【WO2019196965A2】一种治疗恶性黑色素瘤的药物制剂【专利】

)((51)International Patent Classification:A61K 31/404(2006.01)A61K 31/519(2006.01)Declarations under Rule 4.17:A61K 31/426(2006.01)A61K 31/551(2006.01)—as to the identity o f the inventor (Rule 4.17(i))A61K 31/496(2006.01)A61P 35/00(2006.01)—as to applicant's entitlement to apply for and be granted a A61K 31/506(2006.01)patent (Rule 4.17(H))(21)International Application Number:Published:PCT/CZ2019/000018—without international search report and to be republished upon receipt o f that report (Rule 48.2(g))(22)International Filing Date:10April 2019(10.04.2019)(25)Filing Language:English (26)Publication Language:English (30)Priority Data:PV 2018-18111April 2018(11.04.2018)CZ (71)Applicant:UNIVERZITA KARLOVA [CZ/CZ];Ovoc-ny trh 560/5,CZ-11636Praha 1(CZ).(72)Inventor:VACHTENHEIM,Jiri;Janskeho 2233/57,CZ-15500Praha (CZ).(74)Agent:GUTTMANN,Michal et al.;Rott,Ruzicka &Guttmann a spol.,Vyskocilova 1566,14000Praha 4(CZ).(81)Designated States (unless otherwise indicated,for everykind o f national protection available):AE,AG,AL,AM,AO,AT,AU,AZ,BA,BB,BG,BH,BN,BR,BW,BY,BZ,CA,CH,CL,CN,CO,CR,CU,CZ,DE,DJ,DK,DM,DO,DZ,EC,EE,EG,ES,FI,GB,GD,GE,GH,GM,GT,HN,HR,HU,ID,IL,IN,IR,IS,JO,JP,KE,KG,KH,KN,KP,KR,KW,KZ,LA,LC,LK,LR,LS,LU,LY,MA,MD,ME,MG,MK,MN,MW,MX,MY,MZ,NA,NG,NI,NO,NZ,OM,PA,PE,PG,PH,PL,PT,QA,RO,RS,RU,RW,SA,SC,SD,SE,SG,SK,SL,SM,ST,SV,SY,TH,TJ,TM,TN,TR,TT,TZ,UA,UG,US,UZ,VC,VN,ZA,ZM,ZW.(84)Designated States (unless otherwise indicated,for everykind o f regional protection available):ARIPO (BW,GH,GM,KE,LR,LS,MW,MZ,NA,RW,SD,SL,ST,SZ,TZ,UG,ZM,ZW),Eurasian (AM,AZ,BY,KG,KZ,RU,TJ,TM),European (AL,AT,BE,BG,CH,CY,CZ,DE,DK,EE,ES,FI,FR,GB,GR,HR,HU,IE,IS,IT,LT,LU,LV,MC,MK,MT,NL,NO,PL,PT,RO,RS,SE,SI,SK,SM,TR),OAPI (BF,BJ,CF,CG,Cl,CM,GA,GN,GQ,GW,KM,ML,MR,NE,SN,TD,TG).(54)Title:PHARMACY PREPARATION FOR MALIGNANT MELANOMA TREATMENT(57)Abstract:The invention relates to a pharmacy preparation for malignant melanoma treatment containing combination of active ingredients,being GANT61,Obatoclax with the advantage of its mesylate salt,and agent selected from the group comprising (+)-JQ1,SGI-7079,GSK343,GSK126,HA15,wherein concentration of active ingredients in the specific triple-combination necessary to eradicate tumor cells is as follows:a)GANT61from 10to 20pmol/l;b)Obatoclax from 150to 300nmol/1;cl)(+)-JQ 1from 125to 500nmol/1;c2)SGI-7079from 125to 500nmol/1;c3)GSK343from 0.25to 1,0pmol/l;c4)GSK126from 25to 100nmol/1;and c5)HA15from 2.5to 10pmol/l.All triple-combinations are highly effective in the experiments carried-out on cell cultures of human melanoma cells,when all tumor cells were eradicated not later than 7th day after application.Pharmacy Preparation for Malignant Melanoma TreatmentField of the Invention:The invention relates to a pharmacy preparation for malignant melanoma treatment by combining three known active ingredients.The application generally solves the issue of targeted treatment for tumor cells.Specifically,the issue of annihilation of cells of one type of tumor(melanoma)is addressed,employing a synergic combination of active ingredients, described below in the application.Background of the Invention:Targeted treatment for neoplastic diseases means treatment by an active chemical(and/or chemicals),certified for use in human medicine by a state authority,for instance by the American agency FDA(Food and Drug Administration)or a transnational agency such as EMEA.In addition,consent granted by Statni stav pro kontrolu leciv(SUKL-State Institute for Drug Control)must be sought to medical use of active ingredients in the Czech Republic. So far,in the vast majority of cases only one compound has been used both for targeted treatment and clinical studies of the stage I-IV(immediately preceding the treatment),for example,an inhibitor of some cell signaling pathway,an inhibitor of function of mutated oncogene,an inhibitor of epigenetic regulation,an inhibitor of anti-apoptotic proteins etc. Currently,more than100,000various chemical inhibitors exist with at least marginal(though statistically significant)negative effect on growth of tumor cells(and/or directly eradicating cells predominantly by apoptosis)in the experimental testing.However,many fewer ingredients(ca.200-300)were used and tested(either experimentally in cell cultures, preclinical studies in immunodeficient so-called nude mice as well as clinical studies carried out directly on patients treated with any tumor).Nevertheless,resistance is the problem of clinical use of single ingredient,acquired ordinarily after several months of“successful”treatment,in essence each time(exceptionally,a tumor is inherently resistant to medication from the very beginning,which cannot be identified without experimental verification).For instance,resistance to vemurafenib or dabrafenib,used to inhibit activity of BRAF oncogene mutation,is typical.Mutations of this oncogene(“driver mutations”)are recognized in malignant melanoma approximately in6%of cases(1).NRA.S represents another typically mutated oncogene in melanoma,approximately in15%of cases。