TECHNICAL FIELD

[0001] CBD cannabinoids and CBD cannabinoid analogues with, inter alia, antimicrobial activity, synthetic methods for the preparation thereof and formulations containing same.

BACKGROUND ART

[0002] Cannabidiol (CBD) is a phytocannabinoid compound of the following structure;

Cannabidiol (CBD)

[0003] Phytocannabinoid compounds are cannabis meroterpenoids and their analogues of botanical origin, and include compounds originating not only from expected plant sources such as Cannabis sativa, Cannabis indica, Cannabis ruderalis and their close relatives, but also from unrelated plant species such as Cassia alata, Desmodia canum, Machaerium multiflorum, Hymenocardia acida, Lindera spp., Amorpha spp., Glycyrrhiza spp., Rhododendron spp., and even phylogenetically unrelated species such as liverworts and fungi (Hanuš, L.O. et al., “Phytocannabinoids: a unified critical inventory”, Natural Product Reports, 2016, 33, 1357- 1392).

[0004] Well over 100 phytocannabinoids have been isolated (see for example “Handbook of Cannabis,” Oxford University Press, First Edition 2014, ISBN 978-0-19-966268-5). Phytocannabinoids have been used in traditional medicine for a long time, and in recent years a number of phytocannabinoids have been approved by the FDA and other regulatory authorities for therapeutic uses. For example, (-)-trans-Δ ⁹ -tetrahydrocannabinol (THC) (having an International Non-proprietary name of Dronabinol, and the trade names Marinol™ and Syndros™) is used as an antiemetic and for the relief of sleep apnea, and is approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting. A standardised cannabis extract mixture of primarily THC and CBD marketed under the trade name Sativex™ (with the non-proprietary United States Adopted Name of Nabiximols) has been approved in the UK for spasticity reduction in subjects with multiple sclerosis.

[0005] CBD is a key member of the phytocannabinoid family of compounds with extracts from cannabis species having up to 40% CBD. Under the trade names Epidiolex™ (USA) and Epidyolex™ (European Union) CBD extracted from cannabis has been approved for the treatment of childhood epilepsy. CBD is the first drug derived from cannabis extracts to have received FDA approval.

[0006] CBD has also recently shown potential as an antimicrobial compound, with activity against gram-positive bacteria, and gram-negative bacteria when the bacterial membrane is permeabilized, or when co-administered with polymyxin B (Farha, M.A. et al, “Uncovering the Hidden Antibiotic Potential of Cannabis”, ACS Infectious Diseases, 2020, 6(3), 338-346), as well as anti-fungal activity against Candida albicans (Nalli, Y. et al, “Chemical investigation of Cannabis sativa leading to the discovery of a prenylspirodinone with antimicrobial potential”, Tetrahedron Letters, 2018, 59(25), 2470-2472).

[0007] Apart from the abuse potential of cannabis, something which is less of an issue with CBD than THC due to reduced levels of psycho-activity, one of the main problems with gaining regulatory approval for phytocannabinoid compounds derived from plant extracts is the variability in purity and in levels of impurities present in the extract, and the associated need to provide reproducible approaches to achieving consistently high purity with consistent impurity profiles. Thus, there is a need to provide analogues of phytocannabinoid compounds with reduced abuse potential and/or more favourable or different biological activity and/or improved pharmacokinetics and/or improved bioavailability, and/or that can be synthesized rather than extracted from plants in order to facilitate consistently high levels of purity.

[0008] In one form, the present invention seeks to provide new synthetic CBD analogue compounds and methods for their synthesis.

[0009] Compounds with antimicrobial properties have attracted great interest in recent times as a result of an increase in the prevalence of infections caused by bacteria, resulting in serious or fatal diseases. Furthermore, the regular use of broad spectrum antibiotic formulas has led to the increased occurrence of bacterial strains resistant to some antimicrobial formulations, such as methicillin-resistant Staphylococcus aureus (MSRA).

[0010] Novel antimicrobial compounds have the potential to be highly effective against these types of antibiotic-resistant bacteria. The pathogens, having not previously been exposed to the antimicrobial compounds, may have little to no resistance to the treatment.

[0011] There is no indication that bacterial resistance to antibiotics will stop and for this reason new antibiotics and new treatment options are necessary to achieve a desirable treatment outcome in patients.

[0012] In one form, the present invention seeks to provide a new option for the treatment of bacterial infections, including infections by antibiotic-resistant bacteria. [0013] In one form, the present invention seeks to provide new uses of known phytocannabinoids of the CBD type, more particularly their use as antimicrobial compounds for the treatment or prevention of gram-positive bacteria, and/or gram-negative bacteria, and/or fungal microbes.

[0014] In one form, the present invention seeks to provide new compounds of the CBD analogue type, for use as antimicrobial compounds for the treatment or prevention of gram- positive bacteria, and/or gram-negative bacteria, and/or fungal microbes.

[0015] Many microbes form highly organised structures called biofilms in which they are protected from immune cells and antibiotic killing via several mechanisms. These mechanisms include reduced antibiotic penetration, low metabolic activity, physiological adaptation, antibiotic-degrading enzymes, and selection for genetically resistant variants (Stewart & Costerton Lancet. 2001 358(9276):135-138).

[0016] In one form, the present invention seeks to provide new options for the treatment or prevention of bacterial and/or fungal infections or growths, associated with biofilms.

[0017] The previous discussion of the background art is intended to facilitate an understanding of the present invention only. The discussion is not an acknowledgement or admission that any of the material referred to is or was part of the common general knowledge as at the priority date of the application.

SUMMARY OF INVENTION

[0018] According to one aspect of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I:

(A) _x -B-C

Formula I wherein; x is 1 or 2, and B is a central aryl moiety, covalently bonded to A and C, wherein B is selected from the group consisting of B1 to B33; and B33

A is a cycloalkyl moiety, covalently bonded to B at the position marked with a dashed line , wherein A is selected from the group consisting of A1 to A39;

wherein;

A20 and A21 may be substituted with 0, 1 , 2, 3, 4 or 5 substituents R ₃ ; and

A22, A23, A24, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37 may be substituted with 0, 1 , 2, 3, or 4 substituents R ₃ ; and

C is a side-chain moiety, covalently bonded to B at the position marked with a dashed line , wherein C is selected from the group consisting of C1 to C65;

wherein;

C4, C9, C10, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36 and C37 may be substituted with 0, 1 , 2, 3, 4 or 5 substituents R ₃ ; and

C11 , C12 and C13 may be substituted with 0, 1 , 2, 3 or 4 substituents R ₃ ; and

C38, C39, C40, C41 , C42 and C43 may be substituted with 0, 1 , 2 or 3 substituents R ₃ ; and

C44, C45, C46, C47, C48 and C49 may be substituted with 0, 1 , or 2 substituents R ₃ ; wherein; n is 0, 1 , 2, 3 or 4; m is 0, 1 , 2, 3 or 4; p is 0, 1 , 2 or 3; q is 0, 1 , 2, 3, 4, 5, 6 or 7; r is 0, 1 , 2, 3, 5, or 6; s is 1 , 2 or 3; t is 2 or 3;

R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -SO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ;

R ₂ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _8-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ³ , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , and -C _2-9 alkenyl-O-R ^a ; or where R ₁ and R ₂ are both attached to the same nitrogen atom, they may together form a 3, 4, 5, 6, or 7 membered heterocycloalkyl or heterocycloalkenyl ring, or a 6 membered heterocycloaryl ring;

R ₃ is independently selected, in each instance, from the group consisting of; halogen, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -OH, -O-acetyl, -O-R ^a , -NR ^b R ^c , -S-R ^a , -S(=O)R ^a , -SO ₂ R ^a , -OSO ₂ R ^a , -C(=O)R ^a , -CO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , and -C _2-9 alkenyl-O-R ^a ; R ₄ is independently selected, in each instance, from the group consisting of; H, OH or OR ¹ ;

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; wherein, if the cycloalkyl moiety A is selected from A1 , A2 or A3, and the central aryl moiety B is selected from B1 , B6, B21 or B22 then the side-chain moiety C is selected from the group consisting of C4 to C65; including individual enantiomers, diastereomers, racemates, non-racemates, double bond (E/Z) isomers and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the compounds of Formula I; and, wherein the compound of Formula I is not a compound published before the earliest priority date of the present disclosure, or wherein the compound of Formula I is not a compound hitherto not ascertained by the present inventors as being published before the earliest priority date of the present disclosure.

[0019] In a preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33. In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B2, B4, B5, B7, B10 , B11 , B12, B15, B16, B17, B19 and B20.

[0020] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30.

[0021] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39.

[0022] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A19, and A20.

[0023] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37.

[0024] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; C is selected from the group consisting of; C1 , C2, C3, C4, 05, 06, 07, C8, 050, 051 , 052, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0025] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; C is selected from the group consisting of; 09, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, 033, 034, C35, 036, C37, 038, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0026] In a particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65. [0027] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of ; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, 031 , 032, C33, 034, 035, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0028] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A19, and A20; and

0 is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0029] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of ; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0030] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65 [0031] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of ; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, 030, 031 , 032, 033, 034, 035, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0032] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

0 is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0033] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0034] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A19, and A20; and C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0035] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0036] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0037] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of ; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0038] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0039] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0040] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0041] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0042] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0043] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I, wherein the compound is selected from the group consisting of compounds of the type;

A1-B1-C4; A1-B1-C5; A1-B2-C3; A1-B2-C4; A1-B2-C5; A1-B3-C1 ; A1-B6-C4; A1-B6-C5;

A1-B7-C3; A1-B7-C4; A1-B7-C5; A2-B1-C5; A2-B2-C5; A2-B6-C5; A2-B7-C5; A3-B1-C5;

A3-B2-C5; A3-B6-C5; A3-B7-C5; A4-B1-C1 ; A4-B1 -C5; A4-B2-C1 ; A4-B6-C1 ; A4-B6-C5;

A4-B7-C1 ; A6-B1-C1 ; A6-B6-C1 ; A7-B1-C2; A7-B6-C2; A8-B1-C1 ; A8-B6-C1 ; A9-B1-C1 ;

A9-B1-C2; A9-B6-C1 ; A9-B6-C2; A19-B1-C1 ; A19-B6-C1 ; A20-B1-C1 ; and A20-B6-C1 .

[0044] In another particularly preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I selected from the group consisting of;

(3R,4R)-3-(2,6-dihydroxy-4-pentylphenyl)-N-methyl-4-(prop -1-en-2-yl)cyclohex-1-ene-1-carboxa mide;

(3R,4R)-N-benzyl-3-(2,6-dihydroxy-4-pentylphenyl)-4-(prop -1-en-2-yl)cyclohex-1-ene-1-carboxa mide;

5-pentyl-2-[(1R,6R)-3-(piperazine-1-carbonyl)-6-(prop-1-e n-2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol;

2-[(1R,6R)-3-(methoxymethyl)-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]-5-pentylbenzene-1,3-diol;

2-[(1R,6R)-3-[(benzyloxy)methyl]-6-(prop-1-en-2-yl)cycloh ex-2-en-1-yl]-5-pentylbenzene-1,3-diol

4-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl] -5-(4-phenylbutyl)benzene-1,3-diol;

2-[(1 R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]-5-penty lphenol;

(3R,4R)-3-(2,6-dihydroxy-4-propylphenyl)-4-(prop-1-en-2-y l)cyclohex-1-ene-1-carboxylicacid;

2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl] -5-(4-phenylbutyl)benzene-1,3-diol;

5-heptyl-4-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]benzene-1,3-diol;

2-[(1R,6R)-3-(hydroxymethyl)-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]-5-propylbenzene-1,3-diol;

5-(3-methanesulfonylpropyl)-2-[(1R,6R)-3-methyl-6-(prop-1 -en-2-yl)cyclohex-2-en-1-yl]benzene- 1,3-diol;

5-(3-methanesulfonylpropyl)-4-[(1R,6R)-3-methyl-6-(prop-1 -en-2-yl)cyclohex-2-en-1-yl]benzene- 1,3-diol;

5-(3-methanesulfonylpropyl)-4-[(1R,2S)-5-methyl-2-(propan -2-yl)cyclohexyl]benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-2-[(1S,6S)-3-methyl-6-(propan -2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol;

5-(3-methanesulfonylpropyl)-4-[(1S,6S)-3-methyl-6-(propan -2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol; -(3-methanesulfonylpropyl)-2-[(1R,2S)-5-methyl-2-(propan-2-y l)cyclohexyl]benzene-1,3-diol; -pentyl-2-[(1R,6R)-6-(prop-1-en-2-yl)-3-(trifluoromethyl)cyc lohex-2-en-1-yl]benzene-1,3-diol; -pentyl-4-[(1R,6R)-6-(prop-1-en-2-yl)-3-(trifluoromethyl)cyc lohex-2-en-1-yl]benzene-1,3-diol; -pentyl-4-[(1R,2S)-2-(propan-2-yl)-5-(trifluoromethyl)cycloh exyl]benzene-1,3-diol; -pentyl-2-[(1R,2S)-2-(propan-2-yl)-5-(trifluoromethyl)cycloh exyl]benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-2-[(1R,6R)-6-(prop-1-en-2-yl) -3-(trifluoromethyl)cyclohex-2-en-1-yl] benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-4-[(1R,6R)-6-(prop-1-en-2-yl) -3-(trifluoromethyl)cyclohex-2-en-1-yl] benzene-1 ,3-diol;

2-{3-fluorobicyclo[1.1.1]pentan-1-yl}-5-pentylbenzene-1,3 -diol;

4-[1-hydroxy-2-(propan-2-yl)-5-(trifluoromethyl)cyclohexy l]-5-pentylbenzene-1,3-diol;

2-[1-hydroxy-2-(propan-2-yl)-5-(trifluoromethyl)cyclohexy l]-5-pentylbenzene-1,3-diol;

2-[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]ben zene-1,3,5-triol;

3,5-dihydroxy-4-[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex -2-en-1-yl]phenyl trifluoromethanesulfonate;

(1S,4R,5R,6R)-5-(2,6-dimethoxy-4-pentylphenyl)-1-methyl-4 -(prop-1-en-2-yl)-7-oxabicyclo[4.1.0 ]heptane;

(2R,3R)-2-(2,6-dimethoxy-4-pentylphenyl)-6-methylidene-3- (prop-1-en-2-yl)cyclohexan-1-ol;

4-chloro-2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]-5-pentylbenzene-1,3-diol;

(1'R,5E,6'R)-6-hydroxy-5-(hydroxyimino)-3'-methyl-4-penty l-6'-(prop-1-en-2-yl)-[1,1'-bi(cyclohex ane)]-1(6),2',3-trien-2-one; and

(1'R,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl )-[1,1'-bi(cyclohexane)]-1(6),2',3-triene- 2,5-dione; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds.

[0045] In one aspect, there is provided an antimicrobial composition, comprising an amount of a compound according to Formula I, or Formula I’, effective to treat, inhibit or prevent a microbial infection or biofilm, and one or more carriers and/or excipients

[0046] In one aspect, there is provided a compound according to Formula I, or Formula I’, for use in the treatment, inhibition or prevention of a microbial infection or biofilm.

[0047] In one aspect, there is provided the use of a compound according to Formula I, or Formula I’, or a composition comprising a compound according to Formula I, or Formula I’, for the treatment, inhibition or prevention of a microbial infection or biofilm. [0048] In one aspect, there is provided the use of a compound according to Formula I, or Formula I’, for the manufacture of a medicament for the treatment, inhibition or prevention of a microbial infection or biofilm.

[0049] In a further aspect, there is provided the use of a compound for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is a compound of Formula I’;

(A) _x -B-C

Formula I’ wherein; x is 1 or 2, and B is a central aryl moiety, covalently bonded to A and C; wherein B is selected from the group consisting of B6 and B22;

A is a cycloalkyl moiety, covalently bonded to B at the position marked with a dashed line wherein A is selected from the group consisting of A1 , A2 and A3;

C is a side-chain moiety, covalently bonded to B at the position marked with a dashed line , wherein C is selected from the group consisting of C1 and C3; wherein R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ³ , -SO ₂ R ³ , -C _1-8 alkyl-CO ₂ R ³ , -C _2-8 alkenyl-CO ₂ R ³ , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ³ , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ; and

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds; and, wherein the compound of Formula I’ is not a compound published as possessing antimicrobial activity before the earliest priority date of the present disclosure, or wherein the compound of Formula I’ is not a compound hitherto not ascertained by the present inventors as being published as possessing antimicrobial activity before the earliest priority date of the present disclosure.

[0050] In a preferred aspect, there is provided the use of a compound for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is a compound of Formula I, selected from the group consisting of compounds of the type;

A1-B1-C3; A1-B6-C3; A2-B1-C1 ; A2-B6-C1 ; A3-B1-C1 ; A3-B6-C1 ; A1-B21-C1 and A1-B22-C1.

[0051] In a highly preferred aspect, there is provided the use of a compound of Formula I’, wherein the compound of Formula I’ is selected from the group consisting of compounds of the type;

and wherein R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -SO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ³ , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-8 alkyl-O-R ^a , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ; and

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds; and, wherein the compound of Formula I’ is not a compound published as possessing antimicrobial activity before the earliest priority date of the present disclosure, or wherein the compound of Formula I’ is not a compound hitherto not ascertained by the present inventors as being published as possessing antimicrobial activity before the earliest priority date of the present disclosure.

[0052] In a particularly preferred aspect, there is provided the use of a compound of Formula I’ for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is selected from the group consisting of;

5-heptyl-2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]benzene-1,3-diol;

2-[(1S,6S)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1-yl]-5- pentylbenzene-1,3-diol;

3-methoxy-2-[(1S,6S)-3-methyl-1-yl]-5-pentylphenol;

1,3-dimethoxy-2-[(1S,6S)-3-methyl-6-(propan-2-yl)cyclohex -2-en-1-yl]-5-pentylbenzene;

2-[(1R,2S)-5-methyl-2-(propan-2-yl)cyclohexyl]-5-pentylbe nzene-1,3-diol; and

2,4-bis[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-y l]-5-pentylbenzene-1,3-diol including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds.

[0053] According to one aspect of the invention, there is provided a formulation comprising a cannabinoid or cannabinoid analogue for the treatment or prevention of an infection by a bacteria or fungus, or for the treatment or prevention of the formation of a biofilm, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[0054] According to another aspect of the invention, there is provided a method for the treatment or prevention of an infection by a bacteria or fungus in a subject in need of such treatment comprising the step of: administering a therapeutically or preventative effective amount of a formulation comprising a cannabinoid or cannabinoid analogue wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[0055] According to another aspect of the invention, there is provided the use of a cannabinoid or cannabinoid analogue in the manufacture of medicament in the form of a formulation for the treatment of an infection of a subject by a bacteria or fungus, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[0056] According to another aspect of the invention, there is provided a kit comprising a cannabinoid or cannabinoid analogue for the treatment or prevention of a bacterial or fungal infection in a subject in need of such treatment or prevention, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[0057] In one form of the invention, the fungus is a yeast.

[0058] In one form of the invention, the bacteria is a Gram-positive bacteria.

[0059] In a preferred form of the invention, the Gram-positive bacteria may be a bacteria species of a genus selected from the list: Streptococcus spp., Peptostreptococcus spp., Clostridium spp., Listeria spp., Bacillus spp., Staphylococcus spp., Propionibacterium spp., Kocuria spp., and Corynebacterium spp., and combinations thereof.

[0060] In one form of the invention, the bacteria is a Gram-negative bacteria.

[0061] In a preferred form of the invention, the Gram-negative bacteria may be a bacteria species of a genus selected from the list: Neisseria spp., Legionella spp., Moraxella spp.

[0062] In a preferred form of the invention, the bacteria is a biofilm-forming bacteria.

[0063] In a preferred form of the invention, the bacteria is resistant to at least one antibiotic.

DESCRIPTION OF INVENTION

[0064] In one embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I:

(A) _x -B-C

Formula I wherein; x is 1 or 2, and B is a central aryl moiety, covalently bonded to A and C, wherein B is selected from the group consisting of B1 to B33; A is a cycloalkyl moiety, covalently bonded to B at the position marked with a dashed line , wherein A is selected from the group consisting of A1 to A39; wherein;

A20 and A21 may be substituted with 0, 1 , 2, 3, 4 or 5 substituents R ₃ ; and

A22, A23, A24, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37 may be substituted with 0, 1 , 2, 3, or 4 substituents R ₃ ; and

C is a side-chain moiety, covalently bonded to B at the position marked with a dashed line , wherein C is selected from the group consisting of 01 to C65;  and wherein;

C4, C9, C10, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36 and C37 may be substituted with 0, 1 , 2, 3, 4 or 5 substituents R ₃ ; and

C11, C12 and C13 may be substituted with 0, 1 , 2, 3 or 4 substituents R ₃ ; and

C38, C39, C40, C41 , C42 and C43 may be substituted with 0, 1 , 2 or 3 substituents R ₃ ; and C44, C45, C46, C47, C48 and C49 may be substituted with 0, 1 , or 2 substituents R ₃ ; wherein; n is 0, 1 , 2, 3 or 4; m is 0, 1 , 2, 3 or 4; p is 0, 1 , 2 or 3; q is 0, 1 , 2, 3, 4, 5, 6 or 7; r is 0, 1 , 2, 3, 5, or 6; s is 1 , 2 or 3; t is 2 or 3;

R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO2R ^a , -SO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ;

R ₂ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ³ , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , and -C _2-9 alkenyl-O-R ³ ; or where R ₁ and R ₂ are both attached to the same nitrogen atom, they may together form a 3, 4, 5, 6, or 7 membered heterocycloalkyl or heterocycloalkenyl ring, or a 6 membered heterocycloaryl ring; R ₃ is independently selected, in each instance, from the group consisting of; halogen, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -OH, -O-acetyl, -O-R ^a , -NR ^b R ^c , -S-R ^a , -S(=O)R ^a , -SO ₂ R ^a , -OSO ₂ R ^a , -C(=O)R ^a , -CO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , and -C _2-9 alkenyl-O-R ^a ; R ₄ is independently selected, in each instance, from the group consisting of; H, OH or OR ¹ ;

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _8-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; wherein, if the cycloalkyl moiety A is selected from A1 , A2 or A3, and the central aryl moiety B is selected from B1 , B6, B21 or B22 then the side-chain moiety C is selected from the group consisting of C4 to C65; including individual enantiomers, diastereomers, racemates, non-racemates, double bond (E/Z) isomers and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the compounds of Formula I; and, wherein the compound of Formula I is not a compound published before the earliest priority date of the present disclosure, or wherein the compound of Formula I is not a compound hitherto not ascertained by the present inventors as being published before the earliest priority date of the present disclosure.

[0065] Throughout this specification, where the definitions of Formula I or Formula I’ refer to a variable such as R ₁ , R ₂ , R ₃ , R ₄ , R ^a , R ^b or R ^c being “independently selected, in each instance, from the group consisting of...”, it is to be understood that where a particular compound of Formula I or Formula I’ possesses more than one R ₁ , R ₂ , R ₃ , R ₄ , R ^a , R ^b or R ^c group within the same molecule, each R ₁ , R ₂ , R ₃ , R ₄ , R ^a , R ^b or R ^c is not required to be identical to the other R ₁ , R ₂ , R ₃ , R ₄ , R ^a , R ^b or R ^c group within that molecule. For example, a molecule falling within the scope of Formula I or Formula I’ may have two R ₃ groups, wherein one of the R ₃ groups is an alkyl group and the other R ₃ is a halogen group.

[0066] In a preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33.

[0067] In another preferred aspect, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20.

[0068] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30.

[0069] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39.

[0070] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A19, and A20.

[0071] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37.

[0072] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0073] In another preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which; C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0074] In a particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0075] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0076] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0077] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of ; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, 031 , 032, C33, 034, 035, 036, 037, 038, 039, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0078] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1, C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65

[0079] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B1 , B3, B6, B8, B9, B13, B14, B18, B31 , B32 and B33; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0080] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0081] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11 , A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49. [0082] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C1 , C2, C3, C4, 05, 06, 07, 08, 050, 051 , 052, 053, 054, 055, 056, 057, 058, 059, 060, 061 , 062, 063, 064 and 065.

[0083] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0084] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0085] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B2, B4, B5, B7, B10, B11 , B12, B15, B16, B17, B19 and B20; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, C33, C34, C35, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49. [0086] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A1 , A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A38 and A39; and

C is selected from the group consisting of; C1 , C2, 03, C4, 05, 06, 07, 08, 050, 051 , 052, 053, 054, 055, 056, 057, 058, 059, 060, 061 , 062, 063, 064 and 065.

[0087] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65.

[0088] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A19, and A20; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30, C31 , C32, 033, 034, C35, 036, C37, 038, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0089] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C1 , C2, C3, C4, C5, C6, C7, C8, C50, C51 , C52, C53, C54, C55, C56, C57, C58, C59, C60, C61 , C62, C63, C64 and C65. [0090] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I in which;

B is selected from the group consisting of; B21 , B22, B23, B24, B25, B26, B27, B28, B29 and B30; and

A is selected from the group consisting of; A21 , A22, A23, A24, A25, A26, A27, A28, A29, A30, A31 , A32, A33, A34, A35, A36 and A37; and

C is selected from the group consisting of; C9, C10, C11 , C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 , C22, C23, C24, C25, C26, C27, C28, C29, C30 , 031 , 032, C33, 034, 035, C36, C37, C38, C39, C40, C41 , C42, C43, C44, C45, C46, C47, C48, and C49.

[0091] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I, wherein the compound is selected from the group consisting of compounds of the type;

A1-B1-C4; A1-B1-C5; A1-B2-C3; A1-B2-C4; A1-B2-C5; A1-B3-C1 ; A1-B6-C4; A1-B6-C5; A1-B7-C3; A1-B7-C4; A1-B7-C5; A2-B1-C5; A2-B2-C5; A2-B6-C5; A2-B7-C5; A3-B1-C5; A3-B2-C5; A3-B6-C5; A3-B7-C5; A4-B1-C1 ; A4-B1-C5; A4-B2-C1 ; A4-B6-C1 ; A4-B6-C5; A4- B7-C1 ; A6-B1-C1 ; A6-B6-C1 ; A7-B1 -C2; A7-B6-C2; A8-B1-C1 ; A8-B6-C1 ; A9-B1-C1 ; A9-B1- C2; A9-B6-C1 ; A9-B6-C2; A19-B1-C1 ; A19-B6-C1 ; A20-B1-C1 ; and A20-B6-C1 .

[0092] In another particularly preferred embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity, said compounds being compounds of Formula I selected from the group consisting of;

(3R,4R)-3-(2,6-dihydroxy-4-pentylphenyl)-N-methyl-4-(prop -1-en-2-yl)cyclohex-1-ene-1-carboxa mide;

(3R,4R)-N-benzyl-3-(2,6-dihydroxy-4-pentylphenyl)-4-(prop -1-en-2-yl)cyclohex-1-ene-1-carboxa mide;

5-pentyl-2-[(1R,6R)-3-(piperazine-1-carbonyl)-6-(prop-1-e n-2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol;

2-[(1R,6R)-3-(methoxymethyl)-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]-5-pentylbenzene-1,3-diol;;

2-[(1R,6R)-3-[(benzyloxy)methyl]-6-(prop-1-en-2-yl)cycloh ex-2-en-1-yl]-5-pentylbenzene-1,3-diol

4-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl] -5-(4-phenylbutyl)benzene-1,3-diol;

2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl] -5-pentylphenol;

(3R,4R)-3-(2,6-dihydroxy-4-propylphenyl)-4-(prop-1-en-2-y l)cyclohex-1-ene-1-carboxylicacid;

2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl] -5-(4-phenylbutyl)benzene-1,3-diol;

-heptyl-4-[(1 R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]benzene- 1 ,3-diol; -[(1R,6R)-3-(hydroxymethyl)-6-(prop-1-en-2-yl)cyclohex-2-en- 1-yl]-5-propylbenzene-1,3-diol; -(3-methanesulfonylpropyl)-2-[(1R,6R)-3-methyl-6-(prop-1-en- 2-yl)cyclohex-2-en-1-yl]benzene- ,3-diol; -(3-methanesulfonylpropyl)-4-[(1R,6R)-3-methyl-6-(prop-1-en- 2-yl)cyclohex-2-en-1-yl]benzene- ,3-diol;

5-(3-methanesulfonylpropyl)-4-[(1R,2S)-5-methyl-2-(propan -2-yl)cyclohexyl]benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-2-[(1S,6S)-3-methyl-6-(propan -2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol;

5-(3-methanesulfonylpropyl)-4-[(1S,6S)-3-methyl-6-(propan -2-yl)cyclohex-2-en-1-yl]benzene-1,3 -diol;

5-(3-methanesulfonylpropyl)-2-[(1R,2S)-5-methyl-2-(propan -2-yl)cyclohexyl]benzene-1,3-diol;

5-pentyl-2-[(1R,6R)-6-(prop-1-en-2-yl)-3-(trifluoromethyl )cyclohex-2-en-1-yl]benzene-1,3-diol;

5-pentyl-4-[(1R,6R)-6-(prop-1-en-2-yl)-3-(trifluoromethyl )cyclohex-2-en-1-yl]benzene-1,3-diol;

5-pentyl-4-[(1R,2S)-2-(propan-2-yl)-5-(trifluoromethyl)cy clohexyl]benzene-1,3-diol;

5-pentyl-2-[(1R,2S)-2-(propan-2-yl)-5-(trifluoromethyl)cy clohexyl]benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-2-[(1R,6R)-6-(prop-1-en-2-yl) -3-(trifluoromethyl)cyclohex-2-en-1-yl] benzene-1,3-diol;

5-(3-methanesulfonylpropyl)-4-[(1 R,6R)-6-(prop-1-en-2-yl)-3-(trifluoromethyl)cyclohex-2-en-1- yl] benzene-1 ,3-diol;

2-{3-fluorobicyclo[1.1.1]pentan-1-yl}-5-pentylbenzene-1,3 -diol;

4-[1-hydroxy-2-(propan-2-yl)-5-(trifluoromethyl)cyclohexy l]-5-pentylbenzene-1,3-diol;

2-[1-hydroxy-2-(propan-2-yl)-5-(trifluoromethyl)cyclohexy l]-5-pentylbenzene-1,3-diol;

2-[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl]ben zene-1,3,5-triol;

3,5-dihydroxy-4-[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex -2-en-1-yl]phenyl trifluoromethanesulfonate;

(1S,4R,5R,6R)-5-(2,6-dimethoxy-4-pentylphenyl)-1-methyl-4 -(prop-1-en-2-yl)-7-oxabicyclo[4.1.0 ]heptane;

(2R,3R)-2-(2,6-dimethoxy-4-pentylphenyl)-6-methylidene-3- (prop-1-en-2-yl)cyclohexan-1-ol;

4-chloro-2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2 -en-1-yl]-5-pentylbenzene-1,3-diol;

(1'R,5E,6'R)-6-hydroxy-5-(hydroxyimino)-3'-methyl-4-penty l-6'-(prop-1-en-2-yl)-[1,1'-bi(cyclohex ane)]-1(6),2',3-trien-2-one; and

(1'R,6'R)-6-hydroxy-3'-methyl-4-pentyl-6'-(prop-1-en-2-yl )-[1,1'-bi(cyclohexane)]-1(6),2',3-triene- 2, 5-dione; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds.

[0093] In one embodiment of the invention, there is provided an antimicrobial composition, comprising an amount of a compound according to Formula I, or Formula I’, effective to treat, inhibit or prevent a microbial infection or biofilm, and one or more carriers and/or excipients

[0094] In one embodiment of the invention, there is provided a compound according to Formula I, or Formula I’, for use in the treatment, inhibition or prevention of a microbial infection or biofilm.

[0095] In one embodiment of the invention, there is provided the use of a compound according to Formula I, or Formula I’, or a composition comprising a compound according to Formula I, or Formula I’, for the treatment, inhibition or prevention of a microbial infection or biofilm.

[0096] In one embodiment of the invention, there is provided the use of a compound according to Formula I, or Formula I’, for the manufacture of a medicament for the treatment, inhibition or prevention of a microbial infection or biofilm.

[0097] In one embodiment of the invention, there is provided the use of a compound for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is a compound of Formula I’;

(A) _x -B-C

Formula I’ wherein; x is 1 or 2, and B is a central aryl moiety, covalently bonded to A and C; wherein B is selected from the group consisting of B6 and B22;

A is a cycloalkyl moiety, covalently bonded to B at the position marked with a dashed line , wherein A is selected from the group consisting of A1 , A2 and A3;

C is a side-chain moiety, covalently bonded to B at the position marked with a dashed line , wherein C is selected from the group consisting of C1 and C3; wherein R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -SO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ; and

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds; and, wherein the compound of Formula I’ is not a compound published as possessing antimicrobial activity before the earliest priority date of the present disclosure, or wherein the compound of Formula I’ is not a compound hitherto not ascertained by the present inventors as being published as possessing antimicrobial activity before the earliest priority date of the present disclosure.

[0098] In a further embodiment of the invention, there is provided the use of a compound for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is a compound of Formula I, selected from the group consisting of compounds of the type;

A1-B1-C3; A1-B6-C3; A2-B1-C1 ; A2-B6-C1 ; A3-B1-C1 ; A3-B6-C1 ; A1-B21-C1 and A1-B22-C1.

[0099] In a highly preferred embodiment of the invention, there is provided use of a compound of Formula I’, wherein the compound of Formula I’ is selected from the group consisting of compounds of the type; and (A1) ₂ -B22-C1 wherein R ₁ is independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, -C _2-5 alkenyl-heteroaryl, acetyl, -C(=O)R ^a , -CO ₂ R ^a , -SO ₂ R ^a , -C _1-8 alkyl-CO ₂ R ^a , -C _2-8 alkenyl-CO ₂ R ^a , -C _1-8 alkyl-C(=O)NR ^b R ^c , -C _2-8 alkenyl-C(=O)NR ^b R ^c , -C(=O)NR ^b R ^c , -CH ₂ -O-R ^a , -C _2-9 alkyl-O-R ^a , -C _2-9 alkenyl-O-R ^a , and -SiR _a R _b R _c ; and

R ^a , R ^b and R ^c are independently selected, in each instance, from the group consisting of; H, methyl, ethyl, -C _3-9 alkyl, -C _1-9 haloalkyl, -C _2-9 alkenyl, -C _2-9 haloalkenyl, aryl, heteroaryl, -C _1-5 alkyl-aryl, -C _2-5 alkenyl-aryl, -C _1-5 alkyl-heteroaryl, and -C _2-5 alkenyl-heteroaryl; including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds; and, wherein the compound of Formula I’ is not a compound published as possessing antimicrobial activity before the earliest priority date of the present disclosure, or wherein the compound of Formula I’ is not a compound hitherto not ascertained by the present inventors as being published as possessing antimicrobial activity before the earliest priority date of the present disclosure.

[00100] In a particularly preferred embodiment of the invention, there is provided the use of a compound for the treatment, inhibition or prevention of a microbial infection or biofilm, wherein the compound is a compound according to Formula I’ selected from the group consisting of; 5-heptyl-2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en -1-yl]benzene-1,3-diol;

2-[(1S,6S)-3-methyl-6-(propan-2-yl)cyclohex-2-en-1-yl]-5- pentylbenzene-1,3-diol;

3-methoxy-2-[(1S,6S)-3-methyl-6-(propan-2-yl)cyclohex-2-e n-1-yl]-5-pentylphenol;

1,3-dimethoxy-2-[(1S,6S)-3-methyl-6-(propan-2-yl)cyclohex -2-en-1-yl]-5-pentylbenzene;

2-[(1R,2S)-5-methyl-2-(propan-2-yl)cyclohexyl]-5-pentylbe nzene-1,3-diol; and

2,4-bis[(6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-en-1-y l]-5-pentylbenzene-1,3-diol including individual enantiomers, diastereomers, racemates, non-racemates, and mixtures thereof, as well as salts, isotopologues, crystalline forms, polymorphs, solvates, clathrates, prodrugs and compounds which hydrolyze or metabolize in-vivo to give rise to any of the aforementioned compounds.

[00101] In some embodiments of the invention, the antimicrobial compound is a prodrug of a compound of Formula I, or Formula I’ wherein one or more substituents, functional groups or moieties of the compound is derivatised with a functional group that can hydrolyse and/or metabolize after being administered, to provide the active antimicrobial compound, thereby providing an advantage in terms of penetration and/or delivery of the active compound to the target site, and/or providing an advantage in terms of minimising adverse side effects during delivery of the active compound en route to the target site, and/or providing an advantage in terms of increased half-life or reduced clearance of the active compound, and/or providing some other advantage due to metabolic and/or pharmacokinetic and/or pharmacodynamic and/or drug interaction effect.

[00102] In some embodiments of the invention, the antimicrobial compound is a prodrug of a compound of Formula I, or Formula I’ wherein one or more hydroxy and/or carboxylic acid substituents, is derivatised as an ester, phosphate, or ether moiety, or other prodrug moiety which metabolizes in-vivo to provide an -OH group, or carboxylic acid group.

[00103] According to one embodiment of the invention, there is provided cannabinoid and cannabinoid analogue compounds with antimicrobial activity.

[00104] According to one embodiment of the invention, there is provided a formulation comprising a cannabinoid or cannabinoid analogue for the treatment or prevention of an infection by a bacteria or fungus wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00105] Preferably the bacteria is a biofilm-forming bacteria. Preferably the bacteria is an antibiotic resistant bacteria. The bacteria may be both biofilm-forming and antibiotic resistant. The biofilm may contain colonies of one or more bacteria and/or one or more fungi. [00106] According to another embodiment of the invention, there is provided a method for the treatment or prevention of an infection by a bacteria or fungus in a subject in need of such treatment comprising the step of: administering an effective amount of a formulation comprising a cannabinoid or cannabinoid analogue wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00107] Preferably the bacteria is a biofilm-forming bacteria. Preferably the bacteria is an antibiotic resistant bacteria. The bacteria may be both biofilm-forming and antibiotic resistant. The biofilm may contain colonies of one or more bacteria and/or one or more fungi.

[00108] According to another embodiment of the invention, there is provided the use of a cannabinoid or cannabinoid analogue, in the manufacture of medicament in the form of a topical formulation for the treatment of an infection by a bacteria or fungus in a subject, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00109] Preferably the bacteria is a biofilm-forming bacteria. Preferably the bacteria is an antibiotic resistant bacteria. The bacteria may be both biofilm-forming and antibiotic resistant. The biofilm may contain colonies of one or more bacteria and/or one or more fungi.

[00110] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: between 15 μg/mL and 0.1 μg/mL, 10 μg/mL and 1 μg/mL, 8 μg/mL and 2 μg/mL, or 3 μg/mL and 6 μg/mL.

[00111] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: 0.1 μg/mL, 0.5 μg/mL, 1.0 μg/mL, 1.5 μg/mL, 2.0 μg/mL, 2.5 μg/mL, 3.0 μg/mL, 3.5 μg/mL, 4.0 μg/mL, 4.5 μg/mL, 5.0 μg/mL, 5.5 μg/mL, 6.0 μg/mL, 6.5 μg/mL, 7.0 μg/mL, 7.5 μg/mL, 8.0 μg/mL, 8.5 μg/mL, 9.0 μg/mL, 9.5 μg/mL, 10.0 μg/mL, 10.5 μg/mL, 11.0 μg/mL, 11.5 μg/mL, 12.0 μg/mL, 12.5 μg/mL, 13.0 μg/mL, 13.5 μg/mL, 14.0 μg/mL, 14.5 μg/mL, or 15.0 μg/mL.

[00112] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: between 2 μg/mL and 0.1 μg/mL, 1.8 μg/mL and 0.1 μg/mL, 1 .5 μg/mL and 0.1 μg/mL, or 1 μg/mL and 0.1 μg/mL.

[00113] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: between 2 μg/mL and 1 μg/mL, 1.8 μg/mL and 1 μg/mL, or 1.5 μg/mL and 1 μg/mL.

[00114] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: between 200 mg/mL and 0.1 mg/mL, 50 mg/mL and 1 mg/mL, 40 mg/mL and 2 mg/mL, or 20 mg/mL and 5 mg/mL. [00115] Preferably, the formulation of the present invention contains a cannabinoid or cannabinoid analogue at a concentration of: 0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL, 5.0 mg/mL, 5.5 mg/mL, 6.0 mg/mL, 6.5 mg/mL, 7.0 mg/mL, 7.5 mg/mL, 8.0 mg/mL, 8.5 mg/mL, 9.0 mg/mL, 9.5 mg/mL, 10.0 mg/mL, 10.5 mg/mL, 11.0 mg/mL, 11.5 mg/mL, 12.0 mg/mL, 12.5 mg/mL, 13.0 mg/mL, 13.5 mg/mL, 14.0 mg/mL, 14.5 mg/mL, 15.0 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, 75 mg/mL, 80 mg/mL, 85 mg/mL, 90 mg/mL, 95 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, or 200 mg/mL.

[00116] As used herein, the term “stereoisomer”, and grammatical variations thereof such as “stereoisomers”, “stereoisomerism”, “stereoisomeric”, et cetera, refers to spatial isomerism in the molecular entity to which it is contextually applied. More specifically, the term is to be understood to include molecules having the same molecular formula and sequence of bonded atoms (constitution) but differing in the three-dimensional orientations of their atoms in space. Thus stereoisomers are to be understood as including optical isomers or enantiomers, diastereoisomers, cis-trans or E-Z isomers, conformers, anomers, atropisomers, configurational stereoisomers and epimers of the molecular entity to which the term is applied. By definition, molecules that are stereoisomers of each other represent the same structural isomer, and the same constitutional isomer.

[00117] All chiral, diastereomeric, racemic mixtures, non-racemic mixtures and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention.

[00118] As used herein, the term “isotopologue”, and grammatical variations thereof such as “isotopologue”, et cetera, is to be understood to mean molecules that differ only in their isotopic composition. That is to say, the term refers to molecules having the same chemical formula and bonding arrangement of atoms, but at least one atom has a different number of neutrons than the parent.

[00119] As used herein, the term “prodrug”, and grammatical variations thereof such as “prodrugs”, et cetera, is to be understood to mean a compound that, after administration, is in vivo hydrolyzed or metabolized (i.e., converted within the body) into a pharmacologically active drug. Thus, “prodrug” refers to a compound that is metabolized, for example, hydrolyzed or oxidized, in the host to form a compound of the Formula (I) or Formula (II). Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs may include, for example, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. The skilled addressee will be aware that compounds containing, for example, hydroxyl, carboxylic acid or amine substituents may be derivatized as esters or amides and that such derivatives will be susceptible to in vivo hydrolysis and/or metabolism to yield the parent, underivatized compound. Such derivatives are to be understood as falling within the scope of the term “prodrugs”. Prodrugs can be readily prepared from the compounds of Formula (I) or Formula (II) using methods known in the art. See, for example, Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3): 165 182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1 , pp. 172- 178, 949-982 (1995).

[00120] As used herein, the term “pharmaceutically acceptable”, will be understood to mean a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual along with the compounds or compositions of this invention, without causing substantial deleterious biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.

[00121] Compounds of the Invention may exist in free or salt form, e.g., as acid addition salts. In this specification unless otherwise indicated language such as “Compounds of the Invention” is to be understood as embracing the compounds in any form, for example free or acid addition salt form, or where the compounds contain acidic substituents, in base addition salt form. The Compounds of the Invention are intended for use as pharmaceuticals, therefore pharmaceutically acceptable salts are preferred. Salts which are unsuitable for pharmaceutical uses may be useful, for example, for the isolation or purification of free Compounds of the Invention or their salts or pharmaceutically acceptable salts, are therefore also included. “Pharmaceutically acceptable salts” include, without limitation, sodium, magnesium, calcium, lithium, potassium, chloride, bromide, iodide, hydrochloride, hydrobromide, sulfate, acetate, tartrate, malate and tosylate salts, for example.

[00122] As used herein, the term “alkyl”, by itself or as part of another substituent, will be understood to mean unless otherwise stated, a straight or branched chain hydrocarbon, and where designated, having the number of carbon atoms designated (i.e., “-C _1-10 alkyl” means an alkyl having between one to ten carbon atoms). By way of illustration, but without limitation, the term "-C _1-8 alkyl" refers to a straight chain or branched hydrocarbon moiety having from 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms. "-C _3-9 alkyl" refers to a straight chain or branched hydrocarbon moiety having from 1 , 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms. "-C _1-4 alkyl" refers to a straight chain or branched hydrocarbon moiety having from 1 , 2, 3, or 4 carbon atoms, including methyl, ethyl, n-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. The term “-C _1-9 haloalkyl” refers to a straight chain or branched hydrocarbon moiety having from 1 , 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein one or more of said carbon atoms are substituted with one or more halogen atoms selected from F, Cl, Br or I.

[00123] As used herein, the term ''alkenyl" employed alone or in combination with other terms means, unless otherwise stated, a straight chain or branched hydrocarbon group containing at least one double bond, and where designated, having the number of carbon atoms designated. For example, from two to nine carbon atoms (i.e., -C _2-9 alkenyl). Whenever it appears herein, a numerical range such as "2 to 9" or “2-9”, refers to each integer in the given range; e.g., "2 to 9 carbon atoms" means that the -C _2-9 alkenyl group can consist of 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms. The alkenyl group is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl), propen-1-yl (i.e., allyl), buten-1-yl, penten-1-yl, penta-1,4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1 -butenyl). Examples of -C _2-4 alkenyl groups include ethenyl (C ₂ ), 1 -propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), 2- methylprop-2-enyl (C ₄ ), butadienyl (C ₄ ) and the like. Examples of -C _2-6 alkenyl groups include the aforementioned -C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), 2,3- dimethyl-2-butenyl (C ₆ ) and the like. Additional examples of alkenyl include heptenyl (C ₇ ), octenyl (C ₈ ), octatrienyl (C ₈ ) and the like. Further examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. An example of a functional group representing an alkene is -CH ₂ -CH=CH ₂ . The term “- C _2-9 haloalkenyl” refers to a straight chain or branched hydrocarbon moiety containing at least one double bond, having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, wherein one or more of said carbon atoms are substituted with one or more halogen atoms selected from F, Cl, Br or I.

[00124] As used herein, the term "halo", employed alone or in combination with other terms will be understood to mean, unless otherwise stated, one or more halogen atom substituents independently selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). The term “halo” is understood to be used interchangeably with the term “halogen”. [00125] As used herein, the term "aromatic" refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized π (pi) electrons, where n is an integer.

[00126] As used herein, the term "aryl" employed alone or in combination with other terms means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be fused, such as naphthalene. In a multi-ring group, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the aryl definition, provided the aromatic ring of such groups is attached directly to the parent molecule. The ring or ring system can have 6 to 14 ring atoms (e.g., C _{6- 14} aromatic or C _6-14 aryl). Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range; e.g., " C _6-14 aryl" means that the aryl group can consist of 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like.

[00127] As used herein, the term “hetero” employed in combination with other terms will be understood to mean, unless otherwise stated, replacement of one or more carbon atoms in the other term to which it is applied, with a heteroatom independently selected in each instance from the group consisting of oxygen (O), nitrogen (N), sulfur (S), selenium (Se) or phosphorus (P).

[00128] The term "heteroaryl" as used herein includes 5-, 6- and 7-membered monocyclic or poly cyclic (e.g., bicyclic or tricyclic) aromatic ring systems having ring carbon atoms and 1 , 2, 3, or 4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur. For example, a heteroaryl can have one or two 5-, 6- or 7-membered rings and 1 to 4 heteroatoms selected from N, O, and S. Heteroaryl bicyclic ring systems can include 1 , 2, 3, or 4 heteroatoms in one or both rings. Exemplary heteroaryls include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, oxadiazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, azepine, oxepine, oxazine, triazine, pyrimidine, indole, and benzoimidazole, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics” or “heterocycloaryl rings”, and these three terms are to be understood as interchangeable with the term “heteroaryl”.

[00129] As used herein, the term "cyclo" employed in combination with other terms will be understood to mean, unless otherwise stated, a cyclic moiety. As used herein, the term "cycloalkyl" employed alone or in combination with other terms will be understood to mean, unless otherwise stated, a cycloalkyl moiety, and will therefore be understood to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl moieties, for example. Where a number of carbon atoms is specified, the cycloalkyl moiety will contain the specified number of carbon atoms. The term “heterocycloalkyl” will be understood to mean a cycloalkyl moiety in which one or more carbon atoms of the cycloalkyl moiety has been replaced with a heteroatom selected independently in each instance from the group consisting of O, N, S or Se. The term “cycloalkenyl” will be understood to mean a cycloalkyl moiety in which one or more single bonds of the cycloalkyl moiety has been replaced with a double bond, provided the number of double bonds does not result in an “aromatic” moiety as defined herein. Accordingly, the term “heterocycloalkenyl” will be understood to mean a cycloalkenyl moiety in which one or more carbon atoms of the cycloalkenyl moiety has been replaced with a heteroatom selected independently in each instance from the group consisting of O, N, S or Se.

[00130] The term “-C _1-5 alkyl-aryl” will be understood to mean a substituent comprising an aryl (aromatic) group connected to the parent molecule via a branched chain or straight chain fully saturated linker wherein said linker comprises 1 , 2, 3, 4 or 5 carbon atoms.

[00131] The term “-C _2-5 alkenyl-aryl” will be understood to mean a substituent comprising an aryl (aromatic) group connected to the parent molecule via a branched chain or straight chain linker wherein said linker has at least one double bond, and comprises 2, 3, 4 or 5 carbon atoms.

[00132] The term “-C _1-5 alkyl-heteroaryl” will be understood to mean a substituent comprising an heteroaryl (heteroaromatic) group connected to the parent molecule via a branched chain or straight chain fully saturated linker wherein said linker comprises 1 , 2, 3, 4 or 5 carbon atoms.

[00133] The term “-C _2-5 alkenyl-heteroaryl” will be understood to mean a substituent comprising an heteroaryl (heteroaromatic) group connected to the parent molecule via a branched chain or straight chain linker wherein said linker has at least one double bond, and comprises 2, 3, 4 or 5 carbon atoms.

[00134] It will be understood that the description of compounds herein is limited by principles of chemical bonding and valency known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding with regard to valencies, and to give compounds which are not inherently unstable. Treatment

[00135] The words “treatment” and “treating” are to be understood accordingly as embracing prophylaxis and treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.

[00136] The term “subject” in the context of methods of treatment may include a human or non-human subject.

[00137] As used herein, the term "an effective amount" refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Determination of an effective amount for a given administration is well within the ordinary skill in the pharmaceutical arts.

[00138] The present invention provides for the administration of the therapeutically effective amount of a cannabinoid or cannabinoid analogue to the site of an infection, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00139] The infection may be a topical infection, ocular infection, or infection that can be treated by injected, orally delivered or inhaled cannabinoid (nasal or pulmonary infection).

[00140] The term “infection” as used herein means colonization by a microorganism and/or multiplication of a micro-organism, for example, a biofilm-forming bacteria or fungus. The infection may be unapparent or result in local cellular injury. The infection may be localized, subclinical and temporary or alternatively may spread by extension to become an acute or chronic clinical infection. The infection may also be a latent infection, in which the microorganism is present in a subject, however the subject does not exhibit symptoms of disease associated with the organism.

[00141] The phrase "therapeutically effective amount" as used herein refers to an amount of the cannabinoid sufficient to inhibit bacterial or fungal growth associated with bacterial or fungal carriage or a bacterial or fungal infection of the skin. That is, reference to the administration of the therapeutically effective amount of a cannabinoid according to the methods or formulations of the invention refers to a therapeutic effect in which substantial bacteriocidal, fungicidal, fungiostatic or bacteriostatic activity causes a substantial inhibition of the relevant bacterial or fungal carriage or bacterial or fungal infection. The term “therapeutically effective amount" as used herein, refers to a nontoxic but sufficient amount of the formulation to provide the desired biological, therapeutic, and/or prophylactic result. The desired results include elimination of bacterial or fungal carriage or reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. In relation to a pharmaceutical formulation, effective amounts can be dosages that are recommended in the modulation of a diseased state or signs or symptoms thereof. Effective amounts differ depending on the pharmaceutical formulation used and the route of administration employed. Effective amounts are routinely optimized taking into consideration various factors of a particular patient, such as age, weight, gender, etc. and the area affected by disease or disease causing microorganisms.

[00142] As used herein, “treating” or “treatment” refers to inhibiting the disease or condition, i.e., arresting or reducing its development or at least one clinical or subclinical symptom thereof. “Treating” or “treatment” further refers to relieving the disease or condition, i.e., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject and/or the physician. In the context of treating a bacterial or fungal infection, the term treatment includes reducing or eliminating colonization by bacteria or fungi and/or multiplication of bacteria or fungi, including reducing biofilm formation or disrupting existing biofilms.

[00143] In one form of the invention, reducing or eliminating colonization by bacteria or fungi means reducing or eliminating colonization by bacteria or fungi as measured by % bacteria or fungi killed.

[00144] In one form of the invention, reducing or eliminating colonization by bacteria or fungi means reducing or eliminating colonization by bacteria or fungi as measured by a log ₁₀ reduction in bacteria or fungi.

[00145] The term a “preventative effective amount” as used herein means an amount of the formulation, which when administered according to a desired dosage regimen, is sufficient to at least partially prevent or delay the onset of the microbial infection.

Topical infections

[00146] In one aspect, the formulation is a topical pharmaceutical formulation for the treatment of an infection of a dermal or mucosal surface, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00147] In one form of the invention, the infection is related to one or more of the following conditions: acne, rash, blisters, burns, itch, cellulitis, folliculitis, nail infections, boils, hair infections, scalp infections, impetigo, haemorrhoids, canker sore, gingivitis, periodontitis, vaginitis, nose lesions, swelling, cut, surgical incision, sunburn, cracked skin, and combinations thereof. [00148] In one form of the invention, the infection is an acute bacterial skin and skin structure infection (ABSSSI) where the infection is related to one or more of the following conditions: cellulitis/erysipelas, wound infection, and major cutaneous abscess that have a minimum lesion surface area of approximately 75 cm ² .

[00149] In one form of the invention, the infection is a complicated skin and skin structure infection (cSSSI) where the infection involves deep subcutaneous tissues or needs surgery in addition to antimicrobial therapy.

[00150] In one form of the invention, the infection is a non-complicated or community acquired skin or skin structure infection.

Ocular infections

[00151] In one aspect, the formulation is an ocular pharmaceutical formulation for the treatment of an infection of an ocular infection, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00152] Ocular infections can be divided into (i) infections affecting the cornea and conjunctiva; (ii) infections in the soft tissue surrounding the eye (ocular adnexa and orbit) which can involve the eye indirectly and can spread from the orbit into the brain; and (iii) infections inside the eye (endophthalmitis), often following penetrating ocular trauma or after intraocular surgery. All of the above infections may be treated by the present regime of cannabinoid delivery.

[00153] Preferably, the cannabinoid is applied topically to the eye of the subject. However, the cannabinoid treatment may comprise administering the cannabinoid via intraocular injection, scleral injection, slow release implant or other delivery method.

Infections treated by oral administration

[00154] In one aspect, the formulation is an oral pharmaceutical formulation for the treatment of an infection, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00155] Any bacterial or fungal infection in a subject may be treated using an orally administered cannabinoid or an orally administered cannabinoid analogue regime.

[00156] Preferably, the cannabinoid enters the blood stream via absorption in the Gl tract and is systemically available to the subject. However, the cannabinoid treatment may comprise administering the cannabinoid to the Gl tract for a localised effect.

[00157] In a preferred aspect of the invention, a cannabinoid or cannabinoid analogue compound is administered to the Gl tract for the treatment of a Clostridium difficile infection. Infections treated by injection

[00158] In one aspect, the formulation is an injected pharmaceutical formulation for the treatment of an infection, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00159] Any infection in a subject by bacteria or fungi may be treated using injected cannabinoids.

[00160] The injection treatment regime may be by intravenous injection, intramuscular injection, subcutaneous injection or intraperitoneal injection. The administration may be intraventricularly, intracranially, intracapsularly, intraspinally, or intracisternally. Preferably, the injection is an intravenous injection.

[00161] Preferably, the cannabinoid enters the blood stream via IV administration or a subcutaneous bolus and is systemically available to the subject.

Infections treated by nasal or pulmonary administration

[00162] In one aspect, the formulation is a nasal or pulmonary pharmaceutical formulation for the treatment of an infection, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00163] Any infection in a subject by bacteria or fungi may be treated using a nasal or pulmonary delivered treatment regime.

[00164] Preferably, infections of the nasal cavity, sinuses, respiratory tract and lungs are treated. For example, the present invention may be used to treat: pneumonia; sinus infection; infections associated with cystic fibrosis; infections associated with asthma; infections associated with acute respiratory distress syndrome (ARDS); infections associated with pneumoconiosis; infections associated with interstitial lung disease (ILD).The nasal or pulmonary treatment regime may comprise the administration of between 25mg and 500mg of a cannabinoid to the nasal or pulmonary system of the subject. The cannabinoid may enter the blood stream via absorption in the nasal or pulmonary system and be systemically available to the subject. However, the cannabinoid treatment may alternatively comprise administering the cannabinoid to the nasal or pulmonary system for a localised effect.

Biofilm disruption

[00165] It is believed that the formulations of the present invention are able to disrupt or prevent the formation of biofilms. The biofilms may be generated by either Gram-positive bacteria, Gram-negative bacteria, fungi, or mixtures of thereof. [00166] Without being held to any theory, we believe the cannabinoids are capable of interfering with the biofilm forming activity of a biofilm-forming bacteria and fungi, thereby rendering it more susceptible to the antimicrobial activity of the cannabinoid.

[00167] The term “biofilm-forming bacteria” as used herein means a bacteria that forms a biofilm, where a biofilm is an aggregate of microorganisms, which may include fungal microbes, in which cells are embedded in a self-produced matrix of extracellular polymeric substances that are adherent to each other, and/or a surface; and/or a microbially-derived, sessile community characterised by cells attached to a substratum, interface or to each other, and are embedded in a matrix of extracellular polymeric substances (EPS) that they have produced.

[00168] The formulations of the present invention may disrupt an already existing biofilm, or may reduce or prevent the formation of a biofilm.

[00169] When an existing biofilm is disrupted, the bacteria and/or fungi in the biofilm may be subject to one or more of the following effects: killing of the bacteria and/or fungi within the biofilm; reduction in growth of the bacteria and/or fungi within the biofilm;

- a reduction in the adherence of the bacteria and/or fungi to the surface on which the biofilm has formed; a reduction in the rate of formation of the extracellular polymeric substance (EPS) matrix; a reduction in the viscosity of the EPS matrix.

[00170] When inhibition of biofilm formation occurs, the bacteria and/or fungi in the biofilm may be subject to one or more of the following effects: killing of the bacteria and/or fungi that would form the biofilm prior to or during biofilm formation; reduction in growth of the bacteria and/or fungi that would form the biofilm prior to or during biofilm formation;

- a reduction in the adherence of the bacteria and/or fungi to the surface on which the biofilm will be formed;

- a reduction in the rate of formation of the extracellular polymeric substance (EPS) matrix during biofilm formation; a reduction in the viscosity of the EPS matrix during biofilm formation. [00171] Preferably, the formulations of the present invention cause an inhibition of biofilm growth wherein the OD590 demonstrates a >70% growth inhibition compared to a growth control. An example of this measurement is provided in Example 1 of the present specification.

[00172] Protocols for measuring the above parameters, such as biofilm viability, biomass and EPS matrix formation, may be found in references such as Skogman et al. The Journal of Antibiotics (2012) 65, 453-459 and Merritt et al. Current Protocols in Microbiology 1B.1.1- 1B.1.18, August 2011.

[00173] There is therefore provided a method for the treatment or prevention of biofilm formation by bacteria and/or fungi, comprising the step of: administering a therapeutically effective amount of a formulation comprising a cannabinoid, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00174] There is further provided a formulation comprising a cannabinoid for the treatment or prevention of biofilm formation by a bacteria and/or fungi, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00175] There is further provided the use of a cannabinoid in the manufacture of a medicament for the treatment or prevention of biofilm formation by a bacteria and/or fungi in a subject, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00176] As used herein, the term "an effective amount" refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Determination of an effective amount for a given administration is well within the ordinary skill in the pharmaceutical arts.

[00177] As used herein, the term "diluent" refers to a pharmacologically inert substance that is nevertheless suitable for human consumption, which serves as an excipient in the dosage form. A diluent serves to dilute the active pharmaceutical ingredient in the dosage form, such that tablets of a typical size can be prepared incorporating a wide range of actual doses of the active pharmaceutical ingredient. A diluent need not be included if the content per dosage form of one or both pharmaceutical ingredients is desired to be maximized for a particular dosage unit size. A diluent can comprise a microcrystalline cellulose, for example, AVICEL. Lactose and isomalt are other common diluents. AVICEL, a form of microcrystalline cellulose, is a commercially available product that is formed of acid-treated cellulose, which treatment tends to dissolve more amorphous regions of the cellulose and to leave more crystalline regions of the cellulose. Microcrystalline cellulose can be a diluent in the inventive dosage form. [00178] Other diluents well-known to those skilled in the art include monobasic calcium phosphate, dibasic calcium phosphate and tribasic calcium phosphate. Almost completely water-insoluble, calcium phosphates are particularly well-known pharmacologically inert diluents or fillers that are compatible with a wide range of active pharmaceutical ingredients. By the term "calcium phosphate" is meant herein calcium phosphate in any of its forms, including, for example, monobasic calcium phosphate (Ca(H ₂ PO ₄ ) ₂ ) , dibasic calcium phosphate (CaHPO ₄ ), and tricalcium phosphate (Ca ₂ (PO ₄ )S), including any orthophosphates, pyrophosphates, or superphosphates, or other polymeric phosphates wherein the counterion includes calcium.

[00179] As used herein, the term "excipient" refers to an ingredient of the dosage form that is not medicinally active, but serves to dilute the active pharmaceutical ingredient, assist in dispersion of the tablet in the patient's stomach, bind the tablet together, and serve other functions like stabilizing the active pharmaceutical ingredient against decomposition.

[00180] As used herein, the term “pharmaceutically acceptable carrier,” and grammatical variations thereof, refers to adjuvants, binders, etc. known to the person skilled in the art that are suitable for administration to an individual (e.g., a mammal or non-mammal). The pharmaceutically acceptable carrier(s) and any additional components, as described herein, should be compatible for use in the intended route of administration (e.g., oral, parenteral) for a particular dosage form. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration (FDA).

Bacteria

[00181] In one aspect, the microbe to be treated by the present invention is a Gram- positive bacteria.

[00182] In a preferred form of the invention, the Gram-positive bacteria is a bacteria species of a genus selected from the list: Streptococcus spp., Bacteroides spp., Peptostreptococcus spp., Clostridium spp., Listeria spp., Bacillus spp., Staphylococcus spp., Propionibacterium spp., Kocuria spp., and Corynebacterium spp., and combinations thereof.

[00183] In a preferred form of the invention, the Gram-positive bacteria is a bacteria species of a genus selected from the following genus: Staphylococcus spp., Streptococcus spp., Bacillus spp., Kocuria spp., and Enterococcus spp., and combinations thereof.

[00184] In a preferred form of the invention, the Gram-positive bacteria is selected from the following species: Acidipropionibacterium acidipropionici, Actinomyces naeslundii, Bacteroides thetaiotaomicron, Bacteroides fragilis, Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Bifidobacterium longum, Clostridium difficile, Clostridium perfringens, Corynebacterium jeikeium, Corynebacterium minutissimum, Corynebacterium striatum, Cutibacterium granulosum, Eggerthella lenta, Enterococcus faecalis, Enterococcus gallinarum, Gemella morbillorum, Kocuria rosea, Lactobacillus acidophilus, Listeria monocytogenes, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Staphylococcus warneri, Streptococcus agalactiae, Streptococcus canis, Streptococcus constellates, Streptococcus intermedius, Streptococcus mutans, Streptococcus oralis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus saprophyticus, and combinations thereof.

[00185] In a preferred form of the invention, the Gram-positive bacteria is selected from the following species: Staphylococcus aureus (including MRSA, hVISA, VISA and VRSA), Staphylococcus warneri, Staphylococcus lugdunensis, Staphylococcus epidermidis, Staphylococcus pyogenes, Staphylococcus capitis, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Enterococcus faecium and Enterococcus faecalis (including VRE), Corynebacterium jeikeium, Kocuria rosea, and Propionibacterium acnes, and combinations thereof.

[00186] In a preferred form of the invention, the Gram-positive bacteria is selected from the following species: Staphylococcus aureus (including MRSA hVISA, VISA and VRSA), Staphylococcus warneri, Staphylococcus capitis, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus cereus, Bacillus megaterium, Bacillus subtilis, Enterococcus faeciumand Enterococcus faecalis (including VRE) and Kocuria rosea,, and combinations thereof.

[00187] In one form of the invention, the Gram-positive bacteria is a bacteria other than Staphylococcus aureus or methicillin-resistant Staphylococcus aureus.

[00188] In one form of the invention, the Gram-positive bacteria is Staphylococcus aureus or methicillin-resistant Staphylococcus aureus (MRSA).

[00189] In one aspect, the microbe to be treated by the present invention is a Gram- negative bacteria.

[00190] In a preferred form of the invention, the Gram-negative bacteria is a bacteria species of a genus selected from the list: Acinetobacter spp., Bacteroides Burkholderia spp., Citrobacter spp., Enterobacter spp., Escherichia spp., Fusobacterium spp., Haemophilus spp., Klebsiella spp., Legionella spp., Moraxella spp., Morganella spp., Neisseria spp. Porphyromonas spp., Prevotella spp., Proteus spp., Providencia spp., Pseudomonas spp., Salmonella spp., Serratia spp., Shigella spp., Stenotrophomonas spp., Veillonella spp, and combinations thereof. [00191] In a preferred form of the invention, the Gram-negative bacteria is a bacteria species of a genus selected from the following genus: Neisseria spp., Legionella spp., Moraxella spp., and combinations thereof.

[00192] In a preferred form of the invention, the Gram-negative bacteria is selected from the following species: Acinetobacter baumannii, Bacteroides fragilis, Bacteroides ovatus, Burkholderia cepacia, Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Fusobacterium nucleatum, Haemophilus influenzae, Klebsiella pneumoniae , Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Porphyromonas levii, Prevotella bivia, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Salmonella typhimurium, Serratia marcescens, Shigella dysenteriae, Shigella sonnei, Stenotrophomonas maltophila, Veillonella parvula, and combinations thereof.

[00193] In a preferred form of the invention, the Gram-negative bacteria is selected from the following species: Legionella pneumophila, Moraxella catarrhalis, Neisseria gonorrhoeae, Neisseria meningitidis, and combinations thereof.

Fungi

[00194] In one aspect, the microbe to be treated by the present invention is a fungal microbe.

[00195] In one form of the invention, the fungal microbe is a yeast strain.

[00196] In one form of the invention, the fungal microbe is selected from the group consisting of Alternaria alternata, Alternaria solani, Botrytis cinerea, Colletotrichum lagenarium, Fusarium culmorum, Phaeosphaeria nodorum, Zymoseptoria tritici, Phytophthora cryptogea, Phytophthora infestans, Pythium ultimum, Magnaporthe oryzae, Thanatephorus cucumeris, Ustilago segetum var. avenae, Uromyces appendiculatus, and Puccinia triticina.

[00197] In one form of the invention, the fungal microbe is selected from the group consisting of Candida, Cryptococcus, Aspergillus, Coccidioides immitis, C. posadasii, Histoplasma capsu latum, Blastomyces dermatitidis, and Pneumocystis jirovecii.

[00198] In one aspect, the fungal microbe may be present at the same time as a bacterial microbe, in the subject.

Additional antimicrobials, adjuvants and/or penetrants

[00199] Other active agents may also be incorporated into the formulations of the present invention. [00200] In some embodiments, the compounds of the invention may be administered in combination with one or more additional compounds which act as adjuvants, potentiators or penetrants.

[00201] In some embodiments, the compounds of the invention may be administered in combination with one or more additional adjuvant compounds such as but not limited to HAMLET, or enzyme blockers, capable of inhibiting enzymes that metabolise the cannabinoid and cannabinoid analogue compounds of the invention.

[00202] In some embodiments, the compounds of the invention may be administered in combination with one or more additional penetrant compounds, capable of assisting penetration of the bacterial cell membrane, particularly the Gram-negative bacterial cell membrane, such as but not limited to cationic penetrants, berberine, palmatine, benzalkonium, detergents such as saponin, NOctyl ss D-glucopyranoside (NOG), polyoxyethylene sorbitan (Tween), polyoxyethylene ethers (Triton), Igepal or (3- [( 3- cholamidopropyl) dimethylammonio] -1 - propanesulfonate (CHAPS), - lysozyme type enzymes or bacteriocins such as nisin, ion chelators such as EDTA or EGTA, - fixatives such as formaldehyde, paraformaldehyde, glutaraldehyde, ethanol, streptolysin, osmium tetroxide or ortho-phthalaldehyde, - permeabilizing agents such as polyethylene glycol (PEG), digitonin, monensin, polyethylenimine (PEI), sodium hexametaphosphate, benzalkonium chloride, - cryoprotectants such as DMSO, - antibiotics such as polymyxin B or rifampicin - ions (NaCI, KCI, MgCI 2, sodium hypochlorite) or sucrose, - antiseptics such as betadine, cetrimide, the oil of tea tree and terpinene chlorhexidine.

[00203] In some embodiments, additional antimicrobial agents such as antibacterials, antifungals etc; lubricating agents; agents that reduce biofouling; may be incorporated.

[00204] For example, the formulation may further comprise benzoyl peroxide, erythromycin, clindamycin, doxycycline or meclocycline.

[00205] Additional antimicrobial agents that can be used include, but are not limited to silver compounds (e.g., silver chloride, silver nitrate, silver oxide), silver ions, silver particles, iodine, povidone/iodine, chlorhexidine, 2-p-sulfanilyanilinoethanol, 4,4'-sulfinyldianiline, 4- sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin, amoxicillin, amphotericin B, ampicillin, apalcillin, apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin, aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim, butirosin, capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine, chloramphenicol, chlortetracycline, ciprofloxacin, clarithromycin, clinafloxacin, clindamycin, clomocycline, colistin, cyclacillin, dapsone, demeclocycline, diathymosulfone, dibekacin, dihydrostreptomycin, dirithromycin, doxycycline, enoxacin, enviomycin, epicillin, erythromycin, flomoxef, fortimicin(s), gentamicin(s), glucosulfone solasulfone, gramicidin S, gramicidin(s), grepafloxacin, guamecycline, hetacillin, imipenem, isepamicin, josamycin, kanamycin(s), leucomycin(s), lincomycin, lomefloxacin, lucensomycin, lymecycline, meclocycline, meropenem, methacycline, micronomicin, midecamycin(s), minocycline, moxalactam, mupirocin, nadifloxacin, natamycin, neomycin, netilmicin, norfloxacin, oleandomycin, oxytetracycline, p- sulfanilylbenzylamine, panipenem, paromomycin, pazufloxacin, penicillin N, pipacycline, pipemidic acid, polymyxin, primycin, quinacillin, ribostamycin, rifamide, rifampin, rifamycin SV, rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin, rolitetracycline, rosaramycin, roxithromycin, salazosulfadimidine, sancycline, sisomicin, sparfloxacin, spectinomycin, spiramycin, streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid, sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin, temafloxacin, temocillin, tetracycline, tetroxoprim, thiamphenicol, thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin, tosufloxacin, trimethoprim, trospectomycin, trovafloxacin, tuberactinomycin, vancomycin, azaserine, candicidin(s), chlorphenesin, dermostatin(s), filipin, fungichromin, mepartricin, nystatin, oligomycin(s), ciprof laxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, rosoxacin, amifloxacin, fleroxacin, temafloaxcin, lomefloxacin, perimycin A or tubercidin, and the like.

Subject

[00206] The subject may be any subject capable of colonisation by bacteria and/or fungi.

[00207] The subject may be mammalian, reptilian, or avian. The subject may also be a plant, vegetable fruit or fish, preferably in agricultural contexts although not limited thereto. Preferably, the subject is selected from the group comprising human, canine, avian, porcine, bovine, ovine, equine, and feline. Most preferably, the subject is selected from the group comprising human, bovine, porcine, equine, feline and canine. Most preferably, the subject is human.

[00208] In the case of the treatment, prevention or inhibition of biofilms, the subject may be any substrate, tissue, surface or other material susceptible to undesired colonisation by biofilms. For example, without limitation, the subject may be any of the above described subjects, requiring treatment of an oral surface such as the teeth, gums or oral mucosa. Alternatively, the subject may be the hull of a marine vessel, or the liner of a swimming pool, or a sewer conduit, or any other surface, substrate or material susceptible to undesired colonisation by biofilms. Dosing and Formulations

[00209] In one embodiment of the invention, the cannabinoid is administered to the subject using a dosing regimen selected from the group consisting of: three times daily; two times daily; daily; every second day, every third day, once weekly; once fortnightly and once monthly.

[00210] The pharmaceutical formulation may optionally include a pharmaceutically acceptable excipient or carrier.

[00211] The formulation of the invention may be selected from the group consisting of: an immediate release formulation, a delayed release formulation, a controlled release formulation and a rapid release formulation.

[00212] The formulation of the invention may further comprise an anti-inflammatory agent (such as a corticosteroid). If the topical formulation is a topical formulation, an anticomedolyic agent (such as tretinoin), and/or a retinoid or derivative thereof may also be added.

[00213] The formulations described herein may be formulated by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.

[00214] The formulations described herein may be in the form of a liquid formulation. The liquid formulation may comprise a solution that includes a therapeutic agent dissolved in a solvent. Generally, any solvent that has the desired effect may be used in which the therapeutic agent dissolves and which can be administered to a subject. Generally, any concentration of therapeutic agent that has the desired effect can be used. The formulation in some variations is a solution which is unsaturated, a saturated or a supersaturated solution. The solvent may be a pure solvent or may be a mixture of liquid solvent components. In some variations the solution formed is an in-situ gelling formulation. Solvents and types of solutions that may be used are well known to those versed in such drug delivery technologies.

[00215] The formulation may or may not contain water. Preferably, the formulation does not contain water, i.e. it is non-aqueous. In another preferred embodiment, the formulation does not comprise a preservative. [00216] The administration of the cannabinoids in accordance with the methods and formulations of the invention may be by any suitable means that results in an amount sufficient to treat a microbial infection or to reduce microbial growth at the location of infection. For example, the amount may be sufficient to treat a microbial infection on a subject's skin.

[00217] The cannabinoid may be contained in any appropriate amount and in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the formulation.

[00218] The pharmaceutical or veterinary formulation may be formulated according to the conventional pharmaceutical or veterinary practice (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed; A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds; J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York; Remington's Pharmaceutical Sciences, 18 ^th Edition, Mack Publishing Company, Easton, Pennsylvania, USA).

[00219] Generally, examples of suitable carriers, excipients and diluents include, without limitation, water, saline, ethanol, dextrose, glycerol, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphates, alginate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, polysorbates, talc magnesium stearate, mineral oil or combinations thereof. The formulations can additionally include lubricating agents, pH buffering agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.

[00220] The formulation may be in the form of a controlled-release formulation and may include a degradable or non-degradable polymer, hydrogel, organogel, or other physical construct that modifies the release of the cannabinoid. It is understood that such formulations may include additional inactive ingredients that are added to provide desirable colour, stability, buffering capacity, dispersion, or other known desirable features. Such formulations may further include liposomes, such as emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like. Liposomes for use in the invention may be formed from standard vesicle-forming lipids, generally including neutral and negatively charged phospholipids and a sterol, such as cholesterol.

Topical formulations

[00221] Formulations of the invention may be administered topically. Therefore, contemplated for use herein are formulations adapted for the direct application to the skin.

[00222] The formulation may be in a form selected from the group comprising suspensions, emulsions, liquids, creams, oils, lotions, ointments, gels, hydrogels, pastes, plasters, roll-on liquids, skin patches, sprays, glass bead dressings, synthetic polymer dressings and solids. For instance, the formulations of the invention may be provided in the form of a water-based formulation or ointment which is based on organic solvents such as oils. Alternatively, the formulations of the invention may be applied by way of a liquid spray comprising film forming components and at least a solvent in which the cannabinoids are dispersed or solubilised.

[00223] The formulation of the invention may be provided in a form selected from the group comprising, but not limited to, a rinse, a shampoo, a lotion, a gel, a leave-on preparation, a wash-off preparation, and an ointment.

[00224] Various topical delivery systems may be appropriate for administering the formulations of the present invention depending up on the preferred treatment regimen. Topical formulations may be produced by dissolving or combining the cannabinoids of the present invention in an aqueous or non-aqueous carrier. In general, any liquid, cream, or gel or similar substance that does not appreciably react with the compound or any other of the active ingredients that may be introduced into the formulation and which is non-irritating is suitable. Appropriate non-sprayable viscous, semi-solid or solid forms can also be employed that include a carrier compatible with topical application and have dynamic viscosity preferably greater than water.

[00225] Suitable formulations are well known to those skilled in the art and include, but are not limited to, solutions, suspensions, emulsions, creams, gels, ointments, powders, liniments, salves, aerosols, transdermal patches, etc., which are, if desired, sterilised or mixed with auxiliary agents, e.g. preservatives, stabilisers, emulsifiers, wetting agents, fragrances, colouring agents, odour controllers, thickeners such as natural gums, etc. Particularly preferred topical formulations include ointments, creams or gels.

[00226] Ointments generally are prepared using either (1) an oleaginous base, i.e., one consisting of fixed oils or hydrocarbons, such as white petroleum, mineral oil, or (2) an absorbent base, i.e., one consisting of an anhydrous substance or substances which can absorb water, for example anhydrous lanolin. Customarily, following formation of the base, whether oleaginous or absorbent, the cannabinoids are added to an amount affording the desired concentration.

[00227] Creams are oil/water emulsions. They consist of an oil phase (internal phase), comprising typically fixed oils, hydrocarbons and the like, waxes, petroleum, mineral oil and the like and an aqueous phase (continuous phase), comprising water and any water-soluble substances, such as added salts. The two phases are stabilised by use of an emulsifying agent, for example, a surface active agent, such as sodium lauryl sulfite; hydrophilic colloids, such as acacia colloidal clays, veegum and the like. Upon formation of the emulsion, the cannabinoids can be added in an amount to achieve the desired concentration.

[00228] Gels comprise a base selected from an oleaginous base, water, or an emulsion- suspension base. To the base is added a gelling agent that forms a matrix in the base, increasing its viscosity. Examples of gelling agents are hydroxypropyl cellulose, acrylic acid polymers and the like. Customarily, the cannabinoids are added to the formulation at the desired concentration at a point preceding addition of the gelling agent.

[00229] The amount of antibiotic compounds incorporated into a topical formulation is not critical; the concentration should be within a range sufficient to permit ready application of the formulation such that an effective amount of the cannabinoids is delivered.

Ocular Formulations

[00230] Formulations of the invention may be administered via ocular delivery.

[00231] Ocular delivery encompasses delivery to the sclera, retina, intraocular fluid, tissue surrounding the eyeball. For example, the delivery may be via injection, topical delivery (creams, gels, ointments, sprays, eye drops), intraocular implant or other means.

[00232] Artificial tear vehicles may be used for ocular cannabinoid delivery. More viscous artificial tears use high concentrations of viscosity enhancing agents, such as Celluvisc®, high viscosity carboxymethyl cellulose (CMC) and Refresh Liquigel®, a blend of 0.35% high viscosity CMC and 0.65% low viscosity CMC.

[00233] Gelling agents may be used for cannabinoid delivery. Such agents may be instilled as liquid and then almost immediately triggered to a gel phase. Timoptic gel (gellan gum), AzaSite® (polycarbophil, poloxamer), and Besivance®, (polycarbophil, poloxamer), 0.3% alginate Keltrol® are examples of such agents. Another gelling agent is polycarbophil- poloxamer gels (eg Durasite®).

[00234] Ocular delivery may also comprise injecting the cannabinoid into the sclera, intraocular space or into the area behind the eye. Formulations suitable for ocular injection optionally include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Alternatively, the compounds of the invention are, in certain aspects encapsulated in liposomes and delivered in injectable solutions to assist their transport across cell membrane. Alternatively or in addition such preparations contain constituents of self-assembling pore structures to facilitate transport across the cellular membrane. The carrier, in various aspects, is a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity is maintained, for example and without limitation, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable formulations is in certain aspects brought about by the use in the formulations of agents delaying absorption, for example, aluminum monostearate and gelatin.

Oral Formulations

[00235] Formulations of the invention may be administered orally.

[00236] Contemplated for use herein are oral solid dosage forms, which are described generally in Martin, Remington's Pharmaceutical Sciences, 18th Ed. (1990 Mack Publishing Co. Easton PA 18042) at Chapter 89, which is herein incorporated by reference. Solid dosage forms include tablets, capsules, pills, troches or lozenges, cachets or pellets. Also, liposomal or proteinoid encapsulation may be used to formulate the present formulations (as, for example, proteinoid microspheres reported in U.S. Patent No. 4,925,673). Liposomal encapsulation may be used and the liposomes may be derivatised with various polymers (E.g., U.S. Patent No. 5,013,556). A description of possible solid dosage forms for the therapeutic is given by Marshall, in Modern Pharmaceutics, Chapter 10, Banker and Rhodes ed., (1979), herein incorporated by reference. In general, the formulation will include the compounds described as part of the invention (or a chemically modified form thereof), and inert ingredients which allow for protection against the stomach environment, and release of the biologically active material in the intestine.

[00237] For the cannabinoid of the invention, the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations that will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. In one aspect, the release will avoid the deleterious effects of the stomach environment, either by protection of the formulation or by release of the compounds beyond the stomach environment, such as in the intestine.

[00238] It is believed that the oral bioavailability of cannabinoids is only 4% to 12% and absorption is highly variable. Although most cannabinoids are generally easily absorbed due to their high partition coefficient (P), they are subject to degradation in the stomach and significant first-pass metabolism.

[00239] Preferably, the cannabinoid is released in the lower gastrointestinal tract.

[00240] The dosage regime may be provided using an oral sustained release pharmaceutical formulation comprising a therapeutically effective pharmaceutical formulation according to the invention, and a release retardant. [00241] In one aspect of the present invention the release retardant is a water-soluble, water swellable and/or water insoluble polymer. In particular, water-soluble polymers are selected from the group comprising are ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, an enteric coating; and a semipermeable membrane. In another aspect of the invention the release retardant is a non-polymeric release retardant. More particularly, the non- polymeric release retardant is hydrogenated castor oil. The formulations of the invention may be milled or granulated and compressed into tablets or encapsulated into capsules according to conventional procedures known in the art.

[00242] To ensure full gastric resistance, a coating impermeable to at least pH 5.0 is used. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings may be used as mixed films.

[00243] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This includes without limitation sugar coatings, or coatings that make the tablet easier to swallow. Exemplary capsules consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e. powder; for liquid forms, a soft gelatine shell may be used. The shell material of cachets in certain aspects is thick starch or other edible paper. For pills, lozenges, moulded tablets or tablet triturates, moist massing techniques are also contemplated, without limitation.

[00244] As used herein, the term "sustained release" means the gradual but continuous or sustained release over a relatively extended period of the therapeutic compound content after oral ingestion. The release may continue after the pharmaceutical formulation has passed from the stomach and through until and after the pharmaceutical formulation reaches the intestine. The phrase “sustained release” also means delayed release wherein release of the therapeutic compound is not immediately initiated upon the pharmaceutical formulation reaching the stomach but rather is delayed for a period of time, for example, until when the pharmaceutical formulation reaches the intestine. Upon reaching the intestine, the increase in pH may then trigger release of the therapeutic compound from the pharmaceutical formulation.

[00245] The term "release retardant" is used herein, means a substance that reduces the rate of release of a therapeutic compound from a pharmaceutical formulation when orally ingested. The release retardant may be a polymer or a non-polymer. The release retardant may be used according to any one of several sustained release systems including, for example, a diffusion system, a dissolution system and/or an osmotic system. [00246] In certain aspects, the therapeutic is included in the formulation as fine multiparticulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration is, in certain aspects, a powder, lightly compressed plugs or even as tablets. In one aspect, the therapeutic could be prepared by compression.

[00247] Colourants and flavouring agents are optionally included. For example, compounds may be formulated (such as, and without limitation, by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavouring agents.

[00248] The volume of the therapeutics, in one aspect, diluted or increased with an inert material. These diluents could include carbohydrates, especially mannitol, alpha-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts are also optionally used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[00249] In other embodiments, disintegrants are included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrants include but are not limited to starch including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatine, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite are also contemplated. Another form of the disintegrants is the insoluble cationic exchange resins. Powdered gums are also optionally used as disintegrants and as binders and these include, without limitation, powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[00250] Binders are contemplated to hold the therapeutic compounds together to form a hard tablet and include, without limitation, materials from natural products such as acacia, tragacanth, starch and gelatin. Other binders include, without limitation, methylcellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) are contemplated for use in alcoholic solutions to granulate the therapeutic.

[00251] An antifrictional agent may be optionally included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be optionally used as a layer between the therapeutic and the die wall, and these can include but are not limited to: stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Exemplary soluble lubricants may also be used such as include sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, and Carbowax 4000 and 6000.

[00252] Glidants that might improve the flow properties of the compound during formulation and to aid rearrangement during compression might be optionally added. The glidants may include without limitation starch, talc, pyrogenic silica and hydrated silicoaluminate.

[00253] To aid dissolution of the therapeutic into the aqueous environment, a surfactant might be added in certain embodiments as a wetting agent. Surfactants may include, for example and without limitation, anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be optionally used and could include, without limitation, benzalkonium chloride or benzethomium chloride. The list of potential nonionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. When used, these surfactants could be present in the formulation of the compounds either alone or as a mixture in different ratios.

[00254] Additives which that potentially enhance uptake of the compounds are for instance and without limitation the fatty acids oleic acid, linoleic acid and linolenic acid.

[00255] Controlled release formulation may be desirable. The formulations are also contemplated. In certain aspects, the compounds could be incorporated into an inert matrix that permits release by either diffusion or leaching mechanisms i.e., gums. In some aspects, slowly degenerating matrices may also be incorporated into the formulation. Another form of a controlled release of this therapeutic is by a method based on the Oros therapeutic system (Alza Corp.), i.e. the drug is enclosed in a semipermeable membrane which allows water to enter and push drug out through a single small opening due to osmotic effects. Some enteric coatings also have a delayed release effect.

[00256] In other aspects, a mix of materials might be used to provide the optimum film coating. Film coating may be carried out, for example and without limitation, in a pan coater or in a fluidized bed or by compression coating.

Injectable Formulations

[00257] Formulations of the invention may be administered via injection.

[00258] The formulations suitable for injectable use optionally include sterile aqueous solutions (where water-soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Alternatively, the compounds of the invention are, in certain aspects encapsulated in liposomes and delivered in injectable solutions to assist their transport across cell membrane. Alternatively or in addition such preparations contain constituents of self-assembling pore structures to facilitate transport across the cellular membrane. The carrier, in various aspects, is a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity is maintained, for example and without limitation, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable formulations is in certain aspects brought about by the use in the formulations of agents delaying absorption, for example, aluminum monostearate and gelatin.

[00259] The invention also provides an injectable sustained release pharmaceutical formulation comprising a therapeutically effective pharmaceutical formulation according to the invention, and a release retardant. The release retardant may be, for example, aluminum monostearate and gelatin.

[00260] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in an appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preparation in certain aspects include without limitation vacuum drying and freeze- drying techniques that yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-f iltered solution thereof.

Nasal and Pulmonary Formulations

[00261] Formulations of the invention may be administered via nasal or pulmonary delivery.

[00262] A wide range of mechanical devices designed for pulmonary delivery of therapeutic products exist, including but not limited to nebulizers, metered-dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Missouri; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colorado; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Massachusetts.

[00263] All such devices require the use of formulations suitable for the dispensing of the cannabinoid. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated.

[00264] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise the cannabinoid suspended in water or non-aqueous solvent. The formulation may also include a buffer and a simple sugar (e.g., for stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the cannabinoid caused by atomization of the solution in forming the aerosol.

[00265] Formulations for use with a metered dose inhaler device will generally comprise a finely divided powder containing the cannabinoid suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2 tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[00266] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the cannabinoid and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The cannabinoid should most advantageously be prepared in particulate form with an average particle size of less than 10 microns, most preferably 0.5 to 5 microns, for most effective delivery to the distal lung.

[00267] Nasal delivery of cannabinoids is also contemplated. Nasal delivery allows the passage of the cannabinoid to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the cannabinoid in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

Kits

[00268] The invention also provides kits for use in the instant methods. There is therefore provided a kit comprising a cannabinoid for the treatment or prevention of a bacterial or fungal infection in a subject in need of such treatment or prevention, wherein the cannabinoid or cannabinoid analogue is a compound of Formula I or a compound of Formula I’.

[00269] Kits of the invention include one or more containers comprising a cannabinoid as described herein, and instructions for use in accordance with any one of the methods described herein. The kit may further comprise a description of selecting an individual suitable for treatment based on identifying whether that individual has an infection by a bacteria or fungus wherein the cannabinoid or cannabinoid analogue is a compound of Formula I or a compound of Formula I’. The kit may further comprise a description of administering a cannabinoid as described herein to an individual at risk of developing an infection by a bacteria or fungus wherein the cannabinoid or cannabinoid analogue is a compound of Formula I or a compound of Formula I’.

[00270] Preferably, the cannabinoid or cannabinoid analogue is a compound of Formula I, or Formula I’.

[00271] The instructions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g. multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert. The label or package insert indicates that the composition is used for treating, ameliorating and/or preventing an infection by bacteria or fungi. Instructions may be provided for practising any of the methods described herein.

General

[00272] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variation and modifications. The invention also includes all of the steps, features, formulations and compounds referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

[00273] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, formulations and methods are clearly within the scope of the invention as described herein.

[00274] The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference, which means that it should be read and considered by the reader as part of this text. That the document, reference, patent application or patent cited in this text is not repeated in this text is merely for reasons of conciseness. No admission is made that any of the references constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates.

[00275] Throughout this specification, unless the context requires otherwise, the term antimicrobial is understood to include compounds with antibacterial and/or antifungal properties. [00276] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[00277] As used herein, the term “prodrug” refers to an agent which metabolizes into or undergoes in vivo hydrolysis to form a drug or an active ingredient thereof. The term “prodrug” can be used interchangeably with terms such as “proagent”, “latentiated drugs,” “bioreversible derivatives,” and “congeners” (Harper N.J. Drug latentiation. Prog Drug Res. 1962; 4:221-294; Roche EB. Design of Biopharmaceutical Properties through Prodrugs and Analogs. Washington, D.C.: American Pharmaceutical Association; 1977; Sinkula A A, Yalkowsky S H. Rationale for design of biologically reversible drug derivatives: prodrugs. J Pharm Sci. 1975; 64:181 -210). Usually, the use of the term implies a covalent link between a drug and a chemical moiety, though some authors also use it to characterize some forms of salts of the active drug molecule. Although there is no strict universal definition for a prodrug itself, and the definition may vary from author to author, generally prodrugs can be defined as pharmacologically inert chemical derivatives that can be converted in vivo, enzymatically or nonenzymatically, to the active drug molecules to exert a therapeutic effect (Sinkula A A, Yalkowsky S H. Rationale for design of biologically reversible drug derivatives: prodrugs. J Pharm Sci. 1975; 64:181-210; Stella V J, Charman W N, Naringrekar V H. Prodrugs. Do they have advantages in clinical practice? Drugs. 29:455-473 (1985)).

[00278] Suitable "pharmaceutically acceptable salts" include conventionally used nontoxic salts, for example a salt with an inorganic base such as an alkali metal salt (such as sodium salt and potassium salt), an alkaline earth metal salt (such as calcium salt and magnesium salt), an ammonium salt; or a salt with an organic base, for example, an amine salt (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino) ethane salt, monomethyl-monoethanolamine salt, procaine salt and caffeine salt), a basic amino acid salt (such as arginine salt and lysine salt), tetraalkyl ammonium salt and the like, or other salt forms that enable the pulmonary hypertension reducing agent to remain soluble in a liquid medium, or to be prepared and/or effectively administered in a liquid medium, preferable an aqueous medium. The above salts may be prepared by a conventional process, for example from the corresponding acid and base or by salt interchange.

[00279] Examples of suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methansulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt. The salts may be in some cases hydrates or ethanol solvates.

[00280] Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout. Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.

EXAMPLES

Example 1

Synthesis methods for the preparation of Cannabinoids and Cannabinoid Analogues

[00281] General: Intermediates are characterised by ¹ H NMR (500 MHz, Bruker) or ¹³ C NMR (125 MHz, Bruker). All final compounds are further characterised by HRMS and HPLC. Preparatory HPLC purification was conducted on an Agilent 1100 Prep using methanokwater mixtures. Cannabidiol was supplied by Noramco. 7-hydroxy-1’,3’-diacetylcannabidiol and 7- nor-7-carboxy-1’,3’-diacetylcannabidiol were prepared following the literature procedure of L.O. Hanus, S. Tchilibon, D.E. Ponde, A Breuer, E. Fride and R. Mechoulam; Org. Biomol.Chem., 2005, 3, 1116-1123. S. Tchilibon and R. Mechoulam; Org. Lett. 2000, 2, 3301-3303.

Triphenyl(3-phenylpropyl)phosphonium bromide

[00282] A solution of triphenyl phosphine (12.5 g, 47.7 mmol) and 1-bromo-3- phenylpropane (50.2 mmol) in acetonitrile (250 mL) was heated to reflux for 16 h under an argon atmosphere. The reaction mixture was cooled to RT and the solvent displaced by toluene in vacuo to give a white solid 20.9 g (95 %).

[00283] ¹ H NMR (CDCI ₃ ): δ 1.97 (m, 2H), 3.05 (m, 2H), 3.94 (m, 2H), 7.21 (m, 5H), 7.68 (m, 7H), 7.78 (m, 8H). General Procedure 1A: Qlivetol Analogue Synthesis

[00284] To a cold (-78 °C) suspension of the required phosphonium salt (25 mmol) in anhydrous THF (100 mL) was slowly added n-BuLi (2 M, 25 mmol) under an argon atmosphere. The cooling bath was removed, and the reaction was stirred at RT for 3 h then re-cooled to -78 °C. A solution of 3,5-dibenzyloxybenzaldehyde (25 mmol) in anhydrous THF (20 mL) was added dropwise and the temperature allowed to warm to RT overnight. The reaction was quenched by the addition of saturated ammonium chloride and the product extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated in vacuo. The crude material was purified by silica gel column chromatography (2 % ethyl acetate :hexanes).

[00285] To a solution of the preceding compound (15 mmol) in ethanol (170 mL) was added, under an atmosphere of Argon, 10 % Pd/C (0.25 equivalents). The Argon was displaced three times with Hydrogen and the reaction mixture was stirred overnight at RT. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography (30 % ethyl acetate:hexanes).

5-(4-Phenylbutyl)benzene-1,3-diol (Olivetol Analogue R = phenethyl)

[00286] Prepared following general procedure 1 with triphenyl(3- phenylpropyl)phosphonium bromide and 3,5-dibenzyloxybenzaldehyde, overall yield 79 %.

[00287] ¹ H NMR (CDCI ₃ ): δ 1.62 (m, 4H), 2.54 (m, 2H), 2.64 (m, 2H), 4.75 (br s, 2H), 6.19 (m, 1H), 6.24 (m,1H), 7.20 (m, 3H), 7.29 (m, 2H).

5-Heptylbenzene-1 ,3-diol (Olivetol Analogue R = pentyl)

[00288] Prepared following general procedure 1 with hexyl triphenylphosphonium bromide and 3,5-dibenzyloxybenzaldehyde, overall yield 81 %.

[00289] ¹ H NMR (Solvent): δ 1.90 (t, 3H), 1.31 (m, 8H), 1.59 (m, 2H), 2.51 (m, 2H), 4.86 (br s, 2H), 6.19 (m, 1H), 6.26 (m,1H). General Procedures 1B: Olivetol Analogue Syntheses - heteroatoms in side-chain

SCHEME A

[00290] Sulfinyl-olivetol analogues may synthesised by procedures known in the art, such as the procedure of Voutyritsa, E. et al, Synthesis, 2017, 49, 917-924, which utilises 2,2,2- trifluoroacetophenone as organocatalyst to partially oxidise the corresponding sulfide precursors.

[00291] Sulfonyl-olivetol analogues may be synthesized via complete oxidation of the corresponding sulfide precursors with MCPBA.

SCHEME B [00292] Olivetol analogues having a side-chain directly attached to the phenyl ring via a heteroatom (O, N or S) may be synthesized by the procedures outlined in Schemes A and B above.

[00293] While the olivetol hydroxy groups have been protected utilising methyl protection or methoxymethyl (MOM) protection in Schemes A and B above, it will be understood by the skilled addressee that alternative protecting group strategies may be equally employed. Such alternative protecting groups are well known to the person skilled in the art of organic synthesis, and can be found in the literature, such as, for example, Wuts T.G.M. et al. Protective groups in organic synthesis, 2007, 4 ^th Edition, Wiley, New York.

SCHEME C

[00294] Olivetol analogues having a side-chain attached to the phenyl ring via a heteroatom (O, N or S) separated from the phenyl ring by one carbon may be synthesized by the procedures outlined in Scheme C above.

[00295] As with Scheme A, olivetol analogues containing a sulfinyl group may synthesised by procedures known in the art, such as the procedure of Voutyritsa, E. et al, Synthesis, 2017, 49, 917-924, which utilises 2,2,2-trifluoroacetophenone as organocatalyst to partially oxidise the corresponding sulfide precursors.

[00296] As with Scheme A, olivetol analogues containing a sulfonyl group may be synthesized via complete oxidation of the corresponding sulfide precursors with MCPBA. SCHEME D

[00297] Olivetol analogues having a side-chain attached to the phenyl ring via a heteroatom (O, N or S) separated from the phenyl ring by two or more carbons may be synthesized by the procedures outlined in Scheme C above.

[00298] As with Schemes A and C, olivetol analogues containing a sulfinyl group may synthesised by procedures known in the art, such as the procedure of Voutyritsa, E. et al, Synthesis, 2017, 49, 917-924, which utilises 2,2,2-trifluoroacetophenone as organocatalyst to partially oxidise the corresponding sulfide precursors.

[00299] As with Schemes A and C, olivetol analogues containing a sulfonyl group may be synthesized via complete oxidation of the corresponding sulfide precursors with MCPBA. [00300] While the olivetol hydroxy groups have been protected utilising methyl protection in Scheme C and D, it will be understood by the skilled addressee that alternative protecting group strategies may be equally employed, such as, for example, those disclosed in Wuts T.G.M. et al. Protective groups in organic synthesis, 2007, 4 ^th Edition, Wiley, New York.

[00301] Throughout Schemes A to D, the procedures described for the synthesis of the cannabinoid precursor compounds therein are facile procedures, typically providing good yields of product, and are well known to the skilled addressee. Reaction conditions for all such procedures, including oxidations, reductions, alkylations, deprotections, hydrolyses, hydrogenations and Wittig homologation reactions can be found in many prior literature publications such as, for example, Furniss, B.S. et al, Vogel’s Textbook of Practical Organic Chemistry, 5 ^th Edition, 1989, Longman Scientific & Technical, and Paquette, L.A. et al, EROS Encyclopedia of Reagents for Organic Synthesis, 2 ^nd Edition, 2009, Wiley.

General Procedures 1C: Menthadienol Precursor Analogue Syntheses - Trifluoromethane analogues

SCHEME E

[00302] Trifluoromethane containing menthadienol precursor analogues may be synthesised in racemic form starting from commercially available cyclohexadiene in accordance with Scheme E.

[00303] The procedures described for the synthesis of the menthadienol precursor analogue of Scheme E are facile procedures, typically providing good yields of product, and are well known to the skilled addressee. Reaction conditions for such procedures, can be found in bench top textbook publications such as, for example, Furniss, B.S. et al, Vogel’s Textbook of Practical Organic Chemistry, 5 ^th Edition, 1989, Longman Scientific & Technical, and Paquette, L.A. et al, EROS Encyclopedia of Reagents for Organic Synthesis, 2 ^nd Edition, 2009, Wiley.

SCHEME F

[00304] Trifluoromethane containing menthadienol precursor analogues may also be synthesised with stereospecificity starting from commercially available Limonene oxides in accordance with Scheme F.

[00305] Conversion of Limonene oxides to non-racemic Perillaldehydes may be accomplished in accordance with the previously reported procedures of Tius, M.A. et al, A Convenient Synthesis of (R)-(+)-Perillaldehyde, Synthetic Communications, 1988, Vol. 18, Issue 16-17, pp 1905-1911.

[00306] Facile formation of the silyl enol ether by treatment with TBS-triflate followed by oxidation with meta-chloro-perbenzoic acid (MCPBA) provides the corresponding epoxide. Treatment of the epoxide with hydrofluoric acid and sodium periodate provides the corresponding ketone which may then be converted to the non-racemic trifluoromethyl p- menthandienol in accordance with the procedure provided in the previous Scheme E.

[00307] The procedures described for the synthesis of the menthadienol precursor analogue of Scheme E are facile procedures, typically providing good yields of product, and are well known to the skilled addressee. Reaction conditions for such procedures, can be found in bench top text book publications such as, for example, Furniss, B.S. et al, Vogel’s Textbook of Practical Organic Chemistry, 5 ^th Edition, 1989, Longman Scientific & Technical, and Paquette, L.A. et al, EROS Encyclopedia of Reagents for Organic Synthesis, 2 ^nd Edition, 2009, Wiley. General Procedures 1D: Cyclohexane, Heteorcyclohexane and Bicyclopentane

Syntheses

SCHEME G [00308] Formation of Grignard reagents from olivetol analogues prepared in accordance with Schemes A to D is readily achieved via treatment with butyl lithium and 1 ,2-dibromoethane followed by magnesium.

[00309] Olivetol Grignard reagents provide access to cyclohexane and heterocyclohexane CBD analogues via direct reaction of the corresponding cyclohexanones with the olivetol Grignard reagent, followed by reduction of the tertiary alcohol group using, for example, the prior art process of Yasuda, M. et al, J. Org. Chem., 2016, 81, 9957-9963, which employs chlorodiphenylsilane as hydride source in the presence of a catalytic amount of InCI ₃ showing high chemoselectivity for tertiary alcohols while not reducing primary alcohols and functional groups that are readily reduced by standard methods such as esters, chloro, bromo, and nitro groups. Alternative means to remove the tertiary alcohol group will be apparent to the skilled addressee. Similarly, protection/deprotection strategies for protecting the heteroatoms in heterocyclohexanone precursors during the rection with the Grignard reagent and subsequent hydride reduction of the tertiary alcohol group will be apparent to the skilled addressee as a matter of routine, and are available in standard benchtop textbooks such as, for example, Wuts T.G.M. et al. Protective groups in organic synthesis, 2007, 4 ^th Edition, Wiley, New York.

[00310] Olivetol Grignard reagents also provide access to bicyclopentance CBD analogues, by direct reaction with 1 ,1 ,1-propellane, itself prepared in accordance with the previously reported procedure of Wiberg, K.B. et al, J. Am. Chem. Soc. 104 (19): 5239-5240. The reaction product of 1 ,1 ,1-propellane and olivetol Grignard reagents may then be fluorinated via treatment with N-Fluorobenzenesulfonimide (NFSI) and then deprotected to provide the final bicyclopentance CBD analogue.

[00311] The choice of protecting group on the olivetol phenolic oxygens, and the corresponding deprotection processes to arrive at the final bicyclopentane, cyclohexane and heterocyclohexane analogues is a matter of routine for the skilled addresse, guided by standard benchtop textbooks such as, for example, Wuts T.G.M. et al. Protective groups in organic synthesis, 2007, 4 ^th Edition, Wiley, New York.

[00312] Numerous variants of the above described reactions will be apparent and readily available to the skilled addressee. For example, alternative approaches to preparing Grignard reagents, forming silyl enol ethers, and/or reducing tertiary alcohols will be known to the skilled addressee, guided by standard benchtop textbooks such as, for example, Furniss, B.S. et al, Vogel’s Textbook of Practical Organic Chemistry, 5 ^th Edition, 1989, Longman Scientific & Technical, and Paquette, L.A. et al, EROS Encyclopedia of Reagents for Organic Synthesis, 2 ^nd Edition, 2009, Wiley. General Procedures 1 E: Acid catalysed Electrophillic Aromatic Substitution Reactions of Olivetol

Analogues with Menthadienol analogues

SCHEME H

[00313] The general approach to coupling olivetol analogues with menthadienol analogues to provide the CBD analogues of the present invention utilises the well-established acid catalysed electrophillic aromatic substitution reactions of menthadienol with olivetol (Scheme H), as first reported by Petrzilka, T. et al, (Helv. Chim. Acta 1967, 50, 2111-2113; Helv. Chim. Acta 1967, 50(2), 719-723). This approach affords three distinct and readily separable products, in the form of CBD, abnormal CBD (abn-CBD) and the corresponding bis- adduct, due to the dual reactive sites on the olivetol moiety (Scheme H).

[00314] Applying this approach generally to the olivetol analogues and menthadienol analogues described in the foregoing schemes provides access to many of the CBD analogues in accordance with Formula I, or Formula I’:

[00315] In an exemplary synthesis directed to the bis-adduct MTC-035, a solution of olivetol (5.1 mmol) in DCM (10 mL) was added zinc chloride (6.6 mmol) and water (25 mmol). The mixture was heated at reflux for 30 min whereby a DCM solution (10.0 mL) of two equivalents of (+)-p-mentha-2,8-dien-1-ol (10.2 mmol) was added dropwise over 30 minutes. Heating was continued for 2 h when TLC analysis indicated all (+)-p-mentha-2,8-dien-1-ol was consumed. The crude material was extracted by diethyl ether, washed (water, brine), dried (MgSO4) and concentrated in vacuo. The product was purified by silica gel column chromatography and preparative HPLC, to yield an orange, amorphous solid.

[00316] The proton and carbon-13 NMR spectra were consistent with the proposed structure and in accord with those previously reported in the literature. ⁶ The spectra are complicated by the presence of rotamers in solution.

[00317] HRMS (M+Na) ⁺ : calculated for C ₃₁ H ₄₂ O ₂ Na: 471.3239, found: 471.3240.

[00318] HPLC: 97.6 %. Column = Phenomenex Luna C18 (2) 250 x 4.6mm 5 μm + SecurityGuard C18 RP; Mobile Phase = 5:95:0.025 Water:Acetonitrile:Acetic Acid; Flow Rate = 1.0 ml/min; Temperature = 40°C; UV = 210 nm; Injection = 10 μl; Sample solvent = Mobile Phase; Retention time - a sharp symmetrical peak was observed at 15.342 minutes.

General Procedure 2: CBD and abn-CBD Analogue Synthesis

[00319] In an adaptation of the procedure of US 2013/0171259, a solution of the olivetol analogue (5.1 mmol) in DCM (10 mL) was added zinc chloride (6.6 mmol) and water (25 mmol). The mixture was heated at reflux for 30 min whereby a DCM solution (5.0 mL) of (+)-p-mentha- 2,8-dien-1-ol (5.1 mmol) was added dropwise over 30 minutes. Heating was continued for 2 h when TLC analysis indicated all (+)-p-mentha-2,8-dien-1 -ol was consumed. The crude material was extracted by diethyl ether, washed (water, brine), dried (MgSO ₄ ) and concentrated in vacuo. The desired products were purified by either silica gel column chromatography and/or preparative HPLC.

MTC-007 and MTC-018 (Ri = pentyl, R ₂ = OH)

MTC-007 (Table 1, Compound 9)

[00320] Prepared following general procedure 2, with 5-heptylbenzene-1,3-diol (0.83 g, 4.0 mmol) and (+)-p-mentha-2,8-dien-1-ol (0.61 g, 4.0 mmol) and purified by column chromatography on silica gel using 5 % ethyl acetate in hexane and further purified by preparative HPLC to give a yellow oil (0.20 g, 15 %).

[00321] ¹ H NMR (CDCI ₃ ): δ 0.88 (t, 3H), 1.29 (m, 8H), 1.55 (m, 2H), 1.66 (s, 3H), 1.79 (m,

5H), 2.09 (m, 1H), 2.23 (m, 1H), 2.42 (m, 3H), 3.86 (m, 1H), 4.56 (m, 1H), 4.66 (s, 1H), 4.78 (br s, 1H), 5.57 (s, 1H), 5.98 (br s, 1H), 6.19 (br s 1H), 6.26 (br s, 1H).

[00322] ¹³ C NMR (CDCI ₃ ): δ 14.20, 20.57, 22.77, 23,77, 28.54, 29.29, 29.37, 30.53,

31.07, 31.93, 35.65, 37.35, 46.30, 108.15, 109.83, 110.96, 113.92, 124.30, 140.10, 143.15, 149.40, 154.03, 156.20.

[00323] HRMS (M+H) ⁺ : calculated for C ₂₃ H ₃₅ O ₂ : 343.2637, found: 343.2640.

[00324] HPLC: 99.0 %.

MTC-018 (Table 1, Compound 15)

[00325] Prepared following general procedure 2, with 5-heptylbenzene-1,3-diol (0.83 g, 4.0 mmol) and (+)-p-mentha-2,8-dien-1-ol (0.61 g, 4.0 mmol) and purified by column chromatography on silica gel using 20 % ethyl acetate in hexane to give an orange oil (0.38 g, 28 %).

[00326] ¹ H NMR (CDCI ₃ ): δ 0.88 (t, 3H), 1.30 (m, 4H), 1.46 (m, 2H), 1.53 (s, 3H), 1.79 (m,

5H), 2.09 (m, 1H), 2.24 (m, 1H), 2.48 (m, 1H), 2.59 (m, 1H), 3.53 (m, 1H), 4.46 (s, 1H), 4.64 (s, 1H), 5.03 (br m, 1H), 5.52 (s, 1H), 6.04 (s, 1H), 6.20 (s, 1H), 6.21 (s, 1H).

[00327] ¹³ C NMR (CDCI ₃ ): δ 14.20, 21.48, 22.79, 23.74, 28.27, 29.28, 29.79, 30.40,

31.53, 31.95, 34.16, 40.21 , 45.11 , 102.29, 108.74, 111.50, 120.00, 124.91 , 139.85, 144.09, 147.83, 154.83, 156.59.

[00328] HRMS (M+H) ⁺ : calculated for C ₂₃ H ₃₅ O ₂ :343.2637, found 343.2641 .

[00329] HPLC: 98.9 %. MTC-008 and MTC-017 (Ri = phenethyl, R ₂ = OH)

MTC-008 (Table 1, Compound 16)

[00330] Prepared following general procedure 2 with 5-(4-phenylbutyl)benene-1,3-diol (0.38 g, 1.6 mmol) and (+)-p-mentha-2,8-dien-1-ol (0.24 g, 1.6 mmol) and purified by column chromatography on silica gel using 33 % ethyl acetate in hexane to give a pale yellow oil (0.25 g, 42 %).

[00331] ¹ H NMR (CDCI ₃ ): δ 1.50 (m, 5H), 1.64 (m, 3H), 1.77 (m, 5H), 2.07 (m, 1H), 2.19 (m, 1H), 2.28 (m, 1H), 2.45 (m, 1H), 2.62 (m, 3H), 3.47 (m, 1H), 4.43 (s, 1H), 4.62 (s, 1H), 4.73 (s, 1H), 5.44 (s, 1H), 6.01 (s, 1H), 6.15 (d, 1H), 6.19 (d, 1H), 7.16 (m, 3H), 7.25 (m, 2H).

[00332] ¹³ C NMR (CDCI ₃ ): δ 21.52, 23.75, 28.28, 30.40, 30.96, 31.43, 33.97, 35.88,

40.26, 45.07, 102.38, 108.73, 111.53, 120.09, 134.80, 125.81 , 128.41 , 128.55, 139.90, 142.58, 143.69, 147.86, 154.74, 156.67.

[00333] HRMS (M+H) ⁺ : calculated for C ₂₆ H ₃₃ O ₂ :377.2481 , found 377.2477.

[00334] HPLC: 99.6 %.

MTC-017 (Table 1, Compound 10)

[00335] Prepared following general procedure 2 with 5-(4-phenylbutyl)benene-1 ,3-diol (1.0 g, 4.2 mmol) and (+)-p-mentha-2,8-dien-1 -ol (0.63 g, 4.2 mmol) and purified by column chromatography on silica gel using 4 % ethyl acetate in hexane to give a yellow oil (0.40 g, 25 %).

[00336] ¹ H NMR (CDCI ₃ ): δ 1.63 (m, 8H), 1.80(m, 5H), 2.10 (m, 1H), 2.23 (m, 1H), 240 (td, 1H), 2.48 (t, 2H), 2.62 (t, 2H), 3.85 (m, 1H), 4.56 (s, 1H), 4.61 (br s, 1H), 4.66 (s, 1H), 5.57 (s, 1H), 5.97 (br s, 1H), 6.15 (br s, 1H), 6.25 (br s, 1H), 7.17 (m, 3H), 7.27 (m, 2H).

[00337] ¹³ C NMR (CDCI ₃ ): δ 20.62, 23.78, 28.55, 30.55, 31.10, 45.45, 35.92, 37.38,

46.29, 108.13, 109.93, 110.98, 114.02, 124.24, 125.75, 128.37, 128.55, 140.17, 142.74, 129.45, 154.05, 156.31.

[00338] HRMS (M+H) ⁺ : calculated for C ₂₆ H ₃₃ O ₂ :377.2481, found 377.2479.

[00339] HPLC: 97.6 %. MTC-011 (Ri = propyl, R ₂ = OH), (Table 1, Compound 11)

[00340] Prepared following general procedure 2 with 3-pentylphenol (W02009019868) (0.61 g, 3.7 mmol) and (+)-p-mentha-2,8-dien-1-ol (0.57 g, 3.7 mmol) and purified by column chromatography on silica gel using 5 % diethyl ether in hexane and further purified by preparative HPLC to give a pale yellow oil (0.22 g, 20 %).

[00341] ¹ H NMR (CDCI ₃ ): δ 0.89 (t, 3H), 1.31 (m, 4H), 1.57 (m, 2H), 1.59 (m, 5H), 1.77 (m, 5H), 2.07 (m, 1H), 2.21 (m, 1H), 2.52 (m, 2H), 3.41 (m, 1H), 4.57 (s, 1H), 4.67 (s, 1H), 5.42 (s, 1H), 5.52 (s, 1H), 6.63 (s, 1H), 6.87 (d, 1H).

[00342] ¹³ C NMR (CDCI ₃ ): δ 14.14, 20.95, 22.68, 23.74, 28.58, 30.53, 31.03, 31.69,

35.59, 43.75, 47.38, 111.03, 116.46, 120.54, 124.51 , 127.15, 130.15, 137.32, 142.76, 148.72, 154.14.

[00343] HRMS (M+H) ⁺ : calculated for C ₂₁ H ₃₁ O:299.2375, found 299.2377.

[00344] HPLC: 98.5 %.

MTC-009 (Table 1, Compound 18)

[00345] Prepared by hydrogenation of compound 1 (CBD) in accordance with the procedure of S. Ben-Shabat, L. O. Hanus, G. Katzavian, R. Gallily; J. Med. Chem. 2006, 49, 1113-1117, to produce a yellow oil, in 75 % yield.

[00346] ¹ H NMR (CDCI ₃ ): δ 0.87 (t, 6H), 0.90 (t, 3H), 1.33 (m, 4H), 1.40 (m, 1H), 1.60 (m, 4H), 1.79 (m, 4H), 2.13 (m, 2H0, 2.45 (m, 2H), 3.83 (, 1H), 4.88 (br s, 1H), 5.52 (s, 1H), 6.21 (br m, 3H).

[00347] ¹³ C NMR (CDCI ₃ ): δ 14.14, 16.53, 21.83, 22.27, 22.66, 23.72, 27.97, 30.79,

31.73, 35.64, 43.81 , 107.63, 109.74, 114.16, 125.00, 140.11 , 143.06, 154.56, 156.32.

[00348] HRMS (M+H) ⁺ : calculated for C ₂₁ H ₃₃ O ₂ :317.2481 , found 317.2491.

[00349] HPLC: 99.8 %.

MTC-014 (Table 1, Compound 17)

[00350] Prepared by hydrogenation of compound 1 (CBD) in accordance with the procedure of S. Ben-Shabat, L. O. Hanus, G. Katzavian, R. Gallily; J. Med. Chem. 2006, 49, 1113-1117, to produce a yellow oil, in 91 % yield. [00351] ¹ H NMR (CDCI ₃ ): (major diastereoisomer) δ 0.71 (d, 3H), 0.85 (d, 3H), 0.90 (m, 6H), 1.07 (m, 2H), 1.31 (m, 4H), 1.61 (m, 7H), 1.80 (m, 1H), 2.03 (m, 1H), 2.42 (m, 2H), 3.02 (dt, 1H), 4.78 (s, 1H), 4.84 (s, 1H), 6.12 (s, 1H), 6.18 (s, 1H).

[00352] ¹³ C NMR (CDCI ₃ ): (major diastereoisomer) δ 14.14, 15.95, 21.82, 22.63, 22.67,

25.61 , 28.78, 30.73, 31.75, 33.70, 35.44, 35.63, 38.33, 40.39, 44.80, 108.29, 109.21 , 115.36, 142.04, 154.31 , 155.68.

[00353] HRMS (M+H) ⁺ : calculated for C ₂₁ H ₃₅ O ₂ :319.2637, found 319.2642.

[00354] HPLC: 99.8 %.

MTC-013 (Table 1, Compound 13)

[00355] Prepared by methylation of compound 1 (CBD) in accordance with the procedure of L. O. Hanus, S. Tchilibon, D. E. Ponde, A Breuer, E. Fride and R. Mechoulam; Org. Biomol. Chem., 2005, 3, 1116-1123. S. Tchilibon and R. Mechoulam; Org. Lett. 2000, 2, 3301 - 3303, to produce a colourless oil, in 89 % yield.

[00356] ¹ H NMR (CDCI ₃ ): δ 0.94 (t, 3H), 1.38 (m, 4H), 1.63 (m, 5H), 1.70 (s, 3H), 1.79 (m,

2H), 2.01 (m, 1H), 2.25 (m, 1H), 2.56 (m, 2H), 2.92 (m, 1H), 3.76 (s, 6H), 4.02 (m, 1H), 4.47 (m, 2H), 5.24 (s, 1H), 6.38 (s, 2H).

[00357] ¹³ C NMR (CDCI ₃ ): δ 14.07, 19.10, 22.57, 23.43, 29.75, 30.79, 30.99, 31.71 ,

36.17, 36.42, 45.25, 55.96, 105.07, 109.56, 119.07, 125.99, 131.14, 141.86, 149.53, 158.81.

[00358] HRMS (M+H) ⁺ : calculated for C ₂₃ H ₃₅ O ₂ :343.2637, found 343.2637.

[00359] HPLC: 99.6 %.

MTC-012 (Table 1, Compound 12)

[00360] To a suspension of Cs ₂ CO ₃ (1.6 g, 4.8 mmol) in anhydrous DMF (12 mL) was added compound 1 (CBD) (1.0 g, 3.2 mmol) under an atmosphere of Argon at RT. Methyl iodide (0.20 mL, 3.2 mmol) was added dropwise and the reaction mixture was stirred for two hours then quenched with water. The pH was adjusted to 8-9 and the product extracted with diethyl ether then washed with water and brine and dried (MgSO ₄ ). Filtration and removal of the solvent in vacuo gave an orange syrup. The product was partially purified by silica gel column chromatography (1% ethyl acetate/hexane) then further purified by preparative HPLC to give a colourless oil (0.20 g, 19 %). [00361] ¹ H NMR (CDCI ₃ ): δ 0.89 (t, 3H), 1.32 (m, 4H), 1.59 (m, 2H), 1.66 (s, 3H), 1.78 (m,

5H), 2.08 (m, 1H), 2.23 (m, 1H), 2.42 (m, 1H), 2.50 (m, 2H), 3.70 (s, 3H), 4.00 (m, 1H), 4.33 (s, 1H), 4.50 (s, 1H), 5.58 (s, 1H), 5.99 (br s, 1H), 6.22 (s, 1H), 6.31 (s, 1H).

[00362] ¹³ C NMR (CDCI ₃ ): δ 14.17, 18.88, 22.69, 23.81, 28.27, 30.51, 30.95, 31.70,

35.64, 36.16, 46.80, 55.69, 103.29, 109.68, 111.01 , 115.21 , 124.70, 139.64, 142.81 , 147.42, 155.85, 158.31.

[00363] HRMS (M+H) ⁺ : calculated for C ₂₂ H ₃₃ O ₂ :329.2481 , found 329.2480.

[00364] HPLC: 99.0 %.

MTC-002 (Table 1, Compound 5)

[00365] To a solution of carboxylic acid compound 3 (0.69 g, 1.6 mmol) depicted above, in anhydrous DMF (46 mL) under an atmosphere of Argon, was added N,N- diisopropylethylamine (0.67 mL, 3.9 mmol), HATLI (0.92 g, 2.4 mmol) and methylamine hydrochloride (0.22 g, 3.2 mmol). The reaction mixture was stirred for 1 hour 40 minutes at RT and then poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (60 % ethyl acetate:hexane) to give a yellow gum (0.68 g, 96 %).

[00366] ¹ H NMR (CDCI ₃ ): δ 0.88 (t, 3H), 1.33 (m, 4H), 1.62 (m, 5H), 1.69 (m, 1H), 1.92 (m, 1H), 2.24 (br s 7H), 2.58 (m, 2H), 2.76 (m, 2H), 2.83 (d, 2H), 3.60 (m, 1H), 4.53 (s, 1H), 4.63 (s, 1H), 5.96 (br s, 1H), 6.01 (t, 1H), 6.76 (br s, 2H).

[00367] The preceding compound (0.82 g, 1.9 mmol) was dissolved in ethanol (42 mL) and sodium borohydride (93 mg, 2.5 mmol) was added. The mixture was heated to reflux for three hours after which time further sodium borohydride (80 mg, 2.1 mmol) was added and heating was continued for one hour. The reaction mixture was cooled to RT and the solvent removed in vacuo and the residue was partitioned with ethyl acetate and water. The pH was adjusted to 2 with 2M HCI and the organic layer was washed with brine, dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. The residue was partially purified by silica gel column chromatography (70 % ethyl acetate:hexane) and then further purified by preparative HPLC to give a white solid (130 mg, 19 %).

[00368] ¹ H NMR (CD ₃ OD): δ 0.89 (t, 3H), 1.32 (m, 4H), 1.55 (m, 2H), 1.65 (s, 3H), 1.72

(m, 2H), 1.87 (m, 1H), 2.38 (m, 4H), 3.07 (m, 1H), 4.05 (m, 1H), 4.48 (s, 1H), 6.10 (s, 2H). 6.47 (s,1H).

[00369] ¹³ C NMR (CD ₃ OD): δ 14.37, 19.46, 23.57, 260.03, 26.52, 30.45, 31.98, 32.58,

36.60, 38.01 , 45.46, 108.10, 110.83, 114.60, 131.50, 140.85, 143.21 , 149.87, 157.63, 172.36.

[00370] HRMS (M+Na) ⁺ : calculated for C ₂₂ H ₃₁ NNaO ₃ :380.2202, found 380.2195.

[00371] HPLC: 100.0 %.

MTC-005 (Table 1, Compound 3)

[00372] To a solution of diacetyl protected compound 2 (diacetyl 7-hydroxy-CBD) (0.53 g, 1.3 mmol) in anhydrous DCM (10 mL) under an atmosphere of Argon was added boron trifluoride etherate (5.0 μL, 0.038 mmol). The reaction mixture was cooled to 0°C and trimethylsilyldiazomethane (2.0 M in hexane, 0.64 mL, 1 .3 mmol) was added dropwise. After 30 min, additional boron trifluoride etherate (3.0 μL, 0.024 mmol) and trimethylsilyldiazomethane (0.15 mL, 0.30 mmol) were added and the reaction was allowed to warm to RT over 45 minutes. The reaction was quenched with water and extracted with dichloromethane and the organic layer was dried (MgSO ₄ ), filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (6 % ethyl acetate:hexane) to give a gum (0.14 g, 26 %).

[00373] ¹ H NMR (CDCI ₃ ): δ 0.88 (t, 3H), 1.31 (m, 4H), 1.58 (m, 5H), 1.73 (m, 1H), 1.85 (m, 1H), 2.21 (br s 8H), 2.55 (m, 1H), 2.66 (t, 1H), 3.30 (s, 3H), 3.56 (m, 1H), 3.74 (d, 1H), 3.80 (d, 1H), 4.44 (s, 1H), 4.57 (s, 1H), 5.49 (s, 1H), 6.76 (s, 2H).

[00374] To a solution of the preceding compound (0.15 g, 0.35 mmol) in ethanol (20 mL) was added sodium borohydride (0.018 g, 0.47 mmol) under an atmosphere of Argon. The reaction was heated to reflux for 1 .25 hours and then cooled to RT and the solvent removed in vacuo. The residue was partitioned with ethyl acetate and water and the pH was adjusted to 4 with 1 M HCI and the organic layer was washed with brine, dried (MgSO ₄ ), filtered and the solvent was removed in vacuo. The residue was partially purified by silica gel column chromatography (12% ethyl acetate:hexane) and then further purified by preparative HPLC to give a colourless oil (0.080 g, 66 %).

[00375] ¹ H NMR (CDCI ₃ ): δ 0.88 (t, 3H), 1.30 (m, 4H), 1.56(m, 2H), 1.67 (s, 3H), 1.79 (m, 1H), 1.88 (m, 1H), 2.44 (m, 2H), 2.49 (m, 1H), 3.32 (s, 3H), 3.88 (m, 2H), 3.94 (m, 1H), 4.56 (s, 1H), 4.65 (s, 1H), 4.72 (br s, 1H), 5.59 (br s, 1H), 5.84 (s, 1H), 6.21 (br s, 2H).

[00376] ¹³ C NMR (CDCI ₃ ): δ 14.15, 20.35, 22.67, 26.36, 28.41 , 30.74, 31.64, 35.61 ,

36.99, 46.54, 58.15, 76.32, 108.29, 109.90, 111.13, 113.53, 127.42, 139.82, 143.30, 149.05, 154.08, 155.93.

[00377] HRMS (M+Na) ⁺ : calculated for C ₂₂ H ₃₃ NaO ₃ : 367.2249, found 367.2253.

[00378] HPLC: 97.2 %.

MTC-015 (Table 1, Compound 6, Cannabidivarin)

[00379] This compound was synthesised in accordance with the procedure of US 2013/0171259.

[00380] ¹ H NMR (CD ₃ OD): δ 089 (t, 3H), 1.56 (m, 2H), 1.64 (s, 3H), 1.68 (s, 3H), 1.74 (m, 2H), 2.00 (m, 1H), 2.20 (m, 1H), 2.36 (m, 2H), 3.93 (m, 1H), 4.45 (m, 2H), 4.80 (s, 1H), 5.29 (s, 2H).

[00381] ¹³ C NMR (CD3OD): δ 12.77, 18.16, 22.337, 23.96, 29.34, 30.33, 36.12, 37.43,

45.04, 107.05, 109.12, 114.64, 125.88, 133.04, 141.09, 148.91 , 156.05.

[00382] HRMS (M+H) ⁺ : calculated for C ₁₉ H ₂₇ O ₂ : 287.2013, found 287.2011 .

[00383] HPLC: 98.7 %

MTC-016 (Table 1, Compound 8, 7-nor-7-carboxy-cannabidivarin)

[00384] This compound was prepared via an adaptation of the procedure of L. O. Hanus, S. Tchilibon, D. E. Ponde, A Breuer, E. Fride and R. Mechoulam; Org. Biomol. Chem., 2005, 3, 1116-1123. S. Tchilibon and R. Mechoulam; Org. Lett. 2000, 2, 3301 -3303. [00385] ¹ H NMR (CD ₃ OD): δ 0.91 (t, 3H), 1.57 (m, 2H), 1.65 (s, 3H), 1.72 (m, 1H), 1.83 (m, 1H), 2.25 (m, 1H), 2.37 (t, 2H), 2.45 (m, 1H), 3.03 (m, 1H), 4.05 (m, 1H), 4.48 (m, 2H), 6.09 (s, 2H), 6.86 (s, 1H).

[00386] ¹³ C NMR (CD ₃ OD): δ 12.73, 18.03, 23.93, 24.58, 29.03, 37.00, 37.46, 44.07,

106.68, 109.47, 112.97, 127.33, 141.65, 146.30, 148.44, 156.21 , 170.22.

[00387] HRMS (M+Na) ⁺ : calculated for C ₁₉ H ₂₄ NaO ₄ : 339.1572, found 339.1573.

[00388] HPLC: 100 %

MTC-019 (Table 1, Compound 7, 7-nor-7-hydroxymethyl-cannabidivarin)

[00389] This compound was prepared via an adaptation of the procedure of L. O. Hanus, S. Tchilibon, D. E. Ponde, A Breuer, E. Fride and R. Mechoulam; Org. Biomol. Chem., 2005, 3, 1116-1123. S. Tchilibon and R. Mechoulam; Org. Lett. 2000, 2, 3301 -3303.

[00390] ¹ H NMR (CD ₃ OD): δ 0.91 (t, 3H), 1.58 (m, 2H), 1.66 (s, 3H), 1.77 (m, 1H), 1.82 (m, 1H), 2.21 (m, 2H), 2.38 (t, 2H), 3.05 (m, 1H), 3.96 (m, 2H), 4.01 (m, 1H), 4.49 (m, 2H), 5.55 (s, 1H), 6.12 (s, 2H).

[00391] ¹³ C NMR (CD ₃ OD): δ 12.73, 18.12, 23.94, 25.89, 29.28, 35.98, 37.41, 44.89,

66.19, 107.03, 109.07, 114.40, 127.68, 135.67, 141.17, 148.96, 156.09.

[00392] HRMS (M+Na) ⁺ : calculated for C ₁₉ H ₂₆ NaO ₃ : 325.1780, found 325.1766.

[00393] HPLC: 98.3 %

General Procedure 3: Olivetol Sulfone Analogue Synthesis

[00394] To a cold (0 °C) solution of 3-(3,5-dimethoxyphenyl)propionic acid (10.0 g, 47.6 mmol) in anhydrous methanol (115 mL) under an Argon atmosphere was slowly added concentrated hydrochloric acid (0.75 ml). The cooling bath was removed, and the reaction was stirred at RT for 16 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched by the addition of saturated sodium bicarbonate and the product extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated in vacuo. The crude material (10.7 g, 100 %) was used as is in the next step.

[00395] ¹ H NMR (CDCI ₃ ): δ 6.36 (d, 2H, J= 2.3 Hz), 6.32 (t, 1H, J= 2.3 Hz), 3.77 (s, 6H),

3.68 (s, 3H), 2.89 (m, 2H), 2.62 (m, 2H). BDG 17734

[00396] To a cold (0 °C) solution of BDG 17733 (10.7 g, 47.6 mmol) in anhydrous THF (220 mL) under an Argon atmosphere was slowly added lithium aluminium hydride (5.43 g, 143 mmol). The cooling bath was removed, and the reaction was stirred at RT for 2 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched by the slow addition of sodium hydroxide (2 M) and the product extracted with diethyl ether, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude material (8.25 g, 88 %) was used as is in the next step.

[00397] ¹ H NMR (CDCI ₃ ): δ 6.37 (d, 2H, J= 2.3 Hz), 6.31 (t, 1H, J= 2.3 Hz), 3.78 (s, 6H), 3.68 (t, 2H, J = 6.5 Hz), 2.66 (m, 2H), 1 .90 (m, 2H).

BDG 17736

[00398] To a cold (0 °C) solution of BDG 17734 (8.25 g, 42.0 mmol) in anhydrous chloroform (85 mL) and anhydrous pyridine (6.8 mL) under an Argon atmosphere was slowly added p-toluenesulfonyl chloride (19.5 g, 102 mmol). The cooling bath was removed, and the reaction was stirred at RT for 6 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched with water and the product extracted with diethyl ether, washed with hydrochloric acid (2 M), saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. The crude material (14.1 g, 96 %) was used as is in the next step.

[00399] ¹ H NMR (CDCI ₃ ): δ 7.79 (d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J= 8.0 Hz), 6.29 (t, 1H, J = 2.3 Hz), 6.26 (d, 2H, J = 2.3 Hz), 4.04 (t, 2H, J = 6.2 Hz), 3.76 (s, 6H), 2.60 (t, 2H, J = 7.5 Hz), 2.45 (s, 3H), 1.95 (m, 2H).

BDG 17738

[00400] To a solution of sodium thiomethoxide (8.49 g, 121 mmol) in anhydrous ethanol (400 mL) at RT was slowly added a solution of BDG 17736 (13.8 g, 39.4 mmol) in anhydrous THF (500 mL) under an Argon atmosphere. The reaction was stirred at RT for 3 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched with water and the product extracted with diethyl ether, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude material was used was purified by silica gel column chromatography (25 % ethyl acetate:hexanes) to give the product (8.0 g, 89 %).

[00401] 1H NMR (CDCI ₃ ): δ 6.35 (d, 2H, J = 2.3 Hz), 6.31 (t, 1H, J = 2.3 Hz), 3.78 (s, 6H), 2.67 (t, 2H, J = 7.6 Hz), 2.51 (t, 2H, J = 7.2 Hz), 2.10 (s, 3H), 1 .91 (m, 2H). BDG 17739

[00402] To a cold (0 °C) solution of BDG 17738 (2.61 g, 11.5 mmol) in anhydrous DCM (60 mL) under an Argon atmosphere was slowly added a solution of MCPBA (5.69 g, 33.0 mmol) in anhydrous DCM (90 mL). Stirring was continued at 0 °C for 1.5 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched with sodium hydroxide (2 M) and the product extracted with DCM, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The crude material (2.56 g, 86 %) was used as is in the next step.

[00403] ¹ H NMR (CDCI ₃ ): δ 6.33 (s, 3H), 3.78 (s, 6H), 2.98 (m, 2H), 2.87 (s, 3H), 2.73 (t, 2H, J= 7.4 Hz), 2.18 (m, 2H).

BDG 17740

[00404] To a cold (0 °C) solution of BDG 17739 (2.56 g, 9.91 mmol) in anhydrous DCM (125 mL) under an Argon atmosphere was slowly added neat BBr3 (2.4 mL, 24.9 mmol). The reaction was allowed to warm to RT over 4 h whereby TLC analysis indicated that the reaction was complete. The reaction was quenched with methanol and concentrated in vacuo and the product extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. The crude material (2.28 g, 100 %) was used as is in the coupling step.

[00405] 1H NMR (CDCI3): δ 6.25 (d, 2H, J = 2.3 Hz), 6.22 (t, 1H, J = 2.3 Hz), 4.86 (s, 2H), 2.98 (m, 2H), 2.88 (s, 3H), 2.69 (t, 2H, J = 7.3 Hz), 2.16 (m, 2H).

General Procedure 4: CBD Sulfone Analogue and abn-CBD Sulfone Analogue Synthesis

[00406] To a solution of the BDG 17740 (1.71 g, 7.43 mmol) in anhydrous DCM (60 mL) and anhydrous THF (15 mL) was added p-toluenesulfonyl chloride (0.28g, 1.5 mmol). The mixture was stirred at RT for 15 min whereby a DCM (10 mL) solution of (+)-p-mentha-2,8-dien- 1-ol (1.13 g, 7.42 mmol) was added dropwise over 30 minutes. Stirring was continued for 20 h when TLC analysis indicated all (+)-p-mentha-2,8-dien-1-ol was consumed. The crude material was extracted by DCM, washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The desired products were purified by repeated silica gel column chromatography (1% methanol/chloroform) to give the products as foams (BDG 17753.1 , 163 mg 6 %, BDG 17752.2, 549 mg, 20 %).

MTC-022 (BDG 17753.1)

[00407] ¹ H NMR (CDCI ₃ ): δ 6.20 (br s, 2H), 6.03 (br s, 1H), 5.55 (s, 1H), 5.02 (br s, 1H), 4.63 (m, 1H), 4.52 (br s, 1H), 3.87 (m, 1H), 2.95 (m, 2H), 2.85 (s, 3H), 2.62 (t, 2H, J = 7.2 Hz), 2.39 (m, 1H), 2.23 (m, 1H), 2.15-2.07 (m, 3H), 1.85-1.75 (m, 5H), 1.66 (s, 3H).

[00408] ¹³ C NMR (CDCI ₃ ): δ 157.11 , 155.22, 148.03, 140.78, 140.65, 124.32, 120.22,

111 .72, 108.81 , 103.31 , 54.24, 45.10, 40.90, 40.61 , 32.24, 30.53, 28.38, 23.85, 23.65, 21.81.

[00409] HRMS (M+H)+: calculated for C ₂₀ H ₂₉ O ₄ S: 365.1787, found 365.1779.

[00410] HPLC: 96.4 %.

MTC-023 (BDG 17752.2)

[00411] ¹ H NMR (CDCI ₃ ): δ 6.26 (d, 1H, J = 2.5 Hz), 6.18 (d, 1H, J = 2.5 Hz), 6.09 (s, 1H), 5.49 (s, 1H), 5.25 (s, 1H), 4.66 (s, 1H), 4.47 (s, 1H), 3.47 (m, 1H), 2.98 (m, 2H), 2.89 (s, 3H), 2.84 (m, 1H), 2.48-2.39 (m, 2H), 2.22 (m, 1H), 2.14-2.06 (m, 2H), 2.00 (m, 1H), 1.86-1.73 (m, 5H), 1.50 (s, 3H).

[00412] ¹³ C NMR (CDCI ₃ ): δ 14.20, 21.48, 22.79, 23.74, 28.27, 29.28, 29.79, 30.40,

31.53, 31.95, 34.16, 40.21 , 45.11 , 102.29, 108.74, 111.50, 120.00, 124.91 , 139.85, 144.09, 147.83, 154.83, 156.59.

[00413] HRMS (M+Na) ⁺ : calculated for C ₂₀ H ₂₈ O ₄ NaS: 387.1606, found 387.1610.

[00414] HPLC: 98.3 %.

General Procedure 5: CBD and abn-CBD Trifluoromethyl “A6” Analogue Synthesis

BDG 14643 ((±)-Cryptone)

[00415] BDG 14643 was prepared according to the previously reported procedure. ⁵

BDG 14644

[00416] To a solution of BDG 14643 (3.20 g, 23.2 mmol) and trimethyl(trifluoromethyl)silane (4.0 mL, 27.1 mmol) in anhydrous THF (24 mL) was added anhydrous CsF (5 mg, 0.3 mmol) under an Argon atmosphere. Gas evolution was observed after a few minutes and the reaction turned light yellow. The reaction was stirred for 2 hours then filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (hexanes) to give a colourless liquid (5.8 g, 89 %).

[00417] ¹ H NMR (CDCI3): δ (major diastereomer) 0.14 (s, 9H), 0.89 (d, 3H), 0.92 (d, 3H), 1.66 (m, 4H), 1.94 (m, 1H), 2.12 (m, 1H), 5.73 (dd, 1H), 6.04 (dd, 1H).

BDG 14645

[00418] To a solution of BDG 14644 (5.80 g, 20.7 mmol) in THF (41 mL) was added HCI (4.0 mL, 6.0 M,) dropwise. Analysis by TLC after 1 hour 40 minutes showed the reaction to be complete. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated, the organic layer was washed with water, dilute NaHCO ₃ solution, brine and dried over MgSO ₄ . Filtration and removal of the solvent gave a colourless liquid (4.08 g, 95 %). [00419] ¹ H NMR (CDCI ₃ ): δ (major diastereomer) 0.91 (d, 3H), 0.93 (d, 3H), 1.7 (m, 4H), 1.97 (m, 1H), 2.16 (m, 1H), 5.67 (dd, 1H), 6.11 (dd, 1H).

BDG 14652 (MTC-037)

[00420] To a solution of BDG 14645 (2.00 g, 9.61 mmol) and olivetol (1.73 g, 9.61 mmol) in acetic acid (12 mL) was added p-toluenesulfonic acid hydrate (0.92 g, 4.81 mmol) under an Argon atmosphere. The reaction was heated at reflux for 4 hours then cooled to room temperature, poured into ice-water and extracted with dichloromethane. The layers were separated, the organic layer was washed with water, dilute NaHCO ₃ solution and brine, then dried over MgSO ₄ . Filtration and removal of the solvent in vacuo gave an orange liquid which was placed on a silica gel column and eluted with 3 % ethyl acetate in hexane. Fractions containing a single compound were combined and the solvent removed to give a colourless gum (0.15 g).

[00421] ¹ H NMR (CDCI3): δ 0.89 (t, 3H), 0.93 (d, 3H), 0.94 (d, 3H), 1.32 (m, 4H), 1.45 (m, 1H), 1.58 (m, 3H) 1 .81 (m, 3H), 2.07 (m, 2H), 2.36 (m, 1H), 2.47 (m, 2H), 3.26 (m, 1H), 4.81 (br s, 1H, exchangeable), 6.09 (s, 1H), 6.24 (s, 1H).

[00422] ¹³ C NMR (CDCI3): δ 13.99 (CH3), 16.31 (CH3), 17.69 (CH3), 19.21 (CH2),

22.52 (CH2), 25.61 (CH2), 26.87 (CH2), 30.91 (CH2), 31.55 (CH2), 34.31 (CH), 36.00 (CH2), 37.97 (CH), 40.07 (CH), 91.59 (C-O), 102.95 (CH), 107.76 (CH), 115.70 (C), 127.76 (CF3), 145.03 (C), 151.95 (C), 159.90 (C).

[00423] HRMS (M-(H ₂ O)+H)+: calculated for C ₂₁ H ₃₀ F ₃ O ₂ 371.2198, found 371.2190.

[00424] HPLC: 94.8 %. Column = Phenomenex Luna C18 (2) 250 x 4.6mm 5 μm +

SecurityGuard C18 RP; Mobile Phase = 5:95:0.025 Water:Methanol; Flow Rate = 1.0 ml/min; Temperature = 40°C; UV = 220 nm; Injection = 10 μl; Sample solvent = Mobile Phase; Retention time - a sharp symmetrical peak was observed at 10.065 minutes.

BDG 14663 (MTC-036)

[00425] Later fractions containing a single compound were combined and the solvent removed to give a gum which is undergoing purification by preparative HPLC. The ¹ H NMR data of the crude material has an exchangeable signal around 4-5 ppm. Example 2

Determination of Antimicrobial Activity - 1

[00426] Antimicrobial activity of cannabinoids and analogues was tested against a number of bacterial strains by broth microdilution (BMD) assay with MIC determination at the University of Queensland, MicroMyx LLC, and Monash University. ATCC strains were sourced from the American Type Culture Collection and NRS strains from NARSA (Network on Antimicrobial Resistance in Staphylococcus aureus) via BEI Resources (www.beiresources.org). Cannabinoid analogues were prepared as a 10 mg/mL stock solution in DMSO, then diluted to 2.56 mg/mL.

MIC Assay

[00427] UQ Procedure: The compounds, along with standard antibiotics were serially diluted two-fold in cation-adjusted (CA) Mueller Hinton broth (MHB) (Bacto laboratories, Cat. No. 212322) across the wells of 96-well polystyrene plates (Corning Cat. No. 3370). Standards ranged from 0.03-64 μg mL ^-1 for bacteria and from 0.03-64 μg mL ^-1 for cannabinoid analogues. Bacteria were cultured in CAMHB at 37°C overnight. A sample of each culture was then diluted 40-fold in fresh CAMHB and incubated at 37°C for 2-3 h. The resultant mid-log phase cultures were added to the compound-containing 96-well plates to give a final cell density of 5 × 10 ⁵ CFU mL ^-1 . All the plates were covered and incubated at 37°C for 20 h. MICs were the lowest concentration showing no visible growth.

[00428] Plate Based Variation: MICs were conducted mostly as above except CAMBH Cat. No. was 212322, plates were finally incubated for 20 h, and cannabinoid analogue concentrations ranged from 0.03-256 μg mL ^-1 . MICs were conducted in polystyrene (Corning Cat. No. 3370), polypropylene (Corning Cat. No. 3364) and non-binding surface (NBD) polystyrene (Corning Cat. No. 3641) 96-well plates.

[00429] Micromyx procedure: Prior to testing, aerobic bacteria were streaked from frozen vials onto Tryptic Soy Agar (TSA) with 5% sheep blood (Becton Dickinson [BD], Lot No. 9192895). Neisseria was streaked onto Chocolate agar (BD. Lot No. 9228071). Aerobic bacteria were incubated at 35°C overnight, and Neisseria were incubated at 35°C in 5% CO ₂ for 24 h,. CAMHB (BD, Lot No. 8190586) was used for MIC testing of aerobic organisms.

[00430] MIC values were determined using a broth microdilution procedure described by Clinical and Laboratory Standards Institute (CLSI). In mother plates, the wells of columns 2-12 of standard 96-well microdilution plates (Costar 3795) were filled with 150 μL of the designated diluent for each row of drug. The test article and comparator compounds (300 μL at 101 × the highest concentration to be tested) were dispensed into the appropriate wells in column 1. Two- fold serial dilutions were then made in the mother plates from columns 1-11. The wells of column 12 contained no drug and served as the organism growth control wells for the assay.

[00431] Daughter plates were loaded with 190 μL per well of the appropriate test medium for the tested organism. 2 μL of drug solution from each well of a mother plate was transferred to the corresponding well of each daughter plate. Daughter plates for the testing of anaerobes pre-reduced in a Bactron II anaerobe chamber for 2 h prior to inoculation.

[00432] A standardized inoculum of each test organism was prepared per CLSI methods. Plates were inoculated with 10 μL of the inoculum resulting in a final cell density of approximately 5 x 10 ⁵ CFU mL ^-1 per well.

[00433] Plates for testing of aerobic organisms were incubated at 35°C for the time periods specified in CLSI. Plates were incubated for approximately 16-20 h (aerobes), 20-24 h {Neisseria).

[00434] Following incubation, microplates were removed from the incubator and viewed from the bottom using a plate viewer. The MIC was read and recorded as the lowest concentration of drug that inhibited visible growth of the organism.

Results

[00435] There were clear differences in the structure-activity relationship (SAR) for the Gram-positive activity against MRSA compared to the Gram-negative N. gonorrhoeae. For example, oxidation of the cyclohexene methyl group to a hydroxymethyl (7-hydroxy-cannabidiol [7-OH-CBD], Table 1 , compound 2) or carboxyl group (7-nor-7-carboxy-cannabidiol [7-COOH-CBD], Table 1 , compound 4) was detrimental to MRSA activity (MIC decreased by 1 to 2 units to 16 and >64 μg/mL respectively), but had little impact or even improved N. gonorrhoeae activity (0.125 and 2 μg/mL). In contrast, positioning a carboxyl substituent on the resorcinol aromatic ring had less effect on MRSA potency, with an MRSA MIC of 16-32 μg/mL for cannabidiolic acid (CBDA, Table 1 , compound 14). In the context of CBG or THC backbones, an aromatic carboxyl group had little effect for either bacteria (e.g. tetrahydrocannabivarin [THCV, Table 1 , compound 19] vs tetrahydrocannabivarinic acid [THCVA, Table 1 , compound], CBG (Table 1 , compound 25) and cannabigerolic acid [CBGA, Table 1 , compound 26]). The extra ring cyclization in the (-)-A ⁸ -THC backbone (Table 1 , compound 23) led to a 2- to 4-fold reduction in activity for both S. aureus and N. gonorrhoeae, while the acyclic alkyl substituents found in CBG (Table 1 , compound 25) and CBGA (Table 1 , compound 26) reduced S. aureus activity 2- to 4-fold compared to CBD, but were within the range of CBD N. gonorrhoeae activity. [00436] Extending the CBD aromatic side chain from a pentyl (Table 1 , compound 1) to heptyl chain (Table 1 , compound 9) improved potency for MRSA but reduced it for N. gonorrhoeae, while shortening the side chain to a propyl group (cannabidivarin [CBDV] Table 1 , compound 6) slightly decreased MRSA activity (2-4 μg/mL) but substantially improved N. gonorrhoeae activity (≤0.03-0.5 μg/mL). Unfortunately, the serum reversal effect for MRSA was not improved by the reduction in length of the lipophilic chain (MIC ≥256 μg/mL). A phenylbutyl substituent (Table 1 , compound 10) was equivalent to the n-pentyl group of CBD for both bacteria. The site of attachment of the cyclohexene was not critical but did affect activity - when attached between one of the phenol groups and the alkyl substituent instead of between the phenolic groups (e.g. scaffold CBD vs Abn-CBD Table 1 , compounds 15 and 16 respectively), activity was reduced 2-fold or remained the same.

[00437] The phenol groups were important: when both were methylated (Table 1 , compound 13) activity was lost against both bacteria (≥64 μg/mL). The removal of one phenol group (Table 1 , compound 11) blocked MRSA but N. gonorrhoeae activity was largely maintained demonstrating that the presence of both phenol groups is not essential for antimicrobial activity. Mono-methylation (Table 1 , compound 12) also abolished MRSA activity and substantially reduced N. gonorrhoeae inhibition. This property offers significant potential given the advantages offered by antimicrobial compounds with targeted narrow-band activity. The alkene bonds present in the isopropene-substituted cyclohexenyl substituent were not found to be essential: reduction of both (Table 1 , compound 17) improved both MRSA and N. gonorrhoeae activity, while reduction of just the isoprene group (Table 1 , compound 17) had little effect.

[00438] Finally, we tested the potential to conduct modifications at the 7-methyl position by preparing a methyl amide derivative (Table 1 , compound 5) of 7-COOH-CBD (Table 1 , compound 4) and an O-methyl derivative (Table 1 , compound 3) of 7-OH-CBD (Table 1 , compound 2): both were less active than CBD The O-methyl derivative (Table 1 , compound 3) had the same activity as the hydroxyl parent (Table 1 , compound 2) for MRSA (16 μg mL ^-1 ) but was substantially less active for N. gonorrhoeae (4-16 vs 0.25-2 μg mL ^-1 ). The methyl amide (Table 1 , compound 5) was more active than the acid parent (Table 1 , compound 4) against MRSA (16 vs >64 μg mL ^-1 ) but slightly less active for N. gonorrhoeae (2-4 vs 0.5-2 μg mL ^-1 ).

[00439] The results of antimicrobial testing of cannabinoids and cannabinoid analogues are summarised in Table 1 :

Table 1 : Structure of Cannabinoids and Cannabinoid analogues and summary of effect of modification to different positions on antimicrobial activity against MRSA and N. gonnorrhoeae (MIC, μg mL ^-1 , n = 4).

Determination of Antimicrobial Activity - II

[00440] The experiment was performed to investigate the potential of Cannabidiol (CBD) and CBD analogues for antimicrobial activity against Staphylococcus aureus ATCC 43300 MRSA and Neisseria gonorrhoeae ATCC 19424. The Minimum Inhibitory Concentration (MIC) range determined for CBD and CBD analogs are summarised in Table 2 below. The experiment was performed twice in duplicate (n=4). Individual values are reported when they differ between replicates. 2% DMSO was the final concentration for all tested compounds. [00441] MIC assays establish the lowest concentration of an antimicrobial agent that is able to inhibit visible growth of a microorganism.

[00442] The test compound was serially diluted in Cation-adjusted Mueller Hinton Broth (CaMHB; BD, Cat. No. 212322) two-fold across the wells of polystyrene (PS) 96-well plates (Corning; Cat. No. 3370), plated in duplicate. All plates had flat bottom wells and were covered with low-evaporation lids.

[00443] Bacteria were cultured in CaMHB at 37 °C overnight, then diluted 40-fold and incubated at 37 °C for a further 2-3 h. The resultant mid-log phase cultures were diluted in CaMHB and added to each well of the compound-containing 96-well plates to give a final cell density of 5x105 CFU/mL, and a final compound concentration range of 0.25 -256 μg/mL and 0.06 - 128 μg/mL. The plates were covered and incubated at 37 °C for 20 h.

[00444] Two biological replicates x2 technical replicates were conducted on separate days (final n=4). Inhibition of bacterial growth was determined visually, where the MIC was recorded as the lowest compound concentration with no visible growth. For every plate tested, positive (inoculated media) and negative (media only) growth controls were included. All positive and negative growth controls passed.

Table 2: Test Results REFERENCES

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2. CLSL Performance Standards for Antimicrobial Susceptibility Testing; 29th ed. CLSI supplement Ml 00. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2019.

3. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard— Ninth Edition. CLSI document M11-A9. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2018.

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