Synthetic cannabinoid products

The first industrial group to devote appreciable time and effort in developing a new synthetic cannabinoid analgetic was that of Sisa in Cambridge, MA. This group has reviewed its work [98]. The most active compounds prepared were those in which the terpene ring of the natural product was replaced with a heterocyclic one. 

Immune cells undergo dramatic metabolic and functional changes upon stimulation. The outcome of such stimulation depends on the type of stimuli and is specific for individual subsets of immune cells. Cannabinoids have been shown to have a marked deleterious effect on immune cell function (see reviews by Berdyshev, 2000 Roth et al., 2002 and Klein et al., 2003). In general, endocannabinoids follow the namral and synthetic cannabinoids in their ability to decrease immunogenic responses, but much more work is needed to clarify the regulatory mechanisms that link endocannabinoid metabolism with the functional outcomes of up- or dowmegulation of endocannabinoid production. 

Nabilone is a synthetic cannabinoid with a pharmacological profile comparable to dronabinol. It was developed by Eli Lilly to treat vomiting during cancer treatment, and is marketed as the racemate. [144] However, Eli Lilly has also developed syntheses ofthe enantiomericaUy pure product, starting from )S-pinene. [145,146]... 

The main drawback of the analytical methodologies available is that monitoring of this type of contaminant is limited to selected compounds. Methodologies based on target analysis are insufficient to identify the relevance of new ilhcit drags, such as the synthetic cannabinoids that constitute the commercially available products known as spice, or the substances with stimulant and psychotropic activity derived from cathinone and piperazine. Moreover, further photo- and biodegradation products that... 

First identified Spice included fatty acids (linoleic acid, palmitic acid, oleamide), plant-derivate products (thymol, vanillin), preservatives (paraben family), and vitamins (alpha-tocopherol) [21-24]. Modem Spice products contain only synthetic cannabinoids and plant-derivate substances explaining by home-made manufacturing. 

Since 2012, new types of synthetic cannabinoids emerged rapidly, and the combinations in illegal products can be expected to become more and more diverse. In recent survey publications, the following synthetic cannabinoids QUPIC (PB-22), QUCHIC (BB-22), ADBICA, ADB-FUBINACA, AB-PINACA, AB-FUBINACA, APICA, APINACA, UR-144, JWH-122, AM-2201, and AB-001 have also been reported (Table 7) [7-9]. 

By definition, cannabinoids comprise a variety of distinct chemical classes which bind to the cannabinoid receptor. These include the classical cannabinoids structurally related to tetrahydrocannabinol, the non-classical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and atylsulphonamides and additional compounds that do not fall into these standard classes. According to their production and origin, there are three types of cannabinoids phytocannabinoids, endogenous cannabinoids, and synthetic cannabinoids. 

As discussed in some detail on p. 202 of this review, the enantiomers (-)-HU-210 (which retains the stereochemistry present in THC) and (+)-HU-211 were originally prepared in order to establish whether the activity of the cannabinoids is stereospecific. The synthetic path is shown in Figure 5.2 [25], The intermediate ketones (5 and enantiomer) can be easily crystallized to absolute purity and therefore the final products HU-210 (3) and HU-211 (4) are obtained with e.e. higher than 98.8%. This was a central aim of our synthetic approach in order to make possible the eventual therapeutic use of the [35,4S] enantiomer (4), as the presence of traces of the highly psychotropic [3/J, 4/ ] enantiomer (3) could lead to undesirable side-effects. The enantiomeric purity of thrice recrystallized (3) and (4) was established by h.p.l.c. analysis of the diastereoisomeric bis(MIPA) esters obtained by reaction with (S)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetyl (MTPA) chloride. As expected, we found that HU-211 (4) has no cannabimimetic activity [20-24], However, unexpectedly, we observed that it exhibits pharmacologi-... 

The therapeutic uses of marijuana today arc much more circumscribed. For the most part synthetic products (such as dronabinol [trade name Marinol] and nabilonc [Cesamet]) that chemically resemble the cannabinoids have been used in current treatment efforts because they provide the active elements of THC in a more stable manner (see Joy ct al., 1999 Sussman, Stacy, Dent, Simon, Johnson, 1996). Synthetics also can provide better solubility. Unfortunately, a downside to the synthetics is the absence of the rapid effect experienced when marijuana is smoked. When synthetic THC is taken orally, it is broken down prior to entering the bloodstream and absorption thus is delayed. A recent development with promise is a cannabis oral spray (trade name Sativex), which has been approved in Canada for use as a painkiller for sufferers of multiple sclerosis. 

Scheme 13.25 Solid-supported domino synthesis of cannabinoids. (a) Synthetic strategy, (b) Examples of natural products synthesized through this method.

One of the most common synthetic approaches to the construction of heterocyclic compounds involves the reaction of /3-keto esters with bifunctional nucleophiles. Thus a variety of reactions of (1) with different bifunctional heteronucleophiles, including hydrazine, substituted aminotriazoles, 2-aminopyridines, o-phenylenediamines, and o-aminothiophenol, lead to polynuclear condensed thieno compounds (e.g. 2-8) of potential medicinal interest featuring the pyrazolone, pyrimidinone, benzodiazepine, and benzothiazepine nuclei. Cannabinoid analogs can be prepared through cyclization of the condensation products of (1) with bifunctional oxygenated nucleophiles such as substituted resorcinols. ... 

Members of the cannabinoid class of natural products were accessed using a crossed [2 + 2 + 2] cycloaddition, as shown for the synthesis of cannabinol (86) (Scheme 7.18) [28], Sterically encumbered substituents, on both the diyne and the monoyne reaction partners, were used to direct the regioselective outcome of this crossed alkyne cyclotrimerization. The Cp RuCl(cod) complex (10 mol %) was employed as catalyst, allowing the reaction of diyne 84 with an excess of propar-gyltrimethylsilane under microwave conditions to deliver the pyrane 85 in 88% yield as a single regioisomer. The latter was used as a synthetic intermediate to access cannabinol (86) as well as cannabinodiol within five additional synthetic steps. 

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