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US 2016O120874A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0120874 A1 Pérez Simón et al. (43) Pub. Date: May 5, 2016

(54) AGENTS FOR TREATING MULTIPLE Publication Classification MYELOMA (51) Int. Cl. (71) Applicant: SERVICIO ANDALUZ. DE SALUD, A613 L/5383 (2006.01) Sevilla (ES) A6II 45/06 (2006.01) (72) Inventors: José Antonio Pérez Simón, Sevilla (ES); (52) U.S. Cl. Maria Victoria Barbado González, CPC ...... A6 IK3I/5383 (2013.01); A61K 45/06 Sevilla (ES) (2013.01)

(21) Appl. No.: 14/897,333 (57) ABSTRACT (22) PCT Fled: Jun. 13, 2014 The present invention relates to the use of compounds of a (86) PCT NO.: PCT/ES2O14/070491 nature for inhibiting viability with increasing S371 (c)(1), doses of myeloma cell lines. Furthermore, said compounds (2) Date: Dec. 10, 2015 have been shown not to affect CD34+ cells (normal hemato poietic progenitors) in terms of viability and proliferation. (30) Foreign Application Priority Data For this reason, the invention paves the way for the use of compounds of a cannabinoid nature as a promising therapy Jun. 13, 2013 (ES) ...... P2O133O884 against multiple myeloma and related diseases. Patent Application Publication May 5, 2016 Sheet 1 of 5 US 2016/O120874 A1

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AGENTS FOR TREATING MULTIPLE 0010. Therefore, in another preferred embodiment of the MYELOMA first aspect of the invention the natural cannabinoid agent is a (CBG) type agent, which is selected from the FIELD OF THE INVENTION list consisting of cannabigerol (E)-CBG-Cs; cannabigerol 0001. The present invention is comprised in the field of monomethyl ether (E)-CBGM-CSA; cannabinerolic acid A medicine and the pharmacy and relates to the use of cannab (2)-CBGA-CA; cannabigerovarin (E)-CBGV-C; cannabig inoid agents for preparing a medicinal product for the treat erolic acid A (E)-CBGA-CA; A ment of monoclonal gammopathies in general, and for the monomethyl ether (E)-CBGAM-CSA; cannabigerovarinic treatment of multiple myeloma in particular. acid A(E)-CBGVA-CA, or any combinations thereof. 0011. In another preferred embodiment of the first aspect BACKGROUND OF THE INVENTION of the invention, the natural cannabinoid agent is a cannab ichromene (CBC) type agent, which is selected from the list 0002 Multiple myeloma (MM) is a malignant hemopathy consisting of (+)- CBC-Cs; (+)-cannab characterized by clonal proliferation of plasma cells. ichromenic acid A CBCA-CA; (+)- 0003. The incidence rate of MM is of 4-5 out of 100,000 CBCV-C.; (+)-cannabichromevarinic acid A CBCVA-CA, inhabitants and year. The age of onset is around the 65 years, or any combinations thereof. and although the therapeutic arsenal has been expanded in 0012. In another preferred embodiment, the natural can recent years with the development of new molecules, such as nabinoid agent is a (CBD) type agent, which is proteosome inhibitors or immunomodulatory drugs (IMIDs), selected from the list consisting of: (-)-cannabidiol CBD-Cs: which have been added to conventional treatments such as cannabidiol monomethyl ether CBDM-Cs; cannabidiol melfalan and prednisone, in addition to the hematopoietic CCBD-Ca.; (-)- CBDV-C; cannabidiorcol progenitor cell transplant, MM is still considered an incurable CBD-C; cannabidiolic acid CBDA-Cs; cannabidivarinic disease. acid CBDVA-C, or any combinations thereof. 0004. Therefore, with the treatments available up until 0013. In another preferred embodiment, the natural can now, a five-year survival rate for MM is still low, especially nabinoid agent is a (CBND) type agent, which when compared with other types of cancer. For this reason, is selected from the list consisting of cannabinodiol CBND there is a need to provide alternative treatments with respect Cs; cannabinodivarin CBND-C, or any combinations tO Current treatmentS. thereof. 0014. In another preferred embodiment, the natural can BRIEF DESCRIPTION OF THE INVENTION nabinoid agent is a (THC) type agent, 0005. A first aspect of the invention relates to the use of a which is selected from the list consisting of A-Tetrahydro cannabinoid agent in the preparation of a medicinal product A-THC-Cs: A Tetrahydrocannabinol-CA for the prevention and/or treatment of a monoclonal gamm THC-C, A- A-THCV-C.; A-Tet opathy. In a preferred embodiment, the monoclonal gamm rahydrocannabiorcol A-THCO-C; opathy is selected from the list consisting of multiple A-Tetrahydrocannabinolic acid A A-THCA-Cs A: A-tet myeloma, plasma cell leukemia, Waldenström macroglobu rahydrocannabinolic acid B A-THCA-CSB; A-tetrahydro linemia and amyloidosis. In an even more preferred embodi cannabinolic acid-CA and/or BA-THCA-CA and/or B; ment, the monoclonal gammopathy is multiple myeloma. A-tetrahydrocannabivarinic acid A A-THCVA-CA; A-tet 0006. In another preferred embodiment of the first aspect rahydrocannabiorcolic acid A and/or BA-THCOA-CA and/ of the invention, the cannabinoid agent is selected from natu or B: (-)--trans (6aR, 10aR)-A-Tetrahydrocannabinol ral cannabinoid agents or synthetic cannabinoid agents. In A-THC-Cs: (-)-A-trans-(6aR.10aR)-tetrahydrocannabin another preferred embodiment, the synthetic cannabinoid olic acid A A-THCA-Cs A: (-)-(6aS,10aR)-A-tetrahydro agent is selected from a CB1 receptoragonist, a CB2 cannabinol (-)-cis-A-THC-Cs, or any combinations thereof. agonist, or a mixed agonist. 0015. In another preferred embodiment, the natural can 0007. In another more preferred embodiment, the syn nabinoid agent is an agent of the cannabinol (CBN) type, thetic cannabinoid agent is selected from the list consisting which is selected from the list consisting of cannabinol of: HU-308; JWH-133; L-759,633; PRS 211,375; AM-1241: CBN-Cs; cannabinol-C CBN-C CBN-C: JWH-015; L-759, 656; GW-842, 166X; GP-1a: THC (tet cannabinol-C2 CBN-C; cannabiorcol CBN-C; cannabin rahydrocannabinol); HU-210; L-759, 656: WIN 55,212-2: olic acid ACBNA-CA; cannabinol methyl ether CBNM-Cs. CP 55940; CRA-13; SAB-378; JWH-018 (AM-678); CP or any combinations thereof. 50,556-1 (levonantradiol); cannabidiol--THC, or any combi 0016. In another preferred embodiment, the natural can nations thereof. nabinoid agent is a cannabitriol (CBT) type agent, which is 0008 More preferably, the cannabinoid agent is WIN selected from the list consisting of: (-)-(9R,1OR)-trans-can 55,212-2. nabitriol (-)-trans-CBTC; (+)(9S,10S)-Cannabitriol (+)- 0009. In another preferred embodiment of the first aspect trans-CBTC; (+)-(9R,10S/9S. 10R)-Cannabitriol (+)-cis of the invention, the cannabinoid agent is natural and is CBT-Cs: (-)-(9R,10R)-trans-10-O-Ethyl-cannabitriol (-)- selected from the list consisting of cannabigerol (CBG) type trans-CBT-CEt-Cs; (+)-(9R,10R/9S,10S)-Cannabitriol-C, agents, cannabichromene (CBC) type agents, cannabidiol (+)-trans-CBTC; 8.9-Dihydroxy-A'-tetrahydrocan (CBD) type agents, cannabinodiol (CBND) type agents, tet nabinol 8.9-Di-OH-CBT-Cs; cannabidiolic acid A can rahydrocannabinol (THC) type agents, cannabinol (CBN) nabitriol ester CBDA-C9-OH-CBT-C ester: (-)-(6aR.9S, type agents, cannabitriol (CBT) agents, (CBE) 10S, 10aR)-9,10-Dihydroxy-hexahydrocannabinol, agents, isocannabinoid agents, (CBL) type Cannabiripsol Cannabiripsol-Cs: (-)-6a, 7,10"Trihydroxy agents, cannabicitran (CBT) type agents, cannabichro A-tetrahydrocannabinol (-)-Cannabitetrol; 10-Oxo-A' manone (CBCN) type agents, or any combinations thereof. tetrahydrocannabinol OTHC, or any combinations thereof. In US 2016/O120874 A1 May 5, 2016

another preferred embodiment, the natural cannabinoid agent Thalidomide, Doxyrubicin, Bortezomid, Mozobil, granulo is an agent of the cannabielsoin (CBE) type, which is selected cyte colony-stimulating factor, pomailidomide, carfizomid, from the list consisting of: (5aS,6S-9R.9aR)-Cannabielsoin or any combinations thereof. CBE-C; (5aS,6S,9R,9aR)-C-Cannabielsoin CBE-C; (5aS, 0024. In another preferred embodiment, the combined 6S,9R,9aR)-cannabielsoic acid A CBEA-C. A.; (5aS,6S.9R, preparation of the invention furthermore comprises a phar 9aR)-cannabielsoic acid B CBEA-C. B; (5aS,6S,9R,9aR)- maceutically acceptable carrier. In another preferred embodi C-cannabielsoic acid B CBEA-C B: Cannabiglendol ment, the combined preparation of the invention furthermore COH-iso-HHCV-C. Dehydrocannabifuran DCBF-Cs: comprises another active ingredient. Cannabifuran CBF-Cs, or any combinations thereof. 0017. In another preferred embodiment, the natural can BRIEF DESCRIPTION OF THE DRAWINGS nabinoid agent is an agent of the isocannabinoid type, which (0025 FIG. 1: Myeloma cell line U266 was incubated at is selected from the list consisting of: (-)-A7-trans-(1R,3R, the indicated concentrations with the cannabinoid WIN 6R)-Isotetrahidrocannabinol; (+)-A-1,2-cis-(1R,3R,6S/1S, 55-212.2 for 48 h, and cell viability was determined by means 3S,6R)-Isotetrahidrocannabivarin; (-)-A-trans (1R,3R,6R)- of MTT metabolization. The mean proliferation values of the Isotetrahidrocannabivarin, or any combinations thereof. untreated control cell cultures were taken as 100%. The data 0018. In another preferred embodiment, the natural can corresponds to the means+/-the standard deviation of the nabinoid agent is an agent of the cannabicyclol (CBL) type, triplicates of each of the 4 assays performed. U266 cell viabil which is selected from the list consisting of: (+)-(1 aS.3aR, ity significantly drops (p<0.05) to concentrations of 10 uM 8bR,8cR)-Cannabicyclol CBL-Cs; (+)-(1aS.3aR,8bR,8cR)- and 20 uM to 40%, whereas cell viability inhibition reaches cannabicyclolic acid A CBLA-C A; (+)-(1aS.3aR,8bR. 60% at concentrations of 50 uM. 8cR)-Cannabicyclovarin CBLV-C, or any combinations 0026 FIG. 2: This figure develops the data exemplified in thereof. FIG. 1 and shows how at longer times longer incubation times, 96 h, the drop in cell viability reaches 80% at concen 0019. In another preferred embodiment, the natural can trations of 50 uM. nabinoid agent is an agent of the Cannabicitran (CBL) type, (0027 FIG. 3: The cell viability of line U266 after treat which is selected from the list consisting of Cannabicitran ment for 48 h with the cannabinoid agent was also determined CBTCs, or any combinations thereof. by flow cytometry by means of labeling with 7AAD. The 0020. In another more preferred embodiment, the natural results obtained were similar to those detected with the MTT cannabinoid agent is an agent of the Cannabichromanone assay. As seen in the figure, the cannabinoid has a cytotoxic (CBCN) type, which is selected from: Cannabichromanone effect on cells from concentrations of 10 uM, and this drop in CBCN-Cs; Cannabichromanone-C3: CBCN-C; Cannabi cell viability is significant (p<0.05) according to the Stu coumaronone CBCON-C5, or any combinations thereof. dent's t statistical analysis. 0021. A second aspect of the present invention relates to (0028 FIG. 4: The myeloma cell line MM1.S was incu the use of a pharmaceutical composition comprising one of bated at increasing concentrations with the cannabinoid WIN the cannabinoid agents described in the present invention for 55-212.2 and cell viability was determined by means of the preparing a medicinal product for the prevention and/or treat MTT metabolization. The mean proliferation values of the ment of a monoclonal gammopathy. More preferably, the untreated control cell cultures were taken as 100%. The data monoclonal gammopathy is selected from the list consisting corresponds to the means+/-the standard deviation of the of multiple myeloma, plasma cell leukemia, Waldenström triplicates of each of the 4 assays performed. At incubation macroglobulinemia and amyloidosis. In an even more pre times of 48 h, the cell viability of line MM1.S noticeably ferred embodiment, the monoclonal gammopathy is multiple dropped after concentrations of 10 uM, 20 uM and 50 uM, myeloma. with a cytotoxicity greater than 50%. (0029 FIG. 5: This figure develops the data exemplified in 0022. More preferably, the composition of the second FIG. 4 and shows that when the cell line is treated with the aspect of the invention furthermore comprises another active cannabinoid for longer incubation times (96 h), cell viability ingredient. Even more preferably the active ingredient is is also affected at the same doses of WIN 55-212.2; neverthe selected from the list consisting of Velcade, Melfalan, Pred less this drop is lower than at short incubation times. nisone, Revlimd, Dextamethasone, Thalidomide, Doxyrubi 0030 FIG. 6: CD34+ cells, hematopoietic progenitors (A) cin, Bortezomid, MoZobil, granulocyte colony-stimulating were isolated from peripheral blood, and the cytotoxicity of factor, pomailidomide, carfizomid, or any combinations WIN was determined by the MTT assay after 18 h of incuba thereof. Even more preferably, the pharmaceutical composi tion. The primary cultures of bone marrow were incubated for tion comprises a pharmaceutically acceptable carrier. 18h with the cannabinoid at the same concentrations used in 0023. Another aspect of the invention relates to the use of the preceding assays. The population of polymorphonuclear a combined preparation comprising a cannabioid agent of the cells (B) was identified with anti-CD64, and it was observed invention and another active ingredient in the preparation of a that the cell viability of this population determined by means medicinal product for the simultaneous or sequential com of labeling with 7AAD was not affected by the cannabinoid. bined administration thereof for the treatment of a mono After ex vivo treatment for 18 h with the cannabinoid agent, clonal gammopathy. More preferably, the monoclonal gam it can be seen that the cell viability of the population of mopathy is selected from multiple myeloma, plasma cell lymphocytes (C) in the primary culture of the bone marrow, leukemia, Waldenström macroglobulinemia, amyloidosis, or CD45+, is affected at the concentration of 50 uM, dropping any combinations thereof. In an even more preferred embodi by 40%. However, the population of plasma cells (D) is dras ment, the monoclonal gammopathy is multiple myeloma. tically reduced after incubation at doses of 20 uM and 50 uM, Even more preferably, the active ingredient is selected from the cell viability of this population being reduced in the latter Velcade, Melfalan, Prednisone, Revlimd, Dextamethasone, case by more than 80%. US 2016/O120874 A1 May 5, 2016

DETAILED DESCRIPTION OF THE INVENTION results are illustrated in FIG.3 and as can be seen, said results 0031 Multiple myeloma (MM) is a neoplasia character are very similar to those described above in FIGS. 1 and 2. ized by the clonal proliferation of malignant plasma cells in 0037. Therefore, due to the results described in FIGS. 1 to the bone marrow and is associated with the presence of a 3, it can clearly be determined how the cell viability of estab monoclonal component or protein M in blood and/or serum. lished myeloma cell lines drops significantly (p<0.05) at con 0032 For the purpose of obtaining an effective therapy centrations greater than 10 uMboth at 48 hours and at longer against this disease, the authors of the present invention have incubation times. Surprisingly found that compounds of a cannabinoid nature are capable of inhibiting viability with increasing doses of 0038. For the purpose of verifying the preceding data, the myeloma cell lines, whereas CD34+ cells (normal hemato authors of the present invention analyzed the capacity of the poietic progenitors), granulocytes and lymphocytes are not compound WIN 55,212-2 to inhibit viability of a second affected in terms of viability and proliferation. Therefore, this myeloma cell line, in this case multiple myeloma cell line invention paves the way for the use of compounds of a can MM1.S. The results of these experiments have been faithfully nabinoid nature as a promising therapy against multiple reflected in FIGS. 4 and 5. myeloma and related diseases. 0033. In order to carry out the present finding, the authors 0039. In this sense, in order to carry out these assays the of the present invention assessed whether the cannabinoid authors incubated the myeloma cell line MM1.S at different compound called WIN 55,212-2 with the following chemical concentrations with the cannabinoid agent WIN 55-212.2 for formula (R)-(+)-2,3-Dihydro-5-methyl-3-(4-morpholinyl 48 and 96 hours, and cell viability was determined by means methyl)pyrrolo 1,2,3-de-1.4 benzoxazin-6-yl)-1-naphtal of MTT metabolization. Mean proliferation values of enylmethanone, CAS number 131543-23-2, and structure (I): untreated control cell cultures were taken as 100%. The data corresponds to the means+/-the standard deviation of the triplicates of each of the 4 assays performed. As can be seen Structure (I) in FIGS. 4 and 5, cell viability noticeably dropped after con centrations greater than 1 uM when MM1.S cells were incu bated for 48 hours. Cell viability also drops after 96 hours of exposure to the drug at the same concentrations. It can be deduced from this data that cell line MM1.S is more sensitive to WIN 55,212-2 than cell line U266. This data allows assur ing the potentiality of compound WIN 55,212-2 as an effec tive therapy for the treatment of multiple myeloma and of related diseases. 0040 Finally, the authors of the present invention evalu ated the toxicity of cannabinoid agent WIN 55,212-2, which was determined in terms of cell viability by means of two was capable of inhibiting the viability of established types of assays, one based on the drop in 3(4.5dimethyl-2- myeloma cell lines, such as the myeloma cell line U266 and thiazoyl)-2,5-diphenyltetrazolic bromide (MTT), and the multiple myeloma cell line MM1.S. It is observed that another one based on the interaction of 7AAD. Primary cul compound WIN 55,212-2 is a non-specificagonist of the CB1 tures of mononuclear cells obtained from peripheral blood and CB2 cannabinoid receptors. from healthy donors (CD34+ hematopoietic progenitors) and 0034. In order to determine the effect of the cannabinoid from bone marrow of patients Suffering multiple myeloma compound WIN 55,212-2, myeloma cell line U266 was incu bated for a period of 48 and 96 hours with increasing concen (CD64+, granulocytes (B), CD45+, lymphocytes (C) and trations of WIN 55,212-2 between 0.5 and 50 uM; cell viabil CD38+, plasma cells (D)) were used. ity was determined by means of the MTT metabolization. The 0041 CD34+ hematopoietic progenitor cells were iso MTT assay is based on the capacity of the mitochondrial lated from apheresis of healthy donors by immunomagnetic enzyme. Succinate dehydrogenase, of viable cells for trans methods. To that end, the cells were incubated for 30 minat4° forming the tetrazolium salt MTT into a blue-colored prod C. with magnetic microspheres bound to the anti-CD34 anti uct, MTT formazan, which is proportional to the number of body. Subsequently the cells were selected by means of an living cells present. The mean proliferation values of the immunomagnetic separator, and Subsequently cultured in untreated control cell cultures were taken as 100%. multiwell plates at a cell density of a million cells per milli 0035. As can be seen in FIG.1, concentrations between 10 liter of supplemented RPMI medium plus 20% fetal bovine uM and 20 uM of the compound WIN 55.212-2 were capable of inhibiting cell viability by about 40%, and concentrations serum (FBS). of 50 uM produced an inhibition of cell viability of about 0042. The plasma cells, granulocytes and lymphocytes 60%. Additionally, as seen in FIG. 2, longer incubation peri were obtained from bone marrow samples from patients with ods, specifically 96 hours, produced cell viability inhibition multiple myeloma after hypotonic lysis with ammonium of about 80% at concentrations of 50 uM. chloride (0.16 M in 0.17 M Tris, pH 7.6) for 10 min at room 0036. These same assays were repeated incubating the temperature, for the purpose of removing the erythrocyte cell myeloma cell line U266 for a period of 48 hours with increas population. The cell Suspension resulting from lysis, which ing concentrations of WIN 55.212-2 between 0.5 and 50 uM. only contains mononuclear cells, was seeded in multiwell Nevertheless, cell viability was determined by means of flow plates at the same cell density as the progenitor cells using cytometry instead of by means of MTT metabolization; the supplemented RPMI medium plus 20% fetal bovine serum. US 2016/O120874 A1 May 5, 2016

0043. The primary cultures were incubated in the presence and absence of the cannabinoid agent WIN 55,212-2 at dif Formula (I) ferent concentrations. The range of concentrations assayed with agent WIN 55,212-2 was 0.5-50 micromol. The incuba tion times of the primary cultures in the presence or absence of the cannabinoid agent were 12 or 18 hours. 0044 As can clearly be seen in FIGS. 6A-6D, cell viability was not affected in the populations of hematopoietic progeni tors (A) and granulocytes (B). In the population of lympho cytes (C), loss of viability was only detected at the highest dose. However, WIN produces a drastic drop in the cell viabil ity of plasma cells (D) when they are treated at doses greater than 10 uM. 0045. These results demonstrate that the use of agonist or any pharmaceutically acceptable salts, Solvates and pro compounds of CB1 and/or CB2 cannabinoid receptors, par drugs of said compound. ticularly WIN 55,212-2, show not only cytoxicity against 0051. The term “pharmaceutically acceptable salts and established myeloma cell lines but also that these compounds Solvates' refers to any pharmaceutically acceptable salt, have a low toxicity profile, which paves the way for the use ester, Solvate, or any other compound which, when adminis thereofas a promising therapy against multiple myeloma and tered, is capable of providing (directly or indirectly) a com related diseases. Therefore, an CB1 receptor agonist agent, a pound such as the one described herein. Nevertheless, it will CB2 receptor agonist, or a mixed agonist can be used in the be observed that pharmaceutically unacceptable salts also fall preparation of a medicinal product for the prevention and/or within the scope of the invention, since Such salts can be treatment of a monoclonal gammopathy, particularly for the useful for the preparation of pharmaceutically acceptable prevention and/or treatment of multiple myeloma, plasma salts. The preparation of salts, prodrugs and derivatives can be cell leukemia, Waldenström macroglobulinemia and amyloi carried out by means of methods known in the state of the art. dosis. 0.052 For example, the pharmaceutically acceptable salts of the compounds provided herein are synthesized from the 0046) Therefore, a first aspect of the invention relates to compound of the invention by means of conventional chemi the use of an agent of a cannabinoid nature in the preparation cal methods. In general, such salts are prepared, for example, of a medicinal product for the prevention and/or treatment of by reacting the acid or free base forms of these compounds a monoclonal gammopathy. In a preferred embodiment, the with a stoichiometric amount of the base or the acid suitable monoclonal gammopathy is selected from the list consisting in water or in a solvent organic or in a mixture of both. In of multiple myeloma, plasma cell leukemia, Waldenström general, non-aqueous media Such as ether, ethyl acetate, etha macroglobulinemia and amyloidosis. nol, isopropanol oracetonitrile are preferred. Examples of the acid addition salts include addition salts of mineral acids Such 0047. In another preferred embodiment, the cannabinoid as, for example, hydrochloride, hydrobromide, hydroiodide, agentis selected from natural cannabinoid agents or synthetic Sulfate, nitrate, phosphate, and addition salts of organic acids cannabinoid agents. In another preferred embodiment, the Such as, for example, acetate, maleate, fumarate, citrate, agent of a cannabinoid nature is selected from a CB1 receptor oxalate. Succinate, tartrate, malate, mandelate, methane agonist, a CB2 receptor agonist, or a mixed agonist. Sulfonate and p-toluenesulfonate. 0048. In another more preferred embodiment, the syn 0053 Examples of alkali addition salts include inorganic thetic cannabinoid agent is selected from the list consisting salts such as, for example, sodium, potassium, calcium, of: HU-308; L-759, 633; PRS 21 1375; AM-1241; 2-(3- ammonium, magnesium, aluminum and lithium, and organic methylcylohexyl)-5-(1,1-dimethylheptyl)-resorcinol iso alkali salts such as, for example, ethylenediamine, ethanola mers (0 to 1,797 and 0-1798): 2-(3R-methylcylohexyl)-5-(1,- mine, N.Ndialkylenethanolamine, glucamine and basic 'dimethylheptyl)-resorcinol (0-1826); bicyclic hydroxyl amino acid salts. resorcinol derivatives: 1-4-(1,1-Dimethyl-heptyl)-2,6- 0054 Particularly preferred derivatives or prodrugs are dimethoxy-phenyl-3-methyl-cyclohexanol (0 to 2137, those which increase the bioavailability of the compounds of 0-1966, 0-1967); JWH-015; L-759, 656; GW-842, 166X; the invention when these compounds are administered to the GP-1 as THC, HU-210; L-759, 656: WIN 55,212-2; CP Subject (for example, those which allow an orally adminis 55940; CRA-13 (SAB-378); JWH-018 (AM-678) CP tered compound to be absorbed more quickly in the blood) or 50,556-1 (), cannabidiol--THC, or any combi which improve the delivery of the compound to a biological nations thereof. compartment (for example, the brain or lymphatic system) 0049 More preferably, the cannabinoid agent is WIN with respect to the initial compound. 55,212-2. 0055. In another preferred embodiment, the cannabinoid 0050 WIN 55,212-2 is understood in this specification as agent is natural and is selected from the list consisting of a compound having IUPAC (International Union of Pure and cannabigerol (CBG) type agents, cannabichromene (CBC) Applied Chemistry) (R)-(+)-2,3-Dihydro type agents, cannabidiol (CBD) type agents, cannabinodiol 5-methyl-3-(4-morpholinylmethyl)pyrrolo 1,2,3-de-1.4 (CBND) type agents, tetrahydrocannabinol (THC) type benzoxazin-6-yl)-1-naphtalenylmethanone, CAS number agents, cannabinol (CBN) type agents, cannabitriol (CBT) 131543-23-2, and formula (I): agents, cannabielsoin (CBE) agents, isocannabinoid agents, US 2016/O120874 A1 May 5, 2016 cannabicyclol (CBL) type agents, cannabicitran (CBT) type Cannabiripsol Cannabiripsol-Cs: (-)-6a,7,10' Trihydroxy agents, cannabichromanone (CBCN) type agents, or any A-tetrahydrocannabinol (-)-Cannabitetrol; 10-Oxo-A' combinations thereof. tetrahydrocannabinol OTHC, or any combinations thereof. 0056. In another more preferred embodiment, the natural 0063. In another more preferred embodiment, the natural cannabinoid agent is a cannabigerol (CBG) type agent, which cannabinoid agent is a cannabielsoin (CBE) type agent, is selected from the list consisting of cannabigerol (E)-CBG which is selected from the list consisting of: (5aS,6S.9R, Cs; cannabigerol monomethyl ether (E)-CBGM-CSA; can 9aR)-Cannabielsoin CBE-Cs; (5aS,6S-9R.9aR)-C-Canna nabinerolic acid A (2)-CBGA-Cs A: cannabigerovarin (E)- bielsoin CBE-C; (5aS,6S,9R,9aR)-cannabielsoic acid A CBGV-C; cannabigerolic acid A (E)-CBGA-C. A. CBEA-C. A.; (5aS,6S,9R,9aR)-cannabielsoic acid B CBEA cannabigerolic acid A monomethyl ether (E)-CBGAM-Cs A: CSB; (5aS,6S-9R.9aR)-C-cannabielsoic acid B CBEA-CB; cannabigerovarinic acid A(E)-CBGVA-C, A, or any combi Cannabiglendol-C, OH-iso-HHCV-C. Dehydrocannabifu nations thereof. ran DCBF-Cs; Cannabifuran CBF-Cs, or any combinations 0057. In another more preferred embodiment, the natural thereof. cannabinoid agent is a cannabichromene (CBC) type agent, 0064. In another more preferred embodiment, the natural which is selected from the list consisting of (+)-cannab cannabinoid agent is a isocannabinoid type agent, which is ichromene CBC-Cs; (+)-cannabichromenic acid ACBCA-Cs selected from the list consisting of: (-)-A7-trans-(1R,3R,6R)- A; (+)-cannabichromevarin CBCV-C.; (+)-cannabichrom isotetrahydrocannabinol; (+)-A-1,2-cis-(1R,3R,6S/1S.3S, evarinic acid A CBCVA-CA, or any combinations thereof. 6R)-Isotetrahydro-cannabivarin; (-) A"-trans (1R,3R,6R)- 0058. In another more preferred embodiment, the natural Isotetrahydrocannabivarin, or any combinations thereof. cannabinoid agent is a cannabinodiol (CBND) type agent, 0065. In another more preferred embodiment, the natural which is selected from the list consisting of: (-)-cannabidiol cannabinoid agent is a cannabicyclol (CBL) type agent, CBD-Cs; cannabidiol monomethyl ether CBDM-Cs; canna which is selected from the list consisting of (+)-(1aS.3aR, bidiol-CCBD-Ca.; (-)-cannabidivarin CBDV-C; canna 8bR,8cR)-Cannabicyclol CBL-C; (+)-(1aS,3aR,8bR,8cR)- bidiorcolpaw www wwwwa CBD-C; cannabidiolic acid cannabicyclolic acid A CBLA-C A; (+)-(1aS.3aR.8bR. CBDA-Cs; cannabidivarinic acid CBDVA-C, or any combi 8cR)-Cannabicyclovarin CBLV-C, or any combinations nations thereof. thereof. 0059. In another more preferred embodiment, the natural 0066. In another more preferred embodiment, the natural cannabinoid agent is a cannabinodiol (CBND) type agent, cannabinoid agent is a Cannabicitran (CBL) type agent, which is selected from the list consisting of cannabinodiol which is selected from the list consisting of Cannabicitran CBND-Cs; cannabinodivarin CBND-C, or any combina CBTCs, or any combinations thereof. tions thereof. 0067. In another more preferred embodiment, the natural 0060. In another more preferred embodiment, the natural cannabinoid agent is an agent of the Cannabichromanone cannabinoid agent is a tetrahydrocannabinol (THC) type (CBCN) type, which is selected from the list consisting of: agent, which is selected from the list consisting of A-Tet Cannabichromanone CBCN-Cs; Cannabichromanone-C: rahydrocannabinol A-THC-Cs: A Tetrahydrocannabinol CBCN-C; Cannabicoumaronone CBCON-Cs, or any com CA-THC-C, A-Tetrahydrocannabivarin A-THCV-C. binations thereof. A- A-THCO-C: A-Tetrahydro 0068 A second aspect of the invention relates to the use of cannabinolic acid AA-THCA-CA; A-tetrahydrocannabin a pharmaceutical composition comprising a cannabinoid olic acid BA-THCA-Cs B; A-tetrahydrocannabinolic acid agent described in the present invention for preparing a C. A and/or B: A-THCA-C, A and/or B; medicinal product for the prevention and/or treatment of a A-tetrahydrocannabivarinic acid AA-THCVA-CA; A-tet monoclonal gammopathy. More preferably, the monoclonal rahydrocannabiorcolic acid A and/or BA-THCOA-dA and/ gammopathy is selected from the list consisting of multiple or B: (-)-A-trans (6aR.10aR)-A-Tetrahydrocannabinol myeloma, plasma cell leukemia, Waldenström macroglobu A-THC-Cs: (-)-A-trans-(6aR.10aR)-tetrahydrocannabin linemia and amyloidosis. olic acid A A-THCA-CSA: (-)-(6aS,10aR)-A-tetrahydro 0069. More preferably, the composition furthermore com cannabinol (-)-cis-A-THC-Cs, or any combinations thereof. prises another active ingredient. Even more preferably the 0061. In another more preferred embodiment, the natural active ingredient is selected from Velcade, Melfalan, Pred cannabinoid agent is a cannabinol (CBN) type agent, which is nisone, Revlimd, Dextamethasone, Thalidomide, Doxyrubi selected from the list consisting of cannabinol CBN-Cs: cin, Bortezomid, MoZobil, granulocyte colony-stimulating cannabinol-CCBN C; cannabivarin CBN-C cannab factor, pomailidomide, carfizomid, or any combinations inol-CCBN C; cannabiorcol CBN-C; cannabinolic acid thereof. Even more preferably the pharmaceutical composi A CBNA-CA; cannabinol methyl ether CBNM-Cs, or any tion comprises a pharmaceutically acceptable carrier. combinations thereof. 0070 Another aspect of the invention relates to the use of 0062. In another more preferred embodiment, the natural a combined preparation comprising a cannabinoid agent of cannabinoid agent is a cannabitriol (CBT) type agent, which the invention and another active ingredient in the preparation is selected from the list consisting of: (-)-(9R,10R)-trans of a medicinal product for the simultaneous or sequential cannabitriol (-)-trans-CBT-Cs; (+) (9S.10S)-Cannabitriol combined administration thereof for the treatment of a mono (+)-trans-CBT-Cs; (+)-(9R,10S/9S. 10R)-Cannabitriol (+)- clonal gammopathy. More preferably, the monoclonal gam cis-CBT-Cs: (-)-(9R,10R)-trans-10-O-Ethyl-cannabitriol mopathy is selected from multiple myeloma, plasma cell (-)-trans-CBT-CEt-C; (+)-(9R,10R/9S,10S)-Cannabitriol leukemia, Waldenström macroglobulinemia, amyloidosis, or C(+)-trans-CBT-C; 8.9-Dihydroxy-'-tetrahydrocan any combinations thereof. In an even more preferred embodi nabinol 8.9-Di-OH-CBT-Cs; cannabidiolic acid A can ment, the monoclonal gammopathy is multiple myeloma. nabitriol ester CBDA-C 9-OH-CBT-C ester: (-)-(6aR.9S, Even more preferably the active ingredient is selected from 10S, 10aR)-9,10-Dihydroxy-hexahydrocannabinol, Velcade, Melfalan, Prednisone, Revlimd, Dextamethasone, US 2016/O120874 A1 May 5, 2016

Thalidomide, Doxyrubicin, Bortezomid, Mozobil, granulo or transdermal administration include, but are not limited to, cyte colony-stimulating factor, pomailidomide, carfizomid, iontophoresis, Sonophoresis, electroporation, mechanical or any combinations thereof. pressure, osmotic pressure gradient, occlusive cure, microin 0071. In another preferred embodiment, the combined jections, needle-free injections by means of pressure, micro preparation of the invention furthermore comprises a phar electric patches and any combination thereof. Illustrative maceutically acceptable carrier. In another preferred embodi examples of pharmaceutical dosage forms by oral adminis ment, the combined preparation of the invention furthermore tration include tablets, capsules, granules, Solutions, Suspen comprises another active ingredient. sions, etc., and can contain conventional excipients, such as 0072. As it is used in the context of this specification, the binders, diluents, disintegrants, lubricants, humectants, etc., term “treatment’ means the administration of a compound and can be prepared by conventional methods. The pharma according to the invention to alleviate or eliminate the afore ceutical compositions also can be adapted for the parenteral mentioned pathology or to reduce or eliminate one or more administration thereof in the form of, for example, sterile symptoms associated with said pathology. lyophilized solutions, Suspensions or products in the Suitable 0073. The term “treatment also covers alleviating or dosage form; in this case, said pharmaceutical compositions eliminating the physiological sequelae of the disease. will include Suitable excipients, such as buffers, Surfactants, 0074 As it is used herein, the term “prevention” refers to etc. In any case, the excipients will be chosen depending on the capacity of a compound of the invention to prevent, mini the selected pharmaceutical dosage form. A review of the mize or hinder the onset or the development of a disease or different pharmaceutical dosage forms of drugs and of the state before onset. preparation thereof can be found in the book “Tratado de 0075. The compounds of the invention can be in crystal Farmacia Galénica.” by C. Faul1 Trillo, 10th Edition, 1993, line form as free compounds or Solvates, and both forms are Luzan 5, S.A. de Ediciones. intended to be within the scope of the present invention. I0081. As it is used herein, the term “active ingredient.” Solvation methods are generally known in the art. Suitable “active substance.” “pharmaceutically active substance.” or Solvates are pharmaceutically acceptable Solvates. In a par “pharmaceutically active ingredient’ means any component ticular embodiment, the solvate is a hydrate. that potentially provides pharmacological activity or another 0076. The compounds of the invention or the salts or sol different effect in the diagnosis, cure, mitigation, treatment, vates thereofare preferably in a pharmaceutically acceptable or prevention of a disease, or that affects structure or function form or in a substantially pure form. Pharmaceutically of the body of humans or other animals. The term includes acceptable form is understood, interalia, as having a pharma those components that promote a chemical change in the ceutically acceptable level of purity, excluding normal phar preparation of the drug and are present therein in a modified maceutical additives, such as diluents and excipients, and form envisaged for providing the specific activity or effect. without including any material considered toxic at normal I0082. The compositions of the present invention as well as dosage levels. The levels of purity for the compound of the the combined preparation can beformulated for the adminis invention are preferably above 50%, more preferably above tration thereof to an animal, and more preferably to a mam 70%, and even more preferably above 90%. In a preferred mal, including humans, in a variety of forms known in the embodiment, it is above 95% of the compound of the inven state of the art. Therefore, it can be, without limitation, in a tion, or of the salts, Solvates or prodrugs thereof. sterile aqueous solution or in biological fluids such as serum. 0077. The compounds of the present invention can include The aqueous solutions can be buffered or not buffered and enantiomers depending on the presence of chiral centers or have additional active or inactive components. The additional isomers depending on the presence of multiple bonds (for components include Salts for modulating the ionic force, pre example, Z, E). Individual isomers, enantiomers or diastere servatives including, but not limited to, antimicrobial agents, omers and mixtures thereofare within the scope of the present antioxidant agents, chelating agents and the like, and nutri invention. When a compound with explicit stereochemistry is ents including , dextrose, vitamins and minerals. drawn, the intention is to depict the racemic structure with the Alternatively, the compositions can be prepared for the relative stereochemistry, as well as the enantiomers in differ administration thereof in solid form. The compositions can be ent degrees of purity. In any case, the enantiomers and the combined with several inert excipients or carriers, including diastereoisomers of the compounds depicted with a particular but not limited to, binders such as microcrystalline cellulose, Stereochemistry are also part of the compounds of the inven tragacanth gum, or gelatin; excipients such as starch or lac tion. tose; dispersing agents such as alginic acid or corn starch; 0078 Said compositions can have one or more cannab lubricants such as magnesium Stearate; glidants such as col inoid agents. Said cannabinoid agents could be combined at loidal silicon dioxide; Sweetening agents such as or identical or different proportions, and they could be part of the saccharine; or flavoring agents such as mint or methyl sali same formulation or be formulated in different formulations cylate. for the sequential, combined or simultaneous administration I0083. As it is used in this specification, the term “medici thereof. nal product” refers to any substance used for the prevention, 0079. In another preferred embodiment, the composition diagnosis, alleviation, treatment or curing of diseases in of the invention furthermore comprises a pharmaceutically humans and animals. In the context of the present invention, acceptable carrier. In another preferred embodiment, the the disease is a disease presenting with uncontrolled prolif composition of the invention furthermore comprises another eration of plasma cells in bone marrow; it is preferably a active ingredient. multiple myeloma. 0080. The pharmaceutical compositions of the invention I0084. Such combined preparations or compositions and/ are administered by topical, transdermal, oral, nasal, intra or the formulations thereof can be administered to an animal, muscular, intravenous, intraperitoneal, Subcutaneous, enteral including a mammal, and therefore to humans, in a variety of or parenteral administration. Illustrative examples of topical forms, including, but not limited to, intraperitoneal, intrave US 2016/O120874 A1 May 5, 2016

nous, intramuscular, Subcutaneous, intrathecal, intraventricu density was determined at 450 nm in a plate spectrophotom lar, oral, enteral, parenteral, intranasal or dermal. eter. All the assays were performed in triplicate. 0085. The dosage for obtaining a therapeutically effective amount depends on a range of factors, such as, for example, Viability Analysis by Flow Cytometry the age, weight, sex, tolerance of the mammal. In the sense 0093. For the viability analysis by means of flow cytom used in this description, the expression “therapeutically effec etry, the cells were treated with suitably labeled monoclonal tive amount” refers to the amount of agent or cannabinoid antibodies for the identification of each of the cell types used. agents producing the desired effect, and it will generally be Once labeled; the cells were exposed for 15 minto 7AAD determined, between other causes, by the characteristics of (7-actinomycin D) to evaluate cell viability; the reading was said prodrugs, derivatives or analogues and the therapeutic performed in the cytometer and analyzed with the computer effect to be achieved. The “pharmaceutically acceptable car program adapted for the cytometer. At least 100,000 events riers' and “adjuvants' that can be used in said compositions were acquired, and the mean fluorescence intensity was are those carriers known by persons skilled in the art. obtained. I0086. Another aspect of the invention relates to the use of a dosage form comprising a cannabinoid agent described in the preceding aspects of the invention, in the preparation of a Statistical Analysis medicinal product for the prevention and/or treatment a 0094. The data obtained in the plate spectrophotometer monoclonal gammopathy. and in the cytometer were analyzed quantitatively by com 0087. In a preferred embodiment of this aspect of the parison with the Student's t-test using the statistical program invention, the monoclonal gammopathy is multiple myeloma. SPSS. The results were considered statistically significant 0088. In another preferred embodiment, the combined when p<0.05. preparation of the invention furthermore comprises a phar maceutically acceptable carrier. In another preferred embodi Example 2 ment, the combined preparation of the invention furthermore comprises another active ingredient. Cytoxicity of Cannabinoid Compound WIN 0089. It must be stressed that the term “combined prepa 55.212-2 in Myeloma Cell Line U266 ration' or also juxtaposition' in this specification means that 0.095 To determine the effect of cannabinoid compound the components of the combined preparation do not have to be WIN 55,212-2, myeloma cell line U266 was incubated for a present as a combination, for example in a composition, to be period of 48 and 96 hours with increasing concentrations of available for the separate or sequential application thereof. WIN 55,212-2 between 0.5 and 50 uM; cell viability was Therefore, the expression “juxtaposed’ means that it is not determined by means of MTT metabolization. The MTT necessarily a real combination in view of the physical sepa assay is based on the capacity of the mitochondrial enzyme, ration of the components. Succinate dehydrogenase, of viable cells to transform tetra 0090 Throughout the description and claims the word Zolium salt MTT into a blue-colored product, formazan MTT, “comprises” and variants thereofdo not seek to exclude other which is proportional to the number of living cells present. technical features, additives, components or steps. For the Mean proliferation values of untreated control cell cultures persons skilled in the art, other objects, advantages and fea were taken as 100%. tures of the invention will be understood in part from the 0096. As can be seen in FIG.1, concentrations between 10 description and in part from putting the invention into prac and 20 uM of the compound WIN 55,212-2 were capable of tice. The following examples and drawings are provided by inhibiting cell viability by about 40%, and concentrations of way of illustration and does not seek to be limiting of the 50 uM produced cell viability inhibition of about 60%. Addi present invention. tionally, as reflected in FIG. 2, longer incubation periods, specifically of 96 hours, produced cell viability inhibition of EXAMPLES about 80% at concentrations of 50 uM. 0097. These same assays were repeated, incubating Example 1 myeloma cell line U266 for a period of 48 hours with increas ing concentrations of WIN55.212-2 between 0.5 and 50 uM. Materials and Methods Nevertheless, cell viability was determined by means of flow cytometry instead of by means of MTT metabolization. The MTT Assay Viability Analysis results are illustrated in FIG.3 and as can be seen, such results 0091. The method for the determination of cell viability by are very similar to those already described above in FIGS. 1 means of the MTT assay is based on the capacity that viable and 2. cells have of metabolizing 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazol (MTT) bromide. The metabolic reduction of Example 3 MTT due to the action of the mitochondrial enzyme, succi nate dehydrogenase, gives rise to the insoluble and colored Cytoxicity of Cannabinoid Compound WIN form called formazan, which can be quantified by means of 55.212-2 in Multiple Myeloma Cell Line MM1.S spectrocolorimetry. The amount of living cells is proportional 0098. For the purpose of verifying the results described in to the optical density resulting. Example 1, the authors of the present invention analyzed the 0092. After incubation with , 10 microliters capacity of the compound WIN 55,212-2 to inhibit viability of MTT were added to each well and were incubated 2-4 of a second myeloma cell line, in this case multiple myeloma hours in the same conditions. The reaction is Subsequently cell line MM1.S. The results of these experiments have been stopped, the crystallized formazan is solubilized and optical faithfully reflected in FIGS. 4 and 5. US 2016/O120874 A1 May 5, 2016

0099. In this sense, in order to carry out these assays the cytes (C) loss of viability was only detected at the highest authors incubated myeloma cell line MM1.Sat different con dose. However, WIN produced a drastic a drop in cell viabil centrations with the cannabinoid agent WIN 55-212.2 for 48 ity of plasma cells (D) when treated a doses greater than 10 and 96 hours, and cell viability was determined by means of uM. MTT metabolization. Mean proliferation values of untreated 0105. These results demonstrate that the use of CB1 and/ control cell cultures were taken as 100%. The data corre or CB2 agonist compounds, particu sponds to the means +/- the standard deviation of the tripli larly WIN 55,212-2, show not only cytoxicity against estab cates of each of the 4 assays performed. As can be seen in lished myeloma cell lines, but also these compounds have a FIGS. 4 and 5, cell viability noticeably dropped after concen low toxicity profile, which paves the way for the use thereof trations greater than 1 uM when MM1.S cells were incubated as a promising therapy against multiple myeloma and related for 48 hours. Cell viability also drops after 96 hours of expo diseases. Sure to the drugay the same concentrations. It can be deduced 1. Use of a cannabinoid agent for preparing a medicinal from this data that cell line MM1.S is more sensitive to WIN product for the prevention and/or treatment of a monoclonal 55.212-2 than cell line U266. This data allows asserting the gammopathy. potential of compound WIN 55,212-2 as effective therapy for 2. The use of a cannabinoid agent according to the preced the treatment of multiple myeloma and of related diseases. ing claim, where the monoclonal gammopathy is selected from multiple myeloma, plasma cell leukemia, Waldenström Example 4 macroglobulinemia, amyloidosis, or any combinations thereof. Cytoxicity of Cannabinoid Compound WIN 3. The use of a cannabinoid agent according to either claim 55.212-2 on Mononuclear Cells Obtained from 1 or 2, where the monoclonal gammopathy is multiple Peripheral Blood of Healthy Donors (CD34+ myeloma. Hematopoietic Progenitors) and from Bone Marrow 4. The use of a cannabinoid agent according to any of of Patients Suffering Multiple Myeloma (CD64+, claims 1-3, where the cannabinoid agent is a CB1 receptor Granulocytes (B), CD45+, Lymphocytes (C) V agonist, a CB2 receptor agonist, or a mixed agonist. CD38+, Plasma Cells (D)) 5. The use of a cannabinoid agent according to either claim 0100. The authors of the present invention evaluated the 4 or 5, where the cannabinoid agent is selected from the list toxicity of cannabinoid agent WIN 55,212-2, which was consisting of: determined in terms of cell viability by means of two types of HU-308;JWH-133; L-759,633; PRS 211,375 (also known assays, one based on the drop in 3(4.5dimethyl-2-thiazoyl)- as ); AM-1241; JWH-015; L-759, 656; 2,5-diphenyltetrazolic (MTT) bromide, and another one GW-842, 166X; GP-1 a: THC (Tetrahydrocannabinol): based on the interaction of the 7AAD. Primary cultures of HU-210; L-759, 656: WIN 55,212-2; CP 55940; CRA mononuclear cells obtained from peripheral blood of healthy 13; SAB-378; JWH-018 (also known as AM-678); CP donors (CD34+ hematopoietic progenitors) and from bone 50,556-1 (levonantradol), or any combinations thereof. marrow of patients suffering multiple myeloma (CD64+, 6. The use of a cannabinoid agent according to claim 5. granulocytes (B), CD45+ lymphocytes (C) and CD38+, where the cannabinoid agent is WIN 55,212-2 or any salts or plasma cells (D)) were used. solvates thereof. 0101 CD34+ hematopoietic progenitor cells were iso 7. The use of a cannabinoid agent according to claim 5. lated from healthy donors using apheresis by immunomag where the cannabinoid agent is WIN 55,212-2 or any salts or netic methods. To that end, the cells were incubated for 30 Solvates thereof, and where the monoclonal gammopathy is min at 4°C. with microspheres magnetic bound to the anti multiple myeloma. CD34 antibody. Subsequently the cells were selected by 8. The use of a cannabinoid agent according to claim 4. means of an immunomagnetic separator and then cultured in where the cannabinoid agent is selected from the list consist multiwell plates at a cell density of million cells per milliliter ing of cannabigerol (CBG) type agents, cannabichromene of supplemented RPMI medium plus 20% fetal bovine serum (CBC) type agents, cannabidiol (CBD) type agents, cannab (FBS). inodiol (CBND) type agents, tetrahydrocannabinol (THC) 0102 The plasma cells, granulocytes and lymphocytes type agents, cannabinol (CBN) type agents, cannabitriol were obtained from bone marrow samples from patients with (CBT) agents, cannabielsoin (CBE) agents, isocannabinoid multiple myeloma after hypotonic lysis with ammonium agents, cannabicyclol (CBL) type agents, cannabicitran chloride (0.16 M in 0.17 M Tris, pH 7.6) for 10 min at room (CBT) type agents, cannabichromanone (CBCN) type temperature, for the purpose of removing the erythrocyte cell agents, or any combinations thereof. population. The cell Suspension resulting from lysis, which 9. The use of a cannabinoid agent according to claim 8. only contains mononuclear cells, was seeded in multiwell where the cannabinoid agent of the cannabigerol (CBG) type plates at the same cell density as the progenitor cells using is selected from the list consisting of: cannabigerol (E)-CBG supplemented RPMI medium plus 20% fetal bovine serum. Cs; cannabigerol monomethyl ether (E)-CBGM-C A; can 0103) The primary cultures were incubated in the presence nabinerolic acid A (2)-CBGA-Cs A: cannabigerovarin (E)- and absence of cannabinoid agent WIN 55.212-2 at different CBGV-C; cannabigerolic acid A (E)-CBGA-Cs A: concentrations. The range of concentrations assayed with the cannabigerolic acid A monomethyl ether (E)-CBGAM-CA: agent WIN 55,212-2 was 0.5-50 micromol. The incubation cannabigerovarinic acid A(E)-CBGVA-C A, or any combi times of the primary cultures in the presence or absence of the nations thereof. cannabinoid agent were 12 or 18 hours. 10. The use of a cannabinoid agent according to claim 8. 0104. As can clearly be seen in FIGS. 6A-6D, cell viability where the cannabinoid agent of the type cannabichromene was not affected in the populations of hematopoietic progeni (CBC), is selected from the list consisting of (+)-cannab tors (A) and granulocytes (B). In the population of lympho ichromene CBC-Cs; (+)-cannabichromenic acid A CBCA-Cs US 2016/O120874 A1 May 5, 2016

A; (+)-cannabichromevarin CBCV-C.; (+)-cannabichrom A: (5aS,6S,9R,9aR)-cannabielsoic acid B CBEA-C B; (5aS, evarinic acid A CBCVA-C A, or any combinations thereof. 6S,9R,9aR)-C-cannabielsoic acid B CBEA-CB; Cannabig 11. The use of a cannabinoid agent according to claim 8. lendol-COH-iso-HHCV-C. Dehydrocannabifuran DCBF where the cannabinoid agent of the cannabidiol (CBD) type is Cs; Cannabifuran CBF-Cs, or any combinations thereof. selected from the list consisting of: (-)-cannabidiol CBD-Cs: 17. The use of a cannabinoid agent according to claim 8. cannabidiol monomethyl ether CBDM-Cs; cannabidiol where the cannabinoid agent of the isocannabinoid type, is CCBD-Ca.; (-)-cannabidivarin CBDV-C; cannabidiorcol selected from the list consisting of: (-)-A-trans-(1R,3R,6R)- CBD-C; cannabidiolic acid CBDA-Cs; cannabidivarinic Isotetrahydrocannabinol; (+)-A7-1,2-cis-(1R,3R,6S/1S.3S, acid CBDVA-C, or any combinations thereof. 6R)-Isotetrahydrocannabivarin; (-)-A-trans (1R,3R,6R)- 12. The use of a cannabinoid agent according to claim 8. Isotetrahydrocannabivarin, or any combinations thereof. where the cannabinoid agent of the cannabinodiol (CBND) 18. The use of a cannabinoid agent according to claim 8. type is selected from the list consisting of cannabinodiol where the cannabinoid agent of the cannabicyclol (CBL) type CBND-Cs; cannabinodivarin CBND-C, or any combina is selected from the list consisting of (+)-(1aS.3aR.8bR. tions thereof. 8cR)-Cannabicyclol CBL-Cs; (+)-(1aS.3aR,8bR.8cR)-Can 13. The use of a cannabinoid agent according to claim 8. nabicyclolic acid A CBLA-C A; (+)-(1aS.3aR.8bR.8cR)- where the cannabinoid agent of the tetrahydrocannabinol Cannabiciclovarin CBLV-C, or any combinations thereof. (THC) type is selected from the list consisting of A-Tetrahy 19. The use of a cannabinoid agent according to claim 8. drocannabinol A-THC-Cs; ATetrahydrocannabinol-C where the cannabinoid agent of the Cannabicitran (CBL) type A-THC-C, A-Tetrahydrocannabivarin A-THCV-C.; is selected from the list consisting of Cannabicitran CBT-Cs. A-Tetrahydrocannabiorcol A-THCO-C1: A-Tetrahydro or any combinations thereof. cannabinolic acid A A-THCA-Cs A: A-tetrahydrocannab 20. The use of a cannabinoid agent according to claim 8. inolic acid B A-THCA-Cs B: A-tetrahydrocannabinolic where the cannabinoid agent of the Cannabichromanone acid-CA and/or BA-THCA-CA and/or B: A-tetrahydro (CBCN) type is selected from the list consisting of Cannab cannabivarinic acidAA-THCVA-CA; A-tetrahydrocanna ichromanone CBCN-Cs; Cannabichromanone-C3: CBCN biorcolic acidA and/or BA-THCOA-CA and/or B: (+-trans C: Cannabicoumaronone CBCON-Cs, or any combinations (6aR.10aR)-A-Tetrahydrocannabinol A-THC-Cs: (-)-A- thereof. trans-(6aR.10aR)-tetrahydrocannabinolic acid A A-THCA 21. Use of a composition comprising a cannabinoid agent CA: (-)-(6aS,10aR)-A-tetrahydrocannabinol (-)-cis-A- as defined in any of claims 4-20 in the preparation of a THC-Cs, or any combinations thereof. medicinal product for the prevention and/or treatment of a 14. The use of a cannabinoid agent according to claim 8. monoclonal gammopathy. where the cannabinoid agent of the cannabinol (CBN) type is 22. Use of a composition according to claim 21, where the selected from the list consisting of cannabinol CBN-Cs: composition is a pharmaceutical composition optionally cannabinol-CCBN C; cannabivarin CBN-C cannab comprising one or more pharmaceutically acceptable excipi inol-CCBN-C; cannabiorcol CBN-C; cannabinolic acid A entS. CBNA-C. A.; cannabinol methyl ether CBNM-Cs, or any 23. Use of a combined preparation comprising a cannab combinations thereof. inoid agent as defined in any of claims 4-20 and another active 15. The use of a cannabinoid agent according to claim 8. ingredient Suitable for the treatment of a monoclonal gamm where the cannabinoid agent of the cannabitriol (CBT) type is opathy in the preparation of a medicinal product for the simul selected from the list consisting of: (-)-(9R,10R)-trans-can taneous or sequential combined administration thereof for the nabitriol (-)-trans-CBT-Cs; (+) (9S. 10S)-Cannabitriol (+)- treatment of a monoclonal gammopathy. trans-CBTC; (+)-(9R,10S/9S. 10R)-Cannabitriol (+)-cis 24. The use of a combined preparation according to the CBT-Cs: (-)-(9R,10R)-trans-10-O-Ethyl-cannabitriol (-)- preceding claim, where the monoclonal gammopathy is trans-CBT-CEt-Cs; (+)-(9R,10R/9S,10S)-Cannabitriol-C, selected from multiple myeloma, plasma cell leukemia, (+)-trans-CBT-C; 8.9-Dihydroxy-A'-tetrahydrocan Waldenström macroglobulinemia, amyloidosis, or any com nabinol 8.9-Di-OH-CBT-Cs; cannabidiolic acid A can binations thereof. nabitriol ester CBDA-C-9-OH-CBT-C ester: (-)-(6aR.9S, 25. The use of a combined preparation according to either 10S, 10aR)-9,10-Dihydroxy-hexahydrocannabinol, claim 23 or 24, where the monoclonal gammopathy is mul Cannabiripsol Cannabiripsol-Cs: (-)-6a, 7,10' Trihydroxy tiple myeloma. A-tetrahydrocannabinol (-)-Cannabitetrol; 10-Oxo-A' 26. The use of a combined preparation according to any of tetrahydrocannabinol OTHC, or any combinations thereof. claims 23-25, where the active ingredient is selected from 16. The use of a cannabinoid agent according to claim 8. Velcade, Melfalan, Prednisone, Revlimd, Dextamethasone, where the cannabinoid agent of the cannabielsoin (CBE) type Thalidomide, Doxyrubicin, Bortezomid, Mozobil, granulo is selected from the list consisting of: (5aS,6S.9R,9aR)-Can cyte colony-stimulating factor, pomailidomide, carfizomid, nabielsoin CBE-Cs; (5aS,6S.9R.9aR)-C-Cannabielsoin or any combinations thereof. CBE-C; (5aS,6S.9R.9aR)-cannabielsoic acid A CBEA-Cs k k k k k