Cannabinoid derivatives, methods of making, and use thereof

a technology of cannabinoid derivatives and derivatives, applied in the field of cannabinoid derivatives, can solve the problems of limiting the ability to predict the preferred side chain geometry and the lbp steric requirements of the cb receptor, and achieve the effect of improving the affinity of the cb-1 and/or cb-2 receptors

Inactive Publication Date: 2007-07-19
UNIV OF TENNESSEE RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0026] According to one approach, a Δ8-THC or Δ9-THC compound of the present invention is prepared by reacting an intermediate compound having the structure of formula (II)
[0028] under conditions effective to form a compound according to claim 1 that contains a double bond at the Δ8 or Δ9 position of the C ring.
[0030] with an acid (such as trifluoroacetic acid or hydrobromic acid) under conditions effective to form a compound of the present invention that contains a double bond at the Δ6a-10a position of the C ring.
[0031] Several compounds of the present invention have a demonstrated affinity for either the CB-1 receptor, CB-2 receptor, or both, and several compounds show selectivity of one receptor over the other. The compounds of the present invention offer a major benefit in that a wide diversity of 1′-aromatic THC with one or more functional groups can be prepared in accordance with the present invention. Such compounds were not traditionally available, particularly with the previously known 1′-linear hydrocarbon THC analogs. Moreover, several compounds have shown improved affinity for the CB-1 and / or CB-2 receptor, as well as efficacy for treating a condition that is mediated by a CB receptor, as evidence by in vitro or in vivo testing.
[0032]FIG. 1 is a partial 2D NOESY spectra (300 ms mixing time) of compound 28 showing the NOEs between the aromatic protons H2 / H4 and the methylene, H3′ / H7′, and methyne proton, H2′, on the cyclohexyl ring.

Problems solved by technology

The inherent computational limitations in predicting the conformation of a flexible side chain, in the absence of x-ray crystallographic or high resolution NMR data, somewhat limits the ability to predict the preferred side chain geometry and LBP steric requirements of the CB receptors.

Method used

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  • Cannabinoid derivatives, methods of making, and use thereof
  • Cannabinoid derivatives, methods of making, and use thereof
  • Cannabinoid derivatives, methods of making, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 2

Binding Assays

[0152] Cell membranes from HEK293 cells transfected with the human CB1 cannabinoid receptor and membranes from CHO-K1 cells transfected with the human CB2 cannabinoid receptor were used in the receptor binding assays. Displacement of [3H]CP 55,940 from the CB1 and CB2 receptor preparations by increasing concentrations of the Δ8-THC analogs 23-29 and Δ8-THC were used to determine the binding affinities of the conformationally biased probes (see Table 1 below). The Ki values for Δ8-THC at the hCB1 and hCB2 receptor were 28.5 nM and 25.0 nM, respectively (affinity ratio CB1 / CB2=1.14), compared to a reported value of 47.6 nM for the rCB1 and 39.3 for the mCB2 (affinity ratio CB1 / CB2=1.21) (Busch-Petersen, J. et al., J. Med. Chem. 39:3790 (1996), which is hereby incorporated by reference in its entirety). The LBP probes exhibited a 3 to 143 fold enhancement in binding affinity to the receptor subtypes relative to Δ8-THC. The gem-dimethyl analogs 27-29 and the pentyl dithiol...

example 3

olecular Modeling Studies

[0154] The binding affinities of the dimethyl-cycloalkyl analogs for both the CB1 and CB2 receptors are comparable to that of the highly potent 1′,1′-dimethylheptyl THC (DMHT, Ki=0.77 nM) analog. Molecular modeling analysis of these compounds shows that the linear dimension of DMHT is 7.72 Å compared to 4.55 Å for 28, which is the cyclic carbon equivalent of DMHT. The difference of 3.17 Å in the linear length of the side chain suggested that there is a region in the LBP that accommodates the C3 substituent which can be characterized as a hydrophobic ellipsoid. It remains unclear if this is the same pocket that accommodates the side chain of linear analogs; however, the potential existence of an ellipsoid pocket made it important to characterize the relative geometry of the cyclic side chain with respect to the tricyclic ring system. One facet of this effort utilized 1D and 2D high field NMR spectroscopy to assess the relative side chain geometries; furthermo...

example 4

echanical Calculations

[0157] It seemed reasonable to assume that the gem-dimethyl would adopt a conformer that would maximize the interaction between the conformationally biased side chain and the aromatic ring. However, the conformation of the cyclohexyl analog 28 predicted by NMR and molecular dynamics could not be explained based on molecular mechanics calculations, i.e. electrostatic and steric analysis. To address this issue, semi-empirical and density functional theory (DFT) calculations have been employed to critically evaluate the potential conformers and determine the importance of electronic contributions in the experimental results.

[0158] Geometry optimizations were performed using both the AM1 and PM3 semi-empirical parameterizations with the GAMESS computational chemistry package (Schmidt, M. W. et al., J. Comput. Chem. 14:1347 (1993), which is hereby incorporated by reference in its entirety). The stationary points were confirmed by calculating the Hessian at the opti...

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Abstract

1′-substituted cannabinoid derivatives of delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, and delta-6a-10a-tetrahydrocannabinol that have affinity for the cannabinoid receptor type-1 (CB-1) and / or cannabinoid receptor type-2 (CB-2). Compounds having activity as either agonists or antagonists of the CB-1 and / or CB-2 receptors can be used for treating CB-1 or CB-2 mediated conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is a continuation of application Ser. No. 10 / 850,588, filed May 20, 2004, which application claims the benefit of U.S. Provisional Patent Application Ser. No. 60 / 472,316 filed May 20, 2003, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The present invention relates generally to cannabinoid derivatives of delta-8-tetrahydrocannabinol (Δ8-THC), delta-9-tetrahydrocannabinol (Δ9-THC), and delta-6a-10a-tetrahydrocannabinol (Δ6a-10a-THC) that are active as either agonists or antagonists of the cannibinoid receptor type-1 (CB-1) and / or cannabinoid receptor type-2 (CB-2), and their use for treating CB-1 or CB-2 mediated conditions. BACKGROUND OF THE INVENTION [0003] Delta-9-tetrahydrocannabinol (Δ9-THC) was isolated and identified as the major active constituent of marijuana in 1964 by Mechoulam and coworkers (Gaoni et al., J. Am. Chem. Soc. 86:1646 (1964)). In the following decades, the CB1 and CB...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/35A61K31/381A61K31/4025A61K31/427A61K31/4433A61K31/506C07D311/80C07D405/06C07D405/14C07D407/06C07D409/04C07D417/02
CPCC07D409/04C07D311/80A61P1/04A61P1/12A61P11/00A61P11/06A61P19/02A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/18A61P25/28A61P27/02A61P29/00A61P31/18A61P35/00A61P37/00A61P37/06A61P37/08
Inventor MOORE, BOB M. IIFERREIRA, ANTONIO M.KRISHNAMURTHY, MATHANGI
Owner UNIV OF TENNESSEE RES FOUND
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