Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-05-24
1997-06-03
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549390, 549391, A61K 3135, C07D31180
Patent
active
056355300
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/U.S.92/07718, filed Sep. 11, 1992.
FIELD OF THE INVENTION
The present invention relates to (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and homologs and derivatives thereof, essentially free of the (3R,4R) form, and to processes for their preparation. The invention also relates to pharmaceutical compositions containing said compounds as active ingredients, having anti-inflammatory, analgetic, leucocyte anti-adhesion, antiplatelet activating factor (PAF), and anti-glaucoma activities, as well as properties effective in alleviating certain symptoms due to neuronal injury or loss.
BACKGROUND OF THE INVENTION
The (3S,4S) enantiomers of cannabimimetically active cannabinoids, such as the natural (3R,4R)-delta-1-tetrahydrocannabinol (THC) are generally not cannabimimetic. This lack of undesirable CNS side effects makes them suitable candidates as therapeutic agents. It has been previously shown that the (3S,4S)-7-hydroxy-delta-6-tetrahydrocannabinol 1,1-di-methylheptyl homolog (compound 1a in the appended Figures) is an analgetic, entiemetic and anti-NMDA drug [U.S. Pat. No. 4,876,276; Mechoulam, R., et al., Tetrahedron: Asymmetry, 1, 315 (1990); Feigenbaum, J. J., et al., Proc. Natl. Acad. Sci., 86, 9584 (1989)]. It has also been shown that (3R,4R)-delta-1-tetrahydrocannabinol-7-oic acid (compound 2), which also shows no psychotropic effects, is an anti-inflammatory and analgetic compound [U.S. Pat. No. 4,847,290]. However, the (3S,4S)-tetrahydrocannabinol-7-oic acids have not yet been prepared and their therapeutic activity has been unknown so far. These compounds have now been synthesized and were found to possess unexpected therapeutically important properties.
SUMMARY OF THE INVENTION
The present invention relates to (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids, homologs and derivatives thereof having the general formula: ##STR2## wherein R is a hydrogen atom or a C.sub.1 -C.sub.5 alkyl group, R.sup.1 is a hydrogen atom or a C.sub.1 -C.sub.5 acyl group and R.sup.2 is selected from the group consisting of: (a) a straight-chained or branched C.sub.5- C--.sub.12 alkyl; (b) a group --O--R.sub.4, wherein R.sub.4 is a straight-chained or branched C.sub.2 -C.sub.9 alkyl which may be substituted at the terminal carbon atom by a phenyl group; and (c) a group --(CH.sub.2).sub.n --O--alkyl, where n is an integer of from 1 to 7 and the alkyl group contains from 1 to 5 carbon atoms.
The most preferred compounds are the 1,1-dimethylheptyl (DMH) homologs of (3S,4S)-(+)-delta-6-tetrahydrocannabinol-7-oic acid (hereafter designated HU-235, compound 3a in the appended FIG. 1) and its acetate (hereafter designated HU-245, compound 3c in FIG. 1).
It is stressed that all the compounds are of the (+)-(3S,4S) configuration, essentially free of the (-)-(3R,4R) enantiomer. The compounds of the type defined by general formula (I) are substantially devoid of "cannabis-type" CNS activity.
The invention also relates to processes for the preparation of compounds of general formula (I).
FIG. 1 illustrates the reaction pathways of the processes of the invention.
In a first embodiment the process for the preparation of a compound of formula (I) wherein R is a hydrogen or a C.sub.1 -C.sub.5 alkyl group and R.sup.1 and R.sup.2 are as defined in claim 1, comprises: ##STR3## wherein Y is a straight-chained or branched C.sub.1 -C.sub.5 alkyl, X is a suitable protective group and R.sup.2 is as defined in formula I with a suitable reducing agent to give the corresponding allylic alcohol of formula III: ##STR4## (b) oxidizing the alcohol of formula III with a suitable oxidizing agent to give the corresponding aldehyde of formula IV: ##STR5## (c) oxidizing the aldehyde of formula IV with a suitable oxisizing agent to give the corresponding allylic acid of formula V: ##STR6## and (d) removing the protective group X to give the acid according to formula (I).
Y can be, for example, (trimethyl)methyl.
In stage (a) the protective group OY may optionally be replaced by the group --NR.sup.4 R.sup.5, wherei
REFERENCES:
patent: 4179517 (1979-12-01), Mechoulam et al.
patent: 4847290 (1989-07-01), Burstein
patent: 4876276 (1989-10-01), Mechoulam et al.
patent: 4973603 (1990-11-01), Burstein
patent: 5036014 (1991-07-01), ElSohly et al.
patent: 5144030 (1992-09-01), Wang et al.
patent: 5284867 (1994-02-01), Kloog et al.
patent: 5338753 (1994-08-01), Burstein et al.
Mechoulam et al., Tetrahedron: Asymmetry, vol. 1, No. 5, pp. 315-318 (199 ).
Feigenbaum et al., Proc. Natl. Acad. Sci. USA, vol. 86, pp. 9584-9587 (1989).
Schwartz et al., J. Org. Chem., vol. 51, pp. 5463-5465 (1986).
Breuer Aviva
Burstein Sumner H.
Devane William
Mechoulam Raphael
Chan Nicky
Yissum Research Development Company of the Hebrew University of
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