cannabinol from cannabidiol by condensing puleBIOASSAYOF HOMOLOGS OF TETRAHYDROCANNABINOL AND gone and olivetol. An optically active resin OF HEXAHYDROCANNABINOL closely resembling the desired tetrahydrocanna3-%-Alkylgroup ,-Potencybinol in physical properties was obtained. The Compound I Tetrahydro Hexahydro Methyl 0.18 * 0 . 0 3 product obviously was not pure since its absorp. 4 0 * .30 Propyl 0 26 * 0 04 tion spectrum exhibited two peaks in contrast .37 .12 Butyl .37 * .06 1 . 0 0 (standard) Amyl . Z l * .08 to the one peak of the tetrahydrocannabinol from 1.82 * .40 Hexyl 1 86 .37 cannabidiol. The height of the identical peak 1.05 * . l 5 Heptyl 0 83 * . 1 3 Octyl 0.66 * .13 ,063 was only six-tenths that for the pure compound. 24 The initial measurement of the potency of this Tetrahydrocannabinol Parke, Davis a n d Company [a]*'D Fluid Extract 0.060 material made with a few dogs was reported as -265' 7.3 0 . 8 9 American Fluid Extracts 1.04 * 0.37, but further investigation has re-260' 7.8 .78 thirty to forty different -240' 7.6 * 1.1 samples varied in potency ,003-0.130 sulted in a value of 0.58 * 0.12. It is interesting -165' 9.3 2.9 to note that the ratio of the potencies of the tetra-160" 8.23 2.17 -126' 6 . 5 * 0 . 6 5 Majority varied ,019- ,052 hydrocannabinols made by the two methods paralHexahydrocannahinol Purified red oil 1.24 lels the ratio of the heights of the comparable -70° 3.0 0 . 4 3 Highly purified red oil (Matcbett) 4.33 absorption peaks. (1) For previous paper see Adams, Cain, McPhee and Wearn, A tentative mechanism for the formation of a THIS JOURNAL, 68, 2209 (1941). tetrahydrocannabinol structure (I) has been ad(2) (a) Adams, Loewe, Jelinek and Wolff, ibid., 63, 1971 (1941); f
f
;t
f
f f
f
(b) see also Russell, Todd, Wilkinson, NacDonald and Woolfe. J . Chcm. Soc., 826 (1941).
(3) Adams, Smith and Loewe,THISJOURNAL, 68, 1973 (1941). (4) Chosh, Todd and Wright, J. Chrm. SOC.,137 (1941).
TETRAHYDROCANNABINOL HOMOLOGS AND ANALOGS
March, 1942 CHI,
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tertiary carbon atom at the point of attachment of the isopropyl group and C6Hllb) \ d A < /ACbHll(n) the oxygen bridge and, therefore, a /\ CH rearrangement and dehydrogenation would be necessary in order to obtain 6Hs \CH3 /\ CHs CH3 cannabinol. (1) (11) The fact that the pulegone-olivetol \/C6Hll(n) condensation product possesses conCHyJ,. lp-11(n) siderable marihuana activity is of inter* est quite apart from the objection that y\c/\/ this material is not pure and that its /\ /\ CHs CH3 OH CHs C& OH composition may vary widely depend(111) (IV) ing on the conditions and reagents used ~ a n c e d ,and ~ it has been pointed out that the in the condensation. Accordingly, the series of presence of a compound with a structure analo- pulegone-5-n-alkylresorcinol condensation prodgous to I but with the pyran ring linked between ucts, n-propyl through n-nonyl, have been prethe hydroxyl and n-amyl groups is entirely pos- pared under the same conditions used for the pulesible. Also, the formation of a tetrahydrodi- gone4ivetol condensation.a The potencies of benzofuran of type shown in structure I1 could these products show an interesting displacement of not be ruled out. maximum potency to the n-octylresorcinol memThere exists an alternative mode of reaction ber and a t the same time a broadening of the region between pulegone and olivetol which involves the of high potencies to include the n-hexyl, n-heptyl, addition of the hydrogen atom between the hy- n-octyl members. Also the n-heptyl and n-octyl droxyls in olivetol to the double bond in the products exceed in potency the corresponding synpulegone, with the formation of an intermediate thetic tetrahydrocannabinol homologs ; in the case of type 111. By enolization and dehydration a of the n-octyl product this increment amounts to tetrahydroxanthane (IV) would result. An analo- one hundred per cent. Whether these unexpected gous addition has been shown by Robinson and results have been influenced by the optical activity Wallker6 to be the exclusive reaction in the case or by the presence of varying amounts of impuriof the initial condensation of resorcinol with ties in the individual members of the series has anisylideneacetophenone and with benzylidene- not been determined. p-methoxyacetophenone in the presence of hydroBy reduction of the pulegone-5-n-alkylresorgen chloride and chloranil. cinol products, n-propyl through n-octyl inclusive, In the case a t hand, however, no decision can a series of substances was obtained whose potenas yet be made between the two structural possi- cies were uniformly lower than those of the parent bilities. It might be thought that the peak due substances. The broad region of maximum to the impurity would be much lower than that potency was maintained but was displaced to indue to tetrahydrocannabinol if this impurity had clude the reduced n-amyl, n-hexyl, and n-heptyl the tetrahydroxanthane structure, but this may be products. The potency of the reduced n-heptyl masked by the strong absorption of the tetra- product was the same as that of the corresponding hydrocannabinol in that region. At any rate, it homolog of hexahydrocannabinol. is known definitely that part of the material is The potencies of these various pulegone condentetrahydrocannabinol, since Ghosh, Todd and sation products and derivatives are in Table 11. Wright4 have obtained cannabinol-p-nitrobenzoTABLEI1 ate by dehydrogenation of this material with PULEGONE CONDENSATION PRODUCTS palladium charcoal followed by treatment with Pulegone-5-nReduced 6-n-Alkylalkylresorcinol condensation p-nitrobenzoyl chloride. The fact that 96% of resorcinol condensation product product the theoretical hydrogen is evolved indicates that Propyl 0.24 0.20 .25 0.10 .15 Butyl the predominant substances present have a Amyl .58 .12 .64 0.10 tetrahydrobenzene ring in their molecules. The Hexyl 1 . 2 2 * .12 .78 .22 .83 A 1.7 Heptyl 1.15 * .15 tetrahydrodibenzofuran structure (11) has a .25 Octyl 1 . 3 7 * .25 I I
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