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(12) Patent Application Publication (10) Pub. No.: US 2016/0120874 A1 Pérez Simón Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0120874 A1 Pérez Simón Et Al 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 cannabinoid 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 : : U266/WN 48 : : CNT O5 A uk Of 2O is 50 in ~. U266/WI N96h ?------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ CN NA 1ONA Fig. 2 Patent Application Publication May 5, 2016 Sheet 2 of 5 US 2016/O120874 A1 ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ U266/WNAFACS-48h 80 6 O CN O5u. i Cu, 2OW SON 8.----------------------------------i Fig. 3 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- : T T AAS/WIN-48 OO 68 OO -k: 4. O Patent Application Publication May 5, 2016 Sheet 3 of 5 US 2016/O120874 A1 assssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss AWS/WIN -96h 1OW 50 Fig. 5 CD34+ y WN-3h 2Ou O Fig. 6A Patent Application Publication May 5, 2016 Sheet 4 of 5 US 2016/O120874 A1 CD64. A WIN-18h §8$º CN Q5 uM uNA 10 UNA 2OuNN 5ONN *--------------------------------------------~~~~-----------------------------------------------------------------------------------------------------------------------------------------* Fig. 6B CD45+ / WIN-18h ;--~~~~~~;~~~~~~~;~~~~~~;~~~~~~;~~~~~~~;~~~~~ Fig. 6C Patent Application Publication May 5, 2016 Sheet 5 of 5 US 2016/O120874 A1 120 C38+ / WIN-8h IOO : 60 40 : CK O5uM LN 10 N. 2ON 50 W Fig. 6D US 2016/O120874 A1 May 5, 2016 AGENTS FOR TREATING MULTIPLE 0010. Therefore, in another preferred embodiment of the MYELOMA first aspect of the invention the natural cannabinoid agent is a cannabigerol (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; cannabigerolic acid 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 (+)-cannabichromene CBC-Cs; (+)-cannab characterized by clonal proliferation of plasma cells. ichromenic acid A CBCA-CA; (+)-cannabichromevarin 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 cannabidiol (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.; (-)-cannabidivarin 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 cannabinodiol (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 tetrahydrocannabinol (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 cannabinol A-THC-Cs: A Tetrahydrocannabinol-CA for the prevention and/or treatment of a monoclonal gamm THC-C, A-Tetrahydrocannabivarin 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 receptor 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 cannabivarin 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, cannabielsoin (CBE) 10S, 10aR)-9,10-Dihydroxy-hexahydrocannabinol, agents, isocannabinoid agents, cannabicyclol (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
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