Cannabinoid derivatives substituted with nitrogen-containing groups for treatment of malaria

Abstract

The subject matter of the invention relates to cannabidiol and cannabigerol derivatives alkylated with nitrogen-containing groups of formula (I) and their salts as well as their pharmaceutical, particularly antimalarial, applications.

Description

[0001] CANNABINOID DERIVATIVES SUBSTITUTED WITH NITROGEN-CONTAINING GROUPS FOR TREATMENT OF MALARIA

[0002] Subject matter of the invention

[0003] The subject matter of the invention relates to cannabidiol and cannabigerol derivatives alkylated with nitrogen-containing groups of formula (I) and their salts

[0004]

[0005] as well as their pharmaceutical, particularly antimalarial, application.

[0006] Background of the invention

[0007] Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic phytocannabinoids found in the Cannabis sativa (hemp) plant. They possess a broad spectrum of pharmacological activities: while they exhibit only weak affinity for cannabinoid receptors, they are capable of interacting with numerous other receptors throughout the body. They are potentially applicable in the treatment of neurological disorders, such as epilepsy, anxiety, schizophrenia, and neurodegenerative diseases. Their antioxidant and anti-inflammatory effects are extensively researched; furthermore, cardioprotective, antiviral, and antibacterial properties are also attributed to them. However, due to their poor water solubility, they exhibit low bioavailability; therefore, the synthesis of water-soluble derivatives is considered advantageous.

[0008] Tetrahydrocannabinol (THC, the primary cannabinoid of Cannabis sativa) and CBD are highly lipophilic compounds with very poor water solubility, they are practically insoluble in water, resulting in considerably low oral bioavailability (approximately 6%). https: / / doi.org / 10.1016 / j.yebeh.2016.11.016). CBG possesses similar properties but remains less extensively researched than THC and CBD. Furthermore, oral administration is not advantageous for these cannabinoids, as they undergo significant first-pass metabolism when administered by the oral route. To increase bioavailability, various oils such as sesame oil may be utilized (e.g., Epidiolex®), or alternative delivery routes are chosen, such as nasal, sublingual, or oromucosal sprays (e.g., Sativex®). Among the known alternative drug delivery methods, oral (per os) administration remains the most convenient and common. It offersnumerous advantages, including convenience and ease of use for patients, precise dosing, and lower production costs for both manufacturers and patients. By increasing water solubility, bioavailability is enhanced, meaning a lower dose of the drug is sufficient to achieve the desired therapeutic effect.

[0009] Various methods are used to produce water-soluble CBD, including the formulation of nanoemulsion-based systems, the creation of lipid-based preparations, the development of prodrugs, and the use of nanocarriers or alternative delivery routes (https: / / doi.org / 10.3390 / ijms241914514). However, it must be noted that while CBD itself possesses numerous beneficial effects, none of them are particularly outstanding.

[0010] Increasing water solubility can also be achieved through synthetic modification, by introducing groups onto the parent molecule that are capable of salt formation. One example of this is the amino group, which forms salts with organic or inorganic acids, thereby enhancing the aqueous solubility of the compounds.

[0011] The state of the art (Org. Process Res. Dev. 2024, 28, 7, 2708-2723; 10.1021 / acs.oprd.4c00093) describes the modification of CBD through a Williamson ether synthesis (alkylation) to introduce an allyl group. Patent applications WO2023015253 Al and WO2021113958 Al also disclose alkylation reactions; WO2023015253 Al describes the preparation of CBD and CBG derivatives, while WO2021113958 Al focuses on the synthesis of CBG derivatives. However, none of the reagents employed in the described compounds contain an alkylamino group. Fang et al. (Development of cannabidiol derivatives as potent broad-spectrum antibacterial agents with membrane-disruptive mechanism, European Journal of Medicinal Chemistry, 2024, 266, 116149) describe CBD derivatives disubstituted at the hydroxyl groups with antibacterial activity, including derivatives containing alkylene-amino groups. International patent application W02008107879 Al (Yissum Research Development Company of the Hebrew University of Jerusalem) describes anti-inflammatory CBD derivatives, including CBD derivatives mono- and disubstituted with ethylene-amino groups. According to the state of the art, no water-soluble salt derivatives were prepared from these compounds. Consequently, there remains a need for the synthesis of derivatives where synthetic modification can enhance water solubility and, thereby, efficacy, which also leads to a reduction in the required dosage.

[0012] CBD and CBG possess numerous beneficial biological effects. CBD is already utilized as an active pharmaceutical ingredient in Sativex® and Epidiolex® to alleviate spasticity andreduce the symptoms of epilepsy. Furthermore, beyond its established uses, the therapeutic potential of CBD continues to be explored across a broad clinical landscape, as evidenced by numerous ongoing trials for example, in the treatment of acne (ClinicalTrials.gov ID: NCT03573518) and atopic dermatitis (ClinicalTrials.gov ID: NCT03824405). Its anticancer properties are also being intensively investigated (ClinicalTrials.gov ID: NCT06148038 and NCT04428203). While CBG is less extensively researched, it exhibits several promising beneficial effects similar to those of CBD.

[0013] A recent publication reports that THC inhibits the formation of P-hematin (hemozoin) and the growth of malaria parasites (10.1016 / j.bmcl.2021.128442). In the bloodstream, the parasite degrades hemoglobin, leading to the formation of heme, which the parasite then converts into hemozoin. If this process is inhibited, the released free heme destroys the parasite. However, due to its psychoactive nature, THC is not ideal as an antimalarial agent. Consequently, the effects of CBD were also investigated; while it inhibited P-hematin formation, it exhibited only moderate antimalarial activity.

[0014] Malaria is a severe mosquito-borne disease that infects millions worldwide annually. In 2022, the global number of malaria cases reached 249 million, with an estimated 608,000 deaths resulting from the infection (10.1016 / S2666-5247(24)00016-8). A major challenge in the fight against malaria is the rapid adaptability of the pathogens and the swift emergence of drug resistance. Although several effective antimalarial drugs have been developed over the past decades, parasites can quickly develop mutations, causing the efficacy of these treatments to decline over time. For instance, chloroquine is a long-standing, affordable antimalarial drug, but resistance has already emerged in many regions (10.1126 / science.1074045), while other medications are limited by severe adverse side effects (10.2165 / 00002018-199308040-00004). Therefore, the development of safe and effective novel antimalarial drugs remains a critical global health priority.

[0015] Summary of the Invention

[0016] The CBD and CBG derivatives according to the present invention, which contain amino groups in the side chains linked to the hydroxyl groups, are novel compounds. Furthermore, their water-soluble organic and inorganic salt derivatives also constitute a novelty in the art.

[0017] Certain nitrogen-containing compounds can offer numerous advantages in pharmaceutical therapy. The nitrogen atom is capable of forming Coulomb interactions,hydrogen bonds, and other weak interactions (such as van der Waals forces and dipole-dipole interactions) with various binding sites. These characteristics allow amino-containing compounds to bind with high affinity to various enzymes and receptors as biological targets. The introduction of amino groups can modify or enhance biological activity; furthermore, the incorporated amino groups make the compounds suitable for salt formation that can increase the water solubility of the derivatives, potentially resulting in improved bioavailability compared to the parent compounds. In water-soluble form, cannabinoids are more readily absorbed by the body, allowing them to exert their effects more rapidly and efficiently. Due to enhanced absorption, the system can utilize the active ingredient more effectively. Furthermore, water-soluble formulations enable more precise dosing, which is of paramount importance in therapeutic applications.

[0018] Chemical modification — specifically the introduction of amino groups in this case — not only enhances aqueous solubility and, consequently, bioavailability but also significantly strengthens biological activity. Preliminary studies on the Plasmodium falciparum Kelch 13 (PfK13) C580Y strain demonstrate that the synthesized derivatives possess excellent antimalarial activity. In contrast to the moderate efficacy of CBD and CBG, the antimalarial potency of these novel CBD and CBG derivatives is outstanding. The antimalarial activity of CBG had not been previously investigated; however, our studies revealed that, in contrast to its inherently weak antiparasitic effect, the synthesized derivatives demonstrated surprisingly significant activity. Consequently, additional derivatives were included in further investigations. We evaluated the antimalarial activity of the compounds against Plasmodium falciparum 3D7 and Dd2 strains. 3D7 is a standard drug-sensitive strain (responsive to most antimalarial agents), whereas Dd2 is a multi -drug resistant (MDR) strain, exhibiting resistance to chloroquine among other drugs. Consequently, results obtained against the Dd2 strain serve as critical indicators of robust antimalarial efficacy. We also evaluated the safety profile of the compounds. Cytotoxicity assays were performed on HepG2 cells, and hemolysis tests confirmed that the compounds do not degrade red blood cells. In parallel, based on preliminary screens, a promising lead candidate was selected for further evaluation; IC50 value was determined, and its efficacy was investigated using a Plasmodium berghei ANKA mouse model. (Plasmodium berghei is a malaria species that infects rodents; the ANKA strain is particularly significant as it induces severe neurological symptoms — cerebral malaria — in mice, making it an excellent model for studying disease progression and therapeutic efficacy in vivo 7)Based on the experimental data, derivatives containing aminoalkyl side chains prove to be promising antimalarial agents. As malaria predominantly affects developing countries and impoverished populations, the accessibility and affordability of antimalarial medications are critical considerations. The synthetic route for the discussed compounds is concise, requiring only a single step for the production of the parent molecule, followed by an additional step for salt formation. This short reaction pathway contributes to a simple and cost-effective manufacturing process, which is essential for pharmaceutical feasibility.

[0019] Detailed description of the invention

[0020] The subject of the invention is a compound of formula (I), or a salt thereof

[0021] OR2

[0022]

[0023] (I)

[0024] wherein

[0025]

[0026] R2is -C2-8alkylene-NR4R5, wherein

[0027] R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H,

[0028] or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,

[0029] or R2is -C2-8 alkylene-N+R6R7R8, wherein

[0030] R6, R7R8are independently from each other Ci-6 alkyl, or

[0031] R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;

[0032] R3is H or -C2-8 alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H,

[0033] or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,

[0034] or R3is -C2-8 alkylene-N+R6R7R8, wherein

[0035] R6, R7R8are independently from each other Ci-6 alkyl

[0036] or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,

[0037] with the proviso, that wherein R1is

[0038] f XH

[0039] y

[0040] HQz

[0041]

[0042] and R3and R2have the same meaning, then

[0043] R2is -C2-3alkylene-NR4R5or C5-salkylene-NR4R5,

[0044] wherein R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H, - wherein at least one of R4and R5is other than H; or wherein R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,

[0045] or R2is -C2-8 alkylene-N+R6R7R8,

[0046] wherein R6, R7,R8are independently from each other Ci-6 alkyl, or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;

[0047] and with the further proviso that the compound is not the following:

[0048] 3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5-pentylphenol, which is of the following structure:

[0049]

[0050] Certain terms used in the context of the present invention are defined as follows:

[0051] C2-8alkylene means an aliphatic hydrocarbon group, which may be straight or branched, attached at two points, and contains about 2 to 8 carbon atoms in the chain. A narrower group of alkylene groups contains 2 to 6 carbon atoms, with about 2 to 4 carbon atoms being particularly preferred. Examples of alkylene groups include ethylene, / / -propylene, / / -butylene, / / -pentylene, / / -hexylene, and branched versions thereof, wherein the chain contains 1 to 8 carbons atoms, with ethylene and / / -propylene being particularly preferred.

[0052] A C1-6alkyl refers to an aliphatic hydrocarbon group, which may be straight or branched, and contains about 1 to 6 carbon atoms in the chain. A narrower group of alkyl groups contains about 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, / / -propyl, / -propyl, / / -butyl,.s-butyl, / -butyl, / / -pentyl, 3-pentyl, hexyl, particularly methyl, ethyl and / / -propyl.

[0053] 4- to 7-membered heterocycle is as follows:

[0054] O. V \i £

[0055] § ' N"'v

[0056]

[0057] wherein n’ is 0-3, such as N-piperidinyl, N-pyrrolidinyl, azetidinyl, piperazinyl, particularly N-pyrrolidinyl and N-piperidinyl.

[0058] 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N is such a 4- to 7-membered heterocycle, which, in addition to nitrogen, contains one or more additional nitrogen, oxygen or sulfur atoms, -wherein the nitrogen is optionally substituted by an additional R1group, wherein R1is C1-6 alkyl-, the heterocycle may be, for example morpholinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, in particular morpholinyl, piperazinyl.The compounds of formula (I) according to the invention may exist in the form of a base or an acid addition salt. The salts also form part of the invention. The salts may be particularly pharmaceutically acceptable salts. However, the invention also includes salts suitable for isolating or purifying the compounds of formula (I). A compound of formula (I) according to the invention may form salts with organic or inorganic acids. Inorganic acids may be, for example: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids may be, for example: formic acid, acetic acid, propionic acid, glycolic acid, citric acid, malic acid, butyric acid, tartaric acid, lactic acid, malic acid, glutamic acid, fumaric acid, benzoic acid, malonic acid, maleic acid, salicylic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid. HC1, glycolic acid, citric acid, tartaric acid salts are preferred, and HC1 and glycolic acid salts are particularly preferred.

[0059] The compounds of formula (I) according to the invention may contain one or more asymmetric carbon atoms, and therefore may exist in the form of optical isomers, enantiomers and diastereoisomers, which also form part of the invention.

[0060] In an embodiment, the present invention concerns the compound of formula (I) or a salt thereof, wherein R3is H.

[0061] In a further embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein R3is -C2-8 alkylene-NR4R5, wherein R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H, or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N, or R3is - C2-8 alkylene-N+R6R7R8wherein R6, R7, R8are independently from each other Ci-6 alkyl, or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N; and R2and R3have the same meaning.

[0062] In another embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein R1is

[0063] r;

[0064]

[0065] HXzIn a further embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein R1is

[0066]

[0067] In another embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein

[0068] R2and / or R3is -Ci-7alkylene-CH2-NR4R5or -Ci-7alkylene-CH2-N+R6R7R8, wherein R4R5, R6R7and R8are as defined above.

[0069] In another embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein

[0070] R2and / or R3is C2-3alkylene-NR4R5or C2-3 alkylene-N+R6R7R8, wherein R4R5, R6R7and R8are as defined above.

[0071] In another embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein

[0072] R2and / or R3are selected from the following:

[0073]

[0074] wherein R4and R5are independently from each other Ci-6 alkyl,

[0075] R’ is H or Ci-6 alkyl;

[0076] R”, R’” are independently from each other H or Ci-6 alkyl;

[0077] n” is an integer selected from 0, 1, or 2;

[0078] n’” is an integer selected from 1, 2, 3, 4 and 5;

[0079] n is an integer selected from 1, 2, 3, 4, and 5,

[0080] n’ is an integer selected from 0, 1, 2, and 3,

[0081] X" is a pharmaceutically acceptable counterion, X" is for example Cl" or Br",R6, R7’ R8are independently from each other Ci-6 alkyl or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N.

[0082] According to a further embodiment, the present invention relates to the compound of formula (I) or a salt thereof, wherein

[0083] R2and / or R3are selected from the following:

[0084]

[0085] A further subject of the present invention is the therapeutic use of the compounds of formula (I).

[0086] According to a specific embodiment the subj ect of the invention is a compound of formula (I) or a salt thereof for use in the treatment of malaria,

[0087] wherein

[0088] R1is

[0089]

[0090] R2is -C2-8alkylene-NR4R5, wherein

[0091] R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R’ ”, wherein R” and R’ ’ ’ are independently from each other Ci-6 alkyl or H, or

[0092] R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N, or R2is -C2-8 alkylene-N+R6R7R8, wherein

[0093] R6, R7, R8are independently from each other Ci-6 alkyl, or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;

[0094] R3is H or -C2-8 alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R’ ”, wherein R” and R’ ’ ’ are independently from each other Ci-6 alkyl or H, or

[0095] R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N, or R3is -C2-8 alkylene-N+R6R7R8, wherein

[0096] R6, R7, R8are independently from each other Ci-6 alkyl,

[0097] or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N.

[0098] The invention further relates to the process for preparing the compounds of formula (I). The R2and / or R3group is introduced using the corresponding RHlg reagent in the presence of a base.

[0099] Hlg = Cl, Br, I

[0100]

[0101] If RHlg contains a primary or secondary amino group, the protection of the amino functional group must be ensured.

[0102] General Procedure:

[0103] - CBD or CBG is dissolved in an appropriate solvent (e.g., anhydrous DMF, anhydrous THF, or anhydrous dioxane).

[0104] - A base (e.g., K2CO3 or NaH) is added to the solution.

[0105] - Inert atmosphere may be used, although it is not strictly required.

[0106] - RHlg reagent is added (aminoalkyl halide).

[0107] - The reaction requires a minimum of 20-26 hours to reach completion.

[0108] - If NaH was used as a base, the remaining NaH must be decomposed with MeOH and then with water.- The reaction mixture is evaporated and the product is purified by column chromatography.

[0109] The resulting compound of general formula (I) is optionally converted into a salt, if desired.

[0110] Preparation of HC1 salt:

[0111] The compound is dissolved in a solvent (e.g., anhydrous diethyl ether), and cooling is applied using an ice-water bath.

[0112] Sulfuric acid solution is added dropwise to NaCl. The produced gas is bubbled into the solution of the compound.

[0113] The precipitated salt derivative is filtered off and dried.

[0114] Preparation of other salts:

[0115] The compound is dissolved in a suitable solvent (e.g. methanol),

[0116] organic or inorganic acid is added,

[0117] it is stirred for 30 minutes, then the solvent is evaporated.

[0118] Alternative preparation method for salts:

[0119] Anion-exchange resin is pre-treated with the desired anion,

[0120] the compound (another salt derivative) is dissolved in a suitable solvent (e.g. DMF- water mixture, or acetonitrile-water mixture),

[0121] The resin is added to the solution,

[0122] It is stirred for 2 hours,

[0123] The resin is filtered off, and the solvent is evaporated.

[0124] Brief description of the drawings:

[0125] Figure 1 corresponds to the in vitro antimalarial activity of compound of Example 3 against Plasmodium falciparum 3D7 - IC50 determination with SYBR Green I fluorescence assay (A) and Giemsa-stained microscopic analysis (B).

[0126] Figure 2 corresponds to the in vivo experiments; it shows the parasitemia percentage in mice after infection and treatment with the compound of Example 3 (code PFD-40), alongside the results for the untreated (control) and artesunate-treated groups.Figure 3 corresponds to the in vivo experiments, showing the survival results of mice after infection and treatment with the compound of Example 3 (PFD-40) compared to the untreated control group. It should be noted that the artesunate-treated group is not shown in the diagram, as all mice in that group remained alive after 20 days.

[0127] Examples

[0128] Description of analytical methods:

[0129] 'H NMR (500 and 700 MHz),13C NMR (125 and 176 MHz), and 2D NMR spectra were recorded with a Bruker Avance II 500 and a NEO-700 spectrometer at 298 K or 310 K. Chemical shifts are referenced to Me4Si (0.00 ppm for 1H) and to the solvent residual signals. A MALDI-TOF MS measurements were performed with a Bruker Autoflex Speed mass spectrometer.

[0130] Representative examples of structure numbering for NMR evaluation:

[0131] Example 1:

[0132]

[0133] Cannabidiol (157 mg, 0.5 mmol) and anhydrous potassium carbonate (207 mg, 1.5 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then 3 -chi oro-M-V-di ethyl propan-1 -amine (244pl, 1.5 mmol) was added. The suspension was stirred under argon at room temperature for 26 h. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol 93:7) to yield the compound of Example 1 (91 mg, 43%) as a brownish syrup.

[0134] Rf = 0.60 (dichloromethane / methanol 8:2); 'H NMR (500 MHz, CDCh): 8 (ppm) 6.27 (s, 1H, aromatic CH), 6.21 (s, 1H, aromatic CH), 5.54 (s, 1H, H-2 CH), 4.51 (s, 1H, H-9 CH2a), 4.39 (s, 1H, H-9 CH2b), 3.98 (d, 1H, J= 8.3 Hz, H-3 CH), 3.90 (t, 2H, J= 6.3 Hz, H-l’” CH2), 2.69 - 2.54 (m, 6H, H-3’” CH2, H-4’”C#2, H5’” CH2), 2.51 - 2.41 (m, 3H, H-4 C and H-l” CH2), 2.26 - 2.15 (m, 1H, H-6 CH2a), 2.11 - 2.01 (m, 1H, H-6 CH2b), 1.97 - 1.85 (m, 2H, H-2’” CH2), 1.83 - 1.70 (m, 5H, H-5 CH2andH-7 CH3), 1.64 (s, 3H, H-10 CH3), 1.61 - 1.52 (m, 2H, H-2” CH2), 1.36 - 1.24 (m, 4H, H-3” and H-4” CH2), 1.06 (t, 6H, J= 7.2 Hz, H-6’” and H-7’” CH3), 0.88 (t, 3H, J= 7.1 Hz, H-5” CH3) °C NMR (125 MHz, CDCh): 8 (ppm) 155.9, 147.3, 142.6, 139.2 (4C, quat.), 124.7 (1C, C-2 CH), 115.2 (1C, quat.), 110.9 (1C, C-9 CH2), 109.5 (1C, aromatic CH), 104.0 (1C, aromatic CH), 66.8 (1C, C-1’” CH2), 49.8 (1C, C-3”’ CH2), 47.0 (2C, C-4’” and C-5’” CH2), 46.1 (1C, C-4 CH), 36.1 (1C, C-1” CH2), 35.8 (1C, C-3 CH), 31.6 (1C, C-3” CH2), 30.9 (1C, C-2” CH2), 30.3 (1C, C-6 CH2), 28.1 (1C, C-5 CH2), 27.0 (1C, C-2’” CH2), 23.7 (1C, C-7 CH3), 22.6 (1C, C-4” CH2), 19.7 (1C, C-10 CH3), 14.1 (1C, C-5” CH3), 11.5 (2C, C-6’” and C-7’” CH3); MALDI-TOF MS: m / z calcd for C28H45NO2Na+[M+Na]+: 450.345; found 450.447.

[0135] Example 2:

[0136]

[0137] Cannabidiol (157 mg, 0.5 mmol) and anhydrous potassium carbonate (622 mg, 4.5 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then 3 -chi oro- / f-di ethyl propan- l -amine (733 pl, 4.5 mmol) was added. The suspension was stirred under argon at room temperature for 1week. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol 93:7 —> 7:3) to yield the compound of Example 2 (92 mg, 34%) as a brownish syrup.

[0138] Rf = 0.23 (dichloromethane / methanol 8:2); 'H NMR (500 MHz, CDCh): 8 (ppm) 6.28 (s, 2H, aromatic CH), 5.20 (s, 1H, H-2 CH), 4.42 (s, 1H, H-9 CH2a), 4.40 (s, 1H, H-9 CH2b), 3.97 -3.86 (m, 5H, H-3 CH and H-l”’ CH2), 2.94 - 2.86 (m, 1H, H-4 CH), 2.77 - 2.60 (m, 12H, H-3’” CH2, H-4’”C#2, H5’” CH2), 2.50 - 2.43 (m, 2H, H-l” CH2), 2.16- 2.06 (m, 1H, H-6 CH2a), 2.02 - 1.88 (m, 5H, H-6 CH2b and H-2’” CH2), 1.78 - 1.66 (m, 2H, H-5 CH2), 1.63 (s, 3H, H-7 CH3), 1.59 - 1.50 (m, 5H, H-10 CH3and H-2” CH2), 1.34 - 1.25 (m, 4H, H-3” and H-4” CH2), 1.09 (t, 12H, J= 7.2 Hz, H-6”’ and H-7’” CH3), 0.86 (t, 3H, J= 7.0 Hz, H-5” CH3) °C NMR (125 MHz, CDCh): 6 (ppm) 149.4, 142.0, 130.6 (3C, quat.), 126.9 (1C, C-2 CH), 118.5 (1C, quat.), 109.7 (1C, C-9 CH2), 105.3 (2C, aromatic CH), 66.6 (2C, C-l’” CH2), 49.9 (2C, C-3’” CH2), 47.0 (4C, C-4’” and C-5’” CH2), 44.9 (1C, C-4 CH), 36.6 (1C, C-l” CH2), 36.4 (1C, C-3 CH), 31.7 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 31.0 (1C, C-6 CH2), 29.8 (1C, C-5 CH2), 26.7 (2C, C-2’” CH2), 23.5 (1C, C-7 CH3), 22.6 (1C, C-4” CH2), 19.7 (1C, C-10 CH3), 14.1 (1C, C-5” CH3), 11.0 (4C, C-6’” and C-7’” CH3); MALDI-TOF MS: m / z calcd for C35H6ON202H+[M+H]+: 541.466; found 541.586.

[0139] Example 3:

[0140]

[0141] Cannabigerol (158 mg, 0.5 mmol) and anhydrous potassium carbonate (207 mg, 1.5 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then 3-chloro-7V,7V-diethylpropan-l-amine (244 pl, 1.5 mmol) was added. The suspension was stirred under argon at room temperature for 24 h. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol 93:7) to yield the compound of Example 3 (77 mg, 36%) as a brownish syrup.

[0142] Rf = 0.47 (dichloromethane / methanol 8:2); 'H NMR (500 MHz, CDC13): 5 (ppm) 6.33 (s, 1H, aromatic CH), 6.22 (s, 1H, aromatic CH), 5.23 (t, 1H, J= 7.0 Hz, H-2’ CH), 5.10 - 5.00 (m, 1H, H-6’ CH), 3.95 (t, 2H, J= 5.9 Hz, H-l”’ CH2), 3.33 (d, 2H, J= 7.0 Hz, H-l’ CH2), 2.88 -2.79 (m, 2H, H-3’” CH2), 2.75 (q, 4H, J= 7.2 Hz, H-4’” and H-5’” CH2), 2.46 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.12 - 2.01 (m, 4H, H-2’” CH2and H-5’ CH2), 2.01 - 1.94 (m, 2H, H-4’ CH2), 1.77 (s, 3H, H-9’ CH3), 1.65 (s, 3H, H-8’ CH3), 1.60 - 1.51 (m, 5H, H-10’ CH3and H-2” CH2), 1.37 - 1.24 (m, 4H, H-3” and H-4” CH2), 1.14 (t, 6H, J= 7.2 Hz, H-6’” and H-7’” CH3), 0.87 (t, 3H, = 7.0Hz, H-5” C7 / 3); °C NMR (125 MHZ, CDCh): 8 (ppm) 157.1, 155.5, 142.1, 136.1, 131.6 (5C, quat.), 124.2 (1C, C-6’ CH), 122.9 (1C, C-2’ CH), 113.1 (1C, quat.), 109.0 (1C, aromatic CH), 104.0 (1C, aromatic CH), 66.3 (1C, C-1”’ CH2), 49.6 (1C, C-3”’ CH2), 46.8 (2C, C-4’” and C-5’” CH2), 39.9 (1C, C-4’ CH2), 36.1 (1C, C-1” CH2), 31.6 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 26.7 (1C, C-5’ CH2), 26.0 (1C, C-2’” CH2), 25.7 (1C, C-8’ CH3), 22.6 (1C, C-4” CH2), 22.3 (1C, C-1’ CH2), 17.7 (1C, C-10 CH3), 16.3 (1C, C-9’ CH3), 14.1 (1C, C-5” CH3), 10.5 (2C, C-6’” and C-7’” CH3); MALDI-TOF MS m / z calcd for C28H47NO2H+[M+H]+: 430.361; found 430.462.

[0143] Example 4:

[0144] N

[0145]

[0146] Cannabigerol (316 mg, 1.0 mmol) and anhydrous potassium carbonate (1244 mg, 9 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then 3 -chi oro- / f-di ethyl propan-l -amine (1466 pl, 9 mmol) was added. The suspension was stirred under argon at room temperature for 2 weeks. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane / methanol 9:1 —> 6:4) to yield the compound of Example 4 (410 mg, 76%) as a brownish syrup.

[0147] Rf = 0.26 (dichloromethane / methanol 8:2); 'H NMR (500 MHz, CDCh): 6 (ppm) 6.33 (s, 2H, aromatic CH), 5.26 - 5.20 (m, 1H, H-2’ CH), 5.10 - 5.02 (m, 1H, H-6’ CH), 3.98 (t, 4H, J = 6.2 Hz, H-l’” CH2), 3.32 (d, 2H, J= 7.0 Hz, H-l’ CH2), 2.68 - 2.60 (m, 4H, H-3’” CH2), 2.59 - 2.48 (m, 10H, H-4’” CH2, H-5’” CH2and H-l” CH2), 2.07 - 1.99 (m, 2H, H-5’ CH2), 1.97 -1.88 (m, 6H, H-2’” and H-4’ CH2), 1.75 (s, 3H, H-9’ CH3), 1.63 (s, 3H, H-8’ CH3), 1.61 - 1.53(m, 5H, H-10’ CH3and H-2” CH2), 1.37 - 1.27 (m, 4H, H-3” and H-4” CH2), 1.03 (t, 12H, J = 7.2 Hz, H-6’” and H-7’” CH3), 0.89 (t, 3H, J= 7.0 Hz, H-5” C7 / 3); °C NMR (125 MHz, CDCh): 5 (ppm) 157.3, 141.8, 133.8, 131.1 (4C, quat.), 124.7 (1C, C-6’ CH), 123.6 (1C, C-2’ CH), 115.8 (1C, quat.), 104.8 (2C, aromatic CH), 66.7 (2C, C-l’” CH2), 49.8 (2C, C-3’” CH2), 47.1 (4C, C-4’” and C-5’” CH2), 40.0 (1C, C-4’ CH2), 36.6 (1C, C-l” CH2), 31.7 (1C, C-3” CH2), 31.4 (1C, C-2” CH2), 27.3 (1C, C-5’ CH2), 26.9 (2C, C-2”’ CH2), 25.8 (1C, C-8’ CH3), 22.7 (1C, C-4” CH2), 22.3 (1C, C-l’ CH2), 17.7 (1C, C-10’ CH3), 16.3 (1C, C-9’ CH3), 14.1 (1C, C-5” CH3), 11.8 (4C, C-6’” and C-7’” CH3); MALDI-TOF MS m / z calcd for C35H62N2O2H+[M+H]+: 543.481; found 543.616.

[0148] Example 5:

[0149]

[0150] 4-(2-Chloroethyl) morpholine hydrochloride (558 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabidiol (314 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 22 h. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / ethyl acetate 8:2) to yield the compound of Example 5 (121 mg, 28%) as a brownish syrup.

[0151] Rf = 0.34 (hexane / ethyl acetate 7:3);XHNMR (500 MHz, CDCh): 5 (ppm) 6.30 (s, 1H, aromatic CH), 6.22 (s, 1H, aromatic CH), 6.03 (bs, 1H, OH), 5.54 (s, 1H, H-2 CH), 4.51 (s, 1H, H-9 CH2a), 4.37 (s, 1H, H-9 CH2b), 4.06 - 3.94 (m, 3H, H-3 CH and H-1’” CH2), 3.72 (t, 4H, J = 4.7 Hz, H-4’” and H-6’” CH2), 2.79 - 2.69 (m, 2H, H-2’” CH2), 2.60 - 2.51 (m, 4H, H-3’” and H-5’” CH2), 2.50 -2.38 (m, 3H, H-4 C / f and H-1” CH2), 2.27 - 2.16 (m, 1H, H-6 CH2a), 2.12 - 2.02 (m, 1H, H-6 CH2b), 1.83 - 1.70 (m, 5H, H-5 CH2and H-7 CH3), 1.65 (s, 3H, H-10 CH3), 1.61 - 1.52 (m, 2H, H-2” CH2), 1.36 - 1.24 (m, 4H, H-3” and H-4” CH2), 0.88 (t, 3H, J= 7.0 Hz, H-5” CH3)- °C NMR (125 MHz, CDCh): 5 (ppm) 157.3, 155.9, 147.3, 142.8, 139.6 (5C, quat.), 124.6 (1C, C-2 CH), 115.5 (1C, quat.), 111.0 (1C, C-9 CH2), 110.0 (1C, aromatic CH),104.3 (1C, aromatic CH), 67.1 (2C, C-4’” and C-6’” CH2), 66.4 (1C, C-l’” CH2), 58.0 (1C, C-2’” CH2), 54.2 (2C, C-3’” and C-5’” CH2), 46.2 (1C, C-4 CH), 36.1 (1C, C-l” CH2), 35.8 (1C, C-3 CH), 31.7 (1C, C-3” CH2), 30.9 (1C, C-2” CH2), 30.3 (1C, C-6 CH2), 28.1 (1C, C-5 CH2), 23.8 (1C, C-7 CH3), 22.7 (1C, C-4” CH2), 19.7 (1C, C-10 CH3), 14.2 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C27H4iNO3Na+[M+Na]+: 450.309; found 450.408.

[0152] Example 6:

[0153]

[0154] l-(2-Chloroethyl) piperidine hydrochloride (552 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabidiol (314 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 45 h. The mixture was filtered, washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / ethyl acetate 7:3) to yield the compound of Example 6 (110 mg, 26%) as a brownish syrup.

[0155] Rf = 0.37 (hexane / acetone 7:3); 'H NMR (500 MHz, CDC13): 5 (ppm) 6.28 (s, 1H, aromatic CH), 6.22 (s, 1H, aromatic CH), 5.54 (s, 1H, H-2 CH), 4.50 (s, 1H, H-9 CH2a), 4.36 (s, 1H, H-9 CH2b), 4.07 - 3.93 (m, 3H, H-3 CH and H-1”’ CH2), 2.78 - 2.66 (m, 2H, H-2”’ CH2), 2.57 -2.39 (m, 7H, H-4 CH, H-l” CH2, H-3”’ and H-7’” CH2), 2.27 - 2.16 (m, 1H, H-6 CH2a), 2.12 - 2.01 (m, 1H, H-6 CH2b), 1.84 - 1.70 (m, 5H, H-5 CH2and H-7 CH3), 1.64 (s, 3H, H-10 CH3), 1.63 - 1.53 (m, 6H, H-4’”, H-6’” CH2and H-2” CH2), 1.48 - 1.40 (m, 2H, H-5’” CH2), 1.36 -1.24 (m, 4H, H-3” and H-4” CH2), 0.88 (t, 3H, J= 7.0 Hz, H-5” CH3) °C NMR (125 MHz, CDC13): 5 (ppm) 157.3, 155.9, 147.4, 142.7, 139.4 (5C, quat.), 124.8 (1C, C-2 CH), 115.1 (1C, quat.), 111.0 (1C, C-9 CH2), 109.7 (1C, aromatic CH), 104.2 (1C, aromatic CH), 66.5 (1C, C-T” CH2), 58.2 (1C, C-2’” CH2), 55.2 (2C, C-3’” and C-7’” CH2), 46.3 (1C, C-4 CH), 36.1 (1C, C-l” CH2), 35.8 (1C, C-3 CH), 31.6 (1C, C-3” CH2), 30.9 (1C, C-2” CH2), 30.4 (1C, C-6 CH2), 28.1 (1C, C-5 CH2), 26.0 (2C, C-4’” and C-6’” CH2), 24.3 (1C, C-5’” CH2), 23.8 (1C, C-7CH3), 22.7 (1C, C-4” CH2), 19.6 (1C, C-10 CH3), 14.2(1C, C-5” CH3); MALDI-TOF MS m / z calcd for C28H43NO2Na+[M+Na]+: 448.329; found 448.248.

[0156] Example 7:

[0157]

[0158] 2-Chloro-N, N-dimethylethylamine hydrochloride (432 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabidiol (314 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 6 days. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / acetone 7:3) to yield the compound of Example 7 (35 mg, 9%) as a brownish syrup.

[0159] Rf= 0.29 (hexane / acetone 1:1);XHNMR (700 MHz, CDC13) 56.29 (s, 1H, aromatic CH), 6.22 (s, 1H, aromatic CH), 5.55 (s, 1H, H-2 CH), 4.51 (s, 1H, H-9 CH2a), 4.36 (s, 1H, H-9 CH2b), 4.05 - 3.90 (m, 3H, H-3 CH and H-T” CH2), 2.74 - 2.64 (m, 2H, H-2’” CH2), 2.47 (t, 2H, J = 7.8 Hz, H-l” CH2), 2.42 (bs, 1H, H-4 CH), 2.35 - 2.30 (m, 6H, H-3’” and H-4’” CH3), 2.26 -2.15 (m, 1H, H-6 CH2a), 2.11 - 2.02 (m, 1H, H-6 CH2b), 1.83 - 1.70 (m, 5H, H-5 CH2and H-7 CH3), 1.64 (s, 3H, H-10 CH3), 1.61 - 1.53 (m, 2H, H-2” CH2), 1.35 - 1.26 (m, 4H, H-3” and H-4” CH2), 0.88 (t, 3H, J= 7.2 Hz, H-5” CH3) °C NMR (176 MHz, CDC13) 5 157.3, 155.9, 147.3, 142.8, 139.5 (5C, quat.), 124.7 (1C, C-2 CH), 115.4 (1C, quat.), 111.0 (1C, C-9 CH2), 109.8 (1C, aromatic CH), 104.1 (1C, aromatic CH), 66.8 (1C, C-1”’ CH2), 58.5 (1C, C-2’” CH2), 46.3 (1C, C-4 CH), 46.1 (2C, C-3”’ and C-4’” CH3), 36.1 (1C, C-1” CH2), 35.8 (1C, C-3 CH), 31.7 (1C, C-3” CH2), 30.9 (1C, C-2” CH2), 30.4 (1C, C-6 CH2), 28.1 (1C, C-5 CH2), 23.8 (1C, C-7 CH3), 22.7 (1C, C-4” CH2), 19.6 (1C, C-10 CH3), 14.2 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C25H39NO2Na+[M+Na]+: 408.287; found 408.325.Example 8:

[0160]

[0161] l-(2-chloroethyl) pyrrolidine hydrochloride (510 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (20 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabidiol (314 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 21 h. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / acetone 8:2) to yield the compound of Example 8 (25 mg, 6%) as a brownish syrup.

[0162] Rf= 0.14 (hexane / acetone 7:3);XHNMR (700 MHz, CDCh) 86.29 (s, 1H, aromatic CH), 6.23 (s, 1H, aromatic CH), 6.05 (bs, 1H, OH), 5.55 (s, 1H, H-2 CH), 4.51 (s, 1H, H-9 CH2a), 4.36 (s, 1H, H-9 CH2b), 4.07 - 3.93 (m, 3H, H-3 CH and H-T” CH2), 2.89 - 2.81 (m, 2H, H-2’” CH2), 2.64 - 2.58 (m, 4H, H-3’” and H-6’” CH2), 2.47 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.43 (bs, 1H, H-4 CH), 2.26 - 2.17 (m, 1H, H-6 CH2a), 2.11 - 2.03 (m, 1H, H-6 CH2b), 1.83 - 1.78 (m, 5H, H-5 CH2and H-7 CH3), 1.78 - 1.72 (m, 4H, H-4’” and H-5’” CH2), 1.64 (s, 3H, H-10 CH3), 1.60 - 1.53 (m, 2H, H-2” CH2), 1.35 - 1.25 (m, 4H, H-3” and H-4” CH2), 0.88 (t, 3H, J= 7.1 Hz, H-5” CH3)- °C NMR (176 MHz, CDCh) 6 157.4, 155.9, 147.4, 142.8, 139.5 (5C, quat.), 124.8 (1C, C-2 CH), 115.4 (1C, quat.), 111.1 (1C, C-9 CH2), 109.8 (1C, aromatic CH), 104.2 (1C, aromatic CH), 67.7 (1C, C-1”’ CH2), 55.2 (1C, C-2’” CH2), 54.9 (2C, C-3”’ and C-6’” CH2), 46.3 (1C, C-4 CH), 36.1 (1C, C-1” CH2), 35.8 (1C, C-3 CH), 31.7 (1C, C-3” CH2), 30.9 (1C, C-2” CH2), 30.4 (1C, C-6 CH2), 28.1 (1C, C-5 CH2), 23.8 (1C, C-7 CH3), 23.7 (2C, C-4’” and C-5’” CH2), 22.7 (1C, C-4” CH2), 19.6 (1C, C-10 CH3), 14.2 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C27H4INO2H+[M+H]+: 412.321; found 412.368

[0163] Examples 9 and 10:

[0164] 4-(2-Chloroethyl) morpholine hydrochloride (3349 mg, 18 mmol), anhydrous potassium carbonate (3593 mg, 26 mmol) and tetrabutylammonium iodide (665 mg, 1.8 mmol) weredissolved / suspended in dry dimethylformamide (50 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabigerol (633 mg, 2 mmol) was added. The suspension was stirred under argon at room temperature for 12 days. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / ethyl acetate 7:3, then 1:1) to yield the compound of Example 9 (149 mg, 17%) as a yellow powder and the compound of Example 10 (377 mg, 35%) as a yellow syrup.

[0165] Compound of Example 9:

[0166] I0

[0167] l\L J

[0168] O'

[0169]

[0170] Rf= 0.55 (hexane / acetone 6:4);1H NMR (500 MHz, CDCl3) δ 6.28 (d, 2H, J= 5.3 Hz, aromatic CH), 5.26 - 5.20 (m, 1H, H-2’ CH), 5.10 - 5.02 (m, 1H, H-6’ CH), 4.11 (t, 2H, J= 5.7 Hz, H-T” CH2), 3.79 - 3.70 (m, 4H, H-4’” and H-6’” CH2),. 1 (d, 2H, J= 7.1 Hz, H-l’ CH2), 2.83 (t, 2H, J= 5.7 Hz, H-2’” CH2), 2.67 - 2.58 (m, 4H, H-3’” and H-5’” CH2), 2.48 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.13 - 2.05 (m, 2H, H-5’ CH2), 2.04 - 1.98 (m, 2H, H-4’ CH2), 1.79 (s, 3H, H-9’ CH3), 1.67 (s, 3H, H-8’ CH3), 1.61 - 1.52 (m, 5H, H-10’ CH3and H-2” CH2), 1.37 - 1.24 (m, 4H, H-3” and H-4” CH2), 0.89 (t, 3H, J= 7.0 Hz, H-5” CH3, °C NMR (126 MHz, CDCh) 5 157.0, 155.4, 142.4, 136.9, 131.7 (5C, quat.), 124.1 (1C, C-6’ CH), 122.6 (1C, C-2’ CH), 113.2 (1C, quat.), 109.1 (1C, aromatic CH), 104.5 (1C, aromatic CH), 67.0 (2C, C-4’” and C-6’” CH2), 66.6 (1C, C-l”’ CH2), 57.9 (1C, C-2’” CH2), 54.2 (2C, C-3”’ and C-5’” CH2), 39.9 (1C, C-4’ CH2), 36.1 (1C, C-l” CH2), 31.6 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 26.6 (1C, C-5’ CH2), 25.8 (1C, C-8’ CH3), 22.7 (1C, C-4” CH2), 22.3 (1C, C-l’ CH2), 17.8 (1C, C-10’ CH3), 16.3 (1C, C-9’ CH3), 14.1 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C27H43NO3H+[M+H]+: 430.332; found 430.387; C27H43NO3Na+[M+Na]+: 452.314; found 452.365 Compound of Example 10:

[0171] \0

[0172] hk J

[0173] O'

[0174]

[0175] Rf = 0.48 (hexane / acetone 6:4);1H NMR (500 MHz, CDCl3) δ 6.35 (s, 2H, aromatic CH), 5.21 - 5.15 (m, 1H, H-2’ CH), 5.09 - 5.03 (m, 1H, H-6’ CH), 4.09 (t, 4H, J= 5.8 Hz, H-l’” CH2), 3.75 - 3.66 (m, 8H, H-4’” and H-6’” CH2), 3.31 (d, 2H, J= 7.0 Hz, H-l’ CH2), 2.79 (t, 4H, J = 5.7 Hz, H-2’” CH2), 2.62 - 2.55 (m, 8H, H-3’” and H-5’” CH2), 2.52 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.07 - 2.00 (m, 2H, H-5’ CH2), 1.96 - 1.90 (m, 2H, H-4’ CH2), 1.76 (s, 3H, H-9’ CH3), 1.64 (s, 3H, H-8’ CH3), 1.61 - 1.52 (m, 5H, H-10’ CH3and H-2” CH2), 1.37 - 1.27 (m, 4H, H-3” and H-4” CH2), 0.89 (t, 3H, J = 6.9 Hz, H-5” CH3,13C NMR (126 MHz, CDCh) 8 157.1, 141.9, 134.0, 131.1 (4C, quat.), 124.5 (1C, C-6’ CH), 123.4 (1C, C-2’ CH), 116.0 (1C, quat.), 105.2 (2C, aromatic CH), 67.0 (4C, C-4’” and C-6’” CH2), 66.6 (2C, C-l’” CH2), 57.9 (2C, C-2’” CH2), 54.2 (4C, C-3’” and C-5’” CH2), 39.9 (1C, C-4’ CH2), 36.5 (1C, C-l” CH2), 31.6 (1C, C-3” CH2), 31.3 (1C, C-2” CH2), 26.8 (1C, C-5’ CH2), 25.7 (1C, C-8’ CH3), 22.6 (1C, C-4” CH2), 22.3 (1C, C-l’ CH2), 17.7 (1C, C-10’ CH3), 16.4 (1C, C-9’ CH3), 14.1 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C33H54N2O4H+[M+H]+: 543.416; found 543.468; C33H54N2O4Na+[M+Na]+: 565.398; found 565.447

[0176] Example 11:

[0177]

[0178] l-(2-Chloroethyl) piperidine hydrochloride (3314 mg, 18 mmol), anhydrous potassium carbonate (3593 mg, 26 mmol) and tetrabutylammonium iodide (665 mg, 1.8 mmol) were dissolved / suspended in dry dimethylformamide (140 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabigerol (633 mg, 2 mmol) was added. The suspension was stirred under argon at room temperature for 12 days. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / ethyl acetate 7:3) to yield the compound of Example 11 (175 mg, 20%) as a yellow powder.

[0179] Rf= 0.25 (hexane / ethyl acetate 4:6);1H NMR (500 MHz, CDCl3) δ 6.26 (d, 2H, J= 3.0 Hz, aromatic CH), 5.30 - 5.23 (m, 1H, H-2’ CH), 5.11 - 5.04 (m, 1H, H-6’ CH), 4.13 (t, 2H, J = 6.0 Hz, H-l’” CH2), 3.38 (d, 2H, J = 7.2 Hz, H-l’ CH2), 2.84 (t, 2H, J = 6.0 Hz, H-2’” CH2), 2.66 - 2.53 (m, 4H, H-3’” and H-7’” CH2), 2.46 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.13 - 2.05 (m, 2H, H-5’ CH2), 2.04 - 1.98 (m, 2H, H-4’ CH2), 1.80 (s, 3H, H-9’ CH3), 1.68 (s, 3H, H-8’ CH3),1.67- 1.61 (m, 4H, H-4’” and H-6’” CH2), 1.61 - 1.52 (m, 5H, H-10’ CH and H-2” CH2), 1.50 - 1.42 (m, 2H, H-5’” CH2), 1.36 - 1.25 (m, 4H, H-3” and H-4” CH2), 0.90 (t, 3H, J= 7.0 Hz, H-5” CH3),- °C NMR (126 MHz, CDCh) 6 157.1, 155.5, 142.1, 136.2, 131.5 (5C, quat.), 124.3 (1C, C-6’ CH), 122.9 (1C, C-2’ CH), 113.4 (1C, quat.), 109.0 (1C, aromatic CH), 104.1 (1C, aromatic CH), 66.3 (1C, C-l’” CH2), 58.2 (1C, C-2’” CH2), 55.1 (2C, C-3”’ and C-7’” CH2), 39.9 (1C, C-4’ CH2), 36.1 (1C, C-l” CH2), 31.6 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 26.7 (1C, C-5’ CH2), 25.7 (3C, C-4’” CH2, C-6’” CH2and C-8’ CH3), 24.2 (1C, C-5’” CH2), 22.7 (1C, C-4” CH2), 22.4 (1C, C-l’ CH2), 17.7 (1C, C-10’ CH3), 16.3 (1C, C-9’ CH3), 14.1 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C28H45NO2H+[M+H]+: 428.352; found 428.407; C28H45NO2Na+[M+Na]+: 450.334; found 450.378

[0180] Example 12:

[0181]

[0182] l-(2-chloroethyl) pyrrolidine hydrochloride (510 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (30 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabigerol (316 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 1 day. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / acetone 8:2) to yield the compound of Example 12 (66 mg, 15%) as a brownish syrup.

[0183] Rf= 0.26 (hexane / acetone 1:1);1H NMR (500 MHz, CDCl3) δ 6.26 (s, 2H, aromatic CH), 5.28 - 5.22 (m, 1H, H-2’ CH), 5.11 - 5.04 (m, 1H, H-6’ CH), 4.12 (t, 2H, J= 6.0 Hz, H-l’” CH2), 3.37 (d, 2H, J= 7.1 Hz, H-l’ CH2), 2.95 (t, 2H, J= 6.0 Hz, H-2’” CH2), 2.75 - 2.66 (m, 4H, H-3’” and H-6’” CH2), 2.46 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.13 - 2.05 (m, 2H, H-5’ CH2), 2.04 -1.96 (m, 2H, H-4’ CH2), 1.86 - 1.80 (m, 4H, H-4’” and H-5’” CH2), 1.78 (s, 3H, H-9’ CH3), 1.67 (s, 3H, H-8’ CH3), 1.61 - 1.52 (m, 5H, H-10’ CH3and H-2” CH2), 1.36 - 1.25 (m, 4H, H-3” and H-4” CH2), 0.89 (t, 3H, J= 7.0 Hz, H-5” CH3)13C NMR (126 MHz, CDCh) 6 157.1,155.7, 142.2, 136.4, 131.6 (5C, quat.), 124.3 (1C, C-6’ CH), 122.9 (1C, C-2’ CH), 113.3 (1C, quat.), 109.0 (1C, aromatic CH), 104.2 (1C, aromatic CH), 67.5 (1C, C-l’” CH2), 55.2 (1C, C-2’” CH2), 54.9 (2C, C-3’” and C-6’” CH2), 39.9 (1C, C-4’ CH2), 36.1 (1C, C-l” CH2), 31.7 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 26.7 (1C, C-5’ CH2), 25.8 (1C, C-8’ CH3), 23.6 (2C, C-4’” and C-5”’ CH2), 22.7 (1C, C-4” CH2), 22.4 (1C, C-l’ CH2), 17.8 (1C, C-10’ CH3), 16.3 (1C, C-9’ CH3), 14.2 (1C, C-5” CH3); MALDI-TOF MS: m / z calcd for C27H43NO2H+[M+H]+: 414.337; found 414.358; C27H43NO2Na+[M+Na]+: 436.319; found 436.334.

[0184] Example 13:

[0185]

[0186] 2-Chloro-7V, A-dimethylethylamine hydrochloride (432 mg, 3 mmol), anhydrous potassium carbonate (691 mg, 5 mmol) and tetrabutylammonium iodide (111 mg, 0,3 mmol) were dissolved / suspended in dry dimethylformamide (30 ml). The obtained suspension was stirred for 30 minutes under argon at room temperature then cannabigerol (316 mg, 1 mmol) was added. The suspension was stirred under argon at room temperature for 6 days. The mixture was filtered through a glass filter washed with acetone and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (hexane / acetone 6:4) to yield the compound of Example 13 (30 mg, 8%) as a brownish syrup.

[0187] Rf= 0.27 (hexane / acetone 1:1);1H NMR (700 MHz, CDCl3) 5 6.28 (d, 2H, J = 11.7 Hz, aromatic CH), 5.26 - 5.21 (m, 1H, H-2’ CH), 5.08 - 5.03 (m, 1H, H-6’ CH), 4.07 (t, 2H, J = 5.9 Hz, H-l”’ CH2), 3.37 (d, 2H, J= 7.0 Hz, H-l’ CH2), 2.78 (t, 2H, J= 5.9 Hz, H-2’” CH2), 2.48 (t, 2H, J= 7.8 Hz, H-l” CH2), 2.39 - 2.34 (m, 6H, H-3’” and H-4’” CH3), 2.11 - 2.05 (m, 2H, H-5’ CH2), 2.03 - 1.99 (m, 2H, H-4’ CH2), 1.78 (s, 3H, H-9’ CH3), 1.67 (s, 3H, H-8’ CH3), 1.61 - 1.54 (m, 5H, H-10’ CH3and H-2” CH2), 1.35 - 1.27 (m, 4H, H-3” and H-4” CH2), 0.89 (t, 3H,.7= 7.0 Hz, H-5” CH3)13C NMR (176 MHz, CDC13) 5 157.1, 155.6, 142.4, 137.2, 131.8 (5C, quat.), 124.2 (1C, C-6’ CH), 122.7 (1C, C-2’ CH), 113.0 (1C, quat.), 109.2 (1C, aromatic CH), 104.5 (1C, aromatic CH), 66.8 (1C, C-l”’ CH2), 58.5 (1C, C-2’” CH2), 46.0 (2C, C-3’” and C-4’” CH3), 39.9 (1C, C-4’ CH2), 36.2 (1C, C-l” CH2), 31.7 (1C, C-3” CH2), 31.1 (1C, C-2” CH2), 26.6 (1C, C-5’ CH2), 25.8 (1C, C-8’ CH3), 22.7 (1C, C-4” CH2), 22.4 (1C, C-l’ CH2), 17.8 (1C, C-10’ CH3), 16.3 (1C, C-9’ CH3), 14.2 (1C, C-5” CH3); MALDI-TOF MS: m / z calcdfor C25H41NO2H+[M+H]+: 388.321; found 388.369; C25H41NO2Na+[M+Na]+: 410.303; found 410.343.

[0188] Salt production and water solubility

[0189] HCI salt of example 1

[0190]

[0191] Water solubiHty:

[0192] 2.6 mg / ml

[0193]

[0194] HCI salt of example 5

[0195] Water solubility:

[0196] 0.93 mg / ml

[0197] Biological tests:

[0198] Preliminary anti-malaria results:

[0199] The in vitro antimalarial activity was evaluated using methods known in the state of the art: Bege, M., Singh, V., Sharma, N. et al. In vitro and in vivo antiplasmodial evaluation of sugar-modified nucleoside analogues. SciRep 13, 12228 (2023). https: / / doi.org / 10.1038 / s41598-023-39541-4. The results of the preliminary in vitro investigations of certain compounds according to the invention are presented in Table 1.

[0200] Preliminary investigations were conducted on the Plasmodium falciparum Kelch 13 (PfK13) C580Y strain. To determine the data presented in Table 1, the compounds were applied at a concentration of 5 pM and the reported values represent the percentage of parasite viability in the presence of the compounds. The ECso (half maximal effective concentration) values for the example compounds listed in the table are expected to be well below 5 pM.Table 1. Preliminary antimalarial activities against the Plasmodium falciparum Kelch 13 C580Y strain.

[0201] Viability %

[0202] Example Structure

[0203] (5 hM)

[0204] CH3

[0205] JLH

[0206] 2HA YS1

[0207] Q'O / O / OZO 33.87

[0208] 1 |

[0209] 4 22.31

[0210] I I

[0211] 3 16.68

[0212] HQ'X / X / V'O

[0213] CH3.

[0214] |_i J

[0215] 6 23.86

[0216] CH3

[0217] CBD U< ON 40.17

[0218] HX 40

[0219] i s Oh

[0220] CBG ^-4^. X--^> Z. X-0XX’ZA'-Vx-lx. 52.44

[0221]

[0222] Further investigations:

[0223] The antimalarial activity of the compounds was confirmed by further in vitro and in vivo studies:

[0224] The study aimed to identify antimalarial lead compounds through systematic in vitro and in vivo assessment. The preliminary antimalarial evaluation of the compounds was performed against Plasmodium falciparum (31)7 sensitive and Dd2 resistant strains), followed by their safety assessment using cytotoxicity profile and hemolysis assays. Further the IC50 determination assay and efficacy validation in a Plasmodium berghei ANKA mouse model were performed for the selected potent compounds of the series.

[0225] Methods:

[0226] Parasite culture: Pf3D7, PfDd2 and PfINDO were cultured by following procedure reported by Trager and Jensen (Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science, 1971, 193 (4254), 673-675). SYBR green I based fluorescence assay was performed to measure the growth inhibition effect of the compounds and further dose dependent assay was carried out at different concentrations (Makler, M. T. & Hinrichs, D. J. Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. Amer. J. Trop. Med. Hyg., 1993, 48(2), 205-210).

[0227] Hemolytic activity: Human RBCs were from Rotary Blood Bank, Delhi, India. Effect of compounds on RBCs was checked by hemolytic assay (Evans, B. C. et al. Ex vivo red blood cell hemolysis assay for the evaluation of PH-responsive endosomolytic agents for cytosolic delivery of biomacromolecular drugs. J. Vis. Exp. 2013, 73, e50166).

[0228] In vivo activity: Antiplasmodial activity of the compound was investigated in mice model, Plasmodium berghei ANKA with the help of protocol described previously (Ounjaijean, S., Kotepui, M. & Somsak, V. Antimalarial activity of tinospora baenzigeri against Plasmodium berghei- infected mice. J. Trop. Med. 2019, 2019, 5464519).

[0229] In vitro antiplasmodial activity against Plasmodium falciparum 3D7

[0230] The compounds were screened to identify their efficacy against Pf3D7 at different concentrations (100 pM, 10 pM, 1 pM). Several compounds exhibited dose-dependent growth inhibition against Pf3D7 strain, showing their high therapeutic potential even at lower concentrations (1 pM). At the highest tested concentration of 100 pM, majority of the series, the compound of Example 3, the compound of Example 1, the compound of Example 9, the compound of Example 5, the compound of Example 12, the compound of Example 10,exhibited a total growth inhibition of 100%. When concentrations were reduced to 10 pM, multiple compounds sustained the activity, with the compound of Example 3, the compound of Example 1, the compound of Example 5 showing 100% inhibition. Several compounds also showed remarkable activity at lowest tested concentration of 1 μM, namely the compound of Example 12 with 71% inhibition and the compound of Example 13 with 69.9% inhibition. Table 2. Efficacy against P 3D7 at different concentrations.

[0231] % inhibition % inhibition % inhibition Example at at at

[0232] 100 pM 10 pM 1 pM

[0233] CH3

[0234] LH

[0235] 100 100 67.66568 Example 1

[0236] AJAA CH3

[0237] X i

[0238] 78.03358 77.74129 52.99013 Example 7

[0239] LA HH_ J

[0240] Example 5 100 100 52.54971

[0241] CH3

[0242] A NA

[0243] 94.36971 99.69645 45.22278 Example 8

[0244] I I

[0245] 100 100 41.88162 Example 3

[0246] 1

[0247] Example

[0248] 1 1 99.31881 84.60072 69.89377 13

[0249] 1 100 91.40385 24.77492 Example 9

[0250] r^0

[0251] Example

[0252] 100 97.48699 67.21839 10.

[0253] 0

[0254]

[0255] Example

[0256] 97.7913 91.09056 63.31056 11

[0257] Example

[0258] 100 91.37255 71.12715 12

[0259]

[0260] In vitro antiplasmodial activity against Plasmodium falciparum Dd2

[0261] All the compounds were further screened to identify their efficacy against the chloroquine resistant strain PfDd2 at different concentrations (100 pM, 10 pM, 1 pM). Two compounds of Example 1 and Example 9 showed 100% growth inhibition at 100 pM, while the compound of Example 7 and Example 13 both displayed significant efficacy with more than 90% growth inhibition.

[0262] i Q

[0263] However, variability in the inhibition at different concentrations highlights the need for repeat experiments which are under process.

[0264] \ X \ ( X O ( o

[0265] _J

[0266] Table 3. Antiplasmodial activity against Plasmodium falciparum Dd2 at different concentrations.

[0267] % inhibition % inhibition % inhibition Example at at at

[0268] 100 pM 10 pM 1 pM

[0269] CH3

[0270] Example 1 L 1?'H100 69.90725 5.538744

[0271] CH3

[0272] X 1

[0273] Example 7 L ox92.33265 64.88021 11.47936

[0274] HXXYS

[0275] CH3

[0276] i o

[0277] H _ J

[0278] Example 5 84.22693 67.91278 0.707739

[0279]

[0280] CH3

[0281] u _

[0282] Example 8 1 L'HO 67.45476 59.67733 1.74962

[0283] 1 I

[0284] Example 3 80.86278 62.31943 0

[0285] 1

[0286] Example

[0287] 1 1 90.8788 60.54107 52.3671 13

[0288] Example 9 1 1 100 63.56828 5.003975

[0289] 1^°

[0290] Example

[0291] 59.57325 15.32507 0

[0292] 10

[0293] 0

[0294] Example

[0295] 1 1 47.69343 50.81674 31.19016 11

[0296] Example

[0297] 1 1 70.79078 45.75302 7.26505 12

[0298]

[0299] Cytotoxicity evaluation on HepG2 cells

[0300] The cytotoxicity evaluation of the series on HepG2 human liver cells indicates that all the compounds exhibit high safety profiles, showing significant cell viability at both concentrations (50 pM and 10 pM). At the concentration of 10 pM, majority of the compounds exhibited remarkable biocompatibility, notably the compound of Example 11 (96.7% survival), the compound of Example 9 (89.9% survival), and the compound of Example 8 (89.9% survival). At a higher concentration of 50 pM, all the compounds exhibited survival rates over 55% with the compounds of Example 10 and Example 9 showing the largest safety margins at 79.8% and 78.8% survival, respectively.Table 4. Cytotoxicity of the series on HepG2 human liver cells.

[0301] Example % survival at 10 μM % survival at 50 μM Example 1 73.74061 55.66307

[0302] Example 7 77.32255 67.34264

[0303] Example 5 79.13088 74.78465

[0304] Example 8 89.88846 59.3889

[0305] Example 3 70.95363 58.08805

[0306] Example 13 79.53254 62.83354

[0307] Example 9 89.9293 78.80095

[0308] Example 10 89.25995 79.78825

[0309] Example 11 96.73722 69.29141

[0310] Example 12 87.48561 63.0293

[0311]

[0312] Hemolytic activity on human erythrocytes

[0313] The ideal antimalarial drug should be a "magic bullet": it must kill the Plasmodium parasite inside the red blood cell without damaging the cell itself. The hemolytic activity for the series was assessed by incubating human erythrocytes with compounds at different concentrations (100 μM and 10 μM). All the compounds were identified as non-hemolytic, having very low red blood cell lysis even at higher dosage of 100 μM. This signifies favorable erythrocyte compatibility and implies that the observed antimalarial effects are not attributed to any nonspecific membrane disruption or lysis.

[0314] Table 5. Hemolytic activity on human erythrocytes.

[0315] Example % lysis at 100 μM % lysis at 10 μM

[0316] Example 1 1.501033323 0.427573485

[0317] Example 7 0.678645237 0.565065159

[0318] Example 5 1.201284394 0.506994142

[0319] Example 8 1.494201438 0.866522058

[0320] Example 3 0.49589233 0.506994142

[0321] Example 13 0.730453694 0.817844882

[0322] Example 9 0.580436899 0.439529283

[0323]

[0324] Example 10 0.477104647 0.577020957

[0325] Example 11 0.71906722 0.493615035

[0326] Example 12 0.748672052 0.454901023

[0327]

[0328] In vitro antimalarial activity against Plasmodium falciparum- IC50determination assay The dose response assessment of one of the lead candidate compound of Example 3 against Plasmodium falciparum 3D7 exhibited significant therapeutic efficacy, demonstrating a submicromolar IC50value of 0.3119 μM in the SYBR Green I fluorescence assay (Figure 1. A), whereas confirmatory Giemsa-stained microscopic analysis also showed IC50value of 1.971 μM (Figure 1. B). The constant inhibitory efficacy using independent approaches affirms the compound of Example 3 as promising lead candidate with substantial in vitro activity.

[0329] The half-maximal inhibitory co \n Qcentrations (IC50) of Example 3 along with other potent CBD and CBG derivatives were also evaluated against the chloroquine -sensitive Plasmodium falciparum 3D7 strain and the chloroquine-resistant INDO strain after 48 h of incubation (Table 6.).

[0330] Table 6. Half-maximal inhibitory concentrations of examples against Plasmodium falciparum 3D7 and INDO strains.

[0331] IC50(μg / mL) ± SD

[0332] Example Structure

[0333] Pf3D7 PfINDO

[0334] CBD CBD 1.70 ± 0 1.75 ± 0.21

[0335] 2 CH3

[0336] 0.85 ± 0.07 2.80 ± 0.28

[0337] 6

[0338] 0.60 ± 0 0.85 ± 0.07

[0339] 3 I I

[0340] 0.05 ± 0.03 0.28 ± 0.04

[0341]

[0342]

[0343] In vivo antimalarial activity against Plasmodium berghei (the compound of Example 3) To assess the in vivo antimalarial activity, 7 weeks old, female C57BL / 6 (Black 6) mice, weighing approximately 20 g, were infected with 106Plasmodium berghei-parasitized red blood cells (pRBCs) via intraperitoneal injection. The day of infection is designated as Day 0. The in vivo assessment of one of the lead candidate compound of Example 3 revealed a substantial initial therapeutic effect and slight increase in host survival. The compound of Example 3 achieved approximately 43% inhibition on Day 1, but failed to maintain this suppression revealing its limited in vivo activity. Although, a significant survival advantage was noted, as the treated mice survived until Day 18, indicating slight improvement in mean survival time relative to the untreated control group which had a 100% death by Day 11, suggesting a survival benefit despite limited efficacy, whereas artesunate treatment resulted in long term survival of the host. The results of the in vivo experiments are shown on Figures 2 and 3.

[0344] Conclusion:

[0345] Water solubility tests confirmed that the aqueous solubility of the synthesized derivatives improved by 4 orders of magnitude after salt formation compared to the parent compound (CBD), which is considered a significant enhancement.

[0346] During anti-malarial studies, we identified several compounds with good effects. Most compounds proved to be highly effective against the sensitive 3D7 strain, while several compounds showed promising activity against the chloroquine-resistant Dd2 (and INDO) strain (e g. compounds of Example 1 and 7, as CBD derivatives, and compounds of Example 13 and 9, as CBG derivatives). The antimalarial effect of CBG derivatives is particularly surprising, as there are no examples of antimalarial effect of either CBG or its derivatives in the literature, and according to our studies, CBG had only a weak effect. Based on the studies conducted on the resistant strain (Dd2), the compounds of Example 1 and 7 as CBD derivatives, and the compounds of Example 13 and 9 as CBG derivatives proved to be the most effective, the latter inhibited parasite growth by more than 50% even at the lowestconcentration of 1 μM. Further in vitro and in vivo studies of the most effective derivatives are in progress.

[0347] Cytotoxicity studies and hemolytic activity studies performed on the HepG2 cell line proved that the produced derivatives are safe to use, are non-toxic at the concentrations used (10 μM) and do not destroy red blood cells even at a concentration of 100 μM.

[0348] The IC50 value of the compound of Example 3 was determined by two different methods for the 3D7 strain, both of which yielded promisingly low values (0.3119 μM with SYBR Green I fluorescence assay). For some derivatives, the IC50 value of inhibition was determined for sensitive (3D7) and resistant (INDO) strains. The IC50 value of compound of Example 3 for the INDO strain was also proved to be low, it was 0.65 μM (0.28 μg / ml). In in vivo experiments, the treatment significantly reduced the parasite load during the first few days and extended the survival of the mice by one week.

[0349] The results demonstrate that the synthesized compounds possess promising activity (mostly compounds of Example 1, 7, 9 and 13), certain members of this compound family may be suitable for the development of antimalarial drugs, used either alone or in combination therapy. Their application in combination can be highly advantageous; they may help reduce parasite survival as early as the first few days, enhance the efficacy of the co-administered drug, and allow for dose reduction, thereby minimizing potential side effects.

Claims

Claims1. A compound of formula (I), or a salt thereofwhereinR1isR2is -C2-8alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H,or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R2is -C2-8 alkylene-N+R6R7R8, whereinR6, R7R8are independently from each other Ci-6 alkyl, orR6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;R3is H or -C2-8 alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H,or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R3is -C2-8 alkylene-N+R6R7R8, whereinR6, R7, R8are independently from each other Ci-6 alkylor R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,with the proviso, that wherein R1isI 1J$and R3and R2have the same meaning, thenR2is -C2-3alkylene-NR4R5or C5-salkylene-NR4R5,wherein R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H, - wherein at least one of R4and R5is other than H; or wherein R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R2is -C2-8 alkylene-N+R6R7R8,wherein R6, R7,R8are independently from each other Ci-6 alkyl, or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;and with the further proviso that the compound is not the following:3-(2-aminoethoxy)-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5-pentylphenol, which is of the following structure:

2. The compound according to claim 1, or a salt thereof, wherein R3is H.

3. The compound according to claim 1, or a salt thereof, whereinR3is -C2-8 alkylene-NR4R5,wherein R4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H,or R4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R3is - C2-8 alkylene-N+R6R7R8wherein R6, R7R8are independently from each other Ci-6 alkyl or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;and R2and R3have the same meaning.

4. The compound according to any one of claims 1 to 3, or a salt thereof, wherein R1is[ I., HHV5. The compound according to any one of claims 1 to 3, or a salt thereof, wherein R1isJ-X.-’v -Asv,x x / 6. The compound according to any one of claims 1 to 5, or a salt thereof, wherein R2and / or R3is -Ci-7alkylene-CH2-NR4R5or -Ci-7alkylene-CH2-N+R6R7R8, wherein R4R5, R6, R7and R8are as defined in claim 1.

7. The compound according to any one of claims 1 to 6, or a salt thereof, wherein R2and / or R3is C2-3alkylene-NR4R5or C2-3 alkylene-N+R6R7R8,wherein R4R5, R6, R7and R8are as defined in claim 1.

8. The compound according to any one of claims 1 to 7, or a salt thereof, whereinR2and / or R3are selected from the following:wherein R4and R5are independently from each other Ci-6 alkyl,R’ is H or Ci-6 alkyl;R”, R’” are independently from each other H or Ci-6 alkyl;n” is an integer selected from 0, 1, or 2;n’” is an integer selected from 1, 2, 3, 4 and 5;n is an integer selected from 1, 2, 3, 4, and 5,n’ is an integer selected from 0, 1, 2, and 3,X" is a pharmaceutically acceptable counterion, X" is for example Cl" or Br", R6, R7, R8are independently from each other Ci-6 alkyl or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N.

9. The compound according to any one of claims 1 to 7, or a salt thereof, wherein R2and / or R3are selected from the following:

10. The compound according to claim 1, which is selected from the following: / N\ or a salt thereof.

11. Pharmaceutical composition, which contains a compound according to any one of claims 1 to 10, or a salt thereof, and one or more pharmaceutically acceptable excipients.

12. The compound according to any one of claims 1 to 10, or a salt thereof for use as a medicament.

13. A compound of formula (I), or a salt thereofwhereinR1isR2is -C2-8alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H, orR4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R2is -C2-8 alkylene-N+R6R7R8, whereinR6, R7’ R8are independently from each other Ci-6 alkyl, or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;R3is H or -C2-8 alkylene-NR4R5, whereinR4and R5are independently from each other H, Ci-6 alkyl, Ci-6 alkylene-NR”R”’, wherein R” and R’” are independently from each other Ci-6 alkyl or H, orR4and R5together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N,or R3is -C2-8 alkylene-N+R6R7R8, whereinR6, R7, R8are independently from each other Ci-6 alkyl,or R6is Ci-6 alkyl and R7and R8together with the nitrogen atom form a 4- to 7-membered heterocycle, which optionally contains one or more additional heteroatoms selected from O, S, and N;or a compound according to any one of claims 1 to 10 or a salt thereof, for use in the treatment of malaria.

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