KR102646627B1 - Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof - Google Patents
Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof Download PDFInfo
- Publication number
- KR102646627B1 KR102646627B1 KR1020210037828A KR20210037828A KR102646627B1 KR 102646627 B1 KR102646627 B1 KR 102646627B1 KR 1020210037828 A KR1020210037828 A KR 1020210037828A KR 20210037828 A KR20210037828 A KR 20210037828A KR 102646627 B1 KR102646627 B1 KR 102646627B1
- Authority
- KR
- South Korea
- Prior art keywords
- adenosine
- receptor
- cancer
- compound
- pharmaceutical composition
- Prior art date
Links
- 102000007471 Adenosine A2A receptor Human genes 0.000 title claims abstract description 24
- 108010085277 Adenosine A2A receptor Proteins 0.000 title claims abstract description 24
- 102000007470 Adenosine A2B Receptor Human genes 0.000 title claims abstract description 23
- 108010085273 Adenosine A2B receptor Proteins 0.000 title claims abstract description 23
- 239000005557 antagonist Substances 0.000 title abstract description 9
- 230000009977 dual effect Effects 0.000 title abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 abstract description 24
- 239000002126 C01EB10 - Adenosine Substances 0.000 abstract description 12
- 229960005305 adenosine Drugs 0.000 abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- -1 inorganic acid salt Chemical class 0.000 description 15
- 101150051188 Adora2a gene Proteins 0.000 description 14
- 101150078577 Adora2b gene Proteins 0.000 description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 102000009346 Adenosine receptors Human genes 0.000 description 6
- 108050000203 Adenosine receptors Proteins 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LEUADTHIWJLHIR-UHFFFAOYSA-N 4-azido-6-chloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(N=[N+]=[N-])=N1 LEUADTHIWJLHIR-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229910004298 SiO 2 Inorganic materials 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000003042 antagnostic effect Effects 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- QNRDSCLJSYCFQU-UHFFFAOYSA-N CC(C)(C)OC(NC(C=CC=C1)=C1C(C1=CN(C2=NC(N)=NC(Cl)=C2)N=N1)=O)=O Chemical compound CC(C)(C)OC(NC(C=CC=C1)=C1C(C1=CN(C2=NC(N)=NC(Cl)=C2)N=N1)=O)=O QNRDSCLJSYCFQU-UHFFFAOYSA-N 0.000 description 4
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 4
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- WBVIMTCBZMEAHG-UHFFFAOYSA-N tert-butyl N-(2-prop-2-ynoylphenyl)carbamate Chemical compound CC(C)(C)OC(=O)Nc1ccccc1C(=O)C#C WBVIMTCBZMEAHG-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 102100035990 Adenosine receptor A2a Human genes 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101000783751 Homo sapiens Adenosine receptor A2a Proteins 0.000 description 3
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 3
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 3
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 3
- ZTNQNMWLKXQORR-UHFFFAOYSA-N NC1=C(CC2=CN(C3=NC(N)=NC(C4=CC=CO4)=C3)N=N2)C=CC=C1 Chemical compound NC1=C(CC2=CN(C3=NC(N)=NC(C4=CC=CO4)=C3)N=N2)C=CC=C1 ZTNQNMWLKXQORR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- BYGHHEDJDSLEKK-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]benzoic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=C1C(O)=O BYGHHEDJDSLEKK-UHFFFAOYSA-N 0.000 description 2
- BUXIAWLTBSXYSW-UHFFFAOYSA-N 3-[2-amino-6-[1-[[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methylbenzonitrile Chemical compound CC1=C(C=CC=C1C1=CC(=NC(N)=N1)C1=CN(CC2=NC(=CC=C2)C(C)(C)O)N=N1)C#N BUXIAWLTBSXYSW-UHFFFAOYSA-N 0.000 description 2
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- 101710144268 B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 2
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000021309 Germ cell tumor Diseases 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 102100020862 Lymphocyte activation gene 3 protein Human genes 0.000 description 2
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 102000006639 indoleamine 2,3-dioxygenase Human genes 0.000 description 2
- 108020004201 indoleamine 2,3-dioxygenase Proteins 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- LROBJRRFCPYLIT-UHFFFAOYSA-M magnesium;ethyne;bromide Chemical compound [Mg+2].[Br-].[C-]#C LROBJRRFCPYLIT-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- WFMAXGNIZVRSKZ-UHFFFAOYSA-N tert-butyl n-[2-[methoxy(methyl)carbamoyl]phenyl]carbamate Chemical compound CON(C)C(=O)C1=CC=CC=C1NC(=O)OC(C)(C)C WFMAXGNIZVRSKZ-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 102100035984 Adenosine receptor A2b Human genes 0.000 description 1
- 102000004452 Arginase Human genes 0.000 description 1
- 108700024123 Arginases Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CWRMRUZQBXTWRW-UHFFFAOYSA-N CC(C)(C)OC(NC1=C(C(C2=CN(C3=NC(N)=NC(C4=CC=CO4)=C3)N=N2)O)C=CC=C1)=O Chemical compound CC(C)(C)OC(NC1=C(C(C2=CN(C3=NC(N)=NC(C4=CC=CO4)=C3)N=N2)O)C=CC=C1)=O CWRMRUZQBXTWRW-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010073140 Clear cell sarcoma of soft tissue Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000783756 Homo sapiens Adenosine receptor A2b Proteins 0.000 description 1
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 244000147568 Laurus nobilis Species 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- VQZFHDDYAJVIKG-UHFFFAOYSA-N NC1=C(CC2=CN(C3=NC=NC(C4=CC=CO4)=C3)N=N2)C=CC=C1 Chemical compound NC1=C(CC2=CN(C3=NC=NC(C4=CC=CO4)=C3)N=N2)C=CC=C1 VQZFHDDYAJVIKG-UHFFFAOYSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 206010046477 Urethral syndrome Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940121359 adenosine receptor antagonist Drugs 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229950002916 avelumab Drugs 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000013262 cAMP assay Methods 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 201000000292 clear cell sarcoma Diseases 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940125033 etrumadenant Drugs 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005326 heteroaryloxy alkyl group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 229960004717 insulin aspart Drugs 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 208000029559 malignant endocrine neoplasm Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- VOMXSOIBEJBQNF-UTTRGDHVSA-N novorapid Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 VOMXSOIBEJBQNF-UTTRGDHVSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 159000000008 strontium salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
아데노신 A2A 수용체 및 아데노신 A2B 수용체의 이중 길항제, 이를 포함하는 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병(예컨대, 암)의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법을 제공한다. 이에 의하면, 아데노신과 관련된 질병, 예를 들어 암을 효과적으로 예방 또는 치료할 수 있다.Provides a dual antagonist of adenosine A2A receptor and adenosine A2B receptor, a pharmaceutical composition containing the same for preventing or treating diseases (e.g., cancer) related to adenosine A2A receptor and adenosine A2B receptor, and methods of treating and preventing disease using the same. . According to this, adenosine-related diseases, such as cancer, can be effectively prevented or treated.
Description
본 발명은 아데노신 A2A 수용체 및 아데노신 A2B 수용체의 이중 길항제, 이를 포함하는 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병(예컨대, 암)의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 관한 것이다.The present invention relates to a dual antagonist of adenosine A2A receptor and adenosine A2B receptor, a pharmaceutical composition containing the same for preventing or treating diseases (e.g., cancer) related to adenosine A2A receptor and adenosine A2B receptor, and methods for treating and preventing diseases using the same. It's about.
아데노신 수용체는 아데노신을 리간드로 하는 G-단백질-결합 수용체(G protein-coupled receptor: GPCR)에 속하는 단백질로서, 사람에서 A1, A2A, A2B, 및 A3의 4 종류가 알려져 있다. 아데노신 A2A 수용체(adenosine A2A receptor: A2AR)는 기저 핵(basal ganglia), 혈관계, T 림프구, 및 혈소판에 충부하고, 카페인의 주요 표적이 된다. 아데노신 A2B 수용체(adenosine A2B receptor: A2BR)는 아데노신의 존재 하에 아데닐산 고리화효소(adenylate cyclase) 활성을 촉진시킨다.Adenosine receptors are proteins belonging to the G protein-coupled receptor (GPCR), which uses adenosine as a ligand. Four types of adenosine receptors are known in humans: A1, A2A, A2B, and A3. The adenosine A2A receptor (A2AR) is abundant in the basal ganglia, vasculature, T lymphocytes, and platelets and is the primary target of caffeine. Adenosine A2B receptor (A2BR) promotes adenylate cyclase activity in the presence of adenosine.
암 면역치료는 암세포를 근본적으로 제거할 수 있는 치료방법이나, 일부 암세포들이 면역회피를 통해 암세포가 살아남을 수 있다. 암세포는 종양 미세환경에서 세포외 아데노신을 생성하고, 생성된 세포외 아데노신이 면역억제 활성을 촉진함으로써, 암세포가 면역반응을 회피할 수 있다(Nature Reviews Cancer, vol.17, pp.709-724(2017)). 특히, 세포외 아데노신의 수용체들 중 A2AR과 A2BR을 통해 주로 면역세포에서 아데노신에 의한 면역억제 효과가 나타나고 있다. 아데노신에 의한 면역억제 효과를 차단하여 암을 치료하기 위해, 아데노신 수용체를 표적으로 하는 항암제가 개발되고 있다. 최근에는, A2AR과 A2BR의 이중 길항제인 화합물 etrumadenant(AB928, Arcus Biosciences)는 난소암, 삼중 음성 유방암, 대장암 등에 대해 미국 FDA에서 임상시험을 진행 중이다.Cancer immunotherapy is a treatment method that can fundamentally eliminate cancer cells, but some cancer cells can survive through immune evasion. Cancer cells produce extracellular adenosine in the tumor microenvironment, and the produced extracellular adenosine promotes immunosuppressive activity, allowing cancer cells to evade immune responses (Nature Reviews Cancer, vol.17, pp.709-724 ( 2017)). In particular, among the extracellular adenosine receptors, the immunosuppressive effect of adenosine is mainly observed in immune cells through A2AR and A2BR. To treat cancer by blocking the immunosuppressive effect of adenosine, anticancer drugs targeting adenosine receptors are being developed. Recently, the compound etrumadenant (AB928, Arcus Biosciences), a dual antagonist of A2AR and A2BR, is undergoing clinical trials at the US FDA for ovarian cancer, triple-negative breast cancer, and colon cancer.
따라서, 아데노신 수용체와 관련된 질병을 효과적으로 예방 또는 치료하기 위해, A2AR/A2BR의 이중 길항제를 개발할 필요가 있다.Therefore, in order to effectively prevent or treat diseases related to adenosine receptors, there is a need to develop dual antagonists of A2AR/A2BR.
본 발명의 목적은 A2AR 및 A2BR의 이중 길항제를 제공하는 것이다.The object of the present invention is to provide dual antagonists of A2AR and A2BR.
본 발명의 또다른 목적은 A2AR 또는 A2BR와 관련된 질병을 예방 또는 치료하기 위한 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to A2AR or A2BR.
본 발명의 또다른 목적은 A2AR 및 A2BR의 이중 길항제를 이용하여 A2AR 및 A2BR와 관련된 질병을 예방 또는 치료 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating diseases related to A2AR and A2BR using a dual antagonist of A2AR and A2BR.
본 발명의 일 양상은 하기 화학식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다:One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
. .
상기 화학식 1에서, R1은 -(CH2)n-C6 내지 C12의 아릴기이다. 상기 n은 0, 1, 또는 2의 정수일 수 있다.In Formula 1, R 1 is an aryl group of -(CH 2 )nC 6 to C 12 . The n may be an integer of 0, 1, or 2.
상기 C6 내지 C12의 아릴기는 탄소수 6 내지 12의 치환 또는 비치환된 아릴기일 수 있다.The C 6 to C 12 aryl group may be a substituted or unsubstituted aryl group having 6 to 12 carbon atoms.
상기 화학식 1에서, R2는 H, C1 내지 C10의 알킬기, 또는 NR3R4이다. 상기 R3 및 R4는 각각 독립적으로, H, 또는 치환 또는 비치환된 C1 내지 C10의 알킬기일 수 있다.In Formula 1, R 2 is H, an alkyl group of C 1 to C 10 , or NR 3 R 4 . R 3 and R 4 may each independently be H, or a substituted or unsubstituted C 1 to C 10 alkyl group.
상기 C6 내지 C12의 아릴기는 NR5R6으로 치환될 수 있다. 상기 R5 및 R6은 각각 독립적으로, H, 또는 치환 또는 비치환된 C1 내지 C10의 알킬기일 수 있다.The aryl group of C 6 to C 12 may be substituted with NR 5 R 6 . R 5 and R 6 may each independently be H, or a substituted or unsubstituted C 1 to C 10 alkyl group.
상기 화학식 1의 화합물은 화학식 2로 표시되는 화합물일 수 있다:The compound of Formula 1 may be a compound represented by Formula 2:
[화학식 2][Formula 2]
. .
상기 "치환 또는 비치환된"의 용어 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, "치환기"는 도입된 원자단을 말한다. 치환기는 예를 들면, 할로겐 원자, 할로겐 원자로 치환된 C1 내지 C20의 알킬기(예: CCF3, CHCF2, CH2F, CCl3 등), C1 내지 C20의 알콕시, C2 내지 C20의 알콕시알킬, 히드록시기, 니트로기, 시아노기, 아미노기, 아미디노기, 히드라진, 히드라존, 카르복실기나 그의 염, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기나 그의 염, 인산이나 그의 염, 또는 C1 내지 C20 알킬기, C2 내지 C20 알케닐기, C2 내지 C20 알키닐기, C1 내지 C20 헤테로알킬기, C6 내지 C20 아릴기, C6 내지 C20 아릴알킬기, C6 내지 C20 헤테로아릴기, C7 내지 C20헤테로아릴알킬기, C6 내지 C20 헤테로아릴옥시기, 및 C6 내지 C20 헤테로아릴옥시알킬기 또는 C6 내지 C20 헤테로아릴알킬기일 수 있다.The term "substituted" in the above "substituted or unsubstituted" refers to introduction in place of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and "substituent" refers to the introduced atomic group. . Substituents include, for example, a halogen atom, a C 1 to C 20 alkyl group substituted with a halogen atom (e.g. CCF 3 , CHCF 2 , CH 2 F, CCl 3, etc.), C 1 to C 20 alkoxy, C 2 to C 20 alkoxyalkyl, hydroxy group, nitro group, cyano group, amino group, amidino group, hydrazine, hydrazone, carboxyl group or its salt, sulfonyl group, sulfamoyl group, sulfonic acid group or its salt, phosphoric acid or its salt, or C 1 to C 20 alkyl group, C 2 to C 20 alkenyl group, C 2 to C 20 alkynyl group, C 1 to C 20 heteroalkyl group, C 6 to C 20 aryl group, C 6 to C 20 arylalkyl group, C 6 to It may be a C 20 heteroaryl group, a C 7 to C 20 heteroarylalkyl group, a C 6 to C 20 heteroaryloxy group, and a C 6 to C 20 heteroaryloxyalkyl group or a C 6 to C 20 heteroarylalkyl group.
용어 "아릴"은 방향족 고리가 하나 이상의 탄소 고리에 융합된 그룹도 포함한다. 상기 C6 내지 C12의 아릴기는 예를 들면, C6 내지 C10, 또는 C6 내지 C8인 아릴기일 수 있다. 상기 아릴은 페닐기일 수 있다.The term “aryl” also includes groups in which an aromatic ring is fused to one or more carbon rings. For example, the C 6 to C 12 aryl group may be a C 6 to C 10 aryl group, or a C 6 to C 8 aryl group. The aryl may be a phenyl group.
용어 "알킬"은 완전 포화된 분지형 또는 비분지형 (또는, 직쇄 또는 선형) 탄화수소를 말한다. 상기 알킬은 C1 내지 C30, C1 내지 C15, C1 내지 C10, 또는 C1 내지 C6인 알킬기일 수 있다. 알킬의 비제한적인 예로는 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, n-펜틸, 이소펜틸, 네오펜틸, iso-아밀, n-헥실, 3-메틸헥실, 2,2-디메틸펜틸, 2,3-디메틸펜틸, 또는 n-헵틸 등을 들 수 있다.The term “alkyl” refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon. The alkyl may be an alkyl group having C 1 to C 30 , C 1 to C 15 , C 1 to C 10 , or C 1 to C 6 . Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n-hexyl, 3-methyl. Hexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, or n-heptyl.
용어 "입체이성질체"의 "이성질체(isomer)"는 분자식은 같지만 분재 내에 있는 구성 원자의 연결 방식이나 공간 배열이 동일하지 않은 화합물을 말한다. 이성질체는 예를 들면, 구조 이성질체(structural isomers), 및 입체이성질체(stereoisomer)를 포함한다. 상기 입체이성질체는 부분입체 이성질체(diasteromer) 또는 거울상 이성질체(enantiomer)일 수 있다. 거울상이성질체는 왼손과 오른손의 관계처럼 그 거울상과 겹쳐지지 않는 이성질체를 말하고, 광학 이성질체(optical isomer)라고도 한다. 거울상 이성질체는 키랄 중심 탄소에 4개 이상의 치환기가 서로 다른 경우 R(Rectus: 시계방향) 및 S(Sinister: 반시계 방향)로 구분한다. 부분입체이성질체는 거울상 관계가 아닌 입체 이성질체를 말하고, 원자의 공간 배열이 달라 생기는 이성질체이다. 상기 부분입체이성질체는 시스(cis)-트랜스(trans) 이성질체 및 형태이성질체(conformational isomer 또는 conformer)로 나뉠 수 있다.The term "isomer" in the term "stereoisomer" refers to a compound that has the same molecular formula but is not the same in the connection method or spatial arrangement of the constituent atoms within the bonsai. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomers may be diastereomers or enantiomers. Enantiomers refer to isomers that do not overlap with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are classified into R (Rectus: clockwise) and S (Sinister: counterclockwise) when the chiral center carbon has 4 or more different substituents. Diastereomers are stereoisomers that are not mirror images, and are isomers that occur in different spatial arrangements of atoms. The diastereomers can be divided into cis-trans isomers and conformational isomers (conformational isomers or conformers).
용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어 수화물이다.The term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.
용어 "염(salt)"은 화합물의 무기 및 유기산 부가염을 말한다. 상기 약학적으로 허용가능한 염은 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 염일 수 있다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다.The term “salt” refers to inorganic and organic acid addition salts of a compound. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salts include formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, and trifluoroacetate. , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspart. It may be an acid salt. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.
상기 화학식 1의 화합물은 아데노신 A2A 수용체, 아데노신 A2B 수용체, 또는 이들 둘다에 대해 길항제일 수 있다. 상기 아데노신 A2A 수용체는 7개의 막관통 알파 나선을 갖는 G-단백질-결합 수용체(G protein-coupled receptor: GPCR)에 속하는 단백질일 수 있다. 상기 아데노신 A2A 수용체는 ADORA2A, 아데노신 A2A 수용체, A2AR, ADORA2, 또는 RDC8로도 불릴 수 있다. 상기 아데노신 A2A 수용체는 Uniprot No. P29274의 아미노산 서열을 포함하는 단백질일 수 있다. 상기 아데노신 A2B 수용체는 G-단백질 결합 아데노신 수용체일 수 있다. 상기 아데노신 A2B 수용체는 ADORA2B, 아데노신 A2B 수용체, 또는 A2BR로도 불릴 수 있다.The compound of Formula 1 may be an antagonist for the adenosine A2A receptor, the adenosine A2B receptor, or both. The adenosine A2A receptor may be a protein belonging to the G protein-coupled receptor (GPCR) having seven transmembrane alpha helices. The adenosine A2A receptor may also be called ADORA2A, adenosine A2A receptor, A2AR, ADORA2, or RDC8. The adenosine A2A receptor is Uniprot No. It may be a protein containing the amino acid sequence of P29274. The adenosine A2B receptor may be a G-protein coupled adenosine receptor. The adenosine A2B receptor may also be called ADORA2B, adenosine A 2B receptor, or A2BR.
본 발명의 다른 양상은 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트를 환원시켜 일 양상에 따른 화학식 1의 화합물을 수득하는 단계를 포함하는, 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제조하는 방법을 제공한다.Another aspect of the invention is tert-butyl (2-((1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazole-4 -yl) reducing (hydroxy)methyl)phenyl)carbamate to obtain a compound of formula 1 according to one aspect, a stereoisomer, solvate, or pharmaceutically acceptable compound of formula 1, comprising: A method for preparing a possible salt is provided.
상기 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트를 환원시키는 단계는 환원제의 존재 하에서 수행될 수 있다. 상기 환원제는 Et3SiH일 수 있다. 상기 단계는 디클로로메탄(dichloromethane: DCM), 트리플루오로아세트산(trifluoroacetic acid: TFA), 또는 이들의 조합을 포함하는 용매에서 수행될 수 있다.The tert-butyl (2-((1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydrogen The step of reducing oxy)methyl)phenyl)carbamate can be carried out in the presence of a reducing agent. The reducing agent may be Et 3 SiH. The step may be performed in a solvent containing dichloromethane (DCM), trifluoroacetic acid (TFA), or a combination thereof.
상기 방법은 터트-부틸 (2-((1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트과 2-(퓨란-2-일)-4,4,5,5-테트라메틸-1,3,2-디옥사볼로란을 반응시켜 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트를 생성하는 단계를 더 포함할 수 있다.The method is tert-butyl (2-((1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl) Phenyl)carbamate and 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabolorane are reacted to produce tert-butyl (2-((1-( producing 2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)phenyl)carbamate Additional steps may be included.
상기 방법은 터트-부틸 (2-(1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-카르보닐)페닐)카르바메이트를 환원시켜 터트-부틸 (2-((1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트를 생성하는 단계를 더 포함할 수 있다. 상기 단계는 환원제의 존재 하에서 수행될 수 있다. 상기 환원제는 NaBH4일 수 있다.The method uses tert-butyl (2-(1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazole-4-carbonyl)phenyl)carbamate. Reduction to tert-butyl (2-((1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)phenyl ) The step of generating carbamate may be further included. This step may be performed in the presence of a reducing agent. The reducing agent may be NaBH 4 .
상기 방법은 4-아지도-6-클로로피리미딘-2-아민과 터트 부틸 (2-프로피올로일페닐)카르바메이트를 반응시켜 터트-부틸 (2-(1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-카르보닐)페닐)카르바메이트를 생성하는 단계를 더 포함할 수 있다. 상기 단계는 CuSO4·5H2O, 소듐 아스코르베이트, 또는 이들의 조합의 존재 하에서 수행될 수 있다.The method involves reacting 4-azido-6-chloropyrimidin-2-amine with tert-butyl (2-propioloylphenyl) carbamate to produce tert-butyl (2-(1-(2-amino-6 -Chloropyrimidin-4-yl)-1H-1,2,3-triazole-4-carbonyl)phenyl)carbamate may be further included. This step can be performed in the presence of CuSO 4 ·5H 2 O, sodium ascorbate, or a combination thereof.
상기 방법은 4,6-디클로로피리미딘-2-아민과 NaN3를 반응시켜 4-아지도-6-클로로피리미딘-2-아민을 생성하는 단계를 더 포함할 수 있다.The method may further include reacting 4,6-dichloropyrimidin-2-amine with NaN 3 to produce 4-azido-6-chloropyrimidin-2-amine.
상기 방법은 터트-부틸 (2-(메톡시(메틸)카르바모일)페닐)카르바메이트와 에티닐마그네슘 브롬화물를 반응시켜 터트 부틸(2-프로피올로일페닐)카르바메이트를 생성하는 단계를 더 포함할 수 있다.The method involves reacting tert-butyl (2-(methoxy(methyl)carbamoyl)phenyl)carbamate with ethynylmagnesium bromide to produce tert-butyl(2-propioloylphenyl)carbamate. It may further include.
상기 방법은 2-((터트-부톡시카르보닐)아미노)벤조산과 N,O-디메틸히드록시아민을 반응시켜 터트-부틸 (2-메톡시(메틸)카르바모일)페닐)카르바메이트를 생성하는 단계를 더 포함할 수 있다.The method reacts 2-((tert-butoxycarbonyl)amino)benzoic acid with N,O-dimethylhydroxyamine to produce tert-butyl (2-methoxy(methyl)carbamoyl)phenyl)carbamate. A generating step may be further included.
본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는, 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병을 예방 또는 치료하기 위한 약학적 조성물을 제공한다.Another aspect of the present invention is a pharmaceutical for preventing or treating diseases associated with adenosine A2A receptor and adenosine A2B receptor, comprising a compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to one aspect. A composition is provided.
상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, 아데노신 A2A 수용체, 및 아데노신 A2B 수용체는 전술한 바와 같다.The compound of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, adenosine A2A receptor, and adenosine A2B receptor are as described above.
아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병은 암, 염증, 겸상적혈구증 패혈증, 패혈성 쇼크, 뇌수막염, 복막염, 관절염, 용혈성 요도증후군, 녹내장, 고안압증, 및 파킨슨병으로 이루어진 군으로부터 선택된 것일 수 있다.Diseases associated with adenosine A2A receptors and adenosine A2B receptors may be selected from the group consisting of cancer, inflammation, sickle cell sepsis, septic shock, meningitis, peritonitis, arthritis, hemolytic urethral syndrome, glaucoma, ocular hypertension, and Parkinson's disease. there is.
상기 암은 고형암 또는 비고형암일 수 있다. 고형암은 예를 들어 간, 폐, 유방, 피부 등 장기에 암 종양이 발생한 것을 말한다. 비고형암은 혈액 내에서 발생한 암이고, 혈액암으로도 불린다. 상기 암은 암종 (carcinoma), 육종(sarcoma), 조혈세포 유래의 암, 배세포 종양(germ cell tumor), 또는 모세포종(blastoma)일 수 있다. 상기 암은 예를 들어 유방암, 피부암, 두경부암, 췌장암, 폐암, 대장암, 결장직장암, 위암, 난소암, 전립선암, 방광암, 요도암, 간암, 신장암, 투명세포 육종, 흑색종, 뇌척수종양, 뇌암, 흉선종, 중피종, 식도암, 담도암, 고환암, 생식세포종, 갑상선암, 부갑상선암, 자궁 경부암, 자궁 내막암, 림프종, 골수형성이상 증후군(myelodysplastic syndromes: MDS), 골수섬유증(myelofibrosis), 급성 백혈병, 만성 백혈병, 다발성 골수종, 호치킨병 (Hodgkin's Disease), 내분비계암 및 육종으로 이루어진 군으로부터 선택된다.The cancer may be a solid cancer or a non-solid cancer. Solid cancer refers to cancerous tumors that occur in organs such as the liver, lungs, breast, and skin. Non-solid cancer is cancer that occurs in the blood and is also called blood cancer. The cancer may be carcinoma, sarcoma, cancer derived from hematopoietic cells, germ cell tumor, or blastoma. The above cancers include, for example, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, stomach cancer, ovarian cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer, clear cell sarcoma, melanoma, and cerebrospinal tumor. , brain cancer, thymoma, mesothelioma, esophageal cancer, biliary tract cancer, testicular cancer, germ cell tumor, thyroid cancer, parathyroid cancer, cervical cancer, endometrial cancer, lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, acute leukemia , chronic leukemia, multiple myeloma, Hodgkin's disease, endocrine cancer, and sarcoma.
상기 약학적 조성물은 다른 항암제를 더 포함할 수 있다. 상기 항암제는 면역항암제일 수 있다. 상기 면역항암제는 면역 체크포인트 저해제, 면역세포 치료제, 치료용 항체, 항암 백신, 또는 이들의 조합일 수 있다. 상기 면역 체크포인트 저해제는 PD-1(programmed death 1), PD-L1(programmed death ligand 1), CTLA-4(cytotoxic T-lymphocyte-associated antigen 4), VISTA(V-domain Ig suppressor of T cell activation), PD-L2(programmed death ligand 2), IDO(indoleamine 2,3-dioxygenase), 아르기나제(arginase), B7 패밀리 저해성 리간드 B7-H3, B7 패밀리 저해성 리간드 B7-H4, LAG3(lymphocyte activation gene 3), 2B4, BTLA(B and T lymphocyte attenuator), TIM3(T cell membrane protein 3), CD39, 및 CD73으로 이루어진 군으로부터 선택된 하나에 대한 길항제일 수 있다. 상기 면역 체크포인트 저해제는 이필리무맙(ipilimumab), 트레멜리무맙(tremelimumab), 니보루맙(nivolumab), 펨브롤리주맙(pembrolizumab), 피딜리주맙(pidilizumab), MEDI-0680, REGN2810, AMP-224, BMS-936559/MDX-1105, MPDL3280A/RG7446/아테졸리무맙(atezolizumab), MSB0010718C/아베루맙(avelumab), 또는 MEDI4736/둘바루맙(durvalumab)일 수 있다. 상기 약학적 조성물은 단일 조성물 또는 개별적인 조성물일 수 있다. 예를 들어, 상기 화학식 1의 화합물은 경구 투여 제형의 조성물이고, 항암제는 비경구 투여 제형의 조성물일 수 있다.The pharmaceutical composition may further include other anticancer agents. The anticancer agent may be an immunotherapy agent. The immuno-anticancer agent may be an immune checkpoint inhibitor, an immune cell therapeutic agent, a therapeutic antibody, an anti-cancer vaccine, or a combination thereof. The immune checkpoint inhibitors include programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and V-domain Ig suppressor of T cell activation (VISTA). ), PD-L2 (programmed death ligand 2), IDO (indoleamine 2,3-dioxygenase), arginase, B7 family inhibitory ligand B7-H3, B7 family inhibitory ligand B7-H4, LAG3 (lymphocyte activation gene 3), 2B4, BTLA (B and T lymphocyte attenuator), TIM3 (T cell membrane protein 3), CD39, and CD73. The immune checkpoint inhibitors include ipilimumab, tremelimumab, nivolumab, pembrolizumab, pidilizumab, MEDI-0680, REGN2810, and AMP-224. , BMS-936559/MDX-1105, MPDL3280A/RG7446/atezolimumab, MSB0010718C/avelumab, or MEDI4736/durvalumab. The pharmaceutical composition may be a single composition or separate compositions. For example, the compound of Formula 1 may be a composition for oral administration, and the anticancer agent may be a composition for parenteral administration.
용어 "예방"은 상기 약학적 조성물의 투여에 의해 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병의 발생을 억제하거나 그의 발병을 지연시키는 모든 행위를 말한다. 용어 "치료"는 상기 약학적 조성물의 투여에 의해 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.The term “prevention” refers to all actions that inhibit or delay the onset of diseases associated with adenosine A2A receptors and adenosine A2B receptors by administering the pharmaceutical composition. The term “treatment” refers to any action that improves or beneficially changes the symptoms of a disease related to adenosine A2A receptors and adenosine A2B receptors by administering the pharmaceutical composition.
상기 약학적 조성물은 약학적으로 허용가능한 담체를 포함할 수 있다. 상기 담체는 부형제, 희석제 또는 보조제를 포함하는 의미로 사용된다. 상기 담체는 예를 들면, 락토스, 덱스트로스, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리트리톨, 말티톨, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 생리식염수, PBS와 같은 완충액, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 및 미네랄 오일로 이루어진 군으로부터 선택된 것일 수 있다. 상기 조성물은 충진제, 항응집제, 윤활제, 습윤제, 풍미제, 유화제, 보존제, 또는 이들의 조합을 포함할 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used to include an excipient, diluent, or auxiliary agent. The carriers include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl chloride. It may be selected from the group consisting of rolidone, water, physiological saline, buffer solutions such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil. The composition may include fillers, anti-coagulants, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, or combinations thereof.
상기 약학적 조성물은 통상의 방법에 따라 임의의 제형으로 준비될 수 있다. 상기 조성물은 예를 들면, 경구 투여 제형(예를 들면, 분말, 정제, 캡슐, 시럽, 알약, 또는 과립), 또는 비경구 제형(예를 들면, 주사제)으로 제형화될 수 있다. 또한, 상기 조성물은 전신 제형, 또는 국부 제형으로 제조될 수 있다.The pharmaceutical composition can be prepared in any dosage form according to conventional methods. The composition may be formulated, for example, as an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (e.g., injection). Additionally, the composition may be prepared as a systemic formulation or a topical formulation.
상기 약학적 조성물에 있어서, 경구 투여를 위한 고형 제제는 정제, 환제, 산제, 과립제, 또는 캡슐제일 수 있다. 상기 고형 제제는 부형제를 더 포함할 수 있다. 부형제는 예를 들면, 전분, 칼슘 카르보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 또는 젤라틴일 수 있다. 또한, 상기 고형 제제는 마그네슘 스테아레이트, 또는 탈크와 같은 윤활제를 더 포함할 수 있다. 상기 약학적 조성물에 있어서, 경구를 위한 액상 제제는 현탁제, 내용액제, 유제, 또는 시럽제일 수 있다. 상기 액상 제제는 물, 또는 리퀴드 파라핀을 포함할 수 있다. 상기 액상 제제는 부형제, 예를 들면 습윤제, 감미제, 방향제, 또는 보존제를 포함할 수 있다. 상기 약학적 조성물에 있어서, 비경구 투여를 위한 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 또는 및 좌제일 수 있다. 비수성용제 또는 현탁제는 식물성 기름 또는 에스테르를 포함할 수 있다. 식물성 기름은 예를 들면, 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 또는 올리브 오일일 수 있다. 에스테르는 예를 들면 에틸올레이트일 수 있다. 좌제의 기제는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 또는 글리세로젤라틴일 수 있다.In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid preparation may further include excipients. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. Additionally, the solid preparation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the liquid preparation for oral administration may be a suspension, oral solution, emulsion, or syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain excipients such as wetting agents, sweeteners, flavoring agents, or preservatives. In the pharmaceutical composition, preparations for parenteral administration may be sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried products, and suppositories. Non-aqueous solvents or suspensions may contain vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao, laurel, or glycerogelatin.
상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 상기 약학적 조성물의 유효 성분으로 포함한다. "유효 성분"은 약리학적 활성(예를 들면, 항염)을 달성하기 위해 사용되는 생리활성 물질을 말한다.The pharmaceutical composition includes the compound according to one aspect, its stereoisomer, solvate, or pharmaceutically acceptable salt as an active ingredient of the pharmaceutical composition. “Active ingredient” refers to a bioactive substance used to achieve pharmacological activity (e.g., anti-inflammatory).
상기 약학적 조성물은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 유효한 양으로 포함할 수 있다. 용어 "유효한 양"은 예방 또는 치료를 필요로 하는 개체에게 투여되는 경우 질병의 예방 또는 치료의 효과를 나타내기에 충분한 양을 말한다. 상기 유효한 양은 당업자가 선택되는 세포 또는 개체에 따라 적절하게 선택할 수 있다. 상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 예를 들면, 약 0.0001 ㎎/㎏ 내지 약 100 ㎎/㎏, 또는 약 0.001 ㎎/㎏ 내지 약 100 ㎎/㎏의 양을 1일 1회 내지 24회, 2일 내지 1주에 1 내지 7회, 또는 1개월 내지 12개월에 1 내지 24회로 나누어 투여할 수 있다. 상기 약학적 조성물에서 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 전체 조성물 총 중량에 대하여 약 0.0001 중량% 내지 약 10 중량%, 또는 약 0.001 중량% 내지 약 1 중량%로 포함될 수 있다.The pharmaceutical composition may include an effective amount of the compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof. The term “effective amount” refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to an individual in need of such treatment. The effective amount can be appropriately selected by a person skilled in the art depending on the cell or organism selected. The preferred dosage of the pharmaceutical composition varies depending on the individual's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art. However, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt may be administered in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg. Can be administered 1 to 24 times per day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per month to 12 months. In the pharmaceutical composition, the compound, its stereoisomer, solvate, or pharmaceutically acceptable salt may be included in an amount of about 0.0001% to about 10% by weight, or about 0.001% by weight to about 1% by weight, based on the total weight of the composition. You can.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. Methods of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.
본 발명의 다른 양상은 일 양상에 따른 화학식 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 개체에게 투여하는 단계를 포함하는 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병을 예방 또는 치료하는 방법을 제공한다.Another aspect of the present invention is the prevention of diseases associated with the adenosine A2A receptor and the adenosine A2B receptor, comprising administering to a subject a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect. Or provide a treatment method.
상기 화학식 1의 화합물, 입체이성질체, 용매화물, 약학적으로 허용가능한 염, 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병, 예방, 및 치료는 전술한 바와 같다.The compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, diseases, prevention, and treatment related to adenosine A2A receptor and adenosine A2B receptor are as described above.
상기 개체는 포유동물, 예를 들면, 인간, 마우스, 래트, 소, 말, 돼지, 개, 원숭이, 양, 염소, 유인원, 또는 고양이일 수 있다. 상기 개체는 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병과 연관된 증상을 앓고 있거나, 앓을 가능성이 큰 개체일 수 있다.The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject may be suffering from, or is likely to suffer from, symptoms associated with diseases related to adenosine A2A receptors and adenosine A2B receptors.
상기 방법은 상기 개체에 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병을 예방 또는 치료하는 효과의 공지의 유효 성분을 투여하는 단계를 더 포함할 수 있다. 상기 공지의 유효 성분은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염과 동시, 개별, 또는 순차로 상기 개체에 투여될 수 있다.The method may further include administering to the subject a known active ingredient effective in preventing or treating diseases related to adenosine A2A receptors and adenosine A2B receptors. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one aspect, its stereoisomer, solvate, or pharmaceutically acceptable salt.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 약학적 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. Methods of administration may be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal. The pharmaceutical composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.
상기 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 투여량은 예를 들어, 성인 기준으로 약 0.001 ㎎/kg 내지 약 100 ㎎/kg, 약 0.01 ㎎/kg 내지 약 10 ㎎/kg, 또는 약 0.1 ㎎/kg 내지 약 1 ㎎/kg의 범위 내 일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일에 1회, 2주일에 1회, 3주일에 1회, 또는 4주일에 1회 내지 1년에 1회 투여될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the patient's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art. The dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg based on adults. It can be. The administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year.
아데노신 A2A 수용체 및 아데노신 A2B 수용체의 이중 길항제, 이를 포함하는 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병(예컨대, 암)의 예방 또는 치료용 약학적 조성물, 및 이를 이용한 질병의 치료 및 예방 방법에 의하면, 아데노신과 관련된 질병, 예를 들어 암을 효과적으로 예방 또는 치료할 수 있다.According to the dual antagonist of adenosine A2A receptor and adenosine A2B receptor, a pharmaceutical composition containing the same for preventing or treating diseases (e.g., cancer) related to adenosine A2A receptor and adenosine A2B receptor, and methods for treating and preventing diseases using the same, Adenosine-related diseases, such as cancer, can be effectively prevented or treated.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.This will be described in more detail through examples below. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
실시예 1. 4-{4-[(2-아미노페닐)메틸]-1H-1,2,3-트리아졸-1-일}-6-(퓨란-2-일)피리미딘-2-아민의 제조Example 1. 4-{4-[(2-aminophenyl)methyl]-1H-1,2,3-triazol-1-yl}-6-(furan-2-yl)pyrimidin-2-amine manufacture of
단계 1) 터트-부틸 (2-메톡시(메틸)카르바모일)페닐)카르바메이트의 준비Step 1) Preparation of tert-butyl (2-methoxy(methyl)carbamoyl)phenyl)carbamate
CH2Cl2 (40.0 mL) 중 2-((터트-부톡시카르보닐)아미노)벤조산(화합물 2A-1, 4.15 g, 17.4 mmol, 1 당량), N,O-디메틸히드록시아민(화합물 2A-2, 2.22 g, 22.7 mmol, 1.30 당량, HCl), TEA(triethylamine, 5.31 g, 52.4 mmol, 7.30 mL, 3 당량), HBTU(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, 7.96 g, 20.9 mmol, 1.20 당량)의 혼합물을 N2로 3회 탈기(degas) 및 퍼지(purge)하고, 그 후 혼합물을 20℃에서 10 시간 동안 N2 대기 하에서 교반하였다. TLC(석유 에테르/에틸 아세테이트 = 3/1)는 반응물 1이 완전히 소모되고, 하나의 새로운 스팟이 형성되었음을 나타내었다. LCMS는 반응물 1이 완전히 소모되고 원하는 m/z를 갖는 하나의 주요 피크가 검출되었음을 나타내었다. 반응 혼합물을 H2O 40 mL로 희석하고 EtOAc (50 mL*3회)로 추출하였다. 조합한 유기 층을 Na2SO4로 건조시키고, 감압 하에서 여과 및 농축시켜 잔여물을 얻었다. 잔여물은 컬럼 크로마토그래피(SiO2, 석유 에테르/에틸 아세테이트 = 20/1 내지 10/1)로 정제하였다. 터트-부틸 (2-메톡시(메틸)카르바모일)페닐)카르바메이트(화합물 2A-3, 4.80 g, 17.1 mmol, 97.9% 수율)을 흰색 고체로 수득하였다. 1HNMR(400 MHz, DMSO-d 6 ) δ 8.40 (br s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.52 - 7.34 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 3.58 (s, 3H), 3.45 - 3.30 (m, 3H), 1.60 - 1.44 (m, 9H). 2 -((tert-butoxycarbonyl)amino)benzoic acid (Compound 2A-1, 4.15 g, 17.4 mmol, 1 equiv), N , O-dimethylhydroxyamine (Compound 2A) in CH 2 Cl 2 (40.0 mL) -2, 2.22 g, 22.7 mmol, 1.30 equivalents, HCl), TEA (triethylamine, 5.31 g, 52.4 mmol, 7.30 mL, 3 equivalents), HBTU (1H-Benzotriazole-1-yl)-1,1,3,3 -tetramethyluronium hexafluorophosphate, 7.96 g, 20.9 mmol, 1.20 equivalent) was degassed and purged three times with N 2 , and then the mixture was stirred at 20° C. for 10 hours under N 2 atmosphere. TLC (petroleum ether/ethyl acetate = 3/1) showed that reactant 1 was completely consumed and one new spot was formed. LCMS showed that reactant 1 was completely consumed and one major peak with the desired m/z was detected. The reaction mixture was diluted with 40 mL of H 2 O and extracted with EtOAc (50 mL*3 times). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 20/1 to 10/1). Tert-butyl (2-methoxy(methyl)carbamoyl)phenyl)carbamate (Compound 2A-3, 4.80 g, 17.1 mmol, 97.9% yield) was obtained as a white solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.40 (br s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.52 - 7.34 (m, 2H), 7.01 (t, J = 7.6 Hz, 1H), 3.58 (s, 3H), 3.45 - 3.30 (m, 3H), 1.60 - 1.44 (m, 9H).
단계 2) 터트 부틸(2-프로피올로일페닐)카르바메이트의 준비Step 2) Preparation of tert-butyl(2-propioloylphenyl)carbamate
THF (25 mL) 중 터트-부틸 (2-(메톡시(메틸)카르바모일)페닐)카르바메이트(화합물 2A-3, 2.0 g, 7.13 mmol, 1.00 당량) 및 에티닐마그네슘 브롬화물(0.5 M, 71.4 mL, 5 당량)의 혼합물을 N2로 3회 탈기 및 퍼지(purge)하고, 그 후 혼합물을 0℃에서 2 시간 동안 N2 대기 하에서 교반하였다. TLC(석유 에테르/에틸 아세테이트 = 3/1, 반응물 Rf = 0.44, 생성물 Rf = 0.53)는 반응물 1이 잔류하였고, 하나의 주요 새로운 스팟이 검출되었음을 나타내었다. 반응 혼합물을 감압 하에서 농축하여 THF를 제거하였다. 잔여물은 H2O 30 mL로 희석하고 EtOAc(30 mL*3회)로 추출하였다. 조합한 유기 층을 감압 하에서 여과 및 농축시켜 잔여물을 얻었다. 잔여물은 컬럼 크로마토그래피(SiO2, 석유 에테르/에틸 아세테이트 = 20/1 내지 10/1)로 정제하였다. 터트 부틸 (2-프로피올로일페닐)카르바메이트(화합물 2A, 500 mg, 2.04 mmol, 28.6% 수율)을 노란색 액체로 수득하였다. 1HNMR(400 MHz, DMSO-d 6 ) δ 10.62 (br s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.3 Hz, 1H), 3.50 (s, 1H), 1.55 (s, 9H).Tert-butyl (2-(methoxy(methyl)carbamoyl)phenyl)carbamate (Compound 2A-3, 2.0 g, 7.13 mmol, 1.00 eq) and ethynylmagnesium bromide (0.5 eq) in THF (25 mL) M, 71.4 mL, 5 equiv) was degassed and purged three times with N 2 , and then the mixture was stirred at 0° C. for 2 hours under N 2 atmosphere. TLC (petroleum ether/ethyl acetate = 3/1, reactant R f = 0.44, product R f = 0.53) showed that reactant 1 remained and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with 30 mL of H 2 O and extracted with EtOAc (30 mL*3 times). The combined organic layers were filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 20/1 to 10/1). Tert-butyl (2-propioloylphenyl)carbamate (Compound 2A, 500 mg, 2.04 mmol, 28.6% yield) was obtained as a yellow liquid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 10.62 (br s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.3 Hz, 1H), 3.50 (s, 1H), 1.55 (s, 9H).
단계 3) 4-아지도-6-클로로피리미딘-2-아민의 준비Step 3) Preparation of 4-azido-6-chloropyrimidin-2-amine
DMF(dimethylformamide, 50.0 mL) 중 4,6-디클로로피리미딘-2-아민(화합물 1, 5.00 g, 30.4 mmol, 1.00 당량) 및 NaN3(6.02 g, 92.6 mmol, 3.04 당량)의 혼합물을 N2로 3회 탈기 및 퍼지하고, 그 후 혼합물을 50℃에서 5 시간 동안 N2 대기 하에서 교반하였다. TLC(석유 에테르/에틸 아세테이트=5/1, 반응물 Rf =0.44 생성물 Rf =0.53)는 반응물 1이 완전히 소모되고, 하나의 새로운 스팟이 형성되었음을 나타내었다. 4-아지도-6-클로로피리미딘-2-아민(화합물 2, 5.00 g, 29.3 mmol, 96.1% yield)을 노란색 액체로 추가 정제 없이 수득하였다.A mixture of 4,6-dichloropyrimidin-2-amine (Compound 1, 5.00 g, 30.4 mmol, 1.00 equiv) and NaN 3 (6.02 g, 92.6 mmol, 3.04 equiv) in DMF (dimethylformamide, 50.0 mL) was incubated with N 2 After degassing and purging three times, the mixture was stirred at 50° C. for 5 hours under N 2 atmosphere. TLC (petroleum ether/ethyl acetate=5/1, reactant R f =0.44 product R f =0.53) showed that reactant 1 was completely consumed and one new spot was formed. 4-Azido-6-chloropyrimidin-2-amine (Compound 2, 5.00 g, 29.3 mmol, 96.1% yield) was obtained as a yellow liquid without further purification.
단계 4) 터트-부틸 (2-(1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-카르보닐)페닐)카르바메이트의 준비Step 4) of tert-butyl (2-(1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazole-4-carbonyl)phenyl)carbamate preparation
4-아지도-6-클로로피리미딘-2-아민(화합물 2, 1.05 g, 6.16 mmol, 1 당량), DMF (20 mL) 중 터트 부틸 (2-프로피올로일페닐)카르바메이트(화합물 2A, 1.51 g, 6.16 mmol, 1 당량), 소듐 아스코르베이트(243 mg, 1.23 mmol, 0.2 당량), CuSO4·5H2O(153 mg, 615 μmol, 0.1 당량)의 용액을 N2로 3회 퍼지하고, 그 후 혼합물을 25℃에서 4 시간 동안 N2 대기 하에서 교반하였다. TLC(석유 에테르/에틸 아세테이트 = 1/1)는 반응물 1(Rf = 0.70)이 소모되고 더 큰 Rf(= 0.40)를 갖는 주요 새로운 스팟을 검출하였다. LCMS는 원하는 질량을 나타내었다. 반응 혼합물을 H2O 50 mL로 희석하고 DC/MEOH=10/1 50 mL로 추출하였다. 조합된 유기 층을 포화 NaCl 용액 30 mL로 세척하고, Na2SO4로 건조시키고, 감압 하에서 여과 및 농축시켜 잔여물을 얻었다. 잔여물은 컬럼 크로마토그래피(SiO2, 석유 에테르/에틸 아세테이트=5/1 내지 3/1)로 정제하였다. 터트-부틸 (2-(1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-카르보닐)페닐)카르바메이트(화합물 3, 870 mg, 2.09 mmol, 34.0% 수율)을 노란색 고체로 수득하였다. 1HNMR(400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 9.01 (s, 1H), 8.04 - 7.89 (m, 1H), 7.78 (br d, J = 8.1 Hz, 3H), 7.66 - 7.57 (m, 1H), 7.37 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 1.36 (s, 9H); LCMS: 생성물 RT = 2.455분, MS (ESI) m/z = 360.1 [M+H-55]+.4-Azido-6-chloropyrimidin-2-amine (Compound 2, 1.05 g, 6.16 mmol, 1 eq), tert-butyl (2-propioloylphenyl)carbamate (Compound 2) in DMF (20 mL) A solution of 2A, 1.51 g, 6.16 mmol, 1 eq), sodium ascorbate (243 mg, 1.23 mmol, 0.2 eq), CuSO 4 ·5H 2 O (153 mg, 615 μmol, 0.1 eq) was reacted with N 2 at 3 After purging twice, the mixture was stirred at 25° C. for 4 hours under N 2 atmosphere. TLC (petroleum ether/ethyl acetate = 1/1) showed consumption of reactant 1 (R f = 0.70) and detected a major new spot with larger R f (= 0.40). LCMS indicated the desired mass. The reaction mixture was diluted with 50 mL of H 2 O and extracted with 50 mL of DC/MEOH=10/1. The combined organic layers were washed with 30 mL of saturated NaCl solution, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=5/1 to 3/1). Tert-Butyl (2-(1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazole-4-carbonyl)phenyl)carbamate (Compound 3, 870 mg, 2.09 mmol, 34.0% yield) was obtained as a yellow solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 9.84 (s, 1H), 9.01 (s, 1H), 8.04 - 7.89 (m, 1H), 7.78 (br d, J = 8.1 Hz, 3H), 7.66 - 7.57 (m, 1H), 7.37 (s, 1H), 7.25 (t, J = 7.6 Hz, 1H), 1.36 (s, 9H); LCMS: product RT = 2.455 min, MS (ESI) m/z = 360.1 [M+H-55] + .
단계 5) 터트-부틸 (2-((1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트의 준비Step 5) Tert-Butyl (2-((1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl) Preparation of phenyl)carbamate
MeOH (20 mL) 및 THF (20 mL) 중 터트-부틸 (2-(1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-카르보닐)페닐)카르바메이트(화합물 3, 770 mg, 1.85 mmol, 1.00 당량)의 용액에 NaBH4(200 mg, 5.29 mmol, 2.85 당량)을 0℃에서 첨가하였다. 혼합물을 0℃에서 3 시간 동안 교반하였다. TLC(석유 에테르/에틸 아세테이트 = 1/1)는 반응물 1(Rf = 0.70)이 소모되고, 더 큰 Rf(= 0.50)를 갖는 하나의 주요 새로운 스팟을 검출하였음을 나타내었다. LCMS는 원하는 질량을 나타내었다. 반응 혼합물은 0℃에서 H2O 20 mL의 첨가에 의해 퀀칭(quench)하고, 그 후 DCM(dichloromethane) 200 mL 및 MeOH 20 mL로 추출하였다. Na2SO4로 건조시키고, 감압 하에서 여과 및 농축시켜 잔여물을 얻었다. 잔여물은 컬럼 크로마토그래피(SiO2, 석유 에테르/에틸 아세테이트=5/1 내지 2/1)로 정제하였다. 터트-부틸 (2-((1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트(화합물 4, 500 mg, 1.20 mmol, 64.6% 수율)를 흰색 고체로 수득하였다. 1H NMR(E400 MHz, DMSO-d) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.63 (br s, 2H), 7.48 (s, 2H), 7.34 - 7.24 (m, 1H), 7.21 (s, 1H), 7.19 - 7.09 (m, 1H), 6.58 (d, J = 4.8 Hz, 1H), 6.13 (d, J = 4.8 Hz, 1H), 1.33 (s, 9H); LCMS: 생성물 RT = 1.887분, MS (ESI) m/z = 418.2 [M+H]+.Tert-butyl (2-(1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazole-4- in MeOH (20 mL) and THF (20 mL) NaBH 4 (200 mg, 5.29 mmol, 2.85 equiv) was added to a solution of carbonyl)phenyl)carbamate (Compound 3, 770 mg, 1.85 mmol, 1.00 equiv) at 0°C. The mixture was stirred at 0° C. for 3 hours. TLC (petroleum ether/ethyl acetate = 1/1) showed that reactant 1 (R f = 0.70) was consumed and one major new spot with a larger R f (= 0.50) was detected. LCMS indicated the desired mass. The reaction mixture was quenched by addition of 20 mL of H 2 O at 0°C, and then extracted with 200 mL of dichloromethane (DCM) and 20 mL of MeOH. It was dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=5/1 to 2/1). tert-butyl (2-((1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)phenyl)car Bamate (Compound 4, 500 mg, 1.20 mmol, 64.6% yield) was obtained as a white solid. 1 H NMR (E400 MHz, DMSO- d ) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.63 (br s, 2H), 7.48 (s, 2H), 7.34 - 7.24 (m, 1H), 7.21 (s, 1H), 7.19 - 7.09 (m, 1H), 6.58 (d, J = 4.8 Hz, 1H), 6.13 (d, J = 4.8 Hz, 1H), 1.33 (s, 9H); LCMS: product RT = 1.887 min, MS (ESI) m/z = 418.2 [M+H] + .
단계 6) 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트의 준비Step 6) Tert-Butyl (2-((1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl) Preparation of (hydroxy)methyl)phenyl)carbamate
터트-부틸 (2-((1-(2-아미노-6-클로로피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트(화합물 4, 300 mg, 717 μmol, 1 당량), 및 디옥산(18.0 mL) 및 H2O(4.50 mL) 중 2-(퓨란-2-일)-4,4,5,5-테트라메틸-1,3,2-디옥사볼로란(화합물 4A, 167 mg, 861 umol, 1.20 당량)의 용액에, Pd(dppf)Cl2(52.5 mg, 71.8 umol, 0.1 당량) 및 K2CO3(297 mg, 2.15 mmol, 3.00 당량)를 첨가하였다. 혼합물을 90℃에서 3 시간 동안 교반하였다. TLC(석유 에테르/에틸 아세테이트 = 1/1)는 반응물 1(Rf = 0.50)이 소모되고 더 큰 Rf(= 0.30)를 갖는 주요 새로운 스팟이 검출되었음을 나타내었다. LCMS는 원하는 질량을 나타내었다. 반응 혼합물을 H2O 20 mL로 희석하고 DCM/MeOH=10/1 50 mL로 추출하였다. 조합된 유기 층을 NaCl 20 mL로 세척하고, Na2SO4로 건조시키고, 감압 하에서 여과 및 노축시켜 잔여물을 얻었다. 잔여물은 컬럼 크로마토그래피(SiO2, 석유 에테르/에틸 아세테이트=4/1 내지 2/1)로 정제하였다. 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트(화합물 5, 192 mg, 427 μmol, 59.5% 수율)를 노란색 오일로 수득하였다. 1H NMR(400 MHz, CDCl3) δ 8.29 (s, 1H), 7.94 - 7.82 (m, 2H), 7.77 (s, 1H), 7.63 (d, J = 1.1 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.24 (d, J = 3.4 Hz, 1H), 7.11 (dt, J = 1.0, 7.5 Hz, 1H), 6.59 (dd, J = 1.7, 3.4 Hz, 1H), 6.19 (d, J = 3.1 Hz, 1H), 5.20 (s, 2H), 3.46 (d, J = 3.4 Hz, 1H), 1.47 (s, 9H); LCMS: 생성물 RT = 1.990분, MS (ESI) m/z = 450.2 [M+H]+.tert-butyl (2-((1-(2-amino-6-chloropyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy)methyl)phenyl)car Bamate (Compound 4, 300 mg, 717 μmol, 1 equiv), and 2-(furan-2-yl)-4,4,5,5- in dioxane (18.0 mL) and H 2 O (4.50 mL). In a solution of tetramethyl-1,3,2-dioxabolorane (compound 4A, 167 mg, 861 umol, 1.20 equiv), Pd(dppf)Cl 2 (52.5 mg, 71.8 umol, 0.1 equiv) and K 2 CO 3 (297 mg, 2.15 mmol, 3.00 eq) was added. The mixture was stirred at 90° C. for 3 hours. TLC (petroleum ether/ethyl acetate = 1/1) showed that reactant 1 (R f = 0.50) was consumed and a major new spot with larger R f (= 0.30) was detected. LCMS indicated the desired mass. The reaction mixture was diluted with 20 mL of H 2 O and extracted with 50 mL of DCM/MeOH=10/1. The combined organic layers were washed with 20 mL of NaCl, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=4/1 to 2/1). tert-butyl (2-((1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)(hydroxy )Methyl)phenyl)carbamate (Compound 5, 192 mg, 427 μmol, 59.5% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.29 (s, 1H), 7.94 - 7.82 (m, 2H), 7.77 (s, 1H), 7.63 (d, J = 1.1 Hz, 1H), 7.41 - 7.32 ( m, 1H), 7.24 (d, J = 3.4 Hz, 1H), 7.11 (dt, J = 1.0, 7.5 Hz, 1H), 6.59 (dd, J = 1.7, 3.4 Hz, 1H), 6.19 (d, J = 3.1 Hz, 1H), 5.20 (s, 2H), 3.46 (d, J = 3.4 Hz, 1H), 1.47 (s, 9H); LCMS: product RT = 1.990 min, MS (ESI) m/z = 450.2 [M+H] + .
단계 7) 4-{4-[(2-아미노페닐)메틸]-1H-1,2,3-트리아졸-1-일}-6-(퓨란-2-일)피리미딘-2-아민의 제조Step 7) 4-{4-[(2-aminophenyl)methyl]-1H-1,2,3-triazol-1-yl}-6-(furan-2-yl)pyrimidin-2-amine manufacturing
DCM(5.00 mL) 및 TFA(trifluoroacetic acid)(1.00 mL) 중 터트-부틸 (2-((1-(2-아미노-6-(퓨란-2-일)피리미딘-4-일)-1H-1,2,3-트리아졸-4-일)(히드록시)메틸)페닐)카르바메이트(화합물 5, 190 mg, 422.73 μmol, 1 당량)의 용액에 Et3SiH(491 mg, 4.23 mmol, 675 μL, 10.0 당량)을 첨가하였다. 혼합물을 25℃에서 48 시간 동안 교반하였다. LC-MS는 47.0%의 반응물 1이 남았다. 몇개의 새로운 피크들이 LC-MS 상에서 나타났고 25.0%의 원하는 화합물이 검출되었다. 반응 혼합물은 0℃에서 NaHCO3 20 mL의 첨가에 의해 퀀칭하고, 그 후 DCM/MeOH=10/1 20 mL로 추출하였다. 조합된 유기 층을 포화 NaCl 용액 10 mL로 세척하고, Na2SO4로 건조시키고, 감압 하에서 여과 및 농축시켜 잔여물을 얻었다. 잔여물은 prep-HPLC (FA 조건)으로 정제하였다. 불순물은 prep-HPLC(염기 조건)으로 정제하였다. 4-{4-[(2-아미노페닐)메틸]-1H-1,2,3-트리아졸-1-일}-6-(퓨란-2-일)피리미딘-2-아민(실시예 화합물 1, 7.0 mg, 20.9 μmol, 4.95% 수율, 99.6% 순도)를 흰색 고체로 수득하였다. 1HNMR(400MHz, DMSO-d 6) δ 8.27 (s, 1H), 7.96 (d, J =1.0 Hz, 1H), 7.47 (s, 1H), 7.32 (d, J = 3.4 Hz, 1H), 7.20 (br s, 2H), 7.05 - 6.90 (m, 2H), 6.73 (dd, J =1.8, 3.5 Hz, 1H), 6.66 (d, J =7.1 Hz, 1H), 6.52 (dt, J =1.0, 7.4 Hz, 1H), 5.02 (s, 2H), 3.96 (s, 2H); LCMS: 생성물 RT = 1.136분, MS (ESI) m/z = 334.2 [M+H]+; HPLC: AP = 99.6%.Tert-butyl (2-((1-(2-amino-6-(furan-2-yl)pyrimidin-4-yl)-1H- in DCM (5.00 mL) and trifluoroacetic acid (TFA) (1.00 mL) In a solution of 1,2,3-triazol-4-yl)(hydroxy)methyl)phenyl)carbamate (Compound 5, 190 mg, 422.73 μmol, 1 equiv), Et 3 SiH (491 mg, 4.23 mmol, 675 μL, 10.0 equivalent) was added. The mixture was stirred at 25° C. for 48 hours. LC-MS showed that 47.0% of reactant 1 remained. Several new peaks appeared on LC-MS and 25.0% of the desired compound was detected. The reaction mixture was quenched by addition of 20 mL of NaHCO 3 at 0°C and then extracted with 20 mL of DCM/MeOH=10/1. Combined organic layers were saturated with NaCl solution. Washed with 10 mL, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (FA conditions). Impurities were purified by prep-HPLC (basic conditions). 4-{4-[(2-aminophenyl)methyl]-1H-1,2,3-triazol-1-yl}-6-(furan-2-yl)pyrimidin-2-amine (Example compound 1, 7.0 mg, 20.9 μmol, 4.95% yield, 99.6% purity) was obtained as a white solid. 1 HNMR (400 MHz, DMSO- d 6 ) δ 8.27 (s, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.47 (s, 1H), 7.32 (d, J = 3.4 Hz, 1H), 7.20 (br s, 2H), 7.05 - 6.90 (m, 2H), 6.73 (dd, J =1.8, 3.5 Hz, 1H), 6.66 (d, J =7.1 Hz, 1H), 6.52 (dt, J =1.0, 7.4 Hz, 1H), 5.02 (s, 2H), 3.96 (s, 2H); LCMS: product RT = 1.136 min, MS (ESI) m/z = 334.2 [M+H] + ; HPLC: AP = 99.6%.
실시예 2. 실시예 화합물 1의 A2AR 및 A2BR 이중 길항 효과의 확인Example 2. Confirmation of the A2AR and A2BR dual antagonistic effect of Example Compound 1
실시예 1에 기재된 바와 같이 준비된 4-{4-[(2-아미노페닐)메틸]-1H-1,2,3-트리아졸-1-일}-6-(퓨란-2-일)피리미딘-2-아민(실시예 화합물 1)이 아데노신 A2A 수용체(A2AR) 및 아데노신 A2B 수용체(A2BR)에 대해 길항 효과가 있는지 여부를 확인하였다.4-{4-[(2-aminophenyl)methyl]-1H-1,2,3-triazol-1-yl}-6-(furan-2-yl)pyrimidine prepared as described in Example 1 It was confirmed whether -2-amine (Example Compound 1) had an antagonistic effect on adenosine A2A receptor (A2AR) and adenosine A2B receptor (A2BR).
실시예 화합물 1을 DMSO에 용해하여 10 mM 스톡 용액으로 준비하였다. 50% 저해 농도(half maximal inhibitory concentration: IC50)을 결정하기 위해, 화합물을 최고 농도 100 μM로 하고, 10배씩 희석하여 10가지 농도로 준비하였다.Example Compound 1 was prepared as a 10 mM stock solution by dissolving in DMSO. To determine the 50% inhibitory concentration (half maximal inhibitory concentration: IC 50 ), the compound was set to a maximum concentration of 100 μM and diluted 10 times to prepare 10 different concentrations.
HEK293 세포(Life technologies, R705-07)를 96웰-흰색 플레이트의 각 웰 당 약 25,000 세포로 접종하였다. 세포를 접종한 각 웰에 2x106 아데노신 A2aR 또는 5x106 아데노신 A2bR-발현 바쿨로바이러스 입자를 가하고, 밤새 배양하였다. 아데노신 수용체 길항제의 EC80을 결정하기 위해, cAMP 기능 분석법에 사용되는 5-N-에틸카르복스아미도아데노신(ethylcarboxamidoadenosine: NECA)(Tocris, 1691)을 가하고, 용량 반응 시험을 수행하였다. 다음날, 배지를 제거하고, 30 μL의 PBS로 교환하였다. 세포에 7.5 μL의 화합물을 가하고, 37℃ 및 5% CO2에서 30분 동안 배양하였다. 그후, 7.5 μL의 NECA를 EC80에 상응하는 최종 농도로 가하고 37℃ 및 5% CO2에서 60분 동안 배양하였다. Hithunter cAMP assay for biologics(DiscoveRx; 90-0075 series)를 사용하여 발광 신호를 측정하였다. 발광 신호의 변화를 Perkin Elmer Envision에서 모니터링하였다. 발광 신호의 변화로부터 실시예 화합물 1의 IC50을 산출하고, 그 결과를 하기 표 1에 나타내었다.HEK293 cells (Life technologies, R705-07) were seeded at approximately 25,000 cells per well of a 96-well white plate. 2x10 6 Adenosine A2aR or 5x10 6 Adenosine A2bR-expressing baculovirus particles were added to each well inoculated with cells, and cultured overnight. To determine the EC 80 of the adenosine receptor antagonist, 5-N-ethylcarboxamidoadenosine (NECA) (Tocris, 1691), which is used in the cAMP function assay, was added, and a dose response test was performed. The next day, the medium was removed and replaced with 30 μL of PBS. 7.5 μL of compound was added to the cells and incubated for 30 minutes at 37°C and 5% CO 2 . Then, 7.5 μL of NECA was added to a final concentration corresponding to EC 80 and incubated for 60 minutes at 37°C and 5% CO 2 . Luminescent signals were measured using Hithunter cAMP assay for biologics (DiscoveRx; 90-0075 series). Changes in luminescence signal were monitored on Perkin Elmer Envision. The IC 50 of Example Compound 1 was calculated from the change in the emission signal, and the results are shown in Table 1 below.
표 1에 나타난 바와 같이, 실시예 화합물 1은 A2AR 및 A2BR 모두에 대해 길항 활성을 갖는 것을 확인하였다.As shown in Table 1, Example Compound 1 was confirmed to have antagonistic activity against both A2AR and A2BR.
Claims (8)
[화학식 1]
,
상기 화학식 1에서,
R1은 -(CH2)n-C6 내지 C12의 아릴기로서,
상기 n은 0 내지 2의 정수이고,
상기 C6 내지 C12의 아릴기는 NR5R6으로 치환되고,
상기 R5 및 R6은 각각 독립적으로, H 또는 C1 내지 C10의 알킬기이고,
R2는 H, C1 내지 C10의 알킬기, 또는 NR3R4이고,
상기 R3 및 R4는 각각 독립적으로, H 또는 C1 내지 C10의 알킬기이다. A compound represented by the following formula (1), a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:
[Formula 1]
,
In Formula 1,
R 1 is -(CH 2 )nC 6 to C 12 aryl group,
where n is an integer from 0 to 2,
The aryl group of C 6 to C 12 is substituted with NR 5 R 6 ,
R 5 and R 6 are each independently H or an alkyl group of C 1 to C 10 ,
R 2 is H, an alkyl group of C 1 to C 10 , or NR 3 R 4 ,
R 3 and R 4 are each independently H or a C 1 to C 10 alkyl group.
[화학식 2]
.The method of claim 1, wherein the compound of Formula 1 is a compound represented by Formula 2, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof:
[Formula 2]
.
상기 아데노신 A2A 수용체 및 아데노신 A2B 수용체와 관련된 질병은 암인 것인 약학적 조성물.A pharmaceutical composition for preventing or treating diseases associated with adenosine A2A receptor and adenosine A2B receptor, comprising the compound of claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof,
A pharmaceutical composition wherein the disease associated with the adenosine A2A receptor and the adenosine A2B receptor is cancer.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210037828A KR102646627B1 (en) | 2021-03-24 | 2021-03-24 | Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof |
| PCT/KR2022/003617 WO2022203267A1 (en) | 2021-03-24 | 2022-03-15 | Dual antagonist for adenosine a2a receptor and adenosine a2b receptor and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020210037828A KR102646627B1 (en) | 2021-03-24 | 2021-03-24 | Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20220132811A KR20220132811A (en) | 2022-10-04 |
| KR102646627B1 true KR102646627B1 (en) | 2024-03-13 |
Family
ID=83397668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020210037828A KR102646627B1 (en) | 2021-03-24 | 2021-03-24 | Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR102646627B1 (en) |
| WO (1) | WO2022203267A1 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070020397A (en) * | 2003-12-15 | 2007-02-21 | 알미랄 프로데스파르마 에이쥐 | 2,6-bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists |
| US10399962B2 (en) * | 2017-01-20 | 2019-09-03 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
| US11028058B2 (en) * | 2017-07-18 | 2021-06-08 | Nuvation Bio Inc. | Heterocyclic compounds as adenosine antagonists |
| AU2019222747A1 (en) * | 2018-02-16 | 2020-10-08 | Arcus Biosciences, Inc. | Dosing with an azolopyrimidine compound |
| WO2020053263A1 (en) * | 2018-09-11 | 2020-03-19 | Iteos Therapeutics S.A. | Thiocarbamate derivatives as a2a inhibitors, pharmaceutical composition thereof and combinations with anticancer agents |
-
2021
- 2021-03-24 KR KR1020210037828A patent/KR102646627B1/en active IP Right Grant
-
2022
- 2022-03-15 WO PCT/KR2022/003617 patent/WO2022203267A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220132811A (en) | 2022-10-04 |
| WO2022203267A1 (en) | 2022-09-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20210017163A1 (en) | Hydrochloride salt form for ezh2 inhibition | |
| JP6634058B2 (en) | Salt form of human histone methyltransferase EZH2 inhibitor | |
| US9758526B2 (en) | Quinoline-substituted compound | |
| US9890168B2 (en) | 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof | |
| WO2019042445A1 (en) | Compound having bruton's tyrosine kinase (btk)-inhibition and degradation activity | |
| US20210309640A1 (en) | Pharmaceutical salts of pyrimidine derivatives and method of treating disorders | |
| BR112014003146A2 (en) | 3,4-DIHIDRO-1H- [1,8] NAPHYDRIDINES REPLACED WITH ANTIBACTERIAL HOMOPIPERIDINYL, PHARMACEUTICAL COMPOSITION UNDERSTANDING THOSE COMPOUNDS, PROCESSES FOR5 PREPARATION OF THESE AND USE | |
| JPWO2016039398A1 (en) | Nitrogen-containing heterocyclic derivatives, neuroprotective agents, and pharmaceutical compositions for cancer treatment | |
| US11834432B2 (en) | Substituted amino six-membered nitric heterocyclic ring compound and preparation and use thereof | |
| KR20210116572A (en) | Thiazolopyridine derivatives as adenosine receptor antagonists | |
| KR102646627B1 (en) | Dual antagonist of adenosine A2A receptor and adenosine A2B receptor, and use thereof | |
| KR101777475B1 (en) | Novel dihydropyranopyrimidinone derivatives, and use thereof | |
| WO2019001307A1 (en) | Amide compound, composition containing same, and use thereof | |
| KR101872264B1 (en) | New type of cytidine derivative dimer and application thereof | |
| AU2016304331A1 (en) | Method of treating cancer with a combination of benzylideneguanidine derivatives and chemotherapeutic agent. | |
| CN114599656A (en) | Imidazolidinone compound and preparation method and application thereof | |
| KR102621694B1 (en) | Adenosine a2a receptor antagonist and use thereof | |
| KR101995533B1 (en) | Novel [1,2,4]triazolo[4,3-a]quinoxaline amino phenyl derivatives or pharmaceutically acceptable salts thereof, preparation method therof and pharmaceutical composition for use in preventing or treating bromodomain extra-terminal(BET) protein activity related diseases containing the same as an active ingredient | |
| US7304092B1 (en) | Compounds and methods for treating tumors, cancer and hyperproliferative diseases | |
| WO2016078399A1 (en) | New type of cytidine derivative dimer and application thereof | |
| KR20170115315A (en) | Novel heterocyclic derivatives, and use thereof | |
| NZ718201B2 (en) | Hydrochloride salt form for ezh2 inhibition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E701 | Decision to grant or registration of patent right |