NZ724819B2 - Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof - Google Patents
Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof Download PDFInfo
- Publication number
- NZ724819B2 NZ724819B2 NZ724819A NZ72481915A NZ724819B2 NZ 724819 B2 NZ724819 B2 NZ 724819B2 NZ 724819 A NZ724819 A NZ 724819A NZ 72481915 A NZ72481915 A NZ 72481915A NZ 724819 B2 NZ724819 B2 NZ 724819B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- salt
- iii
- compound
- chosen
- alkyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims description 22
- 238000000034 method Methods 0.000 title abstract description 9
- 230000015572 biosynthetic process Effects 0.000 title abstract 3
- 238000003786 synthesis reaction Methods 0.000 title abstract 3
- 102100028662 Sigma intracellular receptor 2 Human genes 0.000 title abstract 2
- 101710109012 Sigma intracellular receptor 2 Proteins 0.000 title abstract 2
- 229940079593 drug Drugs 0.000 title description 17
- 239000003446 ligand Substances 0.000 title description 3
- 230000000259 anti-tumor effect Effects 0.000 title 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 206010042863 synovial sarcoma Diseases 0.000 claims abstract 2
- 150000003839 salts Chemical class 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- -1 anthracycline Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 46
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 8
- 229940041181 antineoplastic drug Drugs 0.000 claims 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 2
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 claims 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims 1
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 claims 1
- 102000015790 Asparaginase Human genes 0.000 claims 1
- 108010024976 Asparaginase Proteins 0.000 claims 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims 1
- 108010006654 Bleomycin Proteins 0.000 claims 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 claims 1
- 108010092160 Dactinomycin Proteins 0.000 claims 1
- ZINBFGBAIFRYSH-UHFFFAOYSA-N Demethoxyviridin Natural products CC12C(O)C(O)C(=O)c3coc(C(=O)c4c5CCC(=O)c5ccc14)c23 ZINBFGBAIFRYSH-UHFFFAOYSA-N 0.000 claims 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims 1
- 108010029961 Filgrastim Proteins 0.000 claims 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims 1
- 108010069236 Goserelin Proteins 0.000 claims 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 claims 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims 1
- 102000014150 Interferons Human genes 0.000 claims 1
- 108010050904 Interferons Proteins 0.000 claims 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims 1
- 108010000817 Leuprolide Proteins 0.000 claims 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims 1
- XOGTZOOQQBDUSI-UHFFFAOYSA-M Mesna Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 claims 1
- 102000029749 Microtubule Human genes 0.000 claims 1
- 108091022875 Microtubule Proteins 0.000 claims 1
- 229930192392 Mitomycin Natural products 0.000 claims 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims 1
- 108010016076 Octreotide Proteins 0.000 claims 1
- 239000012661 PARP inhibitor Substances 0.000 claims 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 claims 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 claims 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims 1
- 229960003437 aminoglutethimide Drugs 0.000 claims 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims 1
- 229960001220 amsacrine Drugs 0.000 claims 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims 1
- 229960002932 anastrozole Drugs 0.000 claims 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims 1
- 229940045799 anthracyclines and related substance Drugs 0.000 claims 1
- 239000002256 antimetabolite Substances 0.000 claims 1
- 229960003272 asparaginase Drugs 0.000 claims 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 claims 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims 1
- 229950005645 barasertib Drugs 0.000 claims 1
- 229960000997 bicalutamide Drugs 0.000 claims 1
- 229960001561 bleomycin Drugs 0.000 claims 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims 1
- 229960002092 busulfan Drugs 0.000 claims 1
- 229960004117 capecitabine Drugs 0.000 claims 1
- 229960004562 carboplatin Drugs 0.000 claims 1
- 229960005243 carmustine Drugs 0.000 claims 1
- 229960004630 chlorambucil Drugs 0.000 claims 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims 1
- 229960003677 chloroquine Drugs 0.000 claims 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims 1
- 229960002436 cladribine Drugs 0.000 claims 1
- 229960002286 clodronic acid Drugs 0.000 claims 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 claims 1
- 238000011260 co-administration Methods 0.000 claims 1
- 229960001338 colchicine Drugs 0.000 claims 1
- 239000003431 cross linking reagent Substances 0.000 claims 1
- 238000000315 cryotherapy Methods 0.000 claims 1
- MKNXBRLZBFVUPV-UHFFFAOYSA-L cyclopenta-1,3-diene;dichlorotitanium Chemical compound Cl[Ti]Cl.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 MKNXBRLZBFVUPV-UHFFFAOYSA-L 0.000 claims 1
- 229960004397 cyclophosphamide Drugs 0.000 claims 1
- 229960003843 cyproterone Drugs 0.000 claims 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 claims 1
- 229960000684 cytarabine Drugs 0.000 claims 1
- 229960003901 dacarbazine Drugs 0.000 claims 1
- 229960000640 dactinomycin Drugs 0.000 claims 1
- 229960000975 daunorubicin Drugs 0.000 claims 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims 1
- SWJBYJJNDIXFSA-KUHUBIRLSA-N demethoxyviridin Chemical compound O=C1C2=C3CCC(=O)C3=CC=C2[C@]2(C)C3=C1OC=C3C(=O)C[C@H]2O SWJBYJJNDIXFSA-KUHUBIRLSA-N 0.000 claims 1
- 229940120124 dichloroacetate Drugs 0.000 claims 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 claims 1
- 229960000452 diethylstilbestrol Drugs 0.000 claims 1
- 229960003668 docetaxel Drugs 0.000 claims 1
- 229960004679 doxorubicin Drugs 0.000 claims 1
- 229960001904 epirubicin Drugs 0.000 claims 1
- 229960005309 estradiol Drugs 0.000 claims 1
- 229930182833 estradiol Natural products 0.000 claims 1
- 229960001842 estramustine Drugs 0.000 claims 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims 1
- 229960005420 etoposide Drugs 0.000 claims 1
- 229960005167 everolimus Drugs 0.000 claims 1
- 229960004177 filgrastim Drugs 0.000 claims 1
- 229960000390 fludarabine Drugs 0.000 claims 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims 1
- 229960002011 fludrocortisone Drugs 0.000 claims 1
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 claims 1
- 229960002949 fluorouracil Drugs 0.000 claims 1
- 229960001751 fluoxymesterone Drugs 0.000 claims 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 claims 1
- 229960002074 flutamide Drugs 0.000 claims 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 claims 1
- 235000008191 folinic acid Nutrition 0.000 claims 1
- 239000011672 folinic acid Substances 0.000 claims 1
- 229960005277 gemcitabine Drugs 0.000 claims 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims 1
- 229940045109 genistein Drugs 0.000 claims 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 claims 1
- 235000006539 genistein Nutrition 0.000 claims 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 claims 1
- 229960002913 goserelin Drugs 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 229960000908 idarubicin Drugs 0.000 claims 1
- 229960001101 ifosfamide Drugs 0.000 claims 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims 1
- 229960002411 imatinib Drugs 0.000 claims 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims 1
- 239000000138 intercalating agent Substances 0.000 claims 1
- 229940079322 interferon Drugs 0.000 claims 1
- 229960004768 irinotecan Drugs 0.000 claims 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 1
- 229960003881 letrozole Drugs 0.000 claims 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims 1
- 229960001691 leucovorin Drugs 0.000 claims 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims 1
- 229960004338 leuprorelin Drugs 0.000 claims 1
- 229960001614 levamisole Drugs 0.000 claims 1
- 229960002247 lomustine Drugs 0.000 claims 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims 1
- 229960004961 mechlorethamine Drugs 0.000 claims 1
- 229960004616 medroxyprogesterone Drugs 0.000 claims 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 claims 1
- 229960001786 megestrol Drugs 0.000 claims 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims 1
- 229960001924 melphalan Drugs 0.000 claims 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims 1
- 229960001428 mercaptopurine Drugs 0.000 claims 1
- 229960004635 mesna Drugs 0.000 claims 1
- 229960000485 methotrexate Drugs 0.000 claims 1
- 210000004688 microtubule Anatomy 0.000 claims 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims 1
- 229960004857 mitomycin Drugs 0.000 claims 1
- 229960000350 mitotane Drugs 0.000 claims 1
- 229960001156 mitoxantrone Drugs 0.000 claims 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims 1
- 230000007524 negative regulation of DNA replication Effects 0.000 claims 1
- 229960002653 nilutamide Drugs 0.000 claims 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims 1
- 229960002700 octreotide Drugs 0.000 claims 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims 1
- 229960000572 olaparib Drugs 0.000 claims 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims 1
- 229960001756 oxaliplatin Drugs 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 229940046231 pamidronate Drugs 0.000 claims 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims 1
- 229960002340 pentostatin Drugs 0.000 claims 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 claims 1
- 229950010632 perifosine Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229960003171 plicamycin Drugs 0.000 claims 1
- 239000002534 radiation-sensitizing agent Substances 0.000 claims 1
- 229960004432 raltitrexed Drugs 0.000 claims 1
- 229960004641 rituximab Drugs 0.000 claims 1
- 229960003787 sorafenib Drugs 0.000 claims 1
- 229960001052 streptozocin Drugs 0.000 claims 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims 1
- 229960001796 sunitinib Drugs 0.000 claims 1
- 229960005314 suramin Drugs 0.000 claims 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 claims 1
- 229960001603 tamoxifen Drugs 0.000 claims 1
- 229960004964 temozolomide Drugs 0.000 claims 1
- 229960000235 temsirolimus Drugs 0.000 claims 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims 1
- 229960001278 teniposide Drugs 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- 229960001196 thiotepa Drugs 0.000 claims 1
- 229960003087 tioguanine Drugs 0.000 claims 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims 1
- 229960000303 topotecan Drugs 0.000 claims 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 1
- 229960000575 trastuzumab Drugs 0.000 claims 1
- 229960001727 tretinoin Drugs 0.000 claims 1
- 238000002604 ultrasonography Methods 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 229960003048 vinblastine Drugs 0.000 claims 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims 1
- 229960004528 vincristine Drugs 0.000 claims 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims 1
- 229960004355 vindesine Drugs 0.000 claims 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 claims 1
- 229960002066 vinorelbine Drugs 0.000 claims 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 32
- 230000004083 survival effect Effects 0.000 abstract description 5
- 230000001939 inductive effect Effects 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 2
- 241000894007 species Species 0.000 abstract 5
- 238000010171 animal model Methods 0.000 abstract 2
- 238000000338 in vitro Methods 0.000 abstract 2
- 238000001727 in vivo Methods 0.000 abstract 2
- 238000010172 mouse model Methods 0.000 abstract 2
- 230000004806 ferroptosis Effects 0.000 abstract 1
- 201000011510 cancer Diseases 0.000 description 25
- 238000003556 assay Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 241001446467 Mama Species 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 230000034994 death Effects 0.000 description 8
- 231100000517 death Toxicity 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 241000238557 Decapoda Species 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- BTIJJDXEELBZFS-QDUVMHSLSA-K hemin Chemical compound CC1=C(CCC(O)=O)C(C=C2C(CCC(O)=O)=C(C)\C(N2[Fe](Cl)N23)=C\4)=N\C1=C/C2=C(C)C(C=C)=C3\C=C/1C(C)=C(C=C)C/4=N\1 BTIJJDXEELBZFS-QDUVMHSLSA-K 0.000 description 5
- 229940025294 hemin Drugs 0.000 description 5
- 230000001817 pituitary effect Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 208000025814 Inflammatory myopathy with abundant macrophages Diseases 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- BKQFRNYHFIQEKN-UHFFFAOYSA-N erastin Chemical compound CCOC1=CC=CC=C1N1C(=O)C2=CC=CC=C2N=C1C(C)N1CCN(C(=O)COC=2C=CC(Cl)=CC=2)CC1 BKQFRNYHFIQEKN-UHFFFAOYSA-N 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 210000000496 pancreas Anatomy 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 210000000952 spleen Anatomy 0.000 description 4
- 239000002775 capsule Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000004392 genitalia Anatomy 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 229910052718 tin Inorganic materials 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 102100037651 AP-2 complex subunit sigma Human genes 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102100030209 Elongin-B Human genes 0.000 description 2
- 235000002917 Fraxinus ornus Nutrition 0.000 description 2
- 244000182067 Fraxinus ornus Species 0.000 description 2
- 101000806914 Homo sapiens AP-2 complex subunit sigma Proteins 0.000 description 2
- 101001011859 Homo sapiens Elongin-A Proteins 0.000 description 2
- 101001011846 Homo sapiens Elongin-B Proteins 0.000 description 2
- 101000881731 Homo sapiens Elongin-C Proteins 0.000 description 2
- 101000836005 Homo sapiens S-phase kinase-associated protein 1 Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 240000003152 Rhus chinensis Species 0.000 description 2
- 235000014220 Rhus chinensis Nutrition 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000010445 mica Substances 0.000 description 2
- 229910052618 mica group Inorganic materials 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 description 2
- 210000003859 smegma Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 2
- IQQRAVYLUAZUGX-UHFFFAOYSA-N 1-butyl-3-methylimidazolium Chemical compound CCCCN1C=C[N+](C)=C1 IQQRAVYLUAZUGX-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- ZOMKCDYJHAQMCU-UHFFFAOYSA-N 4-butyl-1,2,4-triazole Chemical compound CCCCN1C=NN=C1 ZOMKCDYJHAQMCU-UHFFFAOYSA-N 0.000 description 1
- 101150067539 AMBP gene Proteins 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 101100515516 Arabidopsis thaliana XI-H gene Proteins 0.000 description 1
- 229930182670 Astin Natural products 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 1
- 101100042788 Caenorhabditis elegans him-1 gene Proteins 0.000 description 1
- 102000004091 Caspase-8 Human genes 0.000 description 1
- 108090000538 Caspase-8 Proteins 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 241001520656 Creiis Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 241000411902 Dioscorea minima Species 0.000 description 1
- 101100173450 Drosophila melanogaster Gmer gene Proteins 0.000 description 1
- 101100289061 Drosophila melanogaster lili gene Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101150039072 INSA gene Proteins 0.000 description 1
- 241000728904 Iais Species 0.000 description 1
- 201000004029 Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome Diseases 0.000 description 1
- 206010065042 Immune reconstitution inflammatory syndrome Diseases 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- WMFYOYKPJLRMJI-UHFFFAOYSA-N Lercanidipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WMFYOYKPJLRMJI-UHFFFAOYSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- 229910017171 MNH2 Inorganic materials 0.000 description 1
- 241000208467 Macadamia Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 101710150402 Mastin Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100125347 Mus musculus H2ap gene Proteins 0.000 description 1
- 101100237844 Mus musculus Mmp19 gene Proteins 0.000 description 1
- 101100533558 Mus musculus Sipa1 gene Proteins 0.000 description 1
- 102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 238000011887 Necropsy Methods 0.000 description 1
- 241000849798 Nita Species 0.000 description 1
- 241001666145 Noia Species 0.000 description 1
- 241000123069 Ocyurus chrysurus Species 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 235000017284 Pometia pinnata Nutrition 0.000 description 1
- 241000183024 Populus tremula Species 0.000 description 1
- 101100502817 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) fimL gene Proteins 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 101100233916 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) KAR5 gene Proteins 0.000 description 1
- 101000650578 Salmonella phage P22 Regulatory protein C3 Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 101001040920 Triticum aestivum Alpha-amylase inhibitor 0.28 Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 240000003864 Ulex europaeus Species 0.000 description 1
- 235000010730 Ulex europaeus Nutrition 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000000260 Warts Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010048232 Yawning Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 101150117004 atg18 gene Proteins 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 101150026317 cel3 gene Proteins 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940073621 enbrel Drugs 0.000 description 1
- 229940065410 feldene Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009432 framing Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000010437 gem Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002665 ion therapy Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- ZOTBXTZVPHCKPN-HTXNQAPBSA-N kresoxim-methyl Chemical compound CO\N=C(\C(=O)OC)C1=CC=CC=C1COC1=CC=CC=C1C ZOTBXTZVPHCKPN-HTXNQAPBSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000013521 mastic Substances 0.000 description 1
- 229940101532 meted Drugs 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 201000002266 mite infestation Diseases 0.000 description 1
- KRTSDMXIXPKRQR-AATRIKPKSA-N monocrotophos Chemical compound CNC(=O)\C=C(/C)OP(=O)(OC)OC KRTSDMXIXPKRQR-AATRIKPKSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 231100000706 no observed effect level Toxicity 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- LSEKLPKUWRDLKY-UHFFFAOYSA-N protoleucomelone Chemical compound C1=CC(OC(=O)C)=CC=C1C1=C(OC(C)=O)C(OC(C)=O)=C(C=2C(=CC(OC(C)=O)=C(OC(C)=O)C=2)O2)C2=C1OC(C)=O LSEKLPKUWRDLKY-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007665 sagging Methods 0.000 description 1
- 229940063122 sandimmune Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000007103 stamina Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 101150061972 zur gene Proteins 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Abstract
Methods and compositions for treating cancers such as pancreatic cancer and synovial sarcoma are disclosed. Compounds of formula (III) comprising a sigma-2 receptor-binding moiety and a ferroptosis-inducing moiety are described. At least one described molecular species exhibits an IC50 value below 5 μΜ against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed. μΜ against human pancreatic cancer cells in vitro. Administration of this species promoted shrinkage of pancreatic cancer tumors in a murine model system in vivo, and led to 100% survival of experimental animals over a time course in which control therapies provided only 30% or 40% survival. Methods of synthesis of molecular species are also disclosed.
Description
RECEiPTOR 1.1611111?) 13111.1(} 11.11.1(1131'113'43 AS AN'1'1'1‘1'1MUR
{2‘1'311-113‘1'1111‘113S, M1.i‘1'1~i1305 D1" 511111119118 AND {.1 S138 1111?. 111.(.31
{311351; 1119113111131: 111 111311111211 111111111111111113
{111111 133131111011111111 1111111113 1111: 1112111111 1111.? ‘5’. 1317131'1311111111 15111111.1311: No.
131-”m3613 13111111111111'120111, 1.111: 1111111111115 0111111111 1311611311}: 11111011111111.1111. by 112112.11311153.
81111111113111 Regarding131111131‘111’111 5.9131111111111211 Reward: 1711‘ 01111121111111112111
{110121 T1113 119111 1110211111 supper! 3 1:11: 1111111111111 1113111111:- 111 111111115111 1: N111} 11111311
5R 111-111.53.161—1.11.1111: 11.011131111112111 111113“ ;: 1161111111 rights in 1111: 1111121111011.
13111111
{13133} T111:1111136311.1115011111111: 1'81111133 111 513111111113 13101‘12111’11111‘1g 19011311}:1111111
13051117.0113,113111111611appiic11111111 11s 111111111111c1111ica1s 111111112 11111111111111 11111113111131: 111111:
pm‘t‘imiariy, 1211113111111111211111 1111’: 1131111211111 sig111z1~2 1‘121'131111‘11‘ 11~11111g 13111111161118 1111111
51111111113111 111111 1111111 11:11: 1111 1111111111: 11313111111111111111111 111111111.» such as cancar.
13115611111101} 111" 11111311311 1111
{131111} 1’1111131‘1211111: 1311111313113 1111: 111111111 11:11111111: 51: 111 1::111.1:1:1‘1.11:1111, 1111111 1x11111111 11) b1:
£111: 31:1:111111 111111111111 11111151: 1.31, 2113.1]. “1‘11: five-year 1111111111111 1111:: 1'01 11111113121111: 9111311111 13111};
.3% \1’111112111‘1‘1‘3111' 111311111113311 11111111115 11.1111 11.11311: 13 11 desperate 11.111211111111111 11113111111121:
{11115} 8151111112 11361291015 {152R} 1111:111!81‘»1:11p1'e331311. in pancreatic 111101111 1111.131111c31‘cimums
{PDAC} 1313113111111 11:11:11 1315111, 3111111131 1111' 3211 113.111.1111: 82R 111311 1111113 111 PHAC‘ 1213115
11111;! 111111111' 11111111111111.11 111 111:: (:111113131 1,1:1111111111131 1811111111,113111110911111111 111111 1 1181:1111.
SE11. iigands 111511 11111131111111: 1:1:1311-‘1:11111131111 11111112111113?1:111:11101'11171'1113165111111 11111111111: 5111111111 in
11111111113 111" 11111101131111: 11.116111313111111111111111.
11111313] 3211111111111is 1111111111011111111111111111111:11111111111111111;531:1111;11:31:1111:11:111211118111111131131:
111111. 32.11 11g1111ds 11111631119111 11131111111111111111111. 1111111111111111111111» 111111 131111 111: 11:11:11 11:
11:11:52: 11}: SEER 1111 12111111121 £13111: 1111131,13211111131111: c.1111 111311111111111 111111111311111111111:
11111111111 111111111111111111121111 which can 1112.1.1.1: 1113111121311 1113111111311 111111 01111011 (38115.
{1111?} 1311131111. 01 11111112111113:
\ OdeK/
x N CH
C! I ‘ 3.
is a drug with sshmtivfiy i‘br kiliing cafiis with. nncugmic KumS mmmiong by ing calii
{133:}; by an i.r0m:§epcn.d.ent. nunnarpoptmic psrocass {armed fbrroptnsis. H owever, {his drug
underpm‘fbmmi in l mam; tx‘iais.
{008} firasfin has: been dttsm'ihed in US Patent Applicatim‘: it‘ublicmimz 2003133632644 0f
Smdgxareii. BR... as having me“ kifiling propertitzs that are. non—apoptoiic. This rekreme alga
m’i certain i'in anamgs. such as, firasrtin A of’stmcmrc
Erasi‘in B of stmmm‘:
CiQO/Yrk}(\NNNYS CH3
0 CH3
and dewnemyi Erasiin {dfisiguawd "unwound 21”} m" sanctum
tail
WO 53814
(Elise designated bereim:as S“‘x2?}. TEn: imenter in this iimn i183§11¢2d§hfitflb~$
mum}! Er. ragiin has mmm (:2: iiiii. "E'img actixity campas1b};(mini:()E’Iiragi‘in. Dixon, SE at HE,
Cab. E49: {851% ENE, 2.812 describss fimsrin as mediating a nonzigariizutoticS irunwdapendem
uxidatiw aeii éeath {“fermptasis"). E-Emvtwer, Emma :‘afiimmea ck) mi {is-scribe mnmounds
cm‘nprising a bicyciic moiety. and Eh): commands;.21;5crib{E (in mi also mediate ripo'pimic
(:33! {133%}.
{(399} US Pat;m E)'_ E43333 m Mc-Dmm, 1.15:. a! (If. as we}? as Spitzm‘, D. at ab. {Tamer
Res. 3’2: ECEEvlflé}. 2(1E22md m'nick. LR... bi 8E. \‘EOEEUELEE‘(51:10:: 9: 298 303 m})SE
commands Em treating cancer. (‘fo‘tiqtumnds discioseci in {base refer;’11:: inc!Eude muiecums;
hmmg a m:11.1;citing mam} uhEcE) hindisigma—E rumpmr (EU-"n“. C.) €131.) Cancer Res, 6?:
GEOESvfiii ('37., 206?} and an apopiusisinduc:mg. 1,;is}as 3. pmapaptmic;:aptide.
Discioscdi Ciii’zi'pbrzzifis include a sigma—2’. rccepior Eigand such as. an N—subsfiimed 9-
:12:)bix:yciu{,>.3.'1 EffnmambyE pimnyitarbamaie ‘y of Sh‘UC-mi‘iif
/ fi/x
C} {mm-“f!“
wfi'mrein R can be seisci‘ed frmn (En: gmup ting of” a bond, 3. m 311'qu a. ("Ii-(7m
alkyiamim a C. int:m aikyiamid‘L. a C: n{ 3.: barman“! an”3";(2m :11} i, a. {314320hetm‘cmyi. am
egrer and a hydmphiiic pniymer. In amine eom‘igurai‘ibns, Gimp-minds (If {his {imam include.
aikyiamiiw derivatives Ma bicyciic phi:nyiszarhaj113m rnoit‘iy, such as:
(figJL:yC/gm1:11WWNHZ
OCHS
(13551131131116 5’1" 1 19111111311 11:31) 111111 31343 11151111011115
,CH3
NYC:.
‘ 1112
CH3 H
A§1§11111g11 31.11111: campmunds 11156111M511111 1:111:11111:1“1111116123 11171: 11111111111111111111111gtu111111' 1
kiii'11i1g 1:11:11 1-11.11, 1101111. 11111111111 111's 11115111 1'11 111811111115 51'1111-115111111115111 0111111111111 131111 1113211111
(’1111'11111111513}.
SUMMARY
{011:1} Acuord1ngiy, 12111: 1111113111013 Emmi“ (1151:1031: 1113-11 13111111111311111115 and 1‘11111901111115 111111
1111111111115 0!" {hair 111111112313, and. 11111121111113 {11111811111151 11.7511113117111121.1%1'31'11-‘6 1111115, 1111111111111g
1111110115 2215.
{01 ’1} in 11111111113 611113011111181'115, the 1311353111 ng-S 11113311118 1:1111119111111115 ofsh‘uciural
Formu 111. 1
N O
at" x \
21111? $111111 11112111111 11111111111 ‘11- 0311 be 1111 1111i gump suLh as 11 CC111 21113 111 11 C~C :11
hflififi‘Oéfi'yL 1111111 1:11" which can be Subgi’itutfld; X can be; a linking 11101131}! 5111111. 11.51, but 110:
limited 1'11 21 11111-1111 aik‘yi 111111111; and Y 131111 111;: a 113111311101113411611131111; 1111111313' 51.11211 :1: 12111511111, 1111
111 1111a§11g : as 5121511111511 11111561143, 13551171151111berasiin 1111‘ 1111 11171151111 11,111111fiiu.
{012} 111 111110113 C111i111111111m1111 1111: 11111513111 {13111311119115111111111111 12.1111'1111151'1111115 13011111111511'11111
1.1111111111111111 111{111111111111111111111111111'11151111111511. 5.113131312111111 1111111121; 1111311111111, 111' 111-2111103111
WO 53814
it} 2 3'} in. variuus manlm the. premm wachinga inciude Itmtthods uf {treating a
hypm'prmif’eratiw dism-der is? a suifgjecfi‘ in need. thereof, wmprising the step 0fadminic‘stmiing
m the subject a mmpound 0E7 .f'bttfltfifi i.
{Si-£1] in variuus mibodinmxts, 1'31»: present teachiags inciude meflmds of treating at
i‘zgyfieargai‘u!ifhmiivt‘. m in a subjem in used fimmnfl is‘ing {371:3 sequentizfl 0;? so“
administratien Ufa cumpmmfl MFornmia I on; phaz‘maceu‘iimii3" amecpmbh: 531i m; and
muffler fhm‘apeutic agent.
{0 2 ‘5’} in variouai embo-dimmusfi fire- premm lfi-EiifhiflgES irtxziuda co‘mgmumis 0f Furmula i
for use in human {in up}:
{01%} In variant; embodimcnm the present teachings inciuds‘: mm'zpmmds infamy 0)"
Rwanda 1 {hr use in treating a: hyperpmiifizrative dismdar.
{01-7} in variuus amimdiments, {ha pmsen’i teachings inchuie use ul‘a cmmpound {If
Fax-mum i fill? the manufacmre ofa. medicament to treat a hyperpmiif’eraiixc dismdea:
{0 2 55"; in. varirnms cm‘bmfinmma the meanest teachings include cmnpmmds 01‘ a 2:311
{harem} uf structure:
O/CHB QJ‘N’C} §
)7—0 H i“
CH3 0 NWm 7
H I [Dim/{N
C} whemm
21 $5 an r from I {a 5 and R; can be H 01' mmhyi, in Some. configu:m§h:ms-, competmds or
salts mflhese inmma e s and SEIH‘S wharein n can be i and, R: can be H.
1!! some mni‘igumtkms, cmnpuunds m 5.3m; {bf sham: ambudimenis include Cflillpfluflds and.
Saks wherein n (can be. i and R; can bL- H. in various canfigm‘atimm a 3211‘: of a cmnpuund (If
{hem isn‘tbodiimcm‘fi can be an majestic 55m;
{019} in various muimdinmms, them compounds and saii‘s ’ can has [wed in
:nathods nf {Imaiing cant-ems. En varigus camfi gm‘ations, thew mefimds can, cmmpr‘isc
adminifitering 1:0 :3 subject in armed {harefia therapeuticai1y afi‘ecfiw amount any of‘these
cantipamnds 03‘ 3331‘s theremi‘. In. “mimic wnf‘xgmmions? $1 cancer that‘ can be framed? with any {If
(base. campom'ids or salts themafczm 3:12: am: (3.3138613 such am without ih‘nita‘ikm, a mitic‘raatis
canwr m- 21 Symnriai smegma.
{028} in s mnimdimmw, these campaunds and salts {heme}? can be synthesized 23;;
s disclosed herein. In same ‘atiune‘sg these meihmfig can wmps‘isa :‘aacimg a
Gt‘nnpmmd m“ Sammie with a wmpmuud 0f si‘mciut‘a
NWW2‘
n r; can be an integer From i m f? and R; can be. nwihyi or H. in some cmzfigumiions, £1
can be 3 and R1: can be. an H. in 3mm: mafiguratimai n can be :3' and R; can be an H.
{03 E} in Same. cmfigumtiwns, the ' washings inchuie these mrrapmuuds m 5311‘s
iiiweuffiar use in the in‘mimmni 01‘s) swam: in sums aspects, {Em cancer can LN, wimmut
Hmimfigm, a pmmreaiic cancm‘ m 3 swim-$213, wrwma.
{0122} {11 same: mtims, the pfflaflflt teachings; ismiudc use ofthese compmmds 9r
332:3 lhereuffm the nitaxmi’amure 0f 3 msdicamem {m the {maintain ofcamwx in same:
aspemxg fin: cancer can be, wiii'ixmi limimtim, a pau‘mreaiic cancer N a: symmiai smegma.
{823} in. varigus embndiimnis, the prawn 1‘ i‘eashinga inciude ninethuds a? aymheaizing a
cmnpmm‘d 0f Fo‘mfxula; EV:
¢LND.JLO ,« ’QfiN’AW N \\ XI
H EEWMAXHV
0. '
CH3 K444444498
UV}.
cmnprisiug mg map (If ng a uud (5f Simflural F(mania V:
Q‘CHa \F‘“.
WMMNHQ
(v‘3' }
wifh a {:mnpmund 0f strucmrai Fm‘muia \f‘ i:
H CH3
(Vi)
whemm n is as} r {mm 1 to 5; and R3 can be H 01’ mmhyl.
BRiEF FHSSCREPTIQN OF THE DRAWINGS
{€324} MG. 1 Mummies Emstin and dag-4nifl‘hyi Erastm {SW V127}.
{USES} iR? EA'1 Must:m3. wmhwx m‘ cumpmmfis mm«493 and S'x’tW43:35 Uffhfl'
present washings.
{02:3} FIG3 iiiushaim mmmmnc intcmafizatim inhitsiiion of the Sums-scent sigma~3~
iigamiS “1’38 with S“ \«WE by Fnine. 4' cam.
{(327.3} FK3‘ 4..'\F illusnm: \iahUiiy assms of S“ V~495 on unions hmmn {Ai}; and
minim: {F} pancrmtic cancer eel} fines in x-“itro.
{£333} FR}. 5.443 iiiustmte sed apopimis: 3843 death induced by SW V-4§}5 asSayad
We: infitment {m 2'4 hr {'.\f} or Eh: {B}.
{113.91} 13113.. 6 11 1 ferropaptu‘tie 1:12.11 111111111 1111111111111 113-" SW \1’ «“1951.
{0311} 1911‘}. ’1‘ 11111311111111: (1ecre11se 111 111111111 312111113 111 11111131113111: cancer 11111111161111}, SW ‘1’»
491: 11.111111115151111111111 in 11 1111111111: 1111111131 system.
{1131] 1113 11 1111191111113 1131 “-11 $111111-111 111111111911111111: C1111ee1‘1‘0111111111g SW ‘1‘?4911
111111111111111111101111111 1111111111: 111011111 system,
{1332.} F113. 9 1111.11111‘11111131he «:1: 11 1111 “fig 11111111111111111111 ()1 S“ ‘1’ ~11st 11.1111 111111.
11.133] F113. 11’) 11111511111113 11 @1311 11131111113 3.3.1121}! 111112-113 11131111111 with 811131111.
{93.11 1111‘}. 11 A8 11111111111112 11111151“ ‘1«"193 1111111111111:-31'51111ex1pt11ke 1133111111111; 111. ROS
03:5} 2.14 11111311111111.111118‘1‘1 ‘1441119111111911111111111;:x11111111x11. 1111011111111:
pathway.
{1.136} F113. 13 111111311111'1 SW V495 1111111ue311111‘111110110211111RQS 111111311 1:13.11 111.
{113?} 1311‘}. 14:51—15.- 1111111111311: 11111181111 ‘1'"411s1111111116811.111101111011111 111111 1311111111121353 131"\.-'1\«“8.1.
DETAILED ‘DESCRIPWGN
A 11111'111111111’0115 111111 13811111110113
{113-3} T11 1111311111111: understanding 1111111: (1151211131111, 11 1111 tuber. 111" 11311111; 211.111 1‘121’1111111115
-11 2111 211131113111111111 111111111 1151 11111111131:
{031)} When 11'11t1‘111111-e11‘1g e1e1‘11e111‘3 1:11? 1111:. pres-312111 11151111131111: 1.111111: prefimed
1.1111101111111111151 111111.111 1111: 21111", “1111", ”1111:" 111111 "5121111" 1111': 11111111111311 11:1 111131111 111111 the-1‘1:
are 11111: {11‘ 1111111: 1111.111: 111121111311 13,
{1111113} 11111111 \pLULh-ai‘td.11'11L11611E'SE11‘1D1'1313‘113C1 111 11130111‘1‘1111'1111: 11-1111 A‘anfieg 111111?
11'111’1111’11g 1311:3111'1111‘1111 5111;511:1111-211111m (.71111111111111 .-:'121511121153“ .3111}? 5111111111, A111ez‘ican
C11121111ea1 Soc-imy, 311118, except 1111 specified 1113111111.
{1141’} "1111: _\
11211.11 -81," 1111 1 her-1:111, 111111111 111‘ .111 111:11:11111‘11111101‘1, where 11111 11111131111131:
speeifieafiy (11211111311, 1111111115c1111111111111g1111111 1 11111111 11'1e1111111'11g 6 11111111111 111111115.
{0112} 111131121111 “1.011111111131111.“ as 11sed1191ei11, 111111111 111‘ 1.11 13111111111111111111, 1111121115 11111211351 01‘
111113111151 121111121131 which 1:111} 111: 0111101111113.» “1114111111211 113 11101-111911
{1343] "11111181111 “1111-11121 11121121031311." 1111 use-11 1111112111, ne- 111' 111 12111111111111111111. 1111311115
either 1} 111(111110}=e118 11.11113111111‘311 1:11111111'1311111 1m:11123111711112'11112111111313, 111111111111 111111111111 01111-
111111 1111111111? 11111215 can 111:: 1121111111111111x sei acted. 1.111111 the 111111111 1.111111111111111; 111'11,11111111 N,
111 22} 111W‘11C 11131131111111 1111111111 1:111:11 111 11113- 11133111111931; 111111111191.» {we 01 51:1 111113 111131131113‘MS
c11111'p1'1‘111'11g 1111111111111 11112111 111113- 10 111-111 11111111111111.11113 seiemed 110111 1118- gmup12111151511113; 111‘ (.1. S
211111 N
{111114} "1118 1121111 “11111-131 cych‘111111y1," 11s 1:151:11 1113111111. 11.1111113- 111’ in 111111111111111. 11113111111 21
11111111101112.1111: 01112111311111 11111111131 1181111811, 11111111. 11.1111. 111.12: ring 1111111111315“. 1111111131“ ayaioaiky 1111 131111 111‘.
11111111111111.1111. 12131111131115 11111111111 cyck1alky1 1111:111111: 11111311;1.1116111111111211, 13-31 11111111111 211111
125101 1111111; 1'1.
{11115} "1111‘: 11311111 “111111111? heatmcyc11111111111," 113 11513-11 1113112111, 11111118 111‘ 111 01:11111111111110111
1113 11111011111:1r1:1ic1111110113111111131111211111g111>11113e111111131: 111111 5111 11111. 1111.11111er 01‘ 1111:1111
11111111131111 11111: 111111. 111111 131111 111: 10111011111311111:1:11 11.11111 1.111: 111111.111 consisting 0ft), 8 111111 N.
13111111111111;111111111111113113111111111111111111111121111111:1111‘11111‘11111311.111111111111111111111 1113;1‘112111111111‘111.
1111113111111131‘11 31112‘1113111, 1311111 1‘13111111111311. [1011-111 111311511110111111111131113 132111 111': 1.1115211111111111.
{01111} T1111 1111111 “1111111317 2111111111111 113111;! 1111116111.. 11111111: 111‘ 111 (3111111111121111111, 11:11:11: 111 ------
NERfi 1131113113111. R 1,111.11 {1‘ 1111: 11111111111311.11121111)‘ 511111611311 1113111 1111': 111111111 31511111;11111311111151.3111
21111111 211111 11111131 1161131111111111, 2111y 111’ which can be: 11111101111111“ 11111331111111131‘1: 1111111111111111111111", {1113. R
and R 11111 1111111 2111111111 31111111 122111 0111111131118 113 1111111 1111111:- 1:11‘ six—11181111111166
31‘111231‘11111111111211 131111111111'111'111211 1:11:11 be {11111111111111 51111511 11111311.
1114’? 1 "1111‘. 13111111 “1.113!” 111‘ “11.111," as 1131:111‘1131'131111 111: 1111‘ 1'11 13111111111111111111, 111171111111 ~1'3w.
{11115} 2 1111'11‘1“1:1.1:1'11“21s 113111 1111112111. 11113111: 1211 in 51.111111111111103 refers 1:11.10,
{(1119} "111131121111 “1:11;.1‘1121101111111.111“ 1311311 111 1111 11111111131 group -111: 1111 1111111:11.311111111111111
111111113 11113 1811111121111 111),: 111111111311».1311 1111111111
{11150} T111: 1111111 *‘111111‘1111111111111'1”11:; used 1111111111; 11111111: 111‘ in 1111.1111111111111111, 1111113 to 1111 11111511
111111111 111111211": 2111 01‘ 1111‘: i1y111‘11ge11 11103118 111‘111‘1111111131‘31‘1 1131' 1111111111111, 111111113.
{1.151} “1111: 1.111113 “51111111111112.” “51111111111: 111111,“ 111111 “1111111111111.“ 113 11111111 116111111, 11.11.111.101 1‘11
11131111111011, 1111121 1:11 1111‘ \1111 grew 111.111 its 21111011 1111 11.11: 31111111111: 110111 113 1111111 111 :
11111112111011.
{052} T118 {111111 “3111111113111” 85 11511111 118111111, $110111: {11‘ 1.11. 1'111111111’11111, 111135 1:11 W51
{0531 ".1111: 1111111 “511111111111,“ :11: 1131111 1112113111 11111111: 111‘ .111 11111111.1011, 11.1 1.0
~S{C})~.
{11511} 11111121311111 "N~5111’1‘111111111i1’10“ 15 10 21 RS{Z====D)2NR’« group 11-1111 R 111111 R.‘ 1111;
{1121111111 1111171111.
{11551 1111: 11:11:11 “$11111111111111111110” 11:11:13.1 111 a: 4‘1131'1’11111111‘. 151111111. 111111 R 11111 11‘ 1111
defined 1111.
{1{15.611‘ 1111‘- 11-11113 ‘111111“ 11111;! “1.11111," 151151111 1112113111 11111118 111 1110111111111111111111 1121121 11111.
S 1;:111111 1:11 1111 1.1111111 11-111211111 1111: 1111 5.11.{111121111 111111 51111111111113 11111111121311 11111111111111 111“
1111': 111111 11171111173. 11111111313; 51111111311 and 1111111113111 11111 11113111111111 in 1:111: 11111111111111: 111’ 1211111 211111 111111.
{85?} The term “thincm‘bmry§f’ as used here-in, when. aio‘ne includfia ihiufm’myi u-{LiiS'3‘iti
21m} in itemihirmfitm is 3 «uC{S}m gmup,
{05$} ".1"hei‘ern:1 ”Ne-1Mocufhamy’i” refers; 1'0 em ROCQSWRi gfimp, with R and R313
defined hemin.
{€359} Tm: term “(D-vimocarbamyl” refers m a “‘DCT(‘S}NRR '1, gz‘mxp wim R and R‘as
dafiziuad herein.
{9:33} The {slim “thincyanmd’ refcrs in a (\H group.
{063 ’1 The 1mm “Erikainmefimnesuifhnamidm“ re’fars m a K3CS{O):NI{» gx‘cmp with X is
a haiogsn and R as dafined hm‘ein,
{062} The term “mhaimnethzmesuHim?E" mférs m a X_§CS(O}:~-- gran}: where \ is a
hamgm
{0'63} "Pkg: term "(vihaiunwfiumy” mfem to a X3CO--- gmup Wham K is a haiugeu.
{£364} Tm: term “iriszubsiitumd silyi,” as used Em‘sin. Emmi: m if} atim, mm m a
m gmup tmd at its fhffi'fi free vaiences with gmups as iisted herein limiter the
{is n Ufsubsii‘mted amino. i‘ixzmiutsies includetrimmhyxfiyi.term:utyidime’ihy15%ing,
mr’isilyi and the like.
{065} An}: definitim herein {:31} be used in combination with any other definitimn to
describe a cmm‘maii'e gtmsmrai gmup. B5! camxsemim, the trailing {siemem seizing such
dafinifion 1.5 that which zuiachws t0 the patent umfifly. Fm fixaarnpiss, {1m composite group
aflkyizn‘nkm wouid rspr’ewm Em alkyl gmup afitimhed t1) the. parent meiecuie Eirumxgh an amidu
gmum andth {arm at’fikuxyaikfl wmuid reimzsem. an aikmy group atmdwd :0 the gamut
moieuuh: h an aikyi group.
{06:3} The {arm “capizimmfly substituiad” means the. arms-cmiing gmup cam be: Slahstimied
0r unfinbsfiiuted, When tutefl. the subsfimfims Ohm “‘0ptianafl5 tuted" grow can
incimie, without iimitmis‘m. we 0? more suhxé‘imeni's independentfir seiecied {mm the
faimwing groups; or a uim‘ desiguaied m G? gmups. 21mm: {12‘ in, mn‘xbinafim}: aim}.
Howe ‘ alkenyi. {aw-er zfiky‘nyi, Eon-"er alkmm‘yi, fivwcr imim‘oaikyl, kmm‘ Im‘tai‘ocycinaikyh
lower haioaikyi, kmrer haigaikmyi, have:- haimaikynyL lower pcyhaiozflkyi. fewer
pm‘im’kxfikmy, kmer ikyh phany’l, my}, aryhtsxy, lam-var alknxy, r haimflkoxy. :3qu
iiiWfll' anyhxy. czu‘lmnyi, cat‘hmyi, m‘bfln5K1. Howe-r carbuxyeflsr, kiwm' carmxarnida,
wane, i‘iydmgen, haiogeu, hyfirmy, whim, 2111ayum-lino. arylan‘lino. amide. Him). thiui.
alky’iihiu, ’meier haiuaikyit‘hio. ism-var pezrhaimflkfl{him aryithiu, suifbnate. swim: acid,
trianhstiiuted siiyi. N3, SH. SC§-iz. C(QKTHL (7026-13. Cif)2,¥-‘I, pyridinyi, Ei‘limphme. ,
luwer cau'baz'naie. and h1wvsiti' urea. Two subsifituenis cam bejeizrlad, together to firm a fuse-d
11.1121. six», or Seven~111L11'111ered yciie s‘;1‘11e1€:mcyci.11: ring (1111151311113 of zem '10 three
11e1te1‘11e‘11111‘111. ‘17::11‘exer11111e 11111111113; 111e1hylenedioxy or enedioxy. A11 11111113113113;
311113111111e11 010111111111 be 11111111111111111.01 11311, 1113113}. 11111:)? substii‘utefi (8.11.. 31'3
111011113111111111111811 112.51.. £11.1C1’11F} L11 su11s1‘i1iu'1ed 11111 ievei afiywhere111~be1111e1211 1111132
31111311111113? 11.1111. 1‘1101‘11‘131111111111111211 (11.5.; «C3 1-1.1CF 1). Where subsiimems are. 1120111111.111151111111:
quaiifieafiun as 10 51111511111110“, 11111.11 med 11.1111 1111.:11‘113111111ec1 1“ 11m. cmmnp.$31..“1.1
Where a subsfiumm is [11.121111111111113 “1:1.11111111111e11,"’ 1.11:: Substituted 11117111. 1'11 speeificei .13.; .
A 11.131111111111113“. 3112111 sets 01711111101131 su11s111uez1tstn a1111fi10111111‘111111e1y can 111: defined 11;»;
needed; 1‘11 1111:1112. Lakes 1.11:3 uptirmai 311115111‘111'1L11‘1 111111 1)8£15‘ {16511613, 011131 1'11‘11‘1161‘1131111}!
11111111111151 1111:. 1111111512,. .101111113.»: 3111131111111111 11-1111.”
{1113?} T111: 1131111 R 11111131121111 1'1“. appearing 13y 1111111 111111111111 .1 1111111111117 {18111111111111
unless 11111131111111: defined. refers 1:11 11 11115311811151 eeiec 11:11 110111 theLgmur} 1:1‘11111151151111 L11"h).=d111ge:1.
111113.3161LL1111111111 heter‘oaikyl. 1117311.. 11816113111331 and 11611112112316111111113;1.111:1}: 01“ 111111311. 1:211: 11L:
0131111112111}! 51.113111111111611. Such R 211111.11a 1110111111 5111111211 be 1.111111315101111 111 11:: (11111011111131
31111311181126 as defined 11e1L1'11.V1"11L‘.111L‘1 1111 R 511111113 11.2111 11111111111131 Liesr'gnmtien 1211111111., every R
group. 11‘1eluding R. R' 111111 Rn wherein 11 111 an integer, every 3111151111113111, and every: 1281111
311011111 111: 13175111.1011. 1.11 111-: independent. affix-:1“). 01111-117 111 1e1‘111s 1117'se1ee11011 17mm 11. group.
1111 11113.1 1:11.111111111. 51111511111831". 111‘ 11:11:11 111.31. 211315, heterrmycie. R. Lte.}11ecurmure 1.111111 {me
{11118-11111101111111101 L3L‘11e11c simL‘iLre:its (11:1111111011 Liteaeh Lrecurrence is imieperrdeut 0171111:
(11311115111111 at every other: 0ceuxrer1ce. 111131313111 31111 in 1112:: 1111 112131 further reeogmiee 1:11.211;
certain. 11113111115 can be 111111 11111 1111 (1111121311112. or 1:111: (weep-)1; 1-1 1311511112111. 1'11 -1111 01'
618111631115 1111111 {31111111111111 113 11111111311. ”1111113. 113.1 1151131 111* Lax-(1.1111118 (11113:. 1111 11115y'111111e11"11:211 111111113
$11011zis----C1'O_}N1R1--canbeatiawiud1:111.11L13116111:111L31e1}*111:1:1111e1‘111L 01111101111; 1:11L 111110111311
{061:2} 113;,1‘1111‘11811113116351112815031181.111 1111‘ Lonipeunds L‘2:L‘1L1SL~:L1 111311-3111 indwdued
13111511111215 (11' 1111111111115 1:11.11 be ed3311111L‘fiu111y1.111.111 c011t1111e1‘e1111 .112 111-1111111111:
1111: 1112111111313 which. 1:111:1111111 1211171111 {1131118111 {11711}! 111‘121331‘11110111L11711‘11111111‘es 11‘1"1:11:11‘111191‘1181‘11;
preducts 1111111111111315811111711111111 51111.11 11.5.: coavcrsioe {L1 11 1111111111: aste1‘e11mem 11:111uwed
31y \err‘mun L11 1181‘} «31112111011 1.11er1.11001111111L LeLhmqu dire{:1 separation 11:"
c1111ntiun1ers 0:11 chiral. L11111n121111g11zp111'e c::111n111s.11rany (11111311111;311:111131L2 1L1L11 1111011511 in
111R‘1 ..r1‘ 3121111115.: (.011111.11.1111 01 patiicuiar s1e1L0L11LI111xm 111‘- 8113K)?L0111111€1Li<111\ 1112111111111: 111
01111 1:11: made-1111111 wmh LL11 111* 1LL111111111LL Ruewu111 the 1111.1111111101111111 the L‘umpeunde
Liisc'iesefi herein. can 21.1111 215 gmmmrie 111131112111. Addiar'enam. L‘enmeunde can 121131-11
11111101111213; LL11 Humanu‘rL monk-111‘ are 171(11’1L1LL11W1111L dischmure 1111111011111 1111:
compounds 111501131 e111 can exist 111 111N111and is w (:11 as 5011111811 11111115: with
WO 53814
phamtxamnmcaii); acmptabhs s::1¥\-'<:ntt3 such. as “water, 6:113th and the hike. Eu g‘anemi, {the
saivamd $111113 31%.? cansifim'ed ecg'uivzflfini {:3 {I‘m uns‘nivafled farms,
{069} ".1"¥1ei‘em:1 “mum“ rafters to a ctwaiem‘ $111111:ge between 1W1} 31.0.1315, {11‘ N13 moieties
Wham the atoms guinea: Ly the band an: considermi part of larger subsirueiut‘e. A band can be
single, douhie, m trims:- 353 (Imam-‘13): specified. A dashed {fine between twe flaws in a.
g Ufa 'Iuniccuie indie-31:22; {11:11 am additionzfl bond can be present or absent a} {£131
pasii‘ifin;
{0?0’} The {arm dIXtJSx. £13 used hemin is: symayvmms; and is used imm'changeably
with, {ha terms dm‘,” and “co-1311111011“ {as in 111131111:in conditimfl, in that 2131 ffififi‘ti am
ahnermai candit’ion of’me human 0:" 1131mm} body or Mom: of its par‘is that. impairs nominal
fixatiiijnjngg 53 fiy maniibsii'eci by distinguishing Signs and sympmnzxs, and causes {he
human 1251‘ 3117111111 11} have at 101211 (111121111111 m 1; uaiity of lift).
{£3731} T115: term "omnbinatim therapy" nut-ans the admini51121111111531‘11113 or man:
flagrapeutic agents to {re-at a therapeutic madman m.“ disorder described in the preset“
1113133051111: Such,11dminisu‘aimn enmmpasses madnfinish‘mim} nfthese therapeutic agents in
11- subslamiafly sinmiwnesms 4113;111:313 gush as in a magic. capsule having a. fixed 1min afactive
ingredients or in mu’itiphz, separate. capsules far each game ingredient. {:3 addition; such
admittistmtim raise: mmmpagses use Uftflwh type 01’ {therapeutic again in 11 i 1132 manner.
{MB} This phrase- "fimt‘apauti03115:; affective" is inimuied 11: 111131113: 133% 311111111111: ui‘activx‘:
ingredienis used in the treaimmrat (sfa (1151:2151: (1r drismder or an, the efibciing mfa dinicai
{:ndpfiint
{1 ’33} The term “the 11536111512311}: accepmbia” refhrs 170111051: nds {111' 33315,
p‘mdrugs, 1311115111813; msfiterionic 1171311113; 4211:.) which are i‘c- fox“ use. 111 11111; with the
ifissugs 0f patients ’wit‘huui undm‘. {miaityg irritation; and 3.3361gic resmmse, are cal-mmnsmme
M111 :1 17633011112321:beneffirisk rmim and are ive fin.“ their 11118311112115 1351:.
{(174} in the 5311159131 1115611811113; the {em} “mfiia‘iiun” 11113411113 101132;ng11111151111011
3011113115ng particle-5: 1111‘ 5311111110113 that haw sufficient may, {if can produce :31: 133838111 energy
via r inmmctions 1‘0 produce imzizm‘ion (gain. 131' 11335 ofblects‘um}, An exmnplm‘y and
refi innizing miiatim £52111 x~mdiafim1; Means i’m‘ deiivering \ ”adimkm m :1 {argef
{issue 01‘ 1:61? are we}! Mans-1'1 in, the 311. Title 21:11:11,111; of ionizimg radi 313ml waded in a 5;;1715'8-11
can gmwrafly depends as} the nature 0'5’15:1:11C§2H. Megan; fur (iefierrnining Em {sfiéctive 3111011131
of rad 'a lion are wall. Ram-m 5: an. U31:11 herein, the 133111 "1111 effective: 110512" of ionizing
11611111501: 1113 12 {Ease of imfizing radiation 11131 produces an h'mrease in ca}! damage. in"
death.
{@251 “1111: 1121111 "11111111111111 {11.1316113131" 1'1: ‘1‘1‘1‘5 to 1:111: 1131': 1:11 111111‘111111111111111 01‘ 11311111111111:
13111111111311 1111111: {11111111131110.1311311111113111 111111 11112111111311 {1113115113 01711311111113: 111,111 11(111111111211111:
1111111111111.
{1126] "1111: 121111111011111111 1111111131311 1111132111 121111 12\15111s111111‘11111111‘1121111; 111111311131 1111151. The
311131111111:11131111151118» 1111;111:1113 1101,1'1111111111111 111111211 1113111116. 11111115: 11311111 111‘ 11111111, 1111:1'11111,11.g11c111
1111111111313 1121113. 31111111111: 321113 1112111111 1111.351: 11111131311 with 1111111 131'11'1111111111111 11111141331111: 111311.111.
Such 3111111111111111311 311113 111111 11111111111131 111: 131111111121Q61111C1’1113' 11012111311113111. 11131111211131; 1111.111 1113»
1111111111111111111113. 11113111111311: 11111111 11111 1112- 1.31 1111111}.-111 1111': 1311:111111111111 111111 13111111111111011 111 1111:.
1111111111111111‘111 1111133111111 B11211 :11111'11101'15111115 111111: 1:11: 11111111111. 1.11111 111111h111111111111111111
11130131311111111. 1313111131011: 1101111311311: sion 1.311.111: 11111111111111.1311 111111 31111111 0'1" 1111113, 113113111:
131111111111121111116111 $11113: .1’1‘011111‘11135. Selectim, 111111 1.313111511111111 11’. 1113111111311. W11113111113111“
21111111 “11111;:1111111 21.11.12)
{112?} T111: 111.1311 “1111:1'111111'11111‘111131' 11111111: 511111.” 115 11111311 111111111. 1121111111111 1111511113 111'
22.11.11“ 11.1311111111: 1.1311115 011.111: p13111111s 11131111331311 1113111111 which are 111111.111 01111113111111.3111111'
11131313111131“. 111111 11‘11'3-‘1‘31381111125’1113 1111111111111111: 1111 111111111111121'12111, The 511115 131111 b1: 1116111111111 1111111133
1131:. 1111111 13111131111111 11.1111 13111111111111»: 1111:1111 1011113111111111 111‘ 313.1311 31111111213! reacting the 1111111'111111‘1111‘
12.111111111111111 1.11 1.111: 1 1:11“ 1111‘. 17121: 131131: 1111111 :1 5111111131: 11121121. 1'121111111111'1: 1111111. 11111111111311 311113
111C11111fl“°11118. 111111111112.1111111111113. 1:111‘11111e.11111111111113.11131121111111»), 111111.211‘111331111‘111111112
{1:163:11 2}. 11111111111111.13115131131115.01.111131111111113. 13111111111111.11111111111111, 1111111111. 11111111.1111, {1111111111.
11111113: 11111111311113, 11111111111112. 111310111'11'11111151'11311111. 41313180111113: 1:111111151111'11111. 11633111111111“:
11111111113111). 11111111111111; 11311111111111131'11113, 113111111111'1311111113,11.311101131111113. 2~1131111‘11131’12111111111111111111111:
{1.1111111111111118}. 1119111113, 1111111111113... 0111111, [31.»11111111113111111, 111131111y11311111111101.1311;
111111111111111111111111116. 111113111113111311151111111'11111, 11112011111111: 234111:31:11.1111111185111171111111‘s. 1111111111111.
9111110111113. 1.113121113111111, 11111511111116, 113111.3111111113111111). 1.3111151311011116; 1111:1311; 1111111111113.
11.111111131111111. 13311‘11gl1.11111111111:. 51.11.:ci1111111; 51111701111113. 1111111113, 1141111111111. 111111111111211111113.
1111111111121.1111, 11111151111318, 33111111113311. 131811.1‘13111111111, 13111114111111111‘31111‘11111111: {‘p~'111s3'1111:13), 111111
11111181281711.5316. A130. 1111511: gmups 1111111: 01:1111110111'111511111111115311 1111111111 can 111‘. {11131811112611 with
11111. 3111311 311131311 111111
_. 11111311 9.11111111:1 1.1; 1110111111131, 21111111131111'1111; 1111111311111 1111:1111-1._111b111ty1.
1.11111 11111131311. 31111311131; 1110311.111111311,1113111111311. 111111 31511311 1.11 113111111.11111111111113. 111111 1111111113113. 111111
benzyi 111111. 13116111111334 13111111111811. 13111111191133 11113101115 which 12-1111 11‘ 1111111031311. 1:11 1
‘1’11'11111111'111131 11.1‘1:1‘-1:11.111:111‘- 1111111111111 1111.111; 11118 1111;111:111111‘11111113 511'11'115 11'1110111111111‘
13.31111111310111ic. 51111711111.111111.13110111311011;1111111311311111 11131113 11111111.121 311.11.111.11. 12113, 11111313111113. 1.11111
12111113. 51111173: 111111 111511 111: 171111111111 113"11110111111111.1011.11111111 9.1111111111111113 1111111111 211111111 111111211. 111'
afilkzdim: mirth. ion. ‘I'itmcg, {Em present disc‘kwure came 4111;314:1435; sodium, ium,
magnesium, and calcium salts offing cammunds fiisciesed hemin, and tbs: Kim.
{0478} Basic addiiim} 538.3 can he prepamd during the finai imiat‘ion 24m purificaiium of
the campounds by reacting a carbuxy gs‘mm wiih :4 Suitable baae 3114:}: as the hy‘dx‘flxida,
mrhmmte, 0r bicm‘tmnate of a mam} {mini} {41‘ with mmnm'lia or an organis: primary,
524301143333, {43‘ ml‘iiary amine. The cationg m“therapeutiiraMy acceptable Saiis inciudi: Eithium,
smfium, um, caicéum, 44142432416344.4444, and aluminum, as mm {is mntoxis; quammm‘y
amim: 4244444144 such as; mmnimnim‘n, laix‘an‘mihyiammmium, it:li‘ae‘thyiammmziu‘m,
n‘mii‘iyifimina, (ii,n‘mi‘irlyiamirm, triinasiiwizu‘nine, triethykamins, dkfli‘iyiarnhm, ethylamins,
Ufflmtyiaminst-3., pyridine, NN edimethyEmliiine, Nmmthyi'p'iijeridim:, N~41‘mt'hj4‘imorphaiiine,
dicyciohexyiamine, pmeaine, di‘benzyktmiue, ibenzyipheuc’tbyiamims, E «mafia-24444114134142,
and N,N'«dihenzyififilyienadimuine, {Ether rapresemaiiive c aminea useful fm‘ the
4;}:4x'mafinn:{41‘ch additim 321115 imhasfia nedimrn41114:, ethamflamine, m{aiming
piperidime, and zine.
Compounds
{G79} The presem' disc'fosure prmides a mmpnund M‘Stmct‘us‘ai 13013111123. i.
wa/‘L,
N, O
4 X4
N Y
m a .4414 il‘im‘euf, whemin: W is chose-1‘1 fmm upiiunahy Substituted C5’C}(‘1£fi‘}~"i and C5«C‘.m
Imiaroarfl; \ i341 iinking mgiety; 24m} Y i3 :1 krmptom-inducing ); chosen {ham as'astin,
an, arasfln anamg such as erasi‘iwA, emstin‘B, {)1‘ hyi at‘ezSii’n m a simpiifimi synthmi‘c
ez‘asi‘in imbue-tic,
{088} In smut: C(mfigm‘flfi(MS, W can be. a. {75'an aryE.
{033 3} In 3mm) configumfims, W 435m. in: a, Substimmd Cfi—Ci,081’}~'§,.
{032} in Same canfiguratims, W can be a signtnavl magma? .
{(33:13} in 501114: wmi'igurmions, the. linking maiety can coxmn‘ige a: Cstm lime 1‘ cl'raiu.
{£184} in. 50111:: mnfigmrations, this g mniety can fummr gzomprise 1 m morn
hei'm‘mmmm. in. some cmxfigurations, each {)‘i’t‘hr’: I or mere hetemamjms can be indepemimiiy
se’ieciied [mm {the m‘mm mnsiming nf an oxygen, 5; suifur, and a mih‘wgen.
4..-
{($15} in. 3mm: Cfl'fifigtlfaiiiflifi, the g anxiety can ham: a. sizmctm‘fi:
W‘hi‘l’f‘ém LEW 18 a Emmi. and, I , I ‘ I} warn mmger imm 1 :0 If}.
it. i. ‘2 3. it. :3 ()7, 7. 83 9 m‘ 30. 9. En some cmlfigm‘aiinns. :1 === i, in some mnixfiguratimns,
n it 5
{086} in souls: £01133 gumtistms. the ibrmpmsissirichming :‘noia‘iy 0'le9:13}:prufihe
stmctm'ai Fm‘muia 1 am hi) Sflecffid from the group mmsmi‘iiig {sferafiiim e‘rasi'insA, SffiSfifl-B
and flzyinerasfin.
WW} {:1 3mm cnnfigmmims. the fem‘opmaismind11::ng imam m’a mmpmxnd (11‘ {ha
strmtumi Formufia. i can be SI‘RSUH.
{(333} in. 50mg mmmdinfmm‘s. me. presem‘ {eachiflgs ixrmimie mmgmtmds of" Fm'muia H
or a salt thereof. n: W is chow: fi'mn optiunajw substimwd (II-:9«C?1rp aryi and. C543“:
hetemarryi; X 3521 Raking moimy; and R?- is chosen from. hydrogcn and mmhyi.
{089} In $911M? trin’hadimsmsz, the prawn: teachingg incinde mmpmmds mff‘omuma Hi:
H» C ,2. Z:
3‘ N 22 Yam
m a salt thermf. whack}: 221661an and 2’; is indemndenfiy saiscmd 17mm, the gmup
cam-Listing mfg baud, {RC 1::1: aiky‘i, ir aikmyl, (Alina a‘ik'ynyi. {175(k) aryi, (lsvam
hetemaxyi, zur‘jxiaikyi, heteroarymikyi. aim-13:34., 21%icyZimt‘m‘om‘yi_. eay‘cioaiiszy231k};i.
a1kg:2hei’erocychmikyi_., cycioaflgiiaiky’i. amyicyckmikfi, “{C¥‘i3}a{UCHECH2)biCFilhwgw
{Gimzvkfi‘jHi7:PigCnthlafi :i2_}.-.(){_C:¥J§.2)a~m, “('(t:1~12;a8{<‘5%:223-. m
(LT1121;11:1(11211151'121-;““““ _. irithL‘Q'} {(311311““““ ~~~~{(13.11.31511‘1("111111.131‘121;““““ ““““
g .
1111111111311;(01K ‘‘‘‘‘‘ ““““(LT-.1]1L{L13\1\ 111.7112).““““ ,~““““(L31-1213Nf1111LI{L))N{R.‘)
(L‘:.112}.-. “((17112 1331(311N111.’ 11:11.»1...“. -~[L'.T1'i:};.N{R151111)21(3’17121Lw-a.3111‘ is chasm 11mm {'31-
11113.;1 LwLmflMmi~~L 31: 1111611111 LstaaryLC5~Cm1wiiemary‘1,311‘3'111111‘3'1,
1';121130211311211k3=1. anik’yiaryi, a1.111131111111370313'}. 1mi§crucycitmikyiaikfi, 21111111;mamcyc111111123111
1.31611121110'131113-1.1111101 {1.111(331 ‘‘‘‘‘ {L11..1(L1L‘117C11+](1711 21..~~~~~~~ and ~~~~~~ ,
{L117121-1131?L1>L11L.11b{L.11:1\\\\\\\\. \\\\\\1L1121L}{L \\ \\\\\\{L1111331(11“\\\\\\\ \\\\\
{L311:21111111211:1'Li1-1121gw, wiCirhhSLU} {131121-LM, M1_C1‘1.2}51N{RI)(C1‘1.2}1r~“, w
{13112111N11111131011'C1'12:L:------., ------(1'31121:C{L}1N{RE11131121.,------ -----{C1’12fiNLR"jLT-{UJNLRE1
((311121.------ ,r-----((11;135111.113\{11111L ------- (L112111111111310){L;1121-------- “1111:1311: each 0121.
2.3. and? .2.“ can be optionafi 1y subst‘it‘u’im with. 011:: 0r mare gn'mps chosen 110111.11311}: man. 11:16
(3:47.121: 111.k}v‘1; 1:111:11 131‘ 12 1.11.113pmdw11113" chasm from hydrogen, CM? :1.» 311(31'1, and (3:43.111 21:31;
{1211111113 3331:1015- an 11111.1.“ 111L1L11L1'1L111111 81108811 11111111 {3. 1.23 2:L1 41; {1211311 1315 an inkegs;er
mdeLndwih : 1mm1, 3,3 '1. 5, and La; and Y 15 a 1‘01)11.1515a111i11113111g11101131316111.1881}
from 111131111. an amsfin arufiflg web 13 A. erasL‘maL'L (31' (183111131115'1131'1131111 or a
Singfiified 53’1’111181111 m‘aistin c.
{0911} 1n cm‘i‘ai’n embodizmms, a unwound 0111.1): prasem teachings has; structural
131313111113 11-":
11:1 :1 o
‘1’" («'1
‘11“ ‘12 F 1L
H 1.0 CL
¥';\Nx\r¥\1§/’\¢N\f ‘\ kfoxii/[EY-
Réf:l H3
m a 51.111 Limfenfi 116118111111: 2'; is; an, integer {3111713311 17111111 1,. 3, 3,11,. and :1; 31311113 can be saieumd
1113111 hydrmgen 211113 111611131.
{11%} 111501111: mnfiguraii.ons, n can. 131—: 1; and R13 can '133133-1110gan.
111921 1.11 some. mmfigumtimns, :3 mm be 5; and 113 cembe113.:dmgen.
{0931 1111 301111.: mnfigumtisms, the 32111 can he an 0112112116 51111:.
{L194} 1:! 54mm: configumtim‘is, 1.13:3: wingmmnd can 1):: 311051211 From con‘zpotmcis '1 ~34 as
11158103611 herein.
Pharmacwtjcai Compusiitims‘
{$395} While ds {rflhe pressn’i immhil‘igs can he mhninisi'ered as the raw
Chemicai, it £5 2 i353 mtssibie m prawn: them. as; a pham‘xaceuHm} tbrmuiatinm. Aaea‘n‘dingifiu
pmvided harem are pi‘lzu'n'lacamic-31 {bariuiat’ims which {:(nrnpzfiw: mu: at more cunmuumis M“
iii»: present:{teaclliizgs¢,(337011€ 01' more n‘ulacwifiuaiha amap’tabfia Saks, fifii’fi‘i‘fi, ,
amides, 0r mimic-5 thereaf, togeiimr with one an: mere phanmceui‘iaai2y acceptabm carriers
titm‘emi‘and mptimmfiy one 03* mars: mhm ‘i‘h {trapeufic ingredienm The carrims} must be
”acccimabifl" in the sense- of’being coarnpatibfie with the mini? ingradiams of i‘ht‘: 'i‘m‘muia'tion
and um ddeterioms to the ent {hareufi {’mper fonmfimion is giapendent upon the mute. of”
adminigtrmion chases}. A a}: Mike walkknown techniqima é and mcimems can he
used as; suitabie and m; umiarsmod in. the m; mug in Remifigtun’s Pin:mmcemiczii Sciences.
The. phzu‘mamuticaI mmpnsitians disc-1mm hawk; can he mamzfiscmred in any mmumr
knmm in {he an, egg. by 1116333 {ifcanwufimmi mixing, diSSflh-‘ifig, gamut}airing,= dmges—
making, lex-‘igauiing, enmisiifyiag: mmapsaimingg ani‘rapping m contipmssiu-n procasses.
{£196} Th2: 'fi'n‘xmafiatim'lis {mind’s those- ie for NHL ‘al ding
subgumnmus, intradmmai, in’tmniausuu143.13 énhravmmus, intram‘ficulan and intran‘sedul1211'ny
intraperiimam, transznucosai, iramdermak 1'th and. {Ospicai {inciuding demmi, ,
subiinguai and intrameuim} adnfiuislmfiun although the mast suitable. mute can depend 1131011
for exan‘lpie {his condiiian and 3131" of’the recipierfi; The fbm‘mlalions can cmwenienfiy bis
prcmmicd in unit massage form and can. in: prcparecl by any (sft'ha‘. mcihafls wefi knew-n in the:
2m. mfpharmacy. Typically, {beige mathnds inshzda the stap (wii‘bringing mm sawmim‘im} a
mmpmmd uf {his whim“ {MC-Emma or a pharmaceuticai 13x bia 5331, {3mm 3:715:33:
pmdrug 0r Sumac ti‘uc'rcaf(”active- ingredient") with the carrier whiz}: consiiuites mm or man:
ascessm‘y ingredimta in gamma}, the furmuiatimxs are prepared by uniibrmiy and, intimatciiy
bringing im‘o assuciatim: {ha actiw ing‘rmficm with {iquid cm‘riex‘g or finely fi 3::fiid
carrimx: m but}: and {Emae Efrmcssrszfl33 $13331!ng {hrs product Ema the desired fimnuimim,
{09?} Cmnpounds descrihssd herein can he mixtuinistcred as Wilma-‘3:
Chm Afimi n Estration
{098} ’l‘he mmpmmds a? the: t machings can be adminismmd many, including
swailwwing 50 mg mnmound eaten; the: gasi‘mmimam}. tract, 0: is absurbafi mm fin: bland
stream direcfly from the. nmuthw inoiuding subiinguai or butts-a! administrzititm.
{8993} 500123010 mmpusiiimm {03‘ 0301 LLLiL‘LLiLiisir-0mm inciude i fimL‘LLLiLLiiOLis such 03
iabici‘s 0033.3.ad: 00:, bang.» and hard 03“ s0i‘i ApsLLiLLL. ’L‘LiiiCii (:00 003312033 iLqLLLd 30:13..
powders, 03‘ grannies.
{(31.00} in 23 {ethic-t 03‘ 00030303LLiLLsaLL: 30an LL30 0.030030 0i LiLuL pL'L030m 0333 i3»: imm minim
ii05% L0 00001959131.33'3Lwigiii, 030:0: itypicaiiy 3 0i030§129~i3t0 31300: 50% its}! weight {Li‘ihe-
{image ‘1‘01'333.
{iiiiii}1031000030iLiLiLLLLiLL cinSLLi03L2333 0000033 23 0353331003030 mmprisim0, fi0m 0000:
0.5% to : 35‘3-‘17’: i3}! it. 3003's Lynicaiiy L‘mm 0000i 2% to about 2593i: 01‘ Lin: {image
i000 Ex0.00003 oi LiisiLLLL0920053 iLiciLiLie iLLi ceiiuiose 30Lii031303‘ wiciuLLi 003303.033{hyi
ceiiuiose, 03030003300030 3:00.000, 33033333503155igiyL‘L‘oiitione, i1yILiiTUXjLEDI‘Opyi.tfiiiiiimiis. Starch and
the iike.
{0102} 0132. 35, i0? USE. in L3 iaiiiui. LLLciLLdL: LeiLLiin, puiy:iiiyiesia giymi, sugars,
gums. Stare-i3, iL}=’Li.L‘0;-Ky03'00yi ceiiuii303 and iiiif iiiLLt. Suitabie diiuems, i0; use in 0 habit:
13.33.0i0d0 manniiui, i, iLLCmLLc, i‘LLLLLLL 0, SOFhiiDi {0301 Marti‘i
{0 i 03] 300132330 3031300 0003-33 agents and giidams, 0331.00: 3'0 LL Labiei 03‘ 0303003,. can 00
03030.30 in 200010333 {mm abisuiiiiii-‘b 120230001; 3‘34: in): 'W‘t’iigiii, 0.00. inc-hide. p0iy30rbai0 iii),
SiitiiuLLLL‘iodecyi3113.03.02,LLLiLLLLLLisiiicLLn 0030032.
{0104] $000010 ieaiiis, 3‘30 050 in a minim 03 00, can he prL03L30' in 03 i300}
0003.0 {3,192, {0 303003 53% by weight. and 0.3030000LLiciuLLL, zinc 03 30000:.0.30033 stamina. sodium
sisa'n‘yi immigrate and the. iiize-
{9205] "I'Liiaieis can be made by 0030100330333 0.3 30010300., 003‘i0031iiy with 033.0. 03 03003
000 €300; 0300.0300‘: {0300033300 LLLiaiLLLL can iLL 03003030 in 00333333053300 1333330310ka
3133.00.00: Liv:- LLcitivLL ingmdiam in. ii iiiLe—‘iiLLLL-iiL'LL‘L i030: Lilith as: 231300030303 gz’rLLLLLLiLLL-‘L, §i1£iii}’
000033 VL-iii1 iiinLiL‘LS, inmi LiLiLLeLLL‘S or iuiiiicaiing 300000 active. 03‘ (i'ispiazSing Eigfiiit’s. Muided
{Libit‘fi'éi 0203 i333 133003: by 3310020331 in a 313iiabi0 330300300 3 03003.00 mime pmviiereii 0033333033310
0.3033L0L‘LL—1Li Wiii‘l Ei iiquid 00330.0(. iliyss 0r 03533001330; (2-31} i730 2300de Lu ii'LLiiieis {01‘ itieniii’imtimi 0L
:0 ciLzLL‘acierizc different Lonibi'naiiLLLLs of 0003-0 00333001030 003:5.
{ii i {36] i..iL]tL.iLi i'LLLrLrLLuiLLLimLs 0033 0300300 0333000303, 30300003, swims, {ziixiL‘s and
LLLxgiLLLLLLLLLLx which C033 be LLLLL0 5:0 30ft LLL‘iLLLrLi 00033003. Such iiirmuimimm 0031 incimie 0
0300033000003013* EiCCEpiLibifi carrier. for exampie. 335003. 00320330. 33:325-"eti3‘y‘iu330: giyccii.
cgiiuiuse, 03‘ 0.0 0ii. Tins. ihL'LLLLLiLLtiLLL'L can aisc. winds:- 00:. 03013000 LLLmixLiLmg. LLLLL'nts Mai03
303130330033; agents.
{018?} (1.3323005013003 3‘03 03in adLLLiLLisiLLLLiLLn 0203 13:: ‘Luiate-d 03 01333300033: or 30000300
LciszLSL, inciLLLimg LL‘i 91 30030100 LL-LLi~‘ 05000030610 33- itii meric 0001:5330.
WO 53814 2015/023954
{G l (38] in. Eilmlllxtr muhmllmaul; El plmrmacmlical mmposiliou Cfll‘l‘lpl‘lSES a the» ‘ap-eulically
efikctlvz‘. aimtumi ofa nd 0f Fommla {1} or a plmt‘maceul‘icall3: accltp'tablt‘. salt llwwafi
and a plmrmacsaulically acceptable carrier:
Parenteral Admi n. i slralio n
{0189] Commands ofthé: pl‘esant teachings can he adminislamd diracl‘ly lulu the blond
sips-am, l'nusscle, m internal m‘gans by liljfifllfll‘l, leg lily lmlus injgctimil or Cglullmlmls
inl’usisml Suimble means lb? paralllcml administration ingludfl intrarwnlms, immumuscul3r,
subculmmnls lnlmarlerial, inl’raperi‘u’mm-llfi lmcal, inl‘mcmnlah and {he film Suitable.
devices for parents ‘al adminislmlim} include injacmrs (includlng mama and medlwl‘me
ll'lieglors) and inl‘hgion mellwdfi. Tim “lhm'lulatluns can be. presemed in uni‘ludmt‘. 01' multiudose
cmlainers, far example :sealtxl ampoultss and vials.
{0 l. 30] M05: parenteral fm‘n’zulmium 2m: aquemzs snluflnns: cwnl'ail‘zing maipiema,
ing salls‘ hullbring, susperfllng, stabilizing andfur dispersing agenlix, mallmklzemllsc
bacterioslals, 'prsswvallveg, and selules which regular the: lbrmulalitm isomnic will: lillt": blood
ml me lmemlell lecipiem, :le carbuhyalraies,
{82 l l] Parmfiaml farmulatlmls can aim be prapm‘ad in a dehydrate-{l farm (egg by
lixalit'm} m‘ as Sterile- nenuacmrzoug solmlons. Hum: lionuulallmls can be used with a.
suitable vehicle, such as; Sterile wan-3:: Solul>llily—enhancing agams can also be. used in
mlim ml? parenteral Sflltlil‘hfifsl
{l3 l, l '2] i‘tions fill parefll‘el‘al adminlsirallml can Em lininluizllell as imll‘lstllale m‘
nmdificd release, including delayed m- sustalned y'all-3.215: Compounds mm also lw lbrmulgled
as; depot pmpamllous. Such lmxg acting l’brmulal‘iom: can he administers-:1 by implantation
{far example su’bclslzmemlsly Gr inlramuscularly} m‘ by intramuscular ln‘j‘eclicm. Thus, far
example, {lire cunilpmzmls cam. bi: ‘lhnmxlalssd with suitable 16le L‘sr l'lglclmplxoblc llilzllfil‘iiills
(for e as an emulsion in an ameeplabla all) 0: int: exchange resins, or as sparingly
mlubla alives, for e, as 3 sysaringly mluble salt.
“ifoplcal Adminisl‘ml‘zinn
{91.531 in same canfigumlimm cun‘lpmlmix ul‘lhe pwsem leacllililgs can he allmllilisterml
mp'icailly {for example to the. skin, l‘numus linemhsiarleg ear, 11er;, or eyg) m“ transdgl‘mally.
Furmulaliens l‘m‘ tnpical administratien can include, but an: ml d £0? lmimla sulutions,
creams? gals, el‘s, ointmenlgs, :l‘aams, implants, palthsss and the like. Cas‘l‘iers that" an:
phatmascullcallg: le lb}: {apical allministratlml lku‘z'lmlaiimls cam. include warms;
it.)
gingham 11111113111 1311‘ -rin, pc3iye§h5~<lene glycoi and the Him-1 Topicai administraitix‘m can
1111111 E31". mfibn‘neé by, 11111'11xg111111ie1 13i1312‘11'11111111111'11111, 10111011110113}; :113ph131‘139is and the
like,
{{3} i=1] iiy 11112111211156 ingredicm '1' fur minimal 11dn1inisitmti1m £1111 1111111131151: 110111
{1100191110 189511 wf'w {by 11-“eighi)0fthe fixa‘ufiaiiimn. 1:1 earmin eynbodimwh‘ie the. 111:1:1'1-‘13.
ingredicni can. 1101111311312. 115 much as i. {#5311 1s=§wg 1658 than 5% WM; {mm 3‘31}, avg-"1.1: to $3.11 1115111;
{13" fifflm 0.19/11 113 1% wfw of {hi} 11mm 11321111111.
{02 25] Cinnpmitmns for {apical amninisu‘ati1m 131111131: '3‘111‘11111kimd as immefiiate or
:mdified misuse. §nciuding delayed or sustained 11km
l, Buccai, and S11h¥inguéfi Adminisfmtimx
{0} 36] 311119135110171133 {bu-21:131. administration of 111:: conmnunds ni‘the 1111351311? {1311111111115
181111731: 1111313316121 £21}: mixing, the active. agam with a, suimme 11111114135111?ng meipiam such 1111
111mm: buns-r; syy‘ithetic 1110:1103 di: :31 triglyceridgs, 3." 1121113,, xiyethyiene gfiyw‘ig which
are. 1401111111 ordinary imz‘ipemtures but liquid 11:1 {has 1131:1111 ites'nperen'Lum and which wiil
11111-3111111111111 in {31121131311111} and e 1311-: drug
{82 1?] For buccal 01‘5111311115131111} admi 11 1311111111119 the 11011111031111.1113 can taker the form 112"
tabla-i111 i1213611g881 331151311115, 01' gas {111’111111‘211311 in E()'§1\1§1,E1{i()nfii 11121111181: Such ceramsitions
can. 12013153113813.1113 am‘ix-‘E ingrediam in 21 flavm‘fld E31131}; $110.11 213 Sucrose and acacia 01‘
”fig31?3 f113} .
Administrmism by Inhaimimz.
{iii '1 ’38} F1111‘ fimztim'l by inhalai'itm, in some 1:111:11":111113130115, cannpmmda u 1’ (ht:
31 resent: 1261183111133 mm be (11311138117211 $113111 21:} 11151111131111; iiabufixzer pressurized packs or y
convenient 1111321215 ofdeiivcring an 11111111301 spray 1111‘ m: rized packs can 11111311311131: 1-1
51111111331: 91701211811111 such as diciflumdifi1101‘1‘nnethane, [rich1011113111511111“:111111113,
diuhi11111111:ma{1111.11‘1‘112111111'1; 13211711011 dinxidfis 131‘ other 311711111318 gag. in, the. 132131: 11:17:11 pmssux‘ixed
agrosoi, the dosage unit can be 1i§:1:1‘1nine¢fi by providing 11 111111; to ‘fif 11 21712111. 11137111111111.
Afie'rnativeiy, for adminigmfiimx by 11311011 Gr ation, the compmmdg 11121211111111 3.: its
the 111111311131111: 121111 111111: "the farm, 113711 dry powdcr cunmasiiiua,‘ {131‘ example a: pawder mi); 01‘
the cmrnwund and 11 suitabh: pmwie-r 6115:: such: as iamtose- or starch. The. pow-(11:1 1:011'1121051‘113011
1:21:11 he 111711111111 11211 in 1:11:11: 1101111111: 11311111 in. fm‘ 1111,211‘11'pie, camuiea cartridgegfi 1112131111 01‘ Mister
packa frum which the 1301111311217 can be adiministm'fid wi 1'31 1111-: aid {1151111111111111211132‘131‘17.111111115331111".
{01 19'] 0111‘s? 1111111111 1111113111115- 211111 111M115- of 11111111.111551111111111 knuwn 11.1 the 'p11111f11‘111cs‘.11.110111
111‘: 121111 21130 1.111 1:111.‘L'(1 1‘11L11111L1LL‘1111LL11 LO?“§30\1UO§T‘1 111‘ 1:111: 11.111 1.1111113111- 121111 be ed 113' 11113111
the 1113111111111111 techniques 01‘ 131112111111111.3, 3111211 as effective ‘1111‘11'111111111111 1111.111111111111111111111011
66111133. Praferred 111111: 1111: 11 1111111111111 2111111111511 1:01:11111'11i1i1g 1111 fif'i’eci‘ive 11115-12, as
1‘1L11‘eii1 waimd. 1.111111 11.111111111111311: 1162113111111 thereof. 111' the 1151‘11111 11‘1g1‘ediem. ’1'111‘1 31111-61511 111110111711
{11“ 11111111111 11(111111118-1111'136 10 L1 11211112111 11-111 1111. 1.11121: 5110115113111153‘ 01" 1.112 11111111111111 11113111111111.
The spa-1:1 11L: 11051111111111. 11111 71112111111 111111.1111111'1111L1111311111111011 .21 111111111 L11 1211:1013
11112111111111; 1111: 1.1111113» :11 1111;: spas-1111‘: 1:11.11'11111111111 1111111113111 1111:1.11111:, bodyW18111.1111. 131113111
116111111. 111:13. 111111: 1111121111111131111111111. 11111113 01' 211:11'1111113112111011, 171116- of exam-11:111. 1111113.;
1111’12111011 t11L-‘L111'Lc1111;L1111SL11‘11L1 [1:11.111 11"13111111 L111L1 1111;1L1111ve1‘1'13‘ 0111.11: 1.11L11131111L111 01" candition
being treated. .111 11111211111111. 1.11:: mum 1111111131‘1'1111L111 131111 1111132 11111121111117 11g, L111 11112 {31111111111111
and .1111 1111 NIL 11131111. LL11111111121'111111112 €11.11CL11'11111L3 Liieciive 1(11'111111111111115 and
1111.11'11'1111111‘1111L11r1 procedures 611 111101111 1111111.1: 1111 111111 are desn‘111511111 1111111111511 111111111111
11113111111 1'11" .11: is. discusmd 11.1. 11'11‘13111111111113. 1111011131: 31111.11 E... ,Re111i11g11111‘s
F1111111131181111.1211 8151131131211, 111.:1ck13111111511111g (3111.. 1311311111, P21... 1.97:3; 1111611111111. 1:1: 111... 13113..
1311.211‘1112112-81111111:1.130311.11: 19"11111111. “11113131 Decker. New ‘1”L1rk, \‘1 191111: 1111111 Kibbe 1.1111,
131‘13., 1‘111111311001LL11"131111.1111112131111'LL1 13111111111111 1:1 '1 Anmric-an 1’1131‘1113L‘L11111'c111
Assnciatiwn. Wagififigton. 1999.
.1111 111.111.1115 01111121111111111‘
{111.20} 11LxL111111xL1L12111L 111011111;1180111110111‘11'111 1111.111 p1111111‘111c-L1ads-111 01111111051111.1113
111111111“: :1 macting 111011.13 11-11 1.111111111151111: sigma-=2. 111711 and 131111 111.115 1:13 usef'ui in the
11113111111111:111'1117121-‘611111111 (11‘ L1151‘11'de1rs assumfiated 11 62113 111.211 exp-regs 1118 31111111142 1131112111111
1111111110111118 1111111111 1111111111111111 11115111112121
(Saucer
{1'11 '21 _1 1.11 111111.11: 1311': 1.111111 1111111111, 111:: 1.1111111111111115: 11.1111 1111111'1111112‘L’111‘iczi c1111111111111‘111ns 11111112.
31113313111: 1.111531310511112 131111 1.11: 115111111 111 the 11111111116111 L11 1117113-‘1111111111‘1 01‘ cancer.
{:31 2.2: 111 1161111111 @11‘1131)(11H‘181’1{S, 1111.1 1121113811311 116 8111151111 1111111 21111311111112ch1111111111, .111 '11
1:13.11 113111113111111513111111111111111, 16131" 12111111131; 111211111111111, 110111;: 1311111181; 1111311111. 11211113131, 111111111321111281‘,
(3211121111111111 11111111L11'11 11.11‘12L111111 mvi‘cai canwr 111'11L11'12c1111cz111ce17 1.311111111111111 13L1‘.
gastrointezstinai 112111111311. g11'1111111sion111 11.111111111111113. 3111011111. gaflbiadder 121111361; gastric- Gamma
head 11.1111 neck 11111111311, Hodgki 11‘s 13.111111111111111. 11011413113311.1113 13111111101113, 11111131111111 cancer.
.11. 111113111. 1313111 1321111311.: 11.11111111111 11mg tamer 13111111111111111111. 11151.1'1‘33111281’ 51111.11 131.11
2015/023954
11mg: (saucer, :mHaSHmH ate-i3 king cancan mesofimiimmx mult‘sph uttyaiflmai, (regular cane-an
op'xic nerve tumor; :1 ‘33 cancer, Ovarian smear, pituitary tummy y cefltx‘a} nervous
Systs'sm igmphoma, pmsmte cancer, magmatic» taxman pharyngeal. cancer, renai cell
carcimn‘za, reflai {Jammy , skin carncerfl spinai tun‘lm‘, small iaittesiine cancer, sinmach
cancer, synmfial savanna, Tecell lynmhrurmu, itesficuim‘ gamma tin-“mid “nicer, {:hmai cane-an
umgeniiafl 83mm, umthei i211 careimma, Gimme. cancer, vaginai cancer, or Wiima’ humor.
{9 2 ‘33] in pariimiar cmhmiimemsfi {he cancer can be: pancreatic cancer. In pariicuku'
sum-odinmms, the smear can hi: swigviai sarcmm
Cmnbinmisms and (Tumbinmim "i.”hempy
{81' 24] The Campxmnds 0f {hiii pi‘ESGHE’. ngs cam b»: used, giant: (Jr in aitiun with
other pharmacemimii}: e mmpoumis, to treat {:mwditinns such as £1th prwinusiy
sd hareimimve. The cumpmmfifs) mm prawn: washings and. {whey pharmaweuticaiiy
actiw mn‘lgmumfls} can in: adnxin'isterrni aimuiianemsiy (Either in the $31118 dosags‘: {mm-1 or m
separaie (image. €13:an (w iaiiy. Agein‘dmgiy, in (me an’tbmihtnexm “this present
washings cmnm‘ises mefimda f0: framing, a sandman by adfz‘niz‘zis‘i'ering in (he t’ a
ihwmmuticzfllyefiéfliva ammm'l ofom‘: m‘ mum: cmmpmunds of (hr: present teachings and {me
01* mars: addiiimmafi pharmacmfiitalii}! active. ds,
{0125} In amfiher enmhetsdimeliit, {mm is provided a p.11arnmumflica! cm'npositim':
cumprising mm: or mare nds affix: pressem {emchmé‘ga one or mum adafii‘ionai
phammszeuticai1}."active. totripommcisw and a pi:airman:eutimfiy mmapiabls r.
{:11 i '26] in. another enfimdimcm‘, the one m n’nm‘e afiditiuml pharnmcemicaHy 21mm
mmpa’mnds is: seiem‘ed frmn the group consisting {)i’ami—mncer drugs, 3mi~pmiiihmtiw:
{11113.33 arm anti—infiammamry drugs
{01' ‘2? Sigmavfi racapmr binding; mmmnsiti 01:3 dwerébed hare-in are aim aptziunaiiy used
in mmbinmien with. fiber thempmtic mag-ems that Mr: seiecmd fer their eui‘ie value for
the mmfi‘i‘imn m b6 flamed. In generah tbs: mmpmmds {ieggribafi hemin and, in embudinmnts.
Wham mmbinaiion y is etnpiuyed, mhssr mama (it) um ham to he administerml in {hrs
same 33ha;’:naceu‘iiczfl cmnpositism and.a because- nfdifferem physicai and chemical
characteristics, are aptimmii}: adlrninisterssd by different . The initiai adn‘tinistimmn is
gmer‘aiiy made: according to ishmi pmmwls and then, based upon the ubscwafl afflicts,
this fimage, mndeg m“admi‘:nisirmion and ‘iin‘ms offlaminish‘aiion suitrsmuenfly ainodified. in
Certain instanceg, it is: appropriata 1‘0 adminigter :1 sigma-:2. reccpmr binding compound; as
desm‘ibad herein? in combination with cr thampexfl'ic agent By way ()fexzampi‘e 03313; the
'3' '1’
{Emmpeutic efi‘ectivmmss Ufa sigma»? 866;}{01‘ binding cmnpouud is enhanced by
21dminisimimn.cirf‘mmhermmlpmtic agant (which a§sn inchxdes a. {Sm-mamas regimsn} that
2115;} has thempeuiie benefit. Regm‘diegs 0%" {ha disease, {fism‘dmf 0r cnmfit‘im} being ire-aim? the
warm} bane'fii experienced by 83:: : is ei {3131' simply addii'ive a!" the Na therapeutic
agfinl’s m‘ the. patient exgmfiances an m (£42., symrgisiiic} hermfii. :‘kkemativem iffl
aompound disdosaad ficrein has: :1 side , it can be riate to adminigter an agent. to
mines: the shit: af'fest; 01‘ {he therapssutic cfibctiwnesg of’a mmpeunfi describad hmain can bc.
enhanmd by adminisfi‘raifim} {if-em m.
{0 i 23] ”I‘hm‘a.p€uticaiI}: ct‘f‘actiw dosages var}! Whit“ the: drugs are usad in imat‘x‘nsnt
cmnbinations, Methods for ncntafiy determining ihammuticaiiy fh‘fi dosages [if
drugs and other agmn‘a for 118$: in mmbinat‘inn treatmem mgimena are (mummified
methodmiugias. Confifluaflun treatment: flmiwr inciudas pgrimdic irmm'mms then. start and stop
:11 s times is assist with the ciimicai mmmgemem 0? {ha patient, In any case, the
muhipie {'hm‘apcut'ic agents {one {113‘ which is a Sigmavl recepim‘ binding $011190th as
describmi herein) can be administered in any garden 33‘ shunimawusiy‘ If3mm}{anagmsiyg {ha
nmi'tipie therapeutic agem‘s are Optiunaliy provided in a single, unified farm, or in muliipie
\fhmm (by way oi’examp’ie an Egg, either as a singia pi“. m“ as {we separate pills},
{8129] In 3:311:18 ennhmdimems, one at” the therapeutic agents is given in muifipie dams? m
hm}: am: given as mumpia dQSES. Minot simultanmus, the liming between '81:? muitipi‘c doses
aliy varies from mare. 813.5) mm weeks 10 less {ham {web-"e. weekS.
{m 30‘] m, miditimi, the confininatinn meflzodg cmnpmsiiicms and fibmm’iatimg are net to he
mmm the use of only twa age-ms, {ha mm: M snultipis: therapfiuiic mmhhmikms are exist}
euvisiuumi, It is uu'idssrsmod that the dosaga regimm to 1mm, fl’i, m‘ anmiim’ate {he
CgmdhiONS) for wMCh i‘fliiflf‘ is Suughi, ii; {333115311335 madififld in aceerdancc WHITE a variety 0f
factors, These fimtor‘s inciude {he disorder 'ffrs‘mti which the subject sufifers. as weli as the age,
weight? scX diet: and l u‘nuii’tiun 01‘ the subjiect, 7‘th {Em dusage regimen. ataiuaifiiy
mmioysd Wifi‘flS widely, in SOME» mem’s, amt? themi’ore ditviaies- From the dosage
ns; set fart?) Margin
gm 3 ,i] Tm: phatfimacmuiicai agems which main: up the cnmbimuiun ihflmpy bseci
here-in are nmimaiiy a mummified {image fem) m in separate din-sage forms ed for
mbsmm‘iaiiy ianegms MimirdsiraiML The phm‘macwi‘icai agwts that I'm-aka: up the.
mmbimat‘ion therapy are Opi‘iomfi 1}“ also adminismmd gequmfiafiy, with Either agsm being
admirtisterztfi by a rsgimeu «sailing for ”mm—step adminisurafl'iun. The {wowsmp administratis‘m
:‘Egimen uptimmfiy’ cans for smueni’ia} adm'inissnrmiun ufthe aiciwe agan’is or spasm-apart
ViVVVsVV‘VVViVVVV of the separate- VVVzitiVJV: Eigflnis. "1'.in VV: EVVVVVV-Visn 111:). V'VVVViit'VVVEV: {Kim1111311531101}:
sVeps range: VTV'VVVVV a '1va VVViVVVVVVV: VVV sm-verai VVVVVVVVV, VieVVVVVViiVVg VVVVVVVV the pfflgmfiiefi VVV’VVVVVV
piifiii‘linflemli'ica1 VVngVVV‘. such as; pVV-‘VVHVCV-g V1VV'1§V§V*,iViVVVvViiahiiiwpVi..VV;VVVVV b.1111“iiiV: VVVVVHkimetic
VVV‘VVVV‘VV: 0.111315 Phciffl‘ldLLQUCdi agent.
{1'3 1.32] in VEVVVV‘ V:H.ViVVVV1VzVV‘VV:VVV. a sigVV'VVV.~2 .V'ecthVVVVVf binding cVVV‘VVpVVVVV‘VVi iV'VhViVV'VVVV‘ is
VVVVVVVVVViiVVSV:ad in CVVVVVVVVVVVVVEVVVV VV VViV pVVVCLdUR‘V ViVVVV pV‘VVVidV: {11.11111011d1 1VVVVV:V"VVV0 ViVVV'VVVVViimV.
A sigmaQ V'ccepier binding; VVVVVVpVVVVVVd iVViVihiVVVV‘ and an}: VVViViV'VV'VVVVVVi VVVVVV'VVVVVm VVV‘V: VVpViVVVVVViiy
admifliSim‘Gd beibre. during 01 VVViVV‘ViVV VVVVVVVV‘VVVVVV-c701 VV dis:VVse VVV iViVVVV VVVVVi Vin: timing
01' VVdVVViV‘ViVVVEV‘iVVg Vim CVVVV'VVVVVVVEVV'VVVV C(IF‘Viainii‘ig £1 sigVVVVV-E iur binding VpVVVVVVd varies in
SQVVVV: VVVdVVVVVVVVA 17.1w: V‘V:VV QVVVVVVVVEV. :Ei \iLi'flci—V; EEVVVVVV‘VVV bVVVdVVVg VVVVVVVVVVVVVVVVV1\ VV:med 3:. EV
VVVVViny iVVcVVV: andVS Vilifi‘fifii‘wiLVCd VVVVVVVVVVVVVVin VVV 3:133:1ch with a VVVVVVVVVVVVVVVVV V‘VV VimVamp
C(Vfidiiiimifii VVV‘ disc.as'5 in 0:11:21: VVV preVam the VVCCVVrreVVVc-V: {3'1 in ViVxVVVVV. VVV CVVVVdVVVVVVV. V‘V sigma»
2 9313611181 biVVdiV’VVgcVVVVVVpVVVVVVd and LURVQOMHOH’V VVV‘V VVVVVVVVVVVVH VVViVVVVVVVVVVVVd m (d SVViVVCCt
1Liim‘t‘im‘ as SVVVVVV VVV; 1:in VVV'VVV‘ Vila: V:VVVVV:V VVV the:V’VVVVVVVVVVVS ‘91 iViiV: cVVViVVVdVVVVVVVVs mi ViVVV
prawn: mucking: have. been. SiilthWt‘lfli‘Vd(219301113131 ’iVEV'eV'VV, it W111 136: VJi‘j‘V’iOUS in (has: :kiiiad in
ViVV—V art that such VVVVVbVVdiVVVrcVVVVs VVVV: VVV‘VVVMed 1:}: VV 211’ of VVVVVVVin: VVVViy NVVVVVVV‘VVVVS \dfiaik‘tih.
changes, and SVVbVVVVVVt‘V'VVVVs can VVVL1H 1V2H1‘10SE’5K1116V1 in 111128111: “-11.1101inViflpéil'iil‘lg V‘VVVVVV ViVV
VeVVciVV'IVV V1: in same VVVViiVVVeVVV: VVV‘ViVV: present V'eVVVziV.iVVgs.. VVVVV‘VVVVV: 'tiniiifi‘wfi VVV the
V:.VViViVVVdeVrVVe-V‘Vtsa {iflsw’ibfi-{i here-in can be 8111pii)3"8d V'VV practiciag 1131:: 1311336111." {e'ki'llnflb
{V3133} A SigVVVVV—E VrecepVVVr iVVVVdiV'Vg V:V.VVV:VV:VV:VVVVVVV can he used. in eVVVzVViViVVVVVV'VVVV WSVi‘V VVV‘VV‘i—
{.‘ZVI’VC‘GV' (1mgs. inciuding bVVV VVVVV iimV’Vc-d VVV Vin: i'biiOWil‘ig damages»: aikyiafing agems,
:VVVgiVVpVVietiVV i VVVVdV‘VVVf 3.111111.1111G'VEV‘,iiii'til‘xiii‘s“ciiilfls, .VVVVVVVVVVVVhVViVV VVgV‘VVV‘VV‘V. flifl‘m’fl iViVVVVV‘V-V:
inhibitors. B—V‘VVV" iVViVV‘iV’VVVVV‘s. B’i‘ii 11111111111013. Vt~VVVV>V tors, CDK ii VVVVdV-“VVV‘ 6 .‘VVViVibinVVrs.
{313101 VVVVdV‘VVV‘ CDKVV iVViVViVV'VVVV'S. Vzi-‘MS iVVhibiV‘oVs. Ci‘OSSiii'lix'218g VVgVVVVVS. QNA V'epiiCVVVV'VVVV
VVViViiVVVVVrs. VVVVdVVViVei VaigVV‘VVVV-ViV VTVVGVVVV‘ (11111") VVViVViVVVVVVV iVV:VVVVVVVCVVV: V3V‘VVVV 111121L1£3F8L€111Lr fVVVVVVV
{HGFESF’V VV‘ViViiVitVVrs. 1115.112 and HERE VV‘ViVibiVVVV's. iiVV«iiiVV: gV‘V‘VwViV factor 1 mama: {1,6111%
.1) iVViVibVVVVV‘VV, iVV’taV‘CVViVVVVVV's. ME}: 11111311035. VIVVECV'VVVVdVVViV: disrupimrs. VVV'E‘DR iVViVibiVoV‘S. VVVVVVu
EV‘bB V‘yV-Vjsine SV: ’iVVVVVV‘S. PAR i" iVViViiViV'VtVV'VV, 1’1312; iVViViiViVVVV'VV, PKB iVViVV’biVVVVs. 13KB
V'VViVV’bV'VVVV‘s. i31310~111§€ iVV‘VVVVse iViV‘VVVVV, VVVVVVV'VVtVVzi‘fVV: agents. VVVdVVVseVVsiV'izeV‘s, V‘VszVVVVViEVV'VVVVVVV
iVVVVVVVVV'V VVVVVVZZ ligands. SVV'VVVVVi break VVngVIS. iflfimfiomfimfifi ii VVViViiVi'VVVV‘s, VtVVVVVVVV’ necmsis Vac-tur-
V‘eiVVted VVVVVVVVVVV:is—inducing iVVVVVVVV: {“1111Hi. VVVVVVVVVVN VVVVd VVVSV'VViVVV :VVViVV‘ViVCHVViV3V'VVVVV‘ViV 1?ch10:
WES?) tors.
{1: 1.341 Tim CVVVVVVVVVVVVVViVV disc-1 used herein. 'VVVciVVdiVVg VVVVVVVVVVVVVV‘VVEVV of .FVVV‘VVVVVZVV 1. are 31:0
116” 01331111111!" £11111 iddiflfimihitl’ll“ 1'01'E'L’ii'iL-{f1 1185111118111 1111?? (1&3 118€1L1110f 11112.11'1351111'18311
WO 53814
of ntxamtu‘mais who have previously amdmgmm QI‘ are presently umiez‘guing or wifl he.
undm'going treatment fm‘ (tamer. Such 0mm iireartzinemis d»: Chenmfimrgmy.‘ radiation
(hi: ‘apy, 81.1?ng 0;? imummathempy, such as cancer vaccines.
{8135] The insiani‘ compounds are pmicuim‘iy usefifi in mmhhmi‘iun with iimrammic,
antiwancm,‘ autism? radinfim‘amu‘tic . Thusg the. pressm disci031w¢disciosu.;7e pmvides a
m‘ium fifths. prawn“); mmpoundss {sf Fm‘muia i with fimfipcutic, an‘ii-‘cancm‘ andsw
radimherapeufig agent's fur siznuémnesms, sapm‘am m scquemim administratim. The
wmpmméis of this diseiasm‘e and 1h»: mhm‘ amicanwr agent: can act additiwiy m“
isiicaliy. A synergistic cmnbination oi‘i‘hc‘: pmsem gmnpounds and armiher ncm‘
agent 'migm Emmy the use of fewer dosages m“ (mi: N but}: ofthess agent‘s and-"m 1:333 fi‘saquflm
dosages‘ (If mm (.3? bath £3?“th instant cmnps‘mnds and other anticancer agents 2mm m
administm‘ {31:} ageing ieas fi‘equmfiy mu rsduca any Euxiciiy atasuc-ialited with the:
stratim of this agents m a sumac: wi'iimui reaming the efficacy (shim agmis in the.
m‘eai‘mem m? . in addiiium a synergmic {ETTECT might ream? in the improved fizfiicacy {3f
image. agmis in {he treah‘uem nfcanmr‘ 31113.50? {11:} mducimn Many adverse Bf :.§,tm-'mm:d side,
efibcts assmiaied wix‘h (he. use mfeither agem {Santa
{0136] "l“he fhtzmgtsemic agent, anti—cancer agflm and-“m radiafimn ihempy 82111333
adz‘ninistes‘ed awarding in {hampmtic promwis we“ kmwn .‘m the art. it wifl be nt: in
those- skilied in the am: that: the adminisimiimz m“ the iberapeutic age-1m anti—cancer agent
andfm' radiaiiun therapy can be. varied ing on {he (figs-age hazing ts'eaisd and the: krmws':
effects affix: anti—mama agmt mm radiation therapy an that ($352356. Aim, in accmdzmce
with the kmwiedga :fi‘the skiiied ciinicmn, the therapeutic pmmmis {a}; (image: ammum‘s
am} time-s of"adminifi‘n‘atimr} can be. varied in 'se‘iew ui’xhe observe-d ei‘f‘acts {if the. adminigterssd
{Emrfipflmic agents? {Lew ami—nwflasfic Lag-em m mdiai’imx) Cm the patimt, and in View fifths
observefi responses {12" {he {12’ seam to the mimiuismred {hampemic agents, and u’bswved
21d x-‘ersa affizets.
{m 3?] 5331 ranges for xarays range. {mm dafiy dams MSG m 200 I'Oenigeng fur
pmmfiged periods nftime {3 t0 63- weaksk to single {2:35:13 @2000 m (1%?) rmzmgefia Dosage
ranges For mdinisnmgeg vm‘y widen: and depend on ma half—HE ofi'hi: ififlmpfii, rm: strmgth
am} type- ation emifisd, and the upmke kt); {his magmatic @135.
{8133] Any sufiabie means for deiis-"ezring rawiiathm 13;} a tissue can he en‘miuyed in 151::
t dischsurc. Common nmms oi’deiivaring gradiai'i‘un to a tissue is by an zing
miia'iim: SUUYCS i m the ‘bmdy being Hated. Aliamative mathodr; for $83 ivsria‘;g
radiation £0 a: tissue: include, for Example, firsi’ deimli'ing in vim) a, :‘miioiabeled antihudy that
11111111111111781181511-1111 1111 11111111811 11191111: 1111111111 18111111811 by 121813 wring '11'1 1-1111 1111 8138813118
11111011111 1111118 1111131 £211181811 1111111111111} 11111.18 11.111101“. $11 1111118'1i01‘1. 11511111.81888.2111118: 1.18811 111
111813881 3111113; 21111111 11111 11115118 111‘ 8811. 1111.i1.11‘.181§;1-'. 111.8 1‘11111 11111111 1:11.11 b8 118311.11.11:11 111/
11188113 11111 1‘81111‘111111‘118118 83811.1. .15 1181'.11 11818111 11 "181111111111118118 8.5.1.8111" is 11811811111131811111811118
agent. [111‘ 811111111118 11181111181811, 131111821118851318 $131118 1:11:11: 11188311111117111111111318 :11: 11111111111111
therapy. 111.11. 111111111111 1.118 11111111181111.1811 13117111131111.1111.
11.113521] 1311111138 111 81111887 11111.1 1181111188118 11151.180 8. 81753111183 1‘888111111‘111'1111111g 88111110111111
82111 118 1.111111111111311 118811 31115811311115? with 11118 131‘ 1111118 111' 1118 {1111011111111 11811411111311113 8111111111188 111'
11111382111881;13,881118:,. 1, 1} 1111111111111. 21‘318-1118,. 111811111111}; 11111 11111 11111118111211 11:1111 {PLA'E‘IN}.
83111013181111 PLANN). 1:13;;11ip1811’11 {iiUfBXs‘CI'IN}. 81118111112068 {15311 3113331111,. 1111311111111
1111‘s" N} 31111 81,"11111111151111811‘11138 {1"NEON 1‘1"».j; {3 } 11111.1 111811111131111:5 181111311115: 131.11 11.111
1111111811 11:: 111.8 78111118111181.1112 {3’1} '131'NETE.‘131.01.). ‘111.i11g111111i118. 13811113818118 I'NIE’IF‘LN’I‘}. 83211151118
11111111110481. 1.311331%). 11811111111111118 11.11}.313/5113} 13118111138811 11:.‘11‘1KC.) 1.111.11101111
(131.331.11.133? 8.1111 11:181‘111311‘8X818 {_'§1_1~fl:3j.1.i'1\‘1\”1155X};{ 311111111 1.111113111111111 111111 18113811111113.
1113ng 11111 11111 1111111811 1111 11311811311118(5Q1N('.‘()\~*'i\}. 11111118311118 111111 11111811111881 ).1..3}:
{=1} 111118131111181‘2138 11111133111813, 11181811111811.1111 11111 1111111811. 1:11 11511111882111 {CAMW'DSAR),
11111131881111 {HYCEAM'ET’E'N} 111111 8111181881118113’11S1N}; {1} 11111111111 81111111111118. 111111111111. 11111
11111 1111111811 1.11 31.111111111111111 1') {13151311115111.1111 1111:1111‘11‘1118'111 1813111NMYC.N) 111 81111118511
(1311.1:3NQKAN13) £11113. 11.111111113118511 {114.13'1'381311.,1; {6} 2111338158 1818115 11111118. 11101111111183 11111 11111
1111111811 111 811111111111) {SUTEN'I‘} 2111.11. 11883812111111113 1f.1‘-\\1":‘-\.STIN"1; 111113113} 1131118 M11858
11111111111115, 1118111131115; [.1111 11.111 1111111811 1.11 111181111113 fi1'i"1"lfi€). 811111111111»1'"'1'.£‘1RCE\=’A).
3.111111111111111 ("'F‘I’KERB) 111111 1181111711113 {1311131728}.
{0 2 41:1,] T11:- 11111‘111181111} 11181813811118 81181118811 1218- 811118811 1111111 5-13 11111011121811. 811:1.‘11111‘111‘8111.
211111111111. 11.1811‘111111‘112111, 81118111111818. 1111111111g1111811111111118. 111118111111'1118 1181.11. 21111311811118,
81111311021118. 11111811118111, ghmse. 111111811173. 11288131111118. 118g. 11811112111118. 1.1811181211111811.
111811111118118 11181111111111‘11111. bitUXUYLHI 31111181011115 31113111111111 131188183111, 3311811111111,
18.111111101118818. SSPCCfiEibi‘flE, 8111‘1111131111111. 81111111211111}111.111,. 88111380111111, 81111118511118, 11111.
18111111111311 1.1111118111111111 11111111111111.. 815131111111, 811111115111. 111:1. NaC.1 «3111111111 1:1211111111118.
11111111111818.11111111131118 1.1111111111111111 8111811181118. 1.11.1111111111 818 11511111111‘1188.
831‘81811111131111211111.118, )'113f01'lfl, 83‘1111‘811‘5118. 11118111111123.1118. 112181111111'11518111. 1121118111118.
diifliflfiilbicit'l, 11811181311 11.1. 11188811121118. 11801111111118, 1181118111031};1311111111. 118881111111, 118x1‘821131111‘18.
111811.11111311881818.111811881181, 1111181'1113851181 131388111881 88311111111818. 8111:1'111181111'118.
1118111 111111, 811111111111 L’NU‘JIMUHIUIL LtOPOXid 81581811111115. 83811185111188. 17111118515111.
11116811113181:- 13111111101111.1111: 13118111811181}.13111111111011.1018 13111111111118.11111188111111.81111111111
2015/023954
genm‘:i’tahmu‘:e gsmttmmmh, genisieim gussre‘fin‘ hyfimxyuraa, ibrutzmih hicim idahfiis-ib‘
Eifasafmaide, imaiiniix imiquiim:sd, imaxfimm irinm:emm iI‘OE'lfliiesllflfi, ixabepiimm mmtiniix
Eenaiidmnifla, letmmieg knew-Torin, ieupmiidm iwamésolg 10m 125nm, Eunidammg
machimefimmh‘te, mmimxyprogestemnm nwgesitroi, n‘laiphaiam merxzapmpurinm mama,
metihrmim :‘nethon‘exaie,meflmiremte, mithrzu‘m mimn‘lycin, mitosmycin, mitomne,
a, arnitoxamtmnc, izzm nm‘atimb, niiotinib, niiuiamide, macadamia, mnmotidcz,
oiaparih, iatim paciimxeh pmnidmnate, pampamh, pagaspargam pm‘netremfi,
p‘em‘osiaiin, periibsine, p! icainycim pm‘nalidminida, ponaiinib, ner, procarbazine,
z‘aimifene, i‘ailitrexed, regumfinih, rii'uxin'iab, soraibilm Si]‘§:pi¢320{:ifi., sunim‘fib, summim
mmmifin, {enmxohtn‘nicim temsii‘oiin‘ms, teni'posifla tesi‘ustemtm, thafidcmide, {iiioguamiitm
thim‘epm timxmcmc ridq topmecam trmnefinih, trasi‘tmzmab, n‘mmoin, vefiparib,
vinbEasiine, \sincrisiine, \r‘indmine, \v‘ii‘lz‘u‘eihina, wia‘serti‘b‘ vexiimstat, and iu'fledmnic zit-iii
{f3 i 41%] Wi'lm‘e a whim: is surffm‘ing €3me m iii risk OET'Suf‘fbifmg from an finflammatm‘y
canditig‘sm, a Sigiznaal‘ recepmr binding campmmti described herein. is: uptiunaliy used mgefhm‘
with {me {)I' mow: agents 92‘ mefimds fit}? treating an inflammatory madman in any
mmbination. The ‘amuiic agar}isfireaimems Em treating an: anminmzum and-“hr infimnmataw
mz‘sdition il’lflhflifle but are not fiimitad {a an}; 01" £511: 33:30ng exanmfes; { I J Ciraa'tzieostm‘oids,
including hm m): limited In mmismze, dexmnmhasme‘ smd prefinisoieem; {2}
mustemida! anti—3'nflan‘uinzamry {imgs (NSAiflsL inciudmg butmi‘fin1itedtu ibupmfinL,
zmpmxan‘, gammy!)hmphen, aspirim sn {N.~£‘k§_,FON}, fiurbipmfbn {‘ANSAKDJ,
kemwofén, magamzin (DAYPROL didefenac sodium if\r“{ILJIIAR’ENL disi‘ofimac pamssium
{CNEEXE{ARE}, etuduiac {LDDINEL infimmiimcin (ENDGCENL c: {IDEAADGIJ}?
Sufindac {CL-{NOEL}, mime-tin ("TGLE‘z-CTIN), :us-cloihmmmte ("Ex/"IE-C-LDEv‘IE-Nl Inefanaimic
amid {PDN STE-L}, emne {REi_..,-?\ FEN} aim pfimxicm’n {FELDENE}: {'3}
upp‘rfi:ssani‘s, incmdifing but mt iimimd m .tneiiu‘si‘rexate {RHIELLELivi'A"IRJELXL
lei] umsmidez {ARAV’A}, aza‘ahiuprine {'35?vfifRAN}, cyamsps‘winc {N gamma,
SANDIMMUNE} us and cyt-mphmphamide {CYTGXAN}; {4) C820 s,
including bu: not fimifi'cd to rit‘uximab {'R,1"1‘UX,=KN}; {5) Tumm‘ Necs‘csis 1.33.2:02‘ {INF}
biockmrs, iuciuding but am iimiied in etanercapt {‘ENBREL}, infliximab {'REMKI,SKI.3E,} and
adalimm‘nab IRA}; (6} eukiH—E recspim‘ antag‘nnjzsisx ding but my: Eimfiied m
armkim'a ET}; {7"} immgukinyé inhibitm‘s, influding hm not limimd to imiiiaumah
{ACIEMRA}; (3.} imerieukimi ? inhibiting, including but 110: limited 5:) AlNfifi; (9} Janus
Risk-ass inhihimr‘s, inchldmg hm not fiimiiad to itasmcitinih; and (H33) syk himm inciuding
hm: mi iimfied to fiwtzwnzttmib.
IR.) a“;
2015/023954
Compumld Sy‘n‘ihmia
{13142} (7011133011 ads (31”1116111‘1351311‘1‘bzalchings can be ad wing methods iiiuxh‘amd in
gsnera} 33113111915: schmuea and. fipxperimm m1 pmmedums {1.131313% 1113111112 {31311131311 SYE'H'hEfl'iL".
513116111125 and m; {11611111181113} ‘hu‘es m: 13112512111811 for pummfis of ii 1113113 11011 and 1m: m1
intemzied 10 be: 31111111113. 3111111711 g materimg used to prepare mmpmmds (3‘? 1111: 6111: 1:1:aching3
are no 11111113191311}? avid 13bit: 1711'135111 be pmpared using routine 1711131110113 knows}, in the 311.
{.1131 of A131)rem-fittinns
{11114-31 an x 211111120113; 61311113 x dam-317111211 chm-1711131131; 131113173411; 3 {11311131111611
{iintmz‘hyi 51111112111113; QMSD ‘3 13111113111311 2:111 111x162; 11 : hour; "1111? m 11311'ahyfirm‘hmm.
{016141} Same embmiimen 15 1111111: 3111 washings include 111121110111; 01" syni‘hesis {sf
es;n‘n‘pc;mnds 0f Faz‘n'zula W:
1:1 H
”CH1 \U N1
Nix ’“V‘NNK Kv’N\)\N *0
LuIf,
QVCHS
{W}. 121 s mnfigurmims, these mamas mmprise reaming :1 12011113911311 o1" structural
190111111121 V:
1 «.1 O
f)? x. SALT) E
{1‘ ,
CH3 \t’ N”/\’{MNH2
wfih 21 mmpeum! 01‘31‘1711131‘111‘31 1111711111111 V1:
f {L‘JLN
E /\’ N \
O ‘\ K/NWAN O
H R3 ,1;1.\_,,,C1—13
wherein 11 is am integer 1110111 ,1 10 5. and R3 13 12.5!dmgen 01‘ 111611131.
2 45] 2.11 31:11:11: 12111112311111112111113, 11 121111 211': 2; 2 22““ 12.1111 271:: 2131131113611.
{0 2 421] 211 301.111: 12.111113g111‘211:.i1:111s, 11 121111211: 5.: 111112 R“ 12.1111 211'." hydrogen.
{014?} 2'11 11111111: 1:11.112211111112111115.1.211: 111111 131111 2112;: {12:11:13 1'11 1.211: 131101: {11“1'1 111121113211g
2131311 3111.21 1'15 11 122111111 22111221111011. 32111111111111:213111212121: 21111.111w112132111211121111111.
LY1228022022?!121222112. 3021111y221 11111111 211112121312. 1:21:12111115»221111111113. 21311213111111, 221121211111 :121111111111111
211112121211, 212211111111 21111112112121.1128. 22121211111 21'i~-t-211121;111;1‘1121111111111111 2131121212121. 2122117111171
211121121112.21111‘112131111‘11211. {111211331111112111.1»2‘111111223111112131212122, 1111112111111231:1‘1121}-‘121‘1'121:, 111311111111.
11.1111123111112111112‘1'121‘. 111112111111 111.1M1111121111‘112111211121 111' 1111\2111‘11121121'1112
(213111;:212 1111;21111123 '2‘111‘ pmparinu 1‘11111p111111da
{1'1 2 48] "1'21: 22122111111111: 21121111111311 1 211: 1131312 21:1 111331211: 1131112219221: 1111212111125 1122211: present
11111211111“ 19112122221111112 3211112111112 1111111113. 1111211121111: 21112 11112 21111111311 2:111 1:211:31: 12112121111112. 11211131121121:
1.11.1211: 8111:112‘2‘11‘3111111111.1112 11111 1111 1'11 22:11": 11111111111111.1112: 6113111221131! 111. 1211: ;: 111:1; 1:11.11 21::
11.112.111‘131111121212 211 1111‘s: 1111120115 1.3111111101111123 051212 211:1‘111'111. 0.1 11122111161032: 911111.111111111115 112111221.
12111.1. 21221:: 2222212223? 111111‘11'11112112111113 11111111; 11111111113 21111111111 11:1 2211111111 5211221112 in 112. b1:
c11111'111‘1e12 21:1 C13111p1z11md1; 1121211: present11:11.1‘hix1g3.
{(22491 11111>1;.111:3'~111E{2111\11111111‘.»1—7—52-—1..—111~U(11214'2—
1111221111121121111211101.11211111‘.2111111«‘.2~.1.11ih11.\<.1122221111114)»
:92 } 2.11:1;312,211,1111111311112121‘12}.2112113111'111y 2 1121:2521)» 2 ~pi1m1f£1ziny2211113121512} ~32]«1112111115112211224111112} {SW
11—11911.
05243 1
f...
'\ #0:. /,N\
l \n’ \1
- I “VAx/‘Nx «”‘xx ‘x.
N '
‘ xvi 2
\4114 0 H
.1 1
? f. “/11.
2 1220011260022 , \‘O/W
1:11... *
21:11.1:1'1111‘31211111: 2A P12104231:11:13;21912121218211.131221123.3. i '211111::.11~31H.12 {'2}.
{0250] A 1111111111: 112"2.i.~"12.2~i{11~12e‘11123112: {222.0
L" 511111111122111 11112131112111.1111; 2 {10 mi,1
11113 1:01:121322'111 1.111 1ce~2111111A91311211211111 112 12011111911110 232-11131121111121122 .2}1111111111«f~11111: {2:1111:30
12 22 S 1111111021 in 31121312111115 "'-222'.2" {'2S. 1112-11.11.11; 111212312 12111;: 11151:. 2"211‘.1112112111‘£ W115 1122111111 212
mom IieI‘IIpeI‘IIILII‘I: {IVSI‘IIIgIIL Th»: reaction was CIIII‘SITIISIIBCI with SaIIII‘aIEd aqueuu-s NH’ICII ThL‘.
SIIIIII was fiIIfli‘Sd 0171‘ EII‘IIII WEISIIIEILI with TI-IF. The CIIIIIIIIIHL'E‘LI mganic Iaycm were dried over
NIIISQI. IIII'LILII and EVEIPUI‘HIEQ In LII‘Ym-ESS 10 12.1w?JTVLILBGY‘IZVIfigfléIZéI5bI£yCI013.3.IIIIQI'I‘IEII‘Ie-L3I1r
Mas RI.“3531:: 3.21102- 9131. {I8. g,95% Yield) ‘II\MR {1181131116 220235511..III I.32
(III. III}. 3.2% {3, 2H}. 3.02286 1131. 2I£ I,‘2 3:34243 IIII. 2iII. .2. I22.26311. III}. I.SS«I.99
(m. 3H}. 1.38-1.34 (III, 3H}. 1.08433. {III- 2H).
{6251] IIII‘LI‘IIILII‘IIIIL 18.31"I9~IILII2yIgwle’flbib\LIOI?~ IIIIIIIIIIIJIL II.-I ~IL4IILIII0ILI5
£11631I”IfiphfiflyIVICEII‘IIEIICIIH’EG- I311,
{OISE} A XIIIXIIII‘I: LIIII‘IILII‘I-IILLIIIIIL IA (4.8 g, 213.6 11111101), IIIILI>I§-S«NIL-thyIphenyI
Isocyami‘e {3.8 g. 23.5 IIIII‘IIII}. LIIIIIIII-‘III’II LIIIILIIIILIII: (a 'I’LIW {II‘IZIIIS} iII {TI-11363;: {45 I was
5III‘I‘IxI III mom IeIIIpeI‘IIIIII‘Ls overnight The 223266;: .IITIIPIIIII‘E was SIIGII with water, Saturated
21611180113NEII‘ICQIFIBIII‘ILI‘IIIIE.andIhGIIdI’ILIIIW‘CI N22801: IIII: smivem IIas IBIIIOI‘LII BI
I‘LLIIIIZLLI III‘SSSIII‘L‘T and IIIL: I‘LISILIIIL: W215QIII‘IIIIIJILIIIII siiisza gLII LIIIIIIII‘II CIII‘I‘IIIIL‘IILIgI'IIpIIy
{he}; IIILIeLIIIII (ILLMILL‘UILIIIX’IAII‘IIHL IIII:2(1:IIII.1 iIIIII-IteII8292319~<15.IIIILILII»II.3.II“
IIOIIEILIP311*} I)\- *{3~IIILIIIUX\’~‘I IIIGIIIyIflIIICIIVIILJII‘ILIUILIIL {III II IL IanIII} (6. 8g I3.3% .I' 121d).
-IR {(113633} S’FWI’L III}.2164‘?331111 (III) 6:36.86 (m. 21-1}, 5. .‘2;‘II}{III. III}.
3.84 {3. 3H1. 3.81 {S21%},JIM-3.1.1706 2H}. 2 «I2—2.32 I'm ZII .230 {5, 3H). 20 (III.
313}, 1.4551456 I‘m. 311’}. HSmMI-I (m, 2H).
{I} I 53I IIIILI‘IIILIIIIIIIL I C. D~I94I2ILIIIC§ICI013.3. I.11.103336.~3(x-I‘III-“III:“IIIIifIiI‘Iflxyéw
I}y I pheny IIt3241;111:1216 {AI}.
{1.12543} T0 II SDIIIIIOfi III"IIIILI‘IIIL3IIIa.I€ 13 (6.8 1.”?ImmoIIIII IIILIIIIIIIIIIII’LIIIIII ILLLILIII:
{I :1.. 1601111.} was added 211% III-5w IIIIIIIII 1131126221113512321361: (1.35g} EIIIII IIIIIIIIIIIIIIIIII
I’IWIIIIIIL {5 4g. 86531213221 The IIIIIL‘ILII‘L ‘W’LIS refluxed 1111‘ 6 II, CLIIIILLI. IIIILI'LLI wrung}: II pad
DEFINING» I LEVIIIIL‘II‘IIILLI, The {‘{ESIIIIIIII}. IeinIuL “.33 (HS ‘ILIII- LL!IIILII’IyI IICEIIII‘C, LILI with
SIIILIIIIIIIII aqumus NIIIK'20: II IIILI.’ amt-I brim. and IIILII dries; manI N22870: I’III': SL‘IIV‘LBIII' was:
IIII-"Bd III give» IIII: IILIprLIIBLIEII bicyclic am 1m: C.I-{9~.§\.Z‘LII3ICECII‘II3.3. I IIIIIIIIII‘IGII~yIILIII~I2
IIIGIIIIIKyuSIIILIIIIIPIILYIIIIICIII'IIILIIIIIIIL I as {:1 IIRIII IIILIIIII oiI IQIILIIIIIIIIIIILI ‘II NMR. (CDC1I
‘3 2.94 IS. IHIJ II‘i IS, III} 6.x'73I} 20 (m 2H). 39615134 {m- III}.3~'.SI Is. 3III3.33-336? I'm,
213'). 2...“I2.41 1:11 2HI.2.- 381‘II: IIII.1.1113-2 II {III III}, Iii-54.25 I'm. 8H}.
{OISSI IIIILIIIILLIIIIIL 111. I‘I-IIIL (fI~LilIIIIIIIIILXIII92251612112II33.3.1 IIIIIIIz-Iw3U.yi)-I:'”——I2
i1'11?I13£13va5aI‘IISIIII’I—EI‘ISHI’ I} carhaimaIe (ISIII.
{III-36'} A. mILIIIIL LII. \LLOIILILIIII amiIIL 1mm IIII‘LIIIILLIIIII‘L IL‘I3 3.52. II 11 61131131). 181‘6-
IIIIIIIII‘IIILKy«IIIIIIIIIIIIIIIIIIIE: (3.5 3.3;. II 3IIIIIIIIII.I~11{2IIL}. IEImmI‘III and IQL0:: ("I ..._.SL’5
IIIIIILIII III IILLIIIIIIII‘IIL (90 mi-) was SIII‘I‘LLI at III-III»; I'IIgIII. Afiier ’I‘II’II‘IIIIIIII. “I"IiIIfi’iIIB
91311113111191.1111 were 93.111111111115913 311 11. 7311': 1913113111133 1933123119. 11:11.3 11111733711313 by silica gel
91311111111 1:311%1111111111g1211131y (531.1 11191315111113 '1'1’1 1331:3131111111719131.3119) 111 1153191319 913 31119911951919
11311311133113i139~1t1111199113d 113113119 51115.31: g 313% 3139113} {1.1.1 .1 3111311 311111311112
{171.57} 1131111911119551112313.53 111111113) was 19711111911 31:'i'131313.1d1'1:1-:in1':311.131119 {540 11151.,
313.7 111111113} 1.1.1 913121.110} 1 1113...} 1'01? 5 31. T3113 91133911131135 191111913 1111113 H7321 111.311.917.119
130311131111 1:13"N'1‘11L)3ri'1'20 1113.} 11313511131399. T3313 1311x1111: 1.31113 99311111319131.3513: C333Ci2, 1313913 1.1393"
“31.301 13.1113 91.111111117111913. 1.11 give 131.9. 13121311911 11131311113 111113119:.33119~{1‘1~1111131117111921313)4;L
1121131393193113333 11191119151131}.1313? ’~1'2.~1119'13111.1;};'541191:31 31131131911113) 91111191111119 13:1 1'? .9 1.3. 88331
31-19313.) :15 113171,,3'311'3'93391-1'11'13 gIINS1'1R1'CDC331'11 191315- 333), 7 3413,3331137213 881111, 2313},
5J1 305331111 31:31.3-. 8513,3311}3.05—3.87 1"111,2I~3}.21‘1'1'1~2 73. {11.1, 2333,2552591131.233}.
2.3%23391‘111, 233,},2291'3331}, 2 11192.2131113 133.},3.314.3131 {11:1, 23:3}, .1118 .1541131. 353:3}.
31319111191131.2119 3.35.. .313 $1341—3'911133131131911.0113:1111;121:119: 1'7}.
{0358] 3:311)3.33..3‘ 11111111113991.319117g, 221} 11.111111 3}) 111113 {11119313111111 11113111111111. {'83 1.1.1101}
111.11t1113'f11-3'919 111313913 31110 1111: 31911. 111'151—3131113111)"3'3391122-131393131131{2 1‘ZO. 8 1111111133111.
21991911331139 {£31} 1111;}. 3319 19219-13011 1113131119 11.133119331131313 331124 31. 11.331311310331111. £319 11’111
1133311119 111333131919111, and 93'21131311111213 11.1 1,131.1: 17 43111931113191111111 3119911119 .13 21 131111“
1.1933119! 311111313 {'1111111111111111.39). ’H NMR 1C.13.)('33;3} '15. 9.90 {5, 33:3}. 7.85 1'13, J 8.53 332:, 2.33}, 7.01
{13...} 8.4 3-311... 233}, 37113313311 28111,.-I==='E’.3 .332, 23-3.}, 3.33 11...! 7.3 Hz, 3H,}.
3111911319131'1119 3.3" 2~1=1I11111913113191191“.31199131: acid 18}
{1} 3 59'} 1331131113 313113 113 31111311111113.311193' {:1 1113131 11111 31311311133139 {2.2 1:11} in 11191371231111353111119:
{2:3, ‘70 mi-) 3111' 24 31. 3113311111913 3.131 1115131133111; with 333% 3-iC‘3 311311131111 gin-'1': 2—133~
33913113;31116191111131.13991‘59 acid as 12.11 0331113313113 1111311113.) 1;, 879-13 3:39.313}. ‘33 NMR {1311111304311} 5
33.38 1311' 3.. 3H}, 9.91 (S, 3H}... 7.89 {13,11 3 8.13 Hz, 233.}, 7.33 113, .7 m 8.6 332:, 2.3%}, 53.851 {'11, 3313}.
113191-1119111’1119111.(\ ~~1..,02199111:1111’1"191113911291'1". 11911319).
{1331311} ‘7'1-191'313/‘1'111111119 {-51.1313 1: 110.! 133} was 1113139113 11113119 99111131113 113’ 2~21111i1193191129ic
119.31.315.13 g, 36.5 .03) 311 313.11191139131111191'90 1113...} 111113 1311-: 11131111119 was 9111131313 in 1111 i139.—
111111'91' 31:11:31. A 3113111171111 111" 19119913! 91111113119 173.5 1:. 4313.3 111113113) 111 11393131111111.1911:211113 (48'
.1111...) 11111.3 11131391! 1111131 1.131139. 111113 111111111911113 11911 19 3131' 111‘ 1191111911111913111119
11119111331311. "1"319 511331313 11-9171: 37131919111196 washed with 1:11.313 111111.91 31111511111913 by 5% {317.911.1373 9111.917
31.1 3191111119- '3 1.1919 1131131391311) 11331117137..1299.131.1'11'111111111111131113191121111, 1211:3121 as :1 3131139 solid
(7.11 g. 95% 3.1191111}. ‘33 NMR1(1i331-'3S{L)~1i1}5 113.332 1'13. 1131,5152113,.1975 3-12., 13-3}, 8.01% (.13, .1"
z 7 5 Hz, 1H}, 7.133 {1, .7m 7.31 HZ. 333.1, 7.21 (1:, .7 a 7.5 3311:, 333}. 11.45 (3,231).
43113;31:31:41.113. 4J4 314C444017044164413".4}~32342:8414}(3313334164436444144444443114.4441~4434‘4.'}*{14}E{'40}.
{0 4 4144 .4’433333343333‘34 334341334341: {1.1.5 31 42.4 31113304} was 2334343334 32411313 33453:. to 31 11113: 111"
43313231333114.3134: 444 (3.4 g 4-4.5 1.1313104133113342:—314411:sx3,.1231144113e {’2 fig, 44. 5 33133130.4.)333 3:311i1314'3:.35€1
3134.). ".4433: 31341113331: was: 43312333334 331 33:41 33:; 3111411, The rezwtimn 1331”: was (3443214644 13: 31
{8133;31:1‘33333‘3: 37333333414431.1333: 3313331} 334 ice33311113313334 333411343113 314 3:44}. 1‘432- 1‘8331341433g 3304411 31.».
44448431134...'11-‘11341614. 13-4143 1.133348431414 314114343234 3‘11 314331: 2{1341403‘31131334113'4}—.3—32
32141331333‘33433‘33133'441111133.113104133—4331440113:3441f; 135 31 4313333113 3134134 32. 5. 31.53% 3104.34) ‘44 NMR
{Ci‘KI'E-afi 5 44.34 331. J:- 744 4423.. 444,1, 7.283.342.4131. 244.}. 7.- 73.55 3131., 2141. “4.35 {'34. .4?» 2.4
443-: 14".1171163143331. 7443 4 "3.5. (if 11.9 44:3. 4.4443417 {(4. .xf- 1.9 142 14-4.}.4416 313.1?
6.9 44:13,. 244}. 4.23. (1:..4' 33.9 44:3. 344,).
4114161‘441134443416: 14.. 32454430xy3143831334,1-2—(314‘1351‘332411w4v33'4-‘n333143y41q314113332314413—4434434133: 34 41.
{4.14.624 Pip-15133111333: (2.7 g, 32.44 313111114} was 3334133 1311341311331: 111'4.1311131118144313: 44:4 {2.5 g.
S. 0 0 4,} ; {4. -4 31. :32. .4} 1111.1304) 11311341124 {4. 7g, 40.54 1713111314) 111 1111441‘4433 3'75 1114..)4
1123333441331 33311343111: 3.3331543335343334 {14 4124-94} ”('7 131.3'111'31ig414. 343443-11 coming. 41 3.31315 4441‘133‘e14 131134 1431: 14
was 3333543814 31-14143. 33032113314414 41:. 4413: 31331134111‘13334 13110 43131331; 1363:1733 3.1113131311113334.The 311313341113g
residux: was 1443;38:133-114. in 3113.132: and extracigd \1-‘1'14‘-3.~143}4£31‘3:122113: 4413-:- 3341: 4213.32.35 33.33211:
washed with 4.3143133. (41:43:14 03-421 N53280:, 4441231334 331134 3211:3331-1112:314,. T413: 81733343: 1‘35'414113: was
131314143234 4:}: 23141313333 13431333133110311‘311‘343}: {441434. 33111111313134, {1.341343444342144 413 3433133313321413333324 1‘13
3,136.3—3..~3.31133\\p411.33\41~2~33313331M113433341313211134~3,1:413111313312041'11 43344113333: as .3 3.844031 1.144 (2.3
g. 79% 31412414}. 41444431444434.312734 143 810 (14...! ”3‘. 8 44:1. 1441..7575—7. 7 31:11 :?.44).,.'79—17.54} {311.
21:41, 7.28 3'14..'-'—'—'l- 4.41.442. 4H). 711447.08 {11:3, 21.4). 4.415 3'33...’ ('3' .‘1 1.42:. 2441.14 483.2344333. 241.),
.73 (:3 4441.2 .3. 774.133.2441. 2. 4 4 (313. 2444.4 241.- 36.41 4433. .444)
{04634 44'4484'441fii448426 4.4. 4-3244413?“4::-1411.1:513413113341'14«1330“.7: «4“34143331311111111312111111“-- n
3141333334:33‘ 4'1—31431—131‘112431— 4 $14142 401313134431333‘443631211114341yd3: {j 4 21.
{41111-4} A 130134314 31343113311: 3141333434 8 {3641131331. 3113341. A"43.yd113:1};531333343313131113: {281} 313...
2.4 131313134) 433 3301:111311'13‘1'43’: 342 31341.} was 3314143113423:31.3413143313 13f {ECC {501'} mg. 2.34 3131113341431
31121031311143. {'4 3311-.3. A4163 33133311333 3113it'33131n 13.31133333111313. 4m 45. 331341.13 “3431143331334 1311331119143'113:
41 (8414.4 mg. 22 331333114) 113 3:323:1033413‘443 (411 1134..) was 3334143314. 1433211 {10331313333214 .131}; 3313317134 33133.
“4433: 33134411 31.33113 1411:3331!13143131141433: 444131113: was. 23.333133311113134. "4411: 13833411113; 1:324:39- 3 purified
by 01141313133 c4:1‘3:1113310333313334133' 313923 3116113333104 in {4.41:4}41314414184443.1184 13‘: 111 ve- 6142—4444342
.013}-'3:1413:31y 4331433331332 .4—14143y3i1‘33q 13433332044332 ~}='4}113§:3“41y 4.413433431112111.— 4—3-‘41—2—131133—
331411313311433:33234341243333343: 333: 33131314133341.1133 33314414 384? mg. 31.1% 3143:4341. ‘44 N‘3‘4R {C 47367.13} 5 (4.8.9 3'5.
444}. 8274414431.3. 441}.72—7834 3113.444). 7.42-7.52 11311. 2.441.725 {34..41: 41.3 4-433. 44:41. 7.02“
322-
209 {111, 4H3. 4.24 {5, 2H}. 4.05. ('13: #20 HR. 2H). 31,43,419 (111 4H).'I.22leII {111,.. III,
IQ~2I€111114I4120 IIZ. SII3.
{0 1.65] 9~{'t’1a{1’~'I~(21«{4»{I 3~{2~I31I11'1X5'31I1en5‘I)ae‘Iaoxua3,-Ia1IiI1y1Ir1jqu E11321}!Inf}.«31011301653113»
hip-«011115014 ~543!}.«191000111x3=3h1211234311116110 216,313I3~N~§941211I1IeycI0I3 .3. I I 1100:1118 0;—5*I}~,EV~
{24113011133-5111001313211115 3313211011111016 11.311611: $11I1 (SW3 12313;)
{I} I 66] A 3101161111 QI‘Iunihfl I111e1‘:1111:dhli12 II”) {6513 (32611133., 0.95 00 in
{Iichhummefiume {4110.3 was 11001111 511111 1.131111161111.131‘11111011111201'1111: I .I (223 (430 mg; 0.12!
11111101} in dich 1etI1111111 («I 1'11I-3 I'he 11236111: 1311» stiued I11? «I I1 Ihen Ihe ~10'I3011.1 13as
GWEpOI‘LIIECI. This regidue 31:13.3 IIissuIvezI 1711 120111.11th {5 110...}. they; NEIBI'II (I00 1113.3. 2.6 11111101}
x3v-‘213511dthzda The 111132111131 was stirred 1’01? {5 I1. 011111 quenched mm 105“}; IICII 11121101111. AIIGI' the
31031330131315 eva3301‘zfimi. 1'1 21303110 with 20% NIIOI‘I SGIIIIII'H‘I. e’xImeIed 1'I1
die-I1I11m111eII1z11Ie and evapomflw. The 1011120113.: raking was; 311311113 1110111110
eh1'1311111111g1‘2131I13e' (ICI‘III 1111301211112. 0.3% 1 ‘IIIOII 1'11 dishI111'111'1101I12111e} Io ghe {he 3311;101:101 1'15
00;: 231113112: {4150 111131,, 5591'; yieId), III NMII. ICIXI‘Is) 6 8.30 {1.1. .1 28 II}; III; 2.9-4 {:1 III}.
7 ?A'I~'?.?’8 I'm. III-3.3.?.4I~? SI {1112 II},? 2‘3? 213' {111. 3H}'7'II ('31. II-I33 111132.09 I111. 2B,).
686 .! === 8.6 I‘IZ, 2H}. 6.'?3«6.?FI I'm, 2H}, S.IO«5.I6 {111 III) I.62 {111 2B}, I (II {14.2" -== 6,9
III, EN} 3.851;: BIILS'34 15.1 2H}..143—348 {111. III}, 3222110 {1111, EH). IRIS-Z 0311's 2H}.
3(10%I14 {11L IBIS; 73—2510 {11.11. III}. 2.20 {:1 “53.2I9~2I35 (111,, 3H}, I .90 I .96 I'm. 2H"),
I481 .53 {113,7 II I '28 I.3~'I{111.6II} {1.1.16.9 Hz. III} III: 1011091:13 1azc€3
using I 01311533133161 of 0112101; acid in eII'mmI to give: SW III-495 as 11:11 OI'IlwhiIe 300.11 (470 mg,
”I’MILIIII 11131I13£I I611 “C AIna ILxxIIf-MI‘S.01 1 2II2IT13:CaIc11I111icd.“I3:( I1I SI; “.02; N
1:I1£I.I'€1:I'6%.SIII?.06 N ‘3?6
{GMT} {XA‘III‘LVTI0—IIII11133/31I101131II{I4—(2-{p—I{.III~{3“{2-
11'1e1I'1c1313r‘Ic'1I,11.i{I'1’110:111'0131131I(11133-221221hICycInI 3 .3. I 311011—9-
3=I 3 01212341111000) met'hyIIpI1e1111xy} I3~I ~331'p81'21x1'31yI}11101'I151II~13IIaquIn11116100441110) 61110 {III}
13101. (SW 3-5505)
{ N
\Vgrfi‘ . a"; .
01:113 A
.1 1Nx 0».
( \1 fl/ V"V"1»12~.,2“‘11-(“2‘1 1. j
‘1 if '0 L?) H
\I/ i L x".
if" x‘D/W/
CH: \ HOSE-£30011
{0258'} 111181111811131'8 2.11 A11831'!{1«1111111111decy1}134113111111311:11.113. 11.11111'11111nn.111-;'11w‘1 ~121~
1111:{1'11121'541‘16111y11112.113; 1) 1:111:211111'1311: (1311}.
{016191 A 1111111111511 121‘ 56111111111311}? 311111113 11.11111 11111211111111.1311: 1C“. {3.11 g. 1.18 11111101). 1311118
110111111.311111111111111111511112.(151.41g. 12131111111111. 8112.11 221121 11111111.1} 111111 11121;.131182-3 1.2. :191
111111111} 111 111:811111111'11131‘90 1111;111:5111 311111111 211: 112111111 {1113111122111 131111111111111111111.111112111113
12011111111111.1113 1.1111111 81113121111111.1111 111 11101111. 1112': 1112111111122 1121;111:1811-1115 1111111111111 133,: 51111211 1
12011111111 ch111:1111;:1111g11111111y {513-11 11111111311111 111.111111131111111111211.111111) 1.0 giw the (1125111212 1.111.1:111111<1«
{3111113151211 11111311112111.1111: 511 {11.11 g. 8.6% $1111.11) 113:1. 1.1? 221.11. 111111111. 1.111.
{11231in (lg-11111111111113 5.11 (2.9 g 4.1? 11111111113} 111118 1111131111811 with 11313111211111: 111113111112 {‘3’08 11113..
13.9 11111111!) 11.1 111111 1, 1011 1111..) 11:11 .5 h. The 301111-2111 was 311-1111023131'1 211111. 111% 1111111211115
1111111111111 ofNaGH {21) 111.12.} \11'213111‘1111—311. The 11111111111) was extracted with 12CL‘12. 121 {war
118111 111111 31111111131116 10 118 111111131} 21111is1e1A’m1911811111111111213c21319-
11.11111111ssyc!:0[3.3111101131131111'}A?(21111311101);5411121{11111111111131} sfie (11312.2 g 9:13:11
3112.11.11 as 11 112111. 12111111.: m1. 111. 111111 11} 1:1 7.1113 111, 1.11— 11; 1511'}. 13.121.23.311(111.2111.
S.111~5181'm. 111111141111. .111}..10~‘1~1.11‘." 1111.211}. 2.6.1512. 1111.31115-1258 1111. 21!}.
2.39.24?) ([11. . 2.29 {11.311}. 2.112132211111111 1111.183»! 941111. 21-13 '1. 18 ~11514' {111. 2311-1}.
} A 111111111011 111111111111: 1'1'1161'1'11111112116 2.1%. (3143 mg. 111311 11111101) 111,1:111:1131111111161211.3111: ('4
ml.) 1111111 1111111613 11111111 511111111111 01'" 1?. {380 11112,. 11.22 111111111} 1'11 1:111:111111711111211121111: {5'1 1111.»). 'i‘ht:
11118111111111.2111 5111113121 111114 11 1118-11 1111: 31111111111? was 132-1111113111‘11'11111. The residue was 1111131111121? 111
11111111101 {5. 1111.).11181'1 : {11.11.1111}; 2.11 111!) 11:11.3 added. Th1: 11111111111: was 311111111 111111311,
111.1111 (11111111111211 with 111% 1113.1 30111111111. 11111111 30111131111125 31111110111168, 11; was 111151111711 1.11111
11.1% 11138911 50111111111. extracted. with 11.1112111111111191111.1111: 1111121 121-1113131111311. The (1351.111111g 11331111111
was 111111111311 1:131 111111111111 c1120n1a111gmphy{1119.111 111e1112111111. {1.5.1111 11111-11181 1111 1f}11:111011:11'111'3111111'1131
1'11 1211131111. 151111111112 11111 the. 111111111: 12.95 mg 128111113111}. ‘I1'N\1.11.(C1)C‘1311‘1 8211(1'111":,8
1'32. 1111. 2.9515. 1.11)., .33‘1.28 1:111 3111.1~11~- 51 {111.211}.2.23—2.24-{111231'1}. 111113.111}.
2015/023954
102.4108 {m 2H,}, 6.36 {3L ,1 8,2 Hat, 2,}:{Lfiq'1333éifl} (m, 2H), 5.m»5.i.6 (m 1H,): 4.63 {s
216:1} 4.84 {’q.‘ 1'63} HE; 2H,}, 38% {s BHjL 332 {:3 2H} ”443% (m, 43%)., 3,23 33.31 (UL
2313.}, 3.99 {br :3; 2H}, 2.39%.(33 {m 4H),, 2.36450 (m, 33H), 2.29 (:3, 3H,}, .2.3?~2.2~'1 {mg 313),
i.8§§~1.94{m, 2H}; 13404 .5? (m, T33}, 3.23M .30 (m: {Si-i), 1.2,! {3, .3’ 6.9 Hz; 3H). The:
{maiam Bah was prepared using 1 aquivaimi ofumflc add in ethanmi to give SW ’VKSQS as a
flight {mm-n solid {388 mg, @5533?» yiczki), mp ESE—E134- ”C. Amati. ('(3593‘iEfi3N?(f-H1:“23320):
Caimfiai‘m , ‘f—‘Ex C (viiié; H 7.415; N 3.93, Found, 3‘31: {.3 {3438433 H 351th £3.63
Tamra i; Additiengfi Exampies ofdual—dmnain sigmanz recaptm ligand drug mfijugme
mmmtmds, ding Sigmsxfl mmmm iigamfi mastin whinging compounds am} sigg‘nebfi
mr iigand erastisibajmiug caningai’e mmpmmds:
Structure
WO 53814
WO 53814
WO 53814
WO 53814
\\\\\\\x
.........................................................................................................................................................................4
Oi“C
W111
SBQ...
WO 53814
13-0
Biuiogicai Activity Assays
{U 2 73] The fiaiimwing are assays; that can be. ugefi m evaluate the biwjgica} efficacy of
cmnpmmds nf Formula {3.},
{02?ij The nwflmds amfi cmmmsiiians fiascribed hare-in utii‘ize laburatury ie‘uimiques we“
known {0 skified ai'iisansq mm item be foumi in iahme‘xmry mautmis such as Sambmok, 3}: m“
(15., Molecuim (Honing: A I‘dabm'aim‘y Manna}: M ed. (302:: Spring timber Laboratory Fi‘SSS,
Cold Spring {3133‘an N ‘x’; 20m; Spacing i}! L. 3! mi, Cans; A i‘.i(‘n‘at0r}v‘ Mammi, (Said
Spring bm‘ Labm‘afim‘y I-‘mss‘ Cum Spring Hawking, N‘kfi 199$; Nagy; A“, Manipuiaiing {the
Manse Enfa'hryo: A. 1'_,zihct:x'zatnn*}-= Manna} {Tifaird }, Cold Spring m, NY 2003;
H'm‘kmi, fig Using Antibodies: A Labaramry Manual; (303d Spring, Harbor Laimramry Press,
{503d Spring i-hfibm, NY 1999; and Can‘mhex‘s, W), and Cuidharm L. Modem Maihmfls 01‘
Organic. Swathefiis {4&1 Edition), Cambrifigc University ¢ Cambridge, KR 2984,.,I
<3— i
Methods of adIIrIinitstmtiuu of pharmmammalis and {Image re‘ginmsg can be date: minim
IIIICIII‘IIing m standard principiss III‘pharmacy:Iog}: weII known skiiied airtigans‘, Ixsing iIfIIIIIIIIds
pmvidm by SIEII‘IdEIYd ce {Mrs such III; RentIi.ngII_IIfI:‘ the Science and Praclica (If
I-‘IiIaI'march-' (MITIIIISII Ii. Ciemmm ed. 3981 ed. 1995}; Hmdmam .LG., :33 mi, Gamimam (‘1'
IIIII’S ’I‘Im I’IIIEII'nIaCI'Iiogicai Basis of'I‘héfl'éipmiicm ’“inI'Ith ELIII‘EI‘IIII McCil‘awi-IIIL “396.;
and Rowe, RIC.a :Et‘? (III, bmok III' I’ImrmacsMIMI Excigaiems, anih EifiIEOIh
Pharmaceutical I’I‘Izss, 2881 As II In the pmsmI IIeScz'ipIion and IIII: ed {:II'II’stS the
singular Forms “2:", “an” and “this” an: Inm‘nded II} Inc-Iude the pmmi Pawns as we“, unissm the
CIIIII.exI. Ies (IIIE‘II'Sflk-‘iSS.
Toxicity Study M’efimds
{0174] Six aduii femaIe IIIICI': were submtified In mummy. The sIIaIII desigfiatimz of the.
mige was {ffi’I’BL-I’EII PIXWIGHS promdunsg incliuded 4:13,ininiraperimIIeIII IIIIIIIiIIisII‘IIIIIIII QI‘II
I‘err‘optossiswimming drug 01‘ I-‘IIIIICII: cmmroi ever IIII: caurae BITE weeks. Mice ware {USO
pravimueiiy IIIII‘I,3pIIII‘Iited ianemuaiy with a KEKG mmgrafi {Bem'nen DEVI, If: 31.,
Cancer RfiSI 3?: 31432—4442; 20} I}.
Ceii “was
{$311 '75] CFf’I'XCuI, BKPC“3, $690I , FANG! and IVES PaCaAE 863$ Zine-s new: (dimmed
I‘rcsm American ‘I'ype (3131:1312 Caiicatim (ATCC, I‘vianasgas, VA). SYUJ (:31? first; II S}-’“II(WI£II
sarcoma CEII Iine {'I'x’awaifi A, at 32., Cancer Lett. 204-: IOfinI I3, EGG-I}, was III-Miami by 131'.
Brian Van TIRE: {Washh’zgma'l LInII-‘EISIIgI’ Schmi LI'I‘III‘edicIne, SI LIIIIIS, MG). KCK’Q‘) cell line
was IECI II‘OI'II II human MUG I waxpmsaxing parmreaiic mime-r 9f transgenic ITIDIEEE {Besnmr
at III Cancer 'R.c>sea.rc'II 2m i; 1?}: 243344435 "E‘Indar eat III I Immunm 2,08%; 33!: 3 I 1643 I25}.
'I’III: KCKI’} ceII Iine was Immidefi by III: I’in’ku I‘vi’ukhmfiee {Humanity fifNflfih Carmina,
Charming NC). PARC»! mils I [ere mIi‘Iurad in ccu’s I‘w’lfldifit‘d Eagie’a Medium with II»
mM Lxgiumnine, L5 gfi‘L Sodium onate, and 10906 fetal bmim: serum {FREE}. III-1&3.
PIEZCIIAE ceII fine was CIVIH'LII'SQI In I'Juihacco’s II'IIICIII’IMI IIISIIII Medium wIIII IO‘fc‘EI PBS and
% 3101751: serum. BXPC-3, ASPCA and KCHC} (321$ Iinea wens cultured in RPMI» I 6%!
n‘mdium wifi’; MEI-‘25 PBS, SYDJ AIIII sarcuma $38533 ware- cuimmd III Duibficco’s Mfldifiw
EIIgIE‘s MEIIIIIIII with HIE-"II PBS. Aniibimics, panic-Min {300 mgf'mi} and strepmmycin (108
mgfimi) were added In I‘he media and. ceiis ware mainIIIinecl In humidified mr III ‘3? “(I
III-III: 5% C02.
13:?
Statistic-'2;
{0136] 81211151111331 1:11:11 31585 211113 1111111 11111111111131 were. 11811111711181! using 13111831131111 P113111
11111111115118 1815:1811. {1 {S1111 1318,1111. CIA). 118.51.11.13 111818 expre.181-.11 115 11182111..S13 Y1-1. 1:11 :11. 31.11111. 3
11111311gic111 1811118111811. 113511 1111111113 ‘11-‘131‘12 81118111111811 1131’ 81:11-12 fitting 1111111111 1.1111311 1111111111}: 18111121
drug 120116131111‘11131311. (311841 ANCWA 11-1111 1138-11 111 11111113118 the 1111381811888 .111 1111111 11113 111211 and
SW "1-1493 11131111111011 11:31:11 N*1_C 111111211113.) 18318. {3111311118131:11-11 3123 14851111124 111-1811 111
81111111211811.111-111118181111. 11.1 CBC? and 31108111811111511?: 11111111,11111.21 11:» 8011131111 111::- 1'111’1’131‘8111‘38 11.1
the 31.131111111111111 of 1:};‘31’3116 uptake, 831111111185. 31111 9 1111171 1111311313. ‘213 ANO‘VA 1121.1:
11313113(‘1311’1133-‘21‘1-13‘11'3 111118181188 11: 1111111111111111118. 1111211111211141-‘181‘81‘5111111811. 2111111311111; 1111111 11581.1 11111:}
1118 (11138181188 1188811 1.11.8 groups was 130111;)EHEC3 1111111 :1 Eng-1111115118111. A '11—1-111118 1’2 {1.315 was:
81111511181813 significan1 1111‘ 1111 13515
1>1.'8—1181‘.1‘11psy 131111.11'11’1111111111.
{1113?} 1211-1111151: .5: (3.1.3: 332) was :1 831: 1:111:11‘133. The hair 80:11 was shaved 011811111: right:
11111131 11-1131 1151111111 1131:1011111 A 1-8r1= 511111.11 111111111111811111. 1333L3\L[1111{11":11; 1131111111111:1.11 the r1131:
13.11.1111. 3118-18. was 1111': 1112131111. 01‘ 311? 1313811211138- 1117 111111111811. 1‘111'111111‘111 211.111 11111131 3‘11’111-‘1’51‘8
1101111211. Body 111815.;111 1111s 2: 1 1111111111
{0338] 111111138.- 13 ("13): 721?) was 1.1811813 11-1131 ”11381 (1.1111; 3311‘: 111111. 1 11-115 511111 8.11 {EV-'1')? 1111‘:
11113113331111.1111313131133131332111111131. '31Sub-2.1311333121531181118313313111111311211'11111213 1‘.‘11131181111111311111811.
1:111:11111111: 11111131111 $111118 11" 1131 fig!'11 1311333811;11188 11118 11.111:1111111112. 11111111113111“:- 1 41—51’11111
11181811118811‘11-‘211‘. 11.111811 111 1118 3.11.11. {111811111111 11113 1.1121351". "1‘11818111‘1315110 112151-13 01‘ 1:18.11 1111‘
111.111.1112 1'1:d.1.‘11".1118:1.111'1111111011111111111111}- 131111118181111171111111.1011311811211111115 21. grams.
GIT-‘9‘} 38 (31:11) 73‘1 2111 11 18111018- 3111. P11518110:11111111311151; was 111118.11. in 1111‘s
21111111111, 11111111 13111111111111 01 1318 18211 13111115 {)88111111111111513111118 81111111 1116 8118111813 1 1:118 18-111
1‘1;‘111‘13811. 1.1111 1101111111111.1181718111183118521. 33113312111‘1‘308111—‘35 1111111111 11111111811 01-81 1111: 1111311.
13.211111. A 13:111., 3111112111111180115 11111115 111215 111'11'8110881'11118 1111111321.: 51:11:18. This: was 131111.111 811811
11) 1.1111181‘11-1‘11g11113111135. A 13.21341 cm 111111118181 1.11113111211111g 1111‘ 1:118 51111.11.11-11111.11.11-111811 1121131111.}
8111 1313.1118181‘113881‘ 183:1:111181101'81 131: 133.1111 311811: 113.11 111:1 11:15.11 01' 1112111211 111111183801
111211111911. 1111111111 and 11:11:11: 1311 11' 1:11: 1111111111.}131111.}!11-8111111‘ 11-115 21} grams.
{01111171 11211111118 3‘) (3.1.): '33?) 111115 3]?"211131‘3 11111: 1851111113. A 311.1181111111811115 11111118 11121.1: 1111111111118
111-81 1118- 11111118.. ‘3‘183 11111: 8.11111; 111.311.111.11‘1'11211. 3.31818 111111.111 1111111213 111‘ {11311313.1’13151231331‘36 {11‘ 111111111821
'11.;1-‘111‘111111111 1 111111;»- 1‘211 were 1101111113. Bod}- 1181111111 was 19 111111115.
{018.11 Manse 33‘. {11): 73411.1} was 11 1631: (30111171113. T118. 1121111 811111. 11-11:: 331111113111 01181 111.8. right
111111.11”. 11113113111118! 1111-11’1. =1 {1.6112111 111111118181 111111 11111118111151111111118 was 1.1111811 .111 {11.8.
13-3
2015/023954
righI: flank. TIISI‘I: IS-EIS no IIIISIII or I‘ICIIIIIII' discharga III diarrhea. I’I)’{II’EII.I€}I‘I and body fat wem
IIOI‘IIIIII. Body ’II-‘eI’ghI ‘WE‘IS 2.3 gI‘IIIIIS.
{0182] Manse I“ (TD: $33} was: II‘SSI‘III'I with test IIIIIg. The IIIIII‘ com. was IIIImIIII. A. firm
SIIIICII'IIIIII'JIIIIS mass was paIpaIIII: IIVSIIIIIIIg IIII: IIIII‘ SpIIiIa. The SI‘IIIIS was LISIII pIIIpIIIIIS.
SIIggeSIiIIg pQSSIbIfi I'IIIISCII: WIISIIIIg. Them was IIII IIIISIII III: I‘ICIIIIII‘ discharga I'II‘ diarrhea
IIIIOII and badI;II.‘II “me 1’1“!de j II‘i was :32 ngIIS.
Gross Necropsy I?.KIIIIIIIIEIILIIIII.
{0183] Iv.ch'IIII ing MOIISS A. IIII: I'IvII’IdHRGHN thickening noted IIII 33m:IIECIIIIIS):
SSSIIIIIIIIIIIIII WIIS a firm mass IIIIII‘ IIIezISIII’eS 0.5 S 0.?! cm. A 0.4-» x 0.1 cm iI]I§§I£.I:‘3‘I§3(I area was
IIIIISIIIII the Intseni'en near IIII: IIISIIII mien. and \I-iIhIIIII being: IIIIIiIeIIEm ITILIIGory. passiny the
SIIII III am SII IafIsSad II IIIIIIS A7 mm EIIEI 31IISigned {Imus was acted III IIII: I‘c-IIZ
IIIIIg. The beam and. iiwr ware I?TII[II}‘ . ’I‘IISI‘I: ware no gross; ISSIIIIIIS III Ike IIIIeSIIImI mam"
muscuIIISIIISIIIIIII system. urinary sysI’eIII. gImIIII . IIIIII’II. IIIV mus. 533mm. admnai
IIIyI‘IIId. pituitary, III'IddII: ear. III cw:
{0i S-‘Ij RI;ageIIIII'IIgIMOIISL‘ E the \LII)\.L!I&HI..OU\ IIIIISS \MIS mu IIIIOIIIIIatIld. and IIII'IISIIILII
I». {III cm, with an BIIEICIIC'II 3.0 cm IIiIImetsr . The SIIhCIII‘IIITIeIIIIS IIIIISS was ’IIIcaIIII’I
SIIIICIIIIIIISIIIISIy {war the. IIImbIII‘ Spine amt rigm“ Imifiii‘al IIQI‘SIIIII. There was III) infiIImIIOfl iIIitII
the SpIIII: The IIIIISS projected ICHI!IIIIy IIIIIIIIIgiIIg IIpIIII IIII: IIIIIIIIIIIIIII. The fiver W’IIS SIighII}!
pairs. The III-:SI'I‘ III-SIS miIdIy mic. ‘I'IISI'I: were III) grnsskSioIIS in IIIe IISIIIIJIIII'WSIeIII.
i.II.II:SIIIIIII IIIICI. III‘IIIIIry SySIeIII. genital S}ISII:III. ISI'IIFIII. {III-"mus, SpIeeII, Iymph IIIIIISS. atIit‘éiITIa-I,
IIIyI‘IIId. pituitary. IIIIdIIIe ear. or eya.
{0285] RSgIII‘IIIIIII \IIOII'SCL the NUI‘CUIAHL‘OIIN WEISS. mitaSUYfld I. 8 III “Ex I. S cm and
ifl‘fisd It?! SI‘IIJOIIIIIIISS {he II‘II(I~II.II§IIZBI1I‘Spine. The IIIIISS was IISIe—IIIII. firm and SIIgIIIIy
IIIIIIIIIIIIL The h"fi:1’£ and fiver were miidiy 931:). There were IIII ngS IESIIZHTIS III the I‘zIIIII‘y
33.SSWm. -SIIIIIII IIIIS‘I LII‘IIIEIi}-’sySII‘m‘l, EII SySteIII. III'IIIII. IIIyIIIIIS, Spiean. IyIIIpII nodas.
adI‘eIIaII. IIIyI'IzIIII. }3IIIEIIEII'}I"._ IIIIIIIIII: ear, or eys.
{0286] Regarding E‘I/I'IIIISI: I). the SII.I}CIIIIIIII-3IIIIS maSs measured 2.2 .3 {3.8 cm and 233' {Iver
(III: IIIIIIIIIII‘ Spine. III being Iimii‘ed by meaty. the IIIII‘SI'II SIIIIIIIIIS. pflIC-ESSI‘IS fifths:
’SI'II'IIIE: IIIIII have bean. MOIIIIII Iii}; the MINDY. The Iiver was .E.IT.III£II}<" III-SIS. Them were. no grass
ICSIOIIS III the IrIzzSpimImfy SIISISIII. IIIIcSIIIIaI {me-I. IIIiIIIII‘.IIS}SI“.I.em ., gitnitai Sy‘SIEn’I, heart. brain,
I‘hyIIIIIS,SpIeeII_I_-IITlhfifidg'xfidt‘gflcfl IIIyrIII‘II piIIIiIIII‘} IIIIIIIIII: .III' aye
{918?} Reg;IrIiiIIg MIIIISI: Iii. Ihe- IIIIIgS wen:mmtlled pad MILIIQI’. The IIVIZI‘ was SIigI‘IIZI.}"
3331:. {hem \IeIeIIo moss IeSICmSIII IIII: IIIIISIIIISI mu L‘IIIIISIR?HSISISwm IIIIIIIII'y
system. genital sysim'i. heart. brail'i, thymus, spiwm. lymph nmfies. adrenal, ithymid... pituitary,
middie 83:“, m,“ age.
{0188] Regarding Meme F, {here were {we masses Boi'fld in the skin. and Mtbcmaflenus
tissuest. One measured 0.5 x. 0.5 :4. (3.3 cm and was Eocawfi in the skin, and {he m'hisr ed
{15. x 9.5 x {3.2 cm and was in {311:3 subwiaxwmxs -s 1)\-'er1yil'1gme- marnbm‘ Spine, There
were. no gross: Kissimu; in this. respiramry systmm i'megi‘imizi tract. urinary Sysifitm, ganii‘ai
, heart brain, thymus, 592mm, iymph “mics. l, thymid. pituitary. middk‘. em, 01‘
§~3.i5fupaiimiugic Fixaminafim‘l.
{0189] Regarfiiug Msmse A. nfsihi, ma’! infiammamry infiitmtes wem must? in ma
mesaniwic {at ihai incimiad. macmpimges, neutrophm, ¥ynzpifimc5tes and plasma c.6113, A
mamive sl'mgemeric Kymph node was normal. with iymphoid Eriyperpiasia. Ezisfimryi’asis and
dimmtimn affine meduiimy sinuses. In; the lung than: was moderate {ma} hammrhage muted in
one: feline, wifimui iimiiied by misery, iikeiy reiaiied in CO: euthanasia. Thaw were, an
significant 1852:3115 in the brain; hflafi, fiver, kidlfmyg SpittGl'L pancreas, 01‘ gastrsjintflstinal tract.
{(11301 Regardin21 M 0133:: R, mim to moderate ehmmt‘: peritonitis was; mmfi in the
ry and flung, the semsal surfaces; ufthe 5111211? and huge. imitating} 17am and summahg
as we“, as; mmmd the patwmas. This was characterized. by isi‘ihmws 0i” mammimgas,
tmzm‘nphiis, 1'}:1m)hocytcs, and plasma cells. axing mm New 0!" fibrosis. Mild mumsal
hyperpiasia mas: Imtmi in the iiaum. A, nmsmten’c Eymp'h nmie incai‘ad mar the. pmcrcas my.
reactiw, as dem‘ibmi mavimzsly. Nu {axioms were i'mted within in the pancreaiic hyma.
Mild {aerimnitifi was mied around {he gaii Madder and Mung this. capsular surfacc fifths right
Mime}; "Na other Eesions mare named if} this iiwsr m‘ kidneggfis. Miid capsuiar thickening and,
nwsmhdiai ,hypes‘pmaia went nm'ed ahmg; the spleen. ‘1"th was a moderate immase in
axiramadfl{any sryihmpoiesis in {he mi}: pulp 0f {ha . Thurs wars m3 significam issiuns
in the brain, he's-mt or kings.
{0291} ing Mouse (‘3, examination 0%" the iungs revcaied a: few Snm'ii fimi of
mmasfaais of the prinmry tumor. Wifitmm Easing Iin‘ximd by them}; flu: prinmry tumor
d his have {waded harm. as smafi bane- frzlgmemis wm'e noted within um mass. There
were in} significant it‘sims in: thfi- bffiti'fl, hit-art. fiver, kidnay, spice“, pancreas, 0:7
gastminmstimfi tract.
{91%} Regartiing M31159. D. minima! m miid chronic perimniiis wan; muted Mung the
33mm} Sili’fflCE ofihe h, intestinai tract, and Swami the as, with infhimmaiimy
13-3
cells and are-as of l‘ihmsls, 33 (lescrilbmi prevlmsglyu chi of perilfluiils we :3. 3.},50 melted 31mg
{hf} ‘ s ofl‘he liver and lililnfiys. N0 (filler legim‘ls u-‘ere meted. in the
gastrointestinal. tract: pancreaa liver, and kldmey’s. la the Spleen them: was a mailer-ale
lncmas'i: in mlullat}! erythmpoiesls. in the lung {here "were 2 small lhci of
gisyugnmulom3 acted in. mm lung labs. This was of unkm‘mn etiulogy; ml {weigh l‘nalerial
was noted in associatlzzm. ‘l’lsmor on into the lumbar musculature was; evident Tumm‘
wells 31 so clamly :21pproachedzhc: vcrl‘clrn‘al bmfiy and sul‘rmsndm a, amall bone lifagmsam,
wllhmsi ’beiflg lin‘tll‘ed by theory, presmned m l‘fifipffiifififm a dursal zs pmcass of flu:
Vertebral ‘lnmfiy: There wens. no signl'ficzml lesions in {he brain 03113331.
{01 {)3} Regarfiing Mouse. E, in the immaterial fill. mere ware lininlmal l0 mild il‘lllln‘aies of
nmcmplmgflg, lymphacyleg, neutrophils, and plasma cells, A mildly reamive lymph much: was
:1,m:§:c:llmu‘1¥w pancreas, as described prmrilmsly, "I‘llem wme no significant fies-inns noted in
the brain heart lung; liver, lidnaysl pancrrzasg spleen, 0r gastmlmeslilnal travel,
{£1294} Regarding Manse F, mild chmnic lmilis: was noted almg the l Surfilces
01‘ the lnlesilnal {ram and in Elk: lm‘y sm‘mumiing the 311111138??ng 33 described msly.
in one pancwatic lalmll: there. was less 01‘ acinar cells and replacenwnt by linemnphages :m'l
filtu'clblasls, presmnaltsly emmg 2m mtgnslon m” {that mastic!) noted, in the mesemew.
Mild pes‘imuitis was also Ruled an. the capsule and in the mesentezry Sum‘mmllmg the lclilneys.
Nu 0318? lssinms wgr‘c 130323 in the. 3:.3'msi'inai l 331:, liwr, 0r lzldl'mys. l3 ills: spleen the-r3 was a
moderate increaslse in th’mn'ledullm‘}; slyllnopialesls and granulnpolssegisa. That‘s: “6313 no grass
s in the; bmlm heart, lungs, m slmmah.
l‘len'lamlogical Tasting
{0195} A difference noted between. {he drug—Heated and mulml animals was the presence
of minimal m mmlerale chronic perllmllls almg the. samsal guri‘acas {if Elm lmasliml. mac?
and aladmninal organs: and in ”the. mesmisry Surmumllng {the ass mated in the drug
{realm s. Whar‘eax the minim} animals SlKfiA-‘Sd lnllriimzll to mild lbcal
inf’lamnmmr}! lnl‘iltrates in the Il‘lCSEfiTm‘y, Will‘lmll film'sbplasla. Other findings included?
elevailm: MALT and ASl mated in mouse {fl \‘l’itlmut helng limited by mam}; the gy
of lhls l3ml,lyr1gw2tsno: clear. The-m was {101 hismluglc Wigwam: liefImpalioccllulai' lfijm‘yi, 3:;
might be cxpecigd. Wilhml being limited by 133303733, mhcr genitalia} causes included
lmmolysfis ul‘the blond samplg, er bone: injury film] turner lm'asilm.
{lillllffl in 313011143: C there was hum)? invagion 7min lumbar lmzsmllamre, with l‘mgmentatlom
{117535213 without being limiled l3}? them}; likely that Ufa mammal pmcess, 3s wgll as
13-6
psuin‘mnary ,mtttastasis. in mums: 1') than: was invasim) mf'mmor into {ha lumbar nmscuiatum,
21m} 'fni1agmema'tion ofthe» darmi snimms pieces;
Tabie 3: m BRIO-:1 Count Rssaits
Mix-m:
’1‘ Miid ‘ga'iateiet thumping was noted,
Tabia 3: Difi‘éx‘emiai Res-nits
if) Neutm'phiis 1..-yn11p§‘1mytas i‘svhnucytes {iosimwhjla Bass‘mhiia Bands
: =
: 1
.‘ {1.1-1}‘1 1%} was;
=
313% “i‘éfigi""""""""
‘xilXblhmmsc
{mgkflfi} (mgs’dl.._} 31mm):
, (mgs’d’m
{um} {u’f } i
:25 2;? 4:424 «53‘ :35 45:43 51
3 acceptor Binding Pmperties Ofiknnpound SW V-493
{432921 in them: Experinm'ms, competitive g assays of SW" \495 wiih {ha
fluorcwenfiy iabeiefi sigma—2 iigand SW 1‘20 oi’stmcmrc
O 2
2 2 /
H /j'/N‘w/\VW\VXVV \N \z—Nez
2 A? NH
N N
\Q//
ware cz‘mduci‘ed.
{$3198} ASPCA team: {S X Hik‘gfweii} wart“ aseded mm a 6 waif} p'iate far 24 hours befim‘e
treatment. This 94:32:; were then incubated with 4’}, ML '33] and 5%?) £4??? 01"2‘5‘4’5‘ V1495 fer
3011114114195 at SWC. Suhsethmiy, 3811M mffluomewmmy labeled sigmaafi iigand SW 120 was
guided 5m Rm @4311 cukum medimn containing SW V493. Afiszr 30 minute {t’iiiatlmbatmn m
374*{2 £8,335 l-K-‘Ei't‘ washfid twim \S-‘Nih phosphaifi bufibmfi Salim: (PBS) and harvestecl with
{1.05% trypsin EDTA {Life 'I‘izchnn’iugiex Grand, Island, N Y}. “I‘hm‘eafi‘cr, the ceifis was
13-8
WO 53814
(11111114111111.13 111 3060 \ '
1: 101‘11111111129 and 1111‘: peiia‘ta 11we 1121311311 11111111 wifi PBS.
3:1‘11151111135113111111 (11'8‘14-"12E311‘11s‘ de1‘e1111ined by Haw 0140111111121? 1:FAC5C311.}.13b111‘33‘3. {3})
33311511111111.1135, 81111 31151:. .
{131.99} 1'‘LEG31131111115 (10111118111111: inhihilian 11111111115.111011111 10 11410.1 finmuswmiv
111131111113. SW 1.20 (531111155111. [1. {31:111. ('111112111‘ 14811222204209, 20121111. SW V1495 11111111111111
Panc— {1113319. H1191. data indium: efficient; bkmkiug (11‘3“? 12f} 11'11111‘11111iz1111011 wiih increasing
1:091:111111'1111'0115 111‘ SW V4495. "i‘hese 1113114111 11111121111: 11412115514" V4199 {31‘1"1'131'12111‘111 binds $15.3;an
receptors.
8V1- 11’9499 1113115 1.811111% 11‘3" 111114111111 Cancer (31214 1.111115 1 11 \"i 111:1.
{@2110} 11-1 1111131:“11111111111119 34111 1199.1}..9 1:24 {1011113 {18131111113111 {11“11111112111 and
marine. mum-1:11:11: 2111112111781111 417118.11 11111.1 5151113141113 5111111311111 1:111: 1.1111119 with SW V4441: (11' 1:11
1111113111“cmnpuunds SV 1 19 and. 131111111111, 1111141 singly and 111 sun‘sbinatiun, ware 11131411111141}. '1'111‘:
11 11111111.1111: 111‘: iC-m£1111ce1111‘1111'01111143. 11M {111‘ SW V's-49:1 '11'131' 11111111111 1121111: 221111:
1321111161 c1141 11111: 1‘11119—411HULT‘3‘CR1 333) {17le 4A); £1111(5119111111131111'111101111E§"2.3 11214.
fm‘ SW 1111g11i1151 1'11: 11111111111 111111.1311‘22111'1: cancer 12.1.41 line 8.1963 {.A'E‘Q'IC‘R' CR1..—
1763'735'3XFR'3. 4155}; an 31111112.011116111111111“:017.31 11M {11151-313 V4911againsthu1112111112111c111211i1:
311114} H111: MIA 911133—12 {1‘13‘CTC'13‘3' (“3411.44.30 3‘“1‘13 iii 4!: 1; 1111 1C 11111111C1W111111‘t1011 01 3
11M for SW V499:- 1'1131 211111111111 pancreatic 1:111:12111'131212 5.1111 14.513129! {.43‘iTil?“"£7.121..—1fi$233'3}
(.)}; 1111311111. K311: 1111111231111‘21‘111111 01‘" 2.2 113111 1111‘ SW 3149‘s 111111111511 :1 1111111116 11111181113111:
13111111111 {1122-33 11111:. (KCKO 6121111} (Fifi. 41?). in c1_11‘11pa1‘i§1111. 1311131111 111111111 1111112151164 2111 iC‘gu $401}
{11114 sagging: 211.1 41111112111 211111 1111111111: 1111111112111:2111113131131} 3111119 111911111; SK? 1 19 1: 1:11.4114111111
.9111. 1.1350 I» 54 11M 1111111111111 .9141 12111 111103. 1111111111: 11111113183119 91111311310314 41.11.1111 tested; and
equimniar11111111111: 1111' 1311131511 11.1114 SV’ '3 19 ex¥¥1ihiied 11.11 K311411311 11512111111111}! 11111111111
1111113111: pancreatic 1111111111 C1111 3111121: 111511111.
{0?.81] ai 111118011121 1:141 tines {PH}. 41". SW} 1 ME 1 11131161111) 2111;. 51111111111 10
S‘s-1 ‘5: 949.9 131111 1'1 11. .19 {11'1"1{11:11.11 1‘11 1171112131111: 1511:. 113111111111.11mg c1111c121111‘z1110n required 11) 4111}
51331111141111 011:102‘1‘ 13. but the 111122:31:11:11 28111 11413311131111 $.13 11.9.14. 4116111111131‘13011. iCia’s 1‘01
1111:3161 c11111;:11:11111d$t11:31:36 110111111111 551141011111 1121111011111 1161311 11-11111: 11.5 {11340119: :15;11151111.411': 11M:
5V 1 3‘}. (5.2 11314.; ii..1:1111.i11 SN" 1 3‘}, 4.3} 11114.
{OT-£132] 31111111111: 111131111111: that 3111340519 1111‘ more3111111141113111'11111 11111112111 calls.
11:11:..311133'1111 $1111111111 211111 1111114111:- 1111’111111'1‘111511; 11.111112111118133 and 3111111411.} 5111712011111. £11149 611.11111111'9‘11 ‘11::
11111 21111111011311; 1111111111.11111111111111.1145. 121111111 11115931111313! or in 31111111111311.1111.
12 231.111.2221" 2.212 3,“ 212" SW 'V «492;.
{233223} in. 221555: 21>: 2152221152225. 2215 21123511122125 2.1123552212112521 25215221522102211102221525 02’2212': pritsent'
2521121225 225125223221112 1025121525 2152152521212. 2322212355 22.232221 b3, 2212225111111 2111 22131121211355 2:522 222122221
21122211342133, 12 25111211221522: 2:522 52521121 21212212521322. 01‘ 21 51212123211211201'1 2215522112". T215 2221223121125 2212.121
performmdas"2132‘sfor 2513.155 33, 21s 2211 21152252222311 0'2 1120221; 132:22 21222-212222. 21552135 221222.225
gen-5221222312 52‘ 252152.255 27253-213511 59523255 (ROS; 22s 2111 211512532211 52‘ 25121150111031: 55:22 22521221. .2215
5212122111. in 292222. 5.33., 1-34 221‘. 127521211152121)i"A$2‘('3~2 55225 with 52'} 1232' 25512152222, 8‘," .229 or 311:
52221211202221"1112522125212" 23522212212 112215 S‘s-3 2 29 2522. 2:0 2211‘ 22:55 01151121551251212223.!52322111212522.2223 2'2 1232
SW V—zigs. 211 232631. 58, 25521225 1115-:- 521012-‘22 2212' (32152122554320‘3 {23201111535212} 115521.} 5512‘ 4 52.115
5122222 121221 3 33 324295 3 1.1222 2?.21151222312‘21 8‘2" 229. 211‘ 3‘ 2222211222222 5512121115252: 1212522115
02‘ 2212152222. and SW“ 2 29. 2232‘ 7" 2.15.5. ("M2221 2151122152 with SW "34492; 2.12122 21 51' 32212232122212 2125252155
{111121121122121222523.3 3 2212222122 2:225:21221555'3? 215222-7223:22011122212522 202122501'121'2125 32121013002.
{02.2241 211 2-221. 6‘. 17222111225 \
2112': 5215122322 2211' 255 215.322.3512 5215522121 {R (.23'325155 02"15135—2
222222122122 1521218 331232 8‘22. \-' ~4QS. 3 22M 2:12152212311132 S‘s 22 E2 212‘ 3 22‘1”" 2'12 1121 52111212121221:
2212521252: 512 2322152211 and 5‘s H9.112‘21211'15221'V52.0531112502 2511‘ 3'20 min C5225‘ 231V2221 SW ‘2«4232;
2122.22. 21 significant (522322} 2212352255 1'11 ROS 21215112155 *11212243002 55221215321552 251 2322152221, S3? 2 29 511‘ 22
01212112522222“ 221515102". 502151525122 12111212521221.122112511522 5252:2222. 2‘221‘5211 2:2)111111:21111d5 {3‘2" ,2 19 221122
2221 225222 2:21 c52255‘1'22151‘5i22gi} 222‘ 211 52121221313120“, 222152 1122 5225231212 2222': 2:
55111551125222.2522].
{02:05] "57232210112 23232111; 222112156 by 2225521322. 221555 2252221 2111;252:1122: that SW V4492; 15225
215221 12130522712122: 3.2222 2‘52'1‘5212252021'152:22:22 1253222 12121212242212; in 11211151522222: 521111151 55225.
Adininismficsn (.22’SW V4295 (121.21 213253552; 2’52 2117221215 ”2111171521 32225 2'21 Vim
{2.22216} 2‘ 221‘}. T? 3212212222255 232112112355 1'11 21152211 2111212127 2252111112: (1'22 1221123} 21242215:
11222112212321‘5221111 2:21 2122512512 212" {'35 "232.16 111251;: 24222 552212122521552. 21.111134251223221. 5112151122111521215 KCKG
212011551122115153222: 1111211155 51‘251'212152‘202252’.221222215-352‘211‘8'2-22‘" 34921. [2121212211. SV2.29.21.11117>;2122'5
0232171152212 222222 SW 29. 2152122 22 2323222525 12512. SW V4495 22532122215222. 221211121 21121551152211215112, 1552
2:21 11 52 32222222221111 522251522522 221221213111 32115222125 2.225}. "2"11552221522222152125 25311222121 17.111112222111222
212‘212211‘51'5152‘2‘51222342.212: E11 222“1 "2:215 5252115212123 2.21 2221221122 11115 2221111 21211122111, 42) 221.1217“ 312.2
2122215525 218 212221 211 S's-2 ‘2 42255215222552121255‘ 2.0111321252212151:2225252 21121123132110» 40 ,22'91211‘ 2:0
approx. 24-0 mm" 1131' 112212-11 11521212152115.
AdniiinistmtiMX of SW \‘végs (Tan Inm‘szme Survi? V213. (3f adc Cause-r in a Murine. 35*} ads}
System,
{020?} in. these experiments? in a, survi‘m'i améy‘ ofthe mic-e mpm‘ted in Exampic EL thr:
grimy which received SW \-’”~=193 survived 31 $80???) {FR}, 8} In 2111 Lather gmups, thc': mean:
sun-"NR? c‘iusiered at: amm'ld 18 days.
SW "x; «195 s {7811 Death m f’aym‘eafic Carmen
{9208] Cyis‘flnxicity ()fthe drugs was ex-‘aiuai‘ed by CELLTiTER—{i150$; Luniinescem Eel}
viabimy assay (Promega, Madison, W i}. szm—miic as“ lines were {dated a: a {iansity arsf'E: x:
m4 Eweii in white ‘36 waif, dear bfitmm games. far 34 hours prim his sm. Briggs were.
digsoived in DMSD £1216 simian); (finned in wimre mefimm to achieve {he final mncmmmion
of DMSO 1333 than I941. C6115 wars the.“ {mate—d For ‘34 hours and EGG pi {)f’fhe CEUJYETER—
{31.0% reagent was added in {each we“, Tm: {mutants af'i‘he memes were mixed using an whim}
maker anti Bultmquentiy inculmmd fur {0 mismtes a: yawn: {empermum Luminfiscence Signal
was measurad using a muitimmfle micmgfiate reader {3ioTek int-“.mm'mmsi Wimuski,‘ VT).
Difi'emnt drug cancentmfimm was d, in triplicate. To {cw-alums the eificacy of ma
{imga K‘isn aflhe mutupmmds Vex-":15,mic-timed, (m .1 pane? {sf human. and mum": derivefi
pmmmmic cancer cw, imeg m vim). Cans were treatadi fur 2&1- imurs with SW 1; «4-93, 81" l .19,
Erasi‘in, am an aquimoiar H‘Iixilii‘t‘. {ifS’fl i9 and Erastin, then CE1:1.1‘1'1‘EkvfiL033 viabiliiy
assay was permmmd. in was the $8.33? active-3 d, with {Cw ‘9 158 mt SW 19
dem>nsfratt¢d a madam cy, that W'Eli’: augntwm‘ed by adfiimg Erastin, Hmvever, SW V493
Shamx'td mhusl cymimxiciiy with i?~20 {hid reductim'i 01‘:ch as cmmpamd {.0 {ruminant with
the. eminiaoku‘ n‘tiXtm‘E of 83‘s? i ‘i 9 and Emma (Tahie 4 and ? These 1728mm indium: that
SW V495 is selectivciy delivered in mmcreatic canes-2.x cells;
Tahk: :3. 14535:: {gm-'1) of pancreatic? cal! “ms Una-Etta! with diffm‘em s for 2::- hams,
KCKO
SW V495
SW! WfiEmsiin
{Mean : $13M }., n L 3. P ”513.535
{{1289} Sinca E'mstin stramd no effeets m 51H pancreatic can fines, the inventors
parfiwmefi a {gammy comm}! nwnt using SW)»: ceiis. ASPCJ and SYCM GEMS wen:
plaistd in 96 WE}! plate. {wernight i, heated with similar mncfln’im’iiens {if Erasiin 531723}
hours? Viabiiity 3.553;" was peri’mmezc} Eifi‘er 24 hmiu‘s‘. Treatment with :8 ,uM EraSt‘in ed
in the: death of 84% TJJ mus, aw cmnpared to 2% {3f_.~’XSP{‘fw§. cefisf, {p {- {381}, (133%
N). This experiment dammsi‘mites {hm {Em Emstin used is biuaciive amfi the panertmic cal}?
Haws: are resiatam 1:0 E,;‘a§tin.,
SW Nil-495 Inhibim Cysi‘ine 13pm? and Generates Reactiva QXygen bmum
{0210‘} in these- expwimcnis, cystis'm uptake. assay was perfmmcd as usiy described
{Di:<m‘1, SJ. 6%: 31 Ce}! 30:2; 2-49: lflfii‘HiWB)‘ Briefly; ’3 :v; 105 ASPCA cel3§,.='\,k-*e¥i were sawed
o‘vcs'nigm in {‘21 we” plant. ’i'he. next. [33}: nails were. washed mica in pmwm‘nmd Na first;
upmke buffer {£37 {11M choiine chim‘ide, 3 mix-'3 KCL 3 mM (MCI; 2 mM MgCig, 3 mM Dv
35m 0.6? mM h‘ and, if} mM I‘iEPE-S {pH ‘14}; . Subseqmzmbu ceiig ware incubated
far 30 minutes at E‘F't‘C in 1 ml of‘thfl upmke buffer t0 depleta ceihdar iim’im) acids. This buffer
was then I‘epiaced wili‘i. 6630 m. uptakfi blififl containing 280 gm MSW V~c‘3-98 and 0.12 pfii
(80“ i H) 1'miiifn‘nnoi} m?1,—{3{3'1}“‘CEwystmfi {Armriczm zfiw’ied Chmficais, Si quis,
MID} and. incubated f0!“ 3. minuifls at 3?“C. Affirm" that, calls war-a Wished ihrce {imas with ices
mid uptake buffiar and lysed in. 500 pi. {if {L1 M mam; To this iysm—r, ! mi offigimiflmiun
fluid was asideih and mdmamixe mums per minute. were: Obtained by zxxittg a Scisfliiilmicm
counter.
{£112 '3 H iimstin has bean shown to Mock. aysiine Emmi/(c: by inhibiting cystincfgiummam
:mfipofim‘ {syswm MT} resuifing in R83 dapcndem ceii death {'Dimn. et a}, (732% .2623: 1:19;
§(}€3fi~i{}?23.‘ To Mama's this mechmfixn’x ASPCJ wfls wens. Matted in {3 we” mm: ’{m‘ 24
hours. (ire-13$ were. {then treated mm the same cancgntraiion 0f SW iii}, E-yrastin, combinaiim nf
S‘vi 2‘9 and Emsifiin, 523W V4193, and DMSO a9 .22 contmh A fim‘ that 2': cystim: uptake assay
was perfm‘med. {33325 treai‘ed with SW V4195 demonstmt‘ed a im}. in cystine uptake by
359-1: {35? mm lei-33‘ uysieim‘: uptake) as nomparsd {1135(3’3, 419333., and MW; in the cams {mated
with SV 1 £69., Erasiin, mm combinatiim QfSV i 19 and Eragiizn, s‘espactiwiy (@8304, FIG.
HA).
{82 E 2] ROS EE"EE":EE:\:EEE"E":EEEE":EEE" was med using TEEEEEE ROSE" ‘EEXEdE: Detective REE
{E3320 life. whines EEEEEEEEEEEngEEe. NY) EECCOI‘ELEEEEg 3:0: EEEE: EEEEEEEEEE‘EECEEE?E"3.E"‘S Ensimeiitms. HE:E€:E‘E§.~".
ASPCEE eeEEs: "were 3326394 3: a {Misfit}; {if 2 E; H)“ ceiEs’fl' ErEEEEE .1 Mac-Ea". WEE:EEE":Eear 330mm: 9G“
weEE pEaEe EEEE" '24 hams. EEEEEEcEEE were diissEEEE'eEi in {EMSO and EiEEEEEEtEE En euitm’: IEEeEEEEEEEE
£0 achieve 3 EEEEEEE GLEEEeeEEEEEEiiiEEEE LEE EJ‘E‘E‘EEE EesSEE'EEEEE E‘E-‘i AsPE‘. ECE::EE"3 EE'eEE: EE"eaEEE:Ei with 8 ‘1th
{EE‘SVE E9, EE‘EES‘EEEE. £15.3(E.€(E1EEIETE{EE£EE"EEEEKEEEE‘B OES‘E’E E9 and Emtin. REDS:3.35ij“ was: performed
one Emu: after EmEtmeni CE.its eEmaEed in: One EEEEEEE" Eben media: was meaned and
EUGEEL.-'we“ EEE RDSSLEEM‘EEAEEEE. 13:5.EE".mien E31 E‘s was aEEEEeEi. JE‘esceEEts-e signal was EEiEeasEEred
(2531:; a EEEEEEEE~“Had:- EEEELEUpEdEtfi T3"Eider (Bi0-Tek, EV’EEEQOSEEE. VT}. The assay was permruxed in
E) EepEicaiEE.‘3
{(112.3 '3} TEEE.‘ REES EeveE UE‘ EEEE: eeEEE‘E LE WEEEE SE‘E' V493 was E5 mid higher mmpar(mi
to 3mm. ’E‘ErEeE'E": was. no mere-213:: in the: ROS EeE-"ei En, ceEEs Heated with 3V" E E‘}. .EiE‘asEtiEE, and
equiEEEoEarrEEEEEiime EEE'S‘E-‘E 29 EEEEEIE Erastin aE EEEaECEEEEeeEEE‘EEEiion (Fig. EE 8pO(3)003
{5033;301:316 SW 331493. Can Induce": IEEEE‘EE‘Esie Agiepmtie Pathway.
{034] in these experifiiefiis‘". caspase—BEE, E3 "and. (3 .ELEEE‘EEEE'ss m": Eisused "in ASPCxE
eeEEs using the currespnnding (332551933 SEE—(‘31..EIEEE’ Assay according Eff! the EEJEEEEEEEEECEEEE‘EEET’S
insEE‘ueEiens {E’EmnegEL Madison. WE} Ihis Eissa} E3 bassd (in {E 3:":pet‘3EEEE3EE’EEEe.
which13 eiesveEE EB miease anumEuc-i EE. a sEEEEsEmEE. 0E EULEELMESL EEEEEE winksm easpase~
speeifie Euminesceace signais. Creiis Were seeded 53‘ a, Ey 032 .3" EU:b in white ERIE-wen,
cEear Emma: mates ER): 24 EEEEEEE‘EE beihreiEmmment EEEEEE 4 ‘UEVE EEE eenmuums. ”32h COI’EEMEEE
EEere then mixed 113mg" 3 Nate shaker)far 30 see-ends EE:(:1 inc-minim 3E room
‘E’EEYUELGE 90 nannies. Emumuceme signai was n‘sieaEwe-d usim. a EEEEEEEEEimdc
EEtEE‘erEEEfEEEEEze reader {'Eio’l‘ek). Assay was peribmrmd in EXEEEEECEEEEES. and EEK: caspase activity of
EJMSE'J was considered :13 3 base Eine.
{332E531 EEEE: {unseat Emeniom EELEEe "ElmsE1 EEEEEE S‘E’EE:9 Euduees caqusevE depwdem
apoptesis {:EfiaSEEE‘S‘s-‘flgie EE... eE EEE. MOE szem .2007“; 6:48), 311 West: experimenEs. 1 eeEEs
were fixated WEEEE 4 31.34 of SW 3.9493. S‘v“ E 3.9. EE‘EESEEU. and quEEEE‘EEEEar mimnre OE’SV E E9 and
E5. 336:: far 24 ‘EE. Using Ci. ' JERSE‘ECEEEIE'EE Assays. (33.393333 EeveE was measured E0
assess the ae’iixx‘ity EEE‘SFVE E‘E EEEEEEELEEEE of {he SEE M493 (:EEEEEEEEEEEEEEE .EIEELE {1.2:3.1324323"in 9 ENE“SE
V\arel'EELEl‘EEEELLE Er: identify ERE‘EEEZEE Eipoptoiic pmimE)" was iEEEEjEEC MLeEE3 treated wiih SW ‘E’
403 had a: significantEncrezise in easp333232314 9 (3.4 3nd3...7‘ E‘bEEE above e
E‘especiiveiy. “4,22 .UOE, FEI... 2233. Ema F:52. 3'28. Eespeeiive12“). EEE emit;Est. there was an
significant EE’EUease in caspase 8 EE3‘- 0 5 (FIG . 3C).GEEEEB'E‘8011390113368{timed did. not
U1 U.)
EECE'i\-’£fiiz‘~ mg: of (in: sS at a similar waamtmtimfix {Fifi}. . ’I‘rhfis‘t‘. vii-Suits wggsst
that SW V495: 2.21:1 his geiecfiveiy deiivemd to the. wager csiis and iis two {imaging can wm‘k
Symrgisficafiy m activate the ixm‘msic apopiotic pathway,
SW 35 Can hiducc: ROS and Apopmrtic ent: Ce.“ Death.
{01-2.} 61 The present: iHVfimUTS flm'mmsu‘ated that S‘V-‘v’ V «1395 can indum’: mmptmeis and RES
ganex‘mion. To was the mks {:fthesc iwu nmchanisms m: the induction nf can death, the:
afflicts —czarspass inhihimr and antioxidam {m the. efficacy of SW M493 “:2“? tested in
{E1638 experinmnts, ASN.3» i. ceiis were weamfi with M} 33134 (If 1E1.eami0xi(k1an ace-{fl
e {N's-‘sfiffi :38 MW} of pawcaspase inhibitor K‘VAIL and HMSO as a comm: far i hamz
Than, the 3 groups wave Heated with H} RN; L'thW V495 for 5 330mg afier which a
CEHITi"§"§i,Rn(ffl;£)i§‘ iity assay was perfurnfafid. 111:3. results indicated that V‘iabi’iiiy {If
cefls treated with SW V495 aione was d :9 39% scammed. to 6339-43 and 93% in mus
pwti‘e-ated with NRC and EVAD respectiwiy (Fig. 139;) at. {10001}. NAC was finmd m be:
more ei‘f‘éaiive in inhibiting SW V4533 aciivity (Fig. $3.? 3:1 (1082). Them: data dexmmsimie
the. dual functinnality of SW \49\ and indicate that it, can indium hath apflpmic and, RGS
dependant cafl (with.
SW V14¥3s Reduces Tumor (imwth and {inhzmc‘ss Survi‘mi in Moms-221ml fittiem Barium!
Ksnogmi’i 'a‘v‘Imieis uf Pancreaific Cane-er.
{0‘2} 3’] Aninmi Studies wen: pm‘fi13rntmiaccordingto me animai simmer; pmmmi appmvsd
by Washingit'm Univemify Inst'it'u'iionai Animai (Tare Faciiily. In viV-‘o amdim with mice wem
peri‘mmed to mmmzm the ef‘fkcts cf SW ‘64ng SW 1:9, Erastin, a cumbinafi'ixm LVf‘SV '1 1% F}
wiih Erastim and V‘ehicie‘. Tim: which ussd in {he in viva studirzs i521 mixhn‘e (£9594:
cx‘smophx’w and 0 i420; £53313?) mice {6 weeks {1301, Nmmnai Cancer Institute
Mbm‘alm‘ies} were injflctmi in fine right flank with 200 gal; singié: C2311 wapansiun of MAJ?)
ceiis in, RPMI micdim‘n {25 x HWIOS 8:139 per mouse} Mice ware- i'ili'idimflii‘iitd inm four
groups {It ESL eni. was stafimi when the mean {11mm diameter was -~5 mm. Mica
received daiiy inim peritonea} hizjemions with Riff} :mmies in 100: 9.1,!de of SW "VF—495 and
which for 10 days SW £9, Erasi‘im equimQIm mix of 33‘» E W and Ersmi‘in. rs were
nrmasmed aver}; other day er'iith a digiiai mfliper. Sex-mm mice fn'mn: different Hemmer}! groups
ware seat It} the Division ofCmnpawiiva Medicine in CM insfiiutim} for paihoiegic
Evaluatinm Bimini was Qijflwted £31)? campiflte bio-0d cmmi (CBC) and biochen'aica} anaivsis
{A$1 AM“, BUN, mm}, hiiimbin, and Cr}. {.h'gzms were cxamfimd gmgsiy and hisufiogicai by.
WO 53814
{8313] in. the: syngemic master model {KCKO in CS? ELM-3‘5), uni); the. SW V493 was
capaahie of ramming the mam mmm ‘X-‘thiflfl (MG. 143%, p — 0 113083}. Nmm {if the other“
:‘ewagems aimw {Jr in. combimliim. remiied in a reductiun in humor gmwth, and they 331 had
minim? gym-Sam rifles In the which {um’lmi}, {F16. HA, gt: {$.95}. The median StIWi\-’Ei1 fur fin:
gmup {Team} with SW V4.95 was 43 days cunmarefi m {i 34} _} days for This: gather s
(F {(1}; £48, Kapiam— Meier Surviwii curve, p (l {WM}, ()fnoigt, no gross abnon‘naiities in {ha
mice hehawim {grmming} or an}; drugareiated deaths were remrdmi. "This was: suppm‘i‘ed by
1h»: ed serum labs (CBC; A ST, ALT, SUN Mai bifiimhin, and Cr}, {KINGS 5 am} 6}.
in am organs amaiyscs (brain heart, lungs, aiin‘lmmry itract, Mdnays, five-r and
pancreas}, did nut mveefi any mbvimxs signs of’adwwsxe drug Aha». except a mild. 13s:ri‘£0fi:iti&
"Fabie- (‘3: SW V «193 Dam Nat induct: Changes in Binod {j‘y‘miegy {CBC} ia};
'i‘mammm (Ff CfiBLsfi Mice.
r"""““““““““““““ “‘Y‘EfiFETMfiEQEEM
TD TXfiEMMTfiET“
paw HHWgL) f {03311,}
Control I
205 $414 ,4 .u“ g.
.........4
{$3319} Tath 6 cani‘ziins data. from CBC (3f {T573156 mics: {mama wiih SW V3495 am}
whisk: {annual} for M} daysfi The difibmncea in ca.“ swam; between the 2 groups are not
si’ai‘ifiticaify Signiikani.
Tabie ?: STA V-=19s.¥.}ocs Not Tnduce Changes In Serum Chemistry Foiiowing ”Treatment (3%
Tamar g CS7BU§ Mic-e.
BUN (flfx‘eatiaitme AST Gimme. "Thad
('mg:’dl..) (isngdef) '
.J’ {ML} (I‘ngfdm Fromm
{gmg
and veiriiciie {cantrofi} fin: iii] (by-s. Tim differenges in, hintmmw values between the ‘2 gmups
are mt Stai‘imiczfliy significant.
{033 H SW V4193 was aims} , an. a HEAL? paiienbderiwed mange xenngrafit modah
whigh is more )! :‘fifimm’zt. Surgica? PDAC speciarnens {2&3 mm piecm} wars {jhl‘ained
am: :impiamad Submjmnemasly mm {has flanks 0i“ anesthetizefi NOD SCH) mice. Them tumms
wm‘: harvested and implanted in the right flank ufmhymic {mime nude mice {{3 wesks Mitt
Nau‘mxa’f Cam-3r ilnsizitu'ta Lahm‘atorifis). se mficc were {imam} with daiiy 5p. imjecfimis 0?
SW W'- i 3'4 and vehicle for '34 days, Mice were: mndmmized gm '2 gmups (n in {5:}. Drug
r}: was mama whm the mean Imm'mrs‘ r was. ~ {3 mm E‘viica received daiiy mm
mfimmm ingenious" with 31% nmnles Er: 100 13,.1.,;="Wn:u.,tsa MSW V2495 and V'Ehifi'lt fitn- 2
weeks. "manners were rummn‘mi awry mhar day. Mice were: emhanized when 11: mars d
a diameter 01‘“ 2 cm {)1‘ uicemted.
{0222: in am modet SW V3493 miu‘kediy siuwed (in: growth late of 131:: estahiishctd
{tuners (FKL 163C, p "x“ {3.90m j}. The median survival for the. gmup {mama with. SW V4495
was 535' days compared to 33 days fur the ie gran}; (FIG. MD, Kapiam lier smw-‘iva!
curve, p 0.18002}. Mic: migrated the imminent wcfi without ubvioua ufiitargfii: effitcta.
{9&3} S‘x’O—i Symviai sm‘cmm {SS} afis were: 3350 treaied, with 300 jungles SW
V449. Growth inhibitian in :1 mpidiy growing mode! {if-SS was (macaw-ea. Fifi. ME depicts
athy‘mic nude: mice xemgmfi‘ of 5553 as“. fine SW34. treated with SW V49 (3.80 tm’u‘fle-s} for
M days and the.“ ,ihiiowed, p <2 {IQDGL S‘FD xmogmfis required a snmiier dime a’fSW V-«ig
m achiave revsuii's simiim to those achieved against i’flAiii. These. remit; dmmnmate the high
efficacy MSW V—n‘I-‘FJS in bath pmwrealic "cancer and symviafi samoma and indicam its
sew-cave deiivew.
O‘aher Emhndimemts
{9224] Th5: daiaihfi ptim’: setsfhflh above is providefi m aid {E‘msie shiied in 1331s at?
in practicing the present disciosum. Hxnmvmg the dissimum dsscrihed anti claimed herein is.
not m If»: iimitad in map»: by the Spesific embodiments hemin dificiose-d bfiuause thew.
embodimflntfi 8W. inifinded as iflusiraiian af‘severa} alspsets of the. sm‘e. Any imt’
mam-Odiments are imem‘im m: be within the 39033:: {If this discinmn‘e, indeed, vm‘imxs
nmdifica‘tiens fifths digcmsure in additim} {a {base shown and tiescribed herein wiil hecmnis
appm‘mt to those skilled in the 2m: flaw: (in: fiuregming desm‘iptim'x, which this flat diip‘fll‘t fmm
the spirit or 5mm of {im presmt ive discovery. Such madificatims are aim intended? {:3
fail within the. scope {If the. appmded ciaima.
{0325] AH ces cited are hemhy incm‘porawd by rfiemnce; each. in it‘s aniirety.
Appiicam reserves Hm right :0 chaiisnge an}; mutiusiuns prewnimi by the. authors Malay
:ei‘cl‘cnce.
U?m}
Claims (20)
1. A compound of structural Formula III: (III) or a salt thereof, wherein: each of Z1 and Z3 is independently chosen from a bond, C1-C10 alkyl, C2-C10 alkenyl, -(CH2)a(OCH2CH2)b(CH2)c-, -(CH2)aN(R1)(CH2)c-, -(CH2)aN(R1)C(O)(CH2)c- , -(CH2)a(C(O)N(R1)(CH2)c-, -(CH2)aN(R1)C(O)N(R1)(CH2)c-; Z2 is chosen from C1-C10 alkyl, C2-C10 alkenyl, a(OCH2CH2)b(CH2)c-, -(CH2)a(CH2CH2O)b(CH2)c-, -(CH2)aO(CH2)c-, -(CH2)a S(CH2)c-, -(CH2)aN(R1)(CH2)c-, -(CH2)aN(R1)C(O)(CH2)c-, -(CH2)aC(O)N(R1)(CH2)c-, and -(CH2)aN(R1)C(O)N(R1)(CH2)c-; n each of Z1, Z2, and Z3 can be optionally substituted with one or more groups chosen from halo, oxo, and C1-C10 alkyl; each R1 is independently chosen from hydrogen, C1-C10 alkyl, and C1-C10 acyl; each a and c is an integer independently chosen from 0, 1, 2, 3, and 4; each b is an integer independently chosen from 1, 2, 3, 4, 5, and 6; and Y is chosen from CH3 CH3 O O O O N N N CH3 N N N N N H H N N O O N O , O , H , and H N N F O .
2. A compound or salt thereof according to claim 1, wherein Z1 is C1-C10 alkyl.
3. A compound or salt thereof according to claim 1, wherein Z2 is C1-C10 alkyl.
4. A nd or salt thereof according to claim 1, wherein Z3 is C1-C10 alkyl.
5. A compound or salt thereof ing to claim 1, wherein Z1, Z2, and Z3 are each independently C1-C10 alkyl.
6. A compound or salt thereof according to claim 1, wherein Y is CH3 CH3 O O O O N N N CH3 N N N N N H H N N O O O or O .
7. A compound or salt thereof according to claim 6, wherein Y is O .
8. A compound or a salt thereof according to claim 1, wherein the salt is an oxalate or a hydrochloride salt.
9. A compound or a salt thereof according to claim 1, comprising structural a IV N R2 CH3 N O N H n N N O H O O CH3 (IV) or salt thereof, wherein n is an integer chosen from 1, 2, 3, 4, and 5, and R2 is H or methyl.
10. A compound or a salt thereof according to claim 9, wherein n = 1 and R2 is H.
11. A compound or a salt thereof according to claim 9, wherein n = 5 and R2 is H.
12. A compound or a salt f according to claim 1 chosen from: CH3 N O N H N N O H O O CH3 , CH3 N O N H N N O 5 H O O CH3 , CH3 N O N O H N N O H O O CH3 , CH3 N O N O H O N N O H O O CH3 , CH3 H N O N N H O N O N O O CH3 , CH3 N O N H N N O H O O CH3 , CH3 N O N O H O N N O 2 H O O CH3 , O N N H N N O H CH3 , O N N H N N O H 3 CH3 , CH3 N O N O O H O N O N O O CH3 , O N N H N N O H CH3 , CH3 N O N O O H O N O N O O CH3 , O N O N H O N N O H CH3 , CH3 N O N H O N O N O O CH3 , CH3 N O N H S N O N O O CH3 , CH3 N O N H N N O H O O CH3 , CH3 N O N H N N O H O O CH3 , CH3 N O N H S N O O2 O O CH3 , CH3 N O N H S N O O O O CH3 , N CH3 CH3 N O N H N N O H O O CH3 , CH3 N O N S H N N O H O O CH3 , H N CH3 N F O N H N N O H O O CH3 , and H N CH3 N F O N H N N O H O O CH3 .
13. A compound or a salt thereof according to any one of claims 1 to 12, n the salt is an oxalate or a hydrochloride salt.
14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients, adjuvants, or vehicles.
15. Use of a compound or a salt thereof of any one of claims 1 to 13 for the manufacture of a medicament for treating a pancreatic cancer or a synovial a in a t in need thereof.
16. Use of a compound or a salt thereof of any one of claims 1 to 13 for the manufacture of a medicament for treating a pancreatic cancer or a synovial sarcoma in a subject in need thereof, formulated for sequential or co-administration with an additional anticancer drug.
17. The use according to claim 16, wherein the anticancer drug is chosen from an alkylating agent, anthracycline, antimetabolite agent, crosslinking agent, DNA replication inhibitor, intercalator, microtubule disruptor, PARP inhibitor, imetic agent, radiosensitizer, strand break agent, and topoisomerase II inhibitor.
18. The use according to claim 17, wherein the anticancer drug is chosen from aminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib, bcg, bicalutamide, bleomycin, lin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, tin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, trol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, tane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, mine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, min, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, zole, olaparib, octreotide, oxaliplatin, axel, pamidronate, pentostatin, perifosine, plicamycin, porfimer, bazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.
19. The use according to claim 17, further formulated for administration with radiation therapy.
20. The use according to claim 17, further ated for administration with y, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461973366P | 2014-04-01 | 2014-04-01 | |
| US61/973,366 | 2014-04-01 | ||
| PCT/US2015/023954 WO2015153814A1 (en) | 2014-04-01 | 2015-04-01 | Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ724819A NZ724819A (en) | 2020-09-25 |
| NZ724819B2 true NZ724819B2 (en) | 2021-01-06 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2252512T3 (en) | ANTINEOPLASTIC COMBINATIONS. | |
| ES2683356T3 (en) | Cyclic peptidomimetic compounds as immunomodulators | |
| ES2899372T3 (en) | Combination of prostate cancer treatment, pharmaceutical composition and treatment method | |
| Lee et al. | Interaction of tetraspan (in) TM4SF5 with CD44 promotes self‐renewal and circulating capacities of hepatocarcinoma cells | |
| CN109890421A (en) | Efficient polymer e-selectin antagonist | |
| SA518391985B1 (en) | Modulators of 5'-Nucleotidase, ECTO and The Use Thereof | |
| CN107921051A (en) | Suppress the composition and method of arginase activities | |
| SG127738A1 (en) | Heterocyclic compounds based on n6-substituted adenine, methods of their preparation, their use for preparation of drugs, pharmaceutical preparations containing these compounds | |
| CN108271371A (en) | For inhibiting the composition of arginase activities and method | |
| AU2015349390B2 (en) | New type of cytidine derivative and application thereof | |
| ES2282400T3 (en) | ANTITUMOR COMPOSITIONS CONTAINING DERIVATIVES OF TAXANO. | |
| KR19980703420A (en) | Zidovudine, a synergistic blend of 1592Ｕ89 and 3TC or FTC | |
| TWI641374B (en) | Antineoplastic agent containing low-dose irinotecan hydrochloride hydrate | |
| CN104968673B (en) | Fused polypeptide and application method | |
| CN104557909B (en) | 3- acyloxy replaces dextrorotation deoxidation tylophorinine derivative, its preparation method and pharmaceutical composition and purposes | |
| Fenoglio Jr et al. | Ultrastructure of A cardiac rhadomyoma | |
| NZ724819B2 (en) | Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof | |
| NZ724819A (en) | Sigma-2 receptor ligand drug conjugates as antitumor compounds, methods of synthesis and uses thereof | |
| Wolstenholme et al. | Adrenergic Mechanisms | |
| Ball et al. | Transplantable colon tumors as chemotherapy screening models | |
| ES2824400T3 (en) | Antitumor agent including hydrated irinotecan hydrochloride | |
| WO2019241641A3 (en) | Cancer treatment methods | |
| BRPI0707247A8 (en) | tumor vaccine comprising allogeneic or xenogeneic tumor cells | |
| RU2240793C1 (en) | Anti-tumor agent | |
| JPWO2013137433A1 (en) | Novel antitumor agent combining 3 drugs |