HRP20191238T1 - Spojevi koji ekspandiraju hematopoietske matične stanice - Google Patents
Spojevi koji ekspandiraju hematopoietske matične stanice Download PDFInfo
- Publication number
- HRP20191238T1 HRP20191238T1 HRP20191238T HRP20191238T1 HR P20191238 T1 HRP20191238 T1 HR P20191238T1 HR P20191238 T HRP20191238 T HR P20191238T HR P20191238 T1 HRP20191238 T1 HR P20191238T1
- Authority
- HR
- Croatia
- Prior art keywords
- ethyl
- purin
- isopropyl
- ylamino
- pyridin
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims 40
- 210000003958 hematopoietic stem cell Anatomy 0.000 title claims 11
- -1 1H-benzoimidazolyl Chemical group 0.000 claims 110
- 210000004027 cell Anatomy 0.000 claims 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 24
- 238000000034 method Methods 0.000 claims 16
- 210000004700 fetal blood Anatomy 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 11
- 229910052739 hydrogen Inorganic materials 0.000 claims 11
- 150000003839 salts Chemical class 0.000 claims 11
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 10
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 10
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 9
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 claims 9
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 claims 9
- 125000000217 alkyl group Chemical group 0.000 claims 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 9
- 210000000130 stem cell Anatomy 0.000 claims 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 8
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims 8
- 125000004274 oxetan-2-yl group Chemical group [H]C1([H])OC([H])(*)C1([H])[H] 0.000 claims 8
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims 8
- 102000003984 Aryl Hydrocarbon Receptors Human genes 0.000 claims 7
- 108090000448 Aryl Hydrocarbon Receptors Proteins 0.000 claims 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 6
- 125000001414 1,2,4-triazol-5-yl group Chemical group [H]N1N=C([H])N=C1[*] 0.000 claims 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 5
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims 4
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims 4
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims 4
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims 4
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 4
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims 4
- 125000004076 pyridyl group Chemical group 0.000 claims 4
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims 4
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 claims 4
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims 4
- 125000001544 thienyl group Chemical group 0.000 claims 4
- 208000023275 Autoimmune disease Diseases 0.000 claims 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 3
- 230000003042 antagnostic effect Effects 0.000 claims 3
- 239000012636 effector Substances 0.000 claims 3
- 208000018706 hematopoietic system disease Diseases 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 3
- 125000005955 1H-indazolyl group Chemical group 0.000 claims 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- MKXRQMOKMZEWEL-UHFFFAOYSA-N 4-[2-[(9-propan-2-yl-2-thiophen-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(C2=CSC=C2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 MKXRQMOKMZEWEL-UHFFFAOYSA-N 0.000 claims 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 2
- 102000004127 Cytokines Human genes 0.000 claims 2
- 108090000695 Cytokines Proteins 0.000 claims 2
- 208000017604 Hodgkin disease Diseases 0.000 claims 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 2
- 208000034578 Multiple myelomas Diseases 0.000 claims 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 2
- 235000010290 biphenyl Nutrition 0.000 claims 2
- 239000004305 biphenyl Substances 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000002541 furyl group Chemical group 0.000 claims 2
- 239000003102 growth factor Substances 0.000 claims 2
- 125000002883 imidazolyl group Chemical group 0.000 claims 2
- 125000001041 indolyl group Chemical group 0.000 claims 2
- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 claims 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 2
- 230000037361 pathway Effects 0.000 claims 2
- 210000004976 peripheral blood cell Anatomy 0.000 claims 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims 2
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims 2
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims 2
- 125000000335 thiazolyl group Chemical group 0.000 claims 2
- YOMVAJQRTWMHTN-CQSZACIVSA-N (2r)-2-[2-(5-fluoropyridin-3-yl)-6-[2-(1h-indol-3-yl)ethylamino]purin-9-yl]propan-1-ol Chemical compound N1=C2N([C@@H](CO)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 YOMVAJQRTWMHTN-CQSZACIVSA-N 0.000 claims 1
- YOMVAJQRTWMHTN-AWEZNQCLSA-N (2s)-2-[2-(5-fluoropyridin-3-yl)-6-[2-(1h-indol-3-yl)ethylamino]purin-9-yl]propan-1-ol Chemical compound N1=C2N([C@H](CO)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 YOMVAJQRTWMHTN-AWEZNQCLSA-N 0.000 claims 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- SJMRYXNTPFDDIJ-UHFFFAOYSA-N 1-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]imidazolidin-2-one Chemical compound N1=C(C=2C=NC=CC=2)N=C2N(C(C)C)C=NC2=C1NCCN1CCNC1=O SJMRYXNTPFDDIJ-UHFFFAOYSA-N 0.000 claims 1
- XWOPPFVGRVCYHN-UHFFFAOYSA-N 1-[2-[2-(1-benzothiophen-3-yl)-6-[2-(4-hydroxyphenyl)ethylamino]purin-9-yl]ethyl]pyrrolidin-2-one Chemical compound C1=CC(O)=CC=C1CCNC1=NC(C=2C3=CC=CC=C3SC=2)=NC2=C1N=CN2CCN1C(=O)CCC1 XWOPPFVGRVCYHN-UHFFFAOYSA-N 0.000 claims 1
- RDUQOLBALRDWFW-UHFFFAOYSA-N 1-[2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]imidazolidin-2-one Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCN1CCNC1=O RDUQOLBALRDWFW-UHFFFAOYSA-N 0.000 claims 1
- IMUUUWPEMCYPKE-UHFFFAOYSA-N 1-acetyl-1-aminourea Chemical group CC(=O)N(N)C(N)=O IMUUUWPEMCYPKE-UHFFFAOYSA-N 0.000 claims 1
- KOUJPNABZNANBM-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-9-butan-2-yl-n-[2-(1h-indol-3-yl)ethyl]purin-6-amine Chemical compound C1=CC=C2C(C3=NC(NCCC=4C5=CC=CC=C5NC=4)=C4N=CN(C4=N3)C(C)CC)=CSC2=C1 KOUJPNABZNANBM-UHFFFAOYSA-N 0.000 claims 1
- NUFOQUDXWMPUAX-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-9-propan-2-yl-n-(2-thiophen-3-ylethyl)purin-6-amine Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC=1C=CSC=1 NUFOQUDXWMPUAX-UHFFFAOYSA-N 0.000 claims 1
- IMEAXFFCYXJRKQ-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-9-propan-2-yl-n-[3-(1h-pyrazol-4-yl)propyl]purin-6-amine Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCCC=1C=NNC=1 IMEAXFFCYXJRKQ-UHFFFAOYSA-N 0.000 claims 1
- IFTVRWXKABDXQE-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-n-[2-(1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound C1=CC=C2C(C3=NC(NCCC=4C5=CC=CC=C5NC=4)=C4N=CN(C4=N3)C(C)C)=CSC2=C1 IFTVRWXKABDXQE-UHFFFAOYSA-N 0.000 claims 1
- BOWCOOCDTXUFPP-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-n-[2-(4-fluorophenyl)ethyl]-9-phenylpurin-6-amine Chemical compound C1=CC(F)=CC=C1CCNC1=NC(C=2C3=CC=CC=C3SC=2)=NC2=C1N=CN2C1=CC=CC=C1 BOWCOOCDTXUFPP-UHFFFAOYSA-N 0.000 claims 1
- TWXXLRCJWOTYBJ-UHFFFAOYSA-N 2-(1-benzothiophen-3-yl)-n-[2-(4-fluorophenyl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(F)C=C1 TWXXLRCJWOTYBJ-UHFFFAOYSA-N 0.000 claims 1
- UDEZOOYKEQXNNQ-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-9-propan-2-yl-n-(2-pyridin-3-ylethyl)purin-6-amine Chemical compound N1=C(C=2C=C(F)C=NC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=CN=C1 UDEZOOYKEQXNNQ-UHFFFAOYSA-N 0.000 claims 1
- GEBRWSUJJHVSPC-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-9-propan-2-yl-n-[2-(1h-pyrrolo[2,3-b]pyridin-3-yl)ethyl]purin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=CN=C3NC=2)N=C1C1=CN=CC(F)=C1 GEBRWSUJJHVSPC-UHFFFAOYSA-N 0.000 claims 1
- HFWOIPIIXLUQFT-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(1h-indol-3-yl)ethyl]-9-(oxetan-3-yl)purin-6-amine Chemical compound FC1=CN=CC(C=2N=C3N(C4COC4)C=NC3=C(NCCC=3C4=CC=CC=C4NC=3)N=2)=C1 HFWOIPIIXLUQFT-UHFFFAOYSA-N 0.000 claims 1
- PWTFJRRVHPTEFT-GOSISDBHSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(1h-indol-3-yl)ethyl]-9-[(3r)-oxolan-3-yl]purin-6-amine Chemical compound FC1=CN=CC(C=2N=C3N([C@H]4COCC4)C=NC3=C(NCCC=3C4=CC=CC=C4NC=3)N=2)=C1 PWTFJRRVHPTEFT-GOSISDBHSA-N 0.000 claims 1
- DGQLINURGWXVOB-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(1h-indol-3-yl)ethyl]-9-prop-1-en-2-ylpurin-6-amine Chemical compound N1=C2N(C(=C)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 DGQLINURGWXVOB-UHFFFAOYSA-N 0.000 claims 1
- AJTJMSHSZGWYEU-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 AJTJMSHSZGWYEU-UHFFFAOYSA-N 0.000 claims 1
- VSJCVMXROMRODL-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(2-methyl-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2C)N=C1C1=CN=CC(F)=C1 VSJCVMXROMRODL-UHFFFAOYSA-N 0.000 claims 1
- XWHDGJHSMIVWQY-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(4-methyl-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=C(C)C=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 XWHDGJHSMIVWQY-UHFFFAOYSA-N 0.000 claims 1
- BBEPNUYCFSIHLM-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(5-methoxy-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound C12=CC(OC)=CC=C2NC=C1CCNC(C=1N=CN(C=1N=1)C(C)C)=NC=1C1=CN=CC(F)=C1 BBEPNUYCFSIHLM-UHFFFAOYSA-N 0.000 claims 1
- SACZYBUZGREONJ-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(6-methoxy-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound C=1NC2=CC(OC)=CC=C2C=1CCNC(C=1N=CN(C=1N=1)C(C)C)=NC=1C1=CN=CC(F)=C1 SACZYBUZGREONJ-UHFFFAOYSA-N 0.000 claims 1
- CGWYIUKFACKHAO-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(6-methyl-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=C(C)C=C3NC=2)N=C1C1=CN=CC(F)=C1 CGWYIUKFACKHAO-UHFFFAOYSA-N 0.000 claims 1
- USCVVIQRJFVGSC-UHFFFAOYSA-N 2-(5-fluoropyridin-3-yl)-n-[2-(7-methyl-1h-indol-3-yl)ethyl]-9-propan-2-ylpurin-6-amine Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=CC(C)=C3NC=2)N=C1C1=CN=CC(F)=C1 USCVVIQRJFVGSC-UHFFFAOYSA-N 0.000 claims 1
- YOMVAJQRTWMHTN-UHFFFAOYSA-N 2-[2-(5-fluoropyridin-3-yl)-6-[2-(1h-indol-3-yl)ethylamino]purin-9-yl]propan-1-ol Chemical compound N1=C2N(C(CO)C)C=NC2=C(NCCC=2C3=CC=CC=C3NC=2)N=C1C1=CN=CC(F)=C1 YOMVAJQRTWMHTN-UHFFFAOYSA-N 0.000 claims 1
- MJMLJOZYBPYLRI-UHFFFAOYSA-N 2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethylurea Chemical compound C1=CC=C2C(C3=NC(NCCNC(N)=O)=C4N=CN(C4=N3)C(C)C)=CSC2=C1 MJMLJOZYBPYLRI-UHFFFAOYSA-N 0.000 claims 1
- FQEPXUWHZHMTOB-UHFFFAOYSA-N 2-chloro-4-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(C=2C=NC=CC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C(Cl)=C1 FQEPXUWHZHMTOB-UHFFFAOYSA-N 0.000 claims 1
- FFBUQZIDNXUXHP-UHFFFAOYSA-N 2-methoxy-4-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound C1=C(O)C(OC)=CC(CCNC=2C=3N=CN(C=3N=C(N=2)C=2C=NC=CC=2)C(C)C)=C1 FFBUQZIDNXUXHP-UHFFFAOYSA-N 0.000 claims 1
- ASDLEUALOGRFLJ-UHFFFAOYSA-N 2-methyl-4-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(C=2C=NC=CC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C(C)=C1 ASDLEUALOGRFLJ-UHFFFAOYSA-N 0.000 claims 1
- ALSRAJHFOKUVIT-UHFFFAOYSA-N 3-[2-[[2-(1-benzothiophen-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]phenol Chemical compound N1=C(C=2C3=CC=CC=C3SC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=CC(O)=C1 ALSRAJHFOKUVIT-UHFFFAOYSA-N 0.000 claims 1
- QMGQKDDRYGHRAH-UHFFFAOYSA-N 3-[2-[[2-(5-fluoropyridin-3-yl)-9-propan-2-ylpurin-6-yl]amino]ethyl]-1h-indol-6-ol Chemical compound N1=C2N(C(C)C)C=NC2=C(NCCC=2C3=CC=C(O)C=C3NC=2)N=C1C1=CN=CC(F)=C1 QMGQKDDRYGHRAH-UHFFFAOYSA-N 0.000 claims 1
- IVTLBBPXLNAOAW-UHFFFAOYSA-N 3-[6-[2-(4-hydroxyphenyl)ethylamino]-9-propan-2-ylpurin-2-yl]pyridine-2-carbonitrile Chemical compound N1=C(C=2C(=NC=CC=2)C#N)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 IVTLBBPXLNAOAW-UHFFFAOYSA-N 0.000 claims 1
- LTMUJUPPWXQSJA-UHFFFAOYSA-N 3-[6-[2-(4-hydroxyphenyl)ethylamino]-9-propan-2-ylpurin-2-yl]pyridine-4-carbonitrile Chemical compound N1=C(C=2C(=CC=NC=2)C#N)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 LTMUJUPPWXQSJA-UHFFFAOYSA-N 0.000 claims 1
- ZMMYMIXUKCCBJH-UHFFFAOYSA-N 3-fluoro-4-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(C=2C=NC=CC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1F ZMMYMIXUKCCBJH-UHFFFAOYSA-N 0.000 claims 1
- LYXYXVUASNMLGD-UHFFFAOYSA-N 3-methyl-4-[2-[(9-propan-2-yl-2-pyridin-3-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(C=2C=NC=CC=2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1C LYXYXVUASNMLGD-UHFFFAOYSA-N 0.000 claims 1
- QYMWWASELHXUTQ-UHFFFAOYSA-N 4-[2-[(2-imidazo[4,5-b]pyridin-1-yl-9-propan-2-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(N2C3=CC=CN=C3N=C2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 QYMWWASELHXUTQ-UHFFFAOYSA-N 0.000 claims 1
- LSTKYPXBOLVWGQ-UHFFFAOYSA-N 4-[2-[(2-imidazo[4,5-b]pyridin-3-yl-9-propan-2-ylpurin-6-yl)amino]ethyl]phenol Chemical compound N1=C(N2C3=NC=CC=C3N=C2)N=C2N(C(C)C)C=NC2=C1NCCC1=CC=C(O)C=C1 LSTKYPXBOLVWGQ-UHFFFAOYSA-N 0.000 claims 1
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Claims (28)
1. Spoj, naznačen time, što je predstavljen formulom I:
gdje:
G1 se bira od N i CR3;
G2, G3 i G4 se neovisno biraju od CH i N; pod uvjetom da najmanje 1 od G3 i G4 je N;
pod uvjetom da oba G1 i G2 nisu N;
L se bira od -NR5a(CH2)2-, -NR5a(CH2)3-, -NR5aCH(C(O)OCH3)CH2-, -NR5a(CH2)2NR5b-, -NR5a(CH2)2S-, -NR5aCH2CH(CH3)CH2-, -NR5aCH2CH(OH)- i -NR5aCH(CH3)CH2-; pri čemu R5a i R5b se neovisno biraju od vodika i C1-4alkila;
R1 se bira iz niza koji čine fenil, tiofenil, furanil, 1H-benzoimidazolil, izokinolinil, 1H-imidazopiridinil, benzotiofenil, pirimidinil, piridinil, 1H-imidazolil, pirazinil, piridazinil, 1H-pirolil i tiazolil; pri čemu navedeni fenil, tiofenil, furanil, 1H-benzoimidazolil, izokinolinil, 1H-imidazopiridinil, benzotiofenil, pirimidinil, piridinil, 1H-imidazolil, pirazinil, piridazinil, 1H-pirolil ili tiazolil od R1, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine cijano, hidroksi, C1-4alkil, C1-4alkoksi, halo, halo-supstituiran-C1-4alkil, halo-supstituiran-C1-4alkoksi, hidroksi, amino, -C(O)R8a, -S(O)0-2R8a, -C(O)OR8a, i -C(O)NR8aR8b; pri čemu R8a i R8b se neovisno biraju od vodika i C1-4alkila;
R2 se bira od sljedećih: -S(O)2NR6aR6b, -NR6aC(O)R6b, -NR6aC(O)NR6bR6c, fenil, 1H-pirolopiridin-3-il, 1H-indolil, tiofenil, piridinil, 1H-1,2,4-triazolil, 2-oksoimidazolidinil, 1H-pirazolil, 2-okso-2,3-dihidro-1H-benzoimidazolil i 1H-indazolil; pri čemu
R6a, R6b i R6c se neovisno biraju od vodika i C1-4alkila; i navedeni fenil, 1H-pirolopiridin-3-il, 1H-indolil, tiofenil, piridinil, 1H-1,2,4-triazolil, 2-oksoimidazolidinil, 1H-pirazolil, 2-okso-2,3-dihidro-1H-benzoimidazolil ili 1H-indazolil od R2, po izboru je supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine hidroksi, halo, metil, metoksi, amino,
-O(CH2)nNR7aR7b, -S(O)2NR7aR7b, –OS(O)2NR7aR7b i –NR7aS(O)2R7b; pri čemu R7a i R7b se neovisno biraju od vodika i C1-4alkila;
R3 se bira od vodika, C1-4alkila i bifenila; i
R4 se bira iz niza koji čine C1-10alkil, prop-1-en-2-il, cikloheksil, ciklopropil, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, tetrahidro-2H-piran-3-il, tetrahidro-2H-piran-4-il, fenil, tetrahidrofuran-3-il, tetrahidrofuran-2-il, benzil, (4-pentilfenil)(fenil)metil i 1-(1-(2-okso-6,9,12-trioksa-3-azatetradekan-14-il)-1H-1,2,3-triazol-4-il)etil; pri čemu
navedeni alkil, ciklopropil, cikloheksil, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, tetrahidro-2H-piran-3-il, tetrahidro-2H-piran-4-il, fenil, tetrahidrofuran-3-il, tetrahidrofuran-2-il, benzil, (4-pentilfenil)(fenil)metil ili 1-(1-(2-okso-6,9,12-trioksa-3-azatetradekan-14-il)-1H-1,2,3-triazol-4-il)etil, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine hidroksi, C1-4alkil i halo-supstituiran-C1-4alkil;
ili njegova sol.
2. Spoj prema patentnom zahtjevu 1, naznačen time, što spoj ima Formulu Ia:
u kojoj:
L je -NR5a(CH2)2-;
pri čemu R5a se bira od vodika i C1-4alkila;
R1 se bira od niza koji čine fenil, tiofen-2-il, tiofen-3-il, furan-3-il, 1H-benzo[d]imidazol-1-il, izokinolin-4-il, 1H-imidazo[4,5-b]piridin-1-il, benzo[b]tiofen-3-il, pirimidin-5-il, piridin-2-il, piridin-4-il, 1H-imidazol-1-il, pirazin-2-il, piridin-3-il, piridazin-4-il, 1H-pirol-2-il i tiazol-5-il; pri čemu
navedeni fenil, tiofen-2-il, tiofen-3-il, furan-3-il, 1H-benzo[d]imidazol-1-il, izokinolin-4-il, 1H-imidazo[4,5-b]piridin-1-il, benzo[b]tiofen-3-il, pirimidin-5-il, piridini-2-il, piridin-4-il, 1H-imidazol-1-il, pirazin-2-il, piridinil-3-il, piridazin-4-il, 1H-pirol-2-il ili tiazol-5-il od R1, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine cijano, hidroksi, C1-4alkil, C1-4alkoksi, halo, halo-supstituirani-C1-4alkil,
-S(O)0-2R8a i –C(O)OR8a; gdje se R8a bira od vodika i C1-4alkila;
R2 se bira iz niza koji čine -NR6aC(O)NR6bR6c, fenil, 1H-pirolo[2,3-b]piridin-3-il, 1H-indol-3-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il, 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il i 1H-indazol-3-il; pri čemu se
R6a, R6b i R6c neovisno biraju od vodika i C1-4alkila; i navedeni fenil, 1H-pirolo[2,3-b]piridin-3-il, 1H-indol-3-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il, 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il ili 1H-indazol-3-il od R2, po izboru je supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine hidroksi, halo, metoksi, amino,
-OS(O)2NR7aR7b i –NR7aS(O)2R7b;
gdje se R7a i R7b neovisno biraju od vodika i C1-4alkila; i
R4 se bira iz niza koji čine izopropil, metil, etil, prop-1-en-2-il, izobutil, cikloheksil, sek-butil, (S)-sek-butil, (R)-sek-butil, 1-hidroksipropan-2-il, (S)-1-hidroksipropan-2-il, (R)-1-hidroksipropan-2-il, nonan-2-il, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, fenil, tetrahidrofuran-3-il i benzil; pri čemu
navedeni cikloheksil, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, fenil, tetrahidrofuran-3-il ili benzil, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine C1-4alkil i
halo-supstituirani-C1-4alkil.
3. Spoj prema patentnom zahtjevu 1 ili zahtjevu 2, naznačen time, što se R2 bira iz niza koji čine urea, fenil, 1H-indol-2-il, 1H-indol-3-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-3-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il i 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il; pri čemu
navedeni fenil, 1H-indol-2-il, 1H-indol-3-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-3-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il ili 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il od R2, po izboru je supstituiran s hidroksi, metoksi, metilom, halo, amino i amino-sulfonilom.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, naznačen time, što
se R3 bira od vodika, metila i bifenila; i
R4 se bira iz niza koji čine izopropil, metil, etil, prop-1-en-2-il, izobutil, cikloheksil, sek-butil, (S)-sek-butil, (R)-sek-butil, 1-hidroksipropan-2-il, (S)-1-hidroksipropan-2-il, (R)-1-hidroksipropan-2-il, nonan-2-il, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, fenil, tetrahidrofuran-3-il i benzil; pri čemu
navedeni cikloheksil, 2-(2-oksopirolidin-1-il)etil, oksetan-3-il, oksetan-2-il, benzhidril, fenil, tetrahidrofuran-3-il ili benzil, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju od metila i trifluorometila.
5. Spoj prema patentnom zahtjevu 1, naznačen time, što spoj ima formulu Ia:
u kojoj:
L je -NH(CH2)2-;
R1 se bira iz niza koji čine fenil, tiofen-3-il, tiofen-2-il, furan-3-il, furan-2-il, benzo[b]tiofen-3-il, pirimidin-5-il, piridin-4-il, piridin-2-il, pirazin-2-il, piridazin-3-il, piridazin-4-il, 1H-imidazol-1-il, tiazol-4-il, 1H-pirol-2-il,
tiazol-5-il i piridin-3-il; pri čemu
navedeni fenil, tiofen-3-il, tiofen-2-il, furan-3-il, furan-2-il, benzo[b]tiofen-3-il, pirimidin-5-il, piridin-4-il, piridin-2-il, pirazin-2-il, piridazin-3-il, piridazin-4-il, 1H-imidazol-1-il, tiazol-4-il, 1H-pirol-2-il, tiazol-5-il ili piridin-3-il od R1, po izboru je supstituiran s 1 do 3 radikala koji se neovisno biraju iz niza koji čine cijano, metil, metil-sulfonil, metoksi, halo, hidroksi, karboksil, etoksi-karbonil, metil-amino-karbonil i amino;
R2 se bira iz niza koji čine amino-sulfonil, metil-karbonil-amino, urea, fenil, 1H-indol-2-il, 1H-indol-3-il, tiofen-2-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-3-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il, 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il i 1H-indazol-5-il; pri čemu
navedeni fenil, 1H-indol-2-il, 1H-indol-3-il, tiofen-2-il, tiofen-3-il, piridin-2-il, piridin-3-il, piridin-4-il, 1H-1,2,4-triazol-3-il, 1H-1,2,4-triazol-5-il, 2-oksoimidazolidin-1-il, 1H-pirazol-3-il, 1H-pirazol-4-il, 2-okso-2,3-dihidro-1H-benzo[d]imidazol-5-il, i 1H-indazol-5-il od R2, po izboru je supstituiran s hidroksi, metoksi, metilom, halo, aminom i amino-sulfonilom; i
R4 se bira iz niza koji čine izopropil, izobutil, sek-butil, 1-hidroksipropan-2-il, ciklopropil, oksetan-3-il, oksetan-2-il, benzhidril, tetrahidro-2H-piran-3-il, tetrahidro-2H-piran-4-il, fenil, tetrahidrofuran-3-il, tetrahidrofuran-2-il, benzil, (4-pentilfenil)(fenil)metil i 1-(1-(2-okso-6,9,12-trioksa-3-azatetradekan-14-il)-1H-1,2,3-triazol-4-il)etil; pri čemu
navedeni ciklopropil, oksetan-3-il, oksetan-2-il, benzhidril, tetrahidro-2H-piran-3-il, tetrahidro-2H-piran-4-il, fenil, tetrahidrofuran-3-il, tetrahidrofuran-2-il, benzil, (4-pentilfenil)(fenil)metil ili 1-(1-(2-okso-6,9,12-trioksa-3-azatetradekan-14-il)-1H-1,2,3-triazol-4-il)etil, može biti po izboru supstituiran s 1 do 3 radikala koji se neovisno biraju od metila i trifluorometila.
6. Spoj prema patentnom zahtjevu 1, naznačen time, što spoj ima formulu If:
u kojoj:
R2 se bira iz niza koji čine 1H-indol-3-il i fenil po izboru supstituiran s hidroksi; i
R4 se bira iz niza koji čine izopropil, sek-butil, benzhidril, nonan-2-il, oksetan-3-il i tetrahidrofuran-3-il.
7. Spoj prema patentnom zahtjevu 1, naznačen time, što spoj ima formulu Ig:
u kojoj:
R2 se bira niza koji čine 1H-pirolo[2,3-b]piridin-3-il; 1H-indol-3-il po izboru supstituiran s 1 do 2 radikala koji se neovisno biraju iz niza koji čine halo, metil i metoksi; i fenil po izboru supstituiran s 1 do 2 radikala koji se neovisno biraju iz niza koji čine metil, halo i hidroksi;
R4 se bira iz niza koji čine izopropil, sek-butil, 1-hidroksipropan-2-il, prop-1-en-2-il, benzhidril, nonan-2-il, oksetan-3-il i tetrahidrofuran-3-il; i
Ra, Rb i Rc su svaki neovisno odabrani iz niza koji čine vodik, cijano, metil, halo, -SO2CH3 i trifluorometil.
8. Spoj prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, što je odabran iz niza koji čine:
4-(2-(2-(benzo[b]tiofen-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-sek-butil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-benzhidril-2-(benzo[b]tiofen-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-(tetrahidro-2H-piran-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(tiofen-2-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-(4-(trifluorometil)benzil)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-izobutil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-metil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-(4-metilbenzil)-9H-purin-6-ilamino)etil)fenol;
N-(2-(1H-indol-3-il)etil)-2-(benzo[b]tiofen-3-il)-9-izopropil-9H-purin-6-amin;
2-(benzo[b]tiofen-3-il)-9-izopropil-N-(2-(tiofen-3-il)etil)-9H-purin-6-amin;
3-(2-(2-(benzo[b]tiofen-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
2-(benzo[b]tiofen-3-il)-N-(4-fluorofenetil)-9-izopropil-9H-purin-6-amin;
N-(4-aminofenetil)-2-(benzo[b]tiofen-3-il)-9-izopropil-9H-purin-6-amin;
4-(2-(9-izopropil-2-(pirimidin-5-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-fenil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(tiofen-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(furan-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
2-(benzo[b]tiofen-3-il)-N-(4-fluorofenetil)-9-fenil-9H-purin-6-amin;
4-(2-(2-(benzo[b]tiofen-3-il)-9-(nonan-2-il)-9H-purin-6-ilamino)etil)fenol;
N-(2-(1H-indol-3-il)etil)-2-(benzo[b]tiofen-3-il)-9-sek-butil-9H-purin-6-amin;
4-(2-(9-izopropil-2-(piridin-4-il)-9H-purin-6-ilamino)etil)fenol;
etil 5-(6-(4-hidroksifenetilamino)-9-izopropil-9H-purin-2-il)nikotinat;
4-(2-((9-izopropil-2-(5-metoksipiridin-3-il)-9H-purin-6-il)amino)etil)fenol;
4-(2-(2-(6-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(4-metilpiridin-3-il)-9H-purin-6-ilamino)etil)fenol;
5-(6-(4-hidroksifenetilamino)-9-izopropil-9H-purin-2-il)nikotinonitril;
4-(2-(2-(1H-imidazol-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridazin-4-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(pirazin-2-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-2-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(5-(metilsulfonil)piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(5-metilpiridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(4-kloropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-((9-izopropil-2-(4-metiltiofen-3-il)-9H-purin-6-il)amino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)-2-metoksifenol;
N-[2-(6-metoksi-1H-indol-3-il)etil]-9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-amin;
N-[2-(5-metil-1H-indol-3-il)etil]-9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-amin;
1-(2-{[9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-il]amino}etil)imidazolidin-2-on;
N-(2-{[9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-il]amino}etil)piridin-2-amin;
9-(propan-2-il)-N-[3-(1H-pirazol-4-il)propil]-2-(piridin-3-il)-9H-purin-6-amin;
N-{2-[(3-metil-1H-1,2,4-triazol-5-il)sulfanil]etil}-9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-amin;
1-(2-{[2-(1-benzotiofen-3-il)-9-(propan-2-il)-9H-purin-6-il]amino}etil)imidazolidin-2-on;
N-[2-(5-amino-1H-1,2,4-triazol-3-il)etil]-2-(1-benzotiofen-3-il)-9-(propan-2-il)-9H-purin-6-amin;
N-(2-{[2-(1-benzotiofen-3-il)-9-(propan-2-il)-9H-purin-6-il]amino}etil)piridin-2-amin;
2-(1-benzotiofen-3-il)-9-(propan-2-il)-N-[3-(1H-pirazol-4-il)propil]-9H-purin-6-amin;
2-(1-benzotiofen-3-il)-N-[3-(3,5-dimetil-1H-pirazol-4-il)propil]-9-(propan-2-il)-9H-purin-6-amin;
(2-{[2-(1-benzotiofen-3-il)-9-(propan-2-il)-9H-purin-6-il]amino}etil)urea;
N-[2-(1H-indol-3-il)etil]-9-(propan-2-il)-2-(piridin-3-il)-9H-purin-6-amin;
N-(4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenil)metan-sulfonamid;
4-(2-(2-(piridin-3-il)-9-(tetrahidrofuran-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)propil)fenol;
4-(2-(9-(oksetan-3-il)-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-(1-hidroksipropan-2-il)-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenil-sulfamat;
4-(2-(2-(2-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(1-metil-1H-pirol-2-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(tiazol-5-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(1H-benzo[d]imidazol-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(2,4-dimetil-1H-imidazol-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(2-metil-1H-imidazol-1-il)-9H-purin-6-ilamino)etil)fenol;
5-(9-sek-butil-6-(4-hidroksi-3-metilfenetilamino)-9H-purin-2-il)nikotinonitril;
9-izopropil-N-(2-(5-metil-1H-pirazol-3-il)etil)-2-(piridin-3-il)-9H-purin-6-amin;
4-(2-(2-(5-fluoropiridin-3-il)-9-(oksetan-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(5-kloropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(5-(trifluorometil)piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
5-(6-(2-(1H-indol-3-il)etilamino)-9-sek-butil-9H-purin-2-il)nikotinonitril;
N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-metilpiridin-3-il)-9H-purin-6-amin;
(R)-N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-fluoropiridin-3-il)-9H-purin-6-amin;
(S)-N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-fluoropiridin-3-il)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-fluoropiridin-3-il)-9H-purin-6-amin;
(R)-N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-metilpiridin-3-il)-9H-purin-6-amin;
(S)-N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(5-metilpiridin-3-il)-9H-purin-6-amin;
5-(6-(4-hidroksifenetilamino)-9-(oksetan-3-il)-9H-purin-2-il)nikotinonitril;
4-(2-(6-(5-fluoropiridin-3-il)-1-izopropil-1H-pirazolo[3,4-d]pirimidin-4-ilamino)etil)fenol;
4-(2-(6-(benzo[b]tiofen-3-il)-1-izopropil-1H-pirazolo[3,4-d]pirimidin-4-ilamino)etil)fenol;
(R)-4-(2-(2-(5-fluoropiridin-3-il)-9-(tetrahidrofuran-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)-3-metilfenol;
5-(6-(4-hidroksifenetilamino)-9-izopropil-9H-purin-2-il)pikolinonitril;
3-(6-(4-hidroksifenetilamino)-9-izopropil-9H-purin-2-il)izonikotinonitril;
4-(2-(2-(5-fluoropiridin-3-il)-7-izopropil-7H-pirolo[2,3-d]pirimidin-4-ilamino)etil)fenol;
3-(6-(4-hidroksifenetilamino)-9-izopropil-9H-purin-2-il)pikolinonitril;
4-(2-(9-izopropil-2-(6-metilpiridin-3-il)-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(izokinolin-4-il)-9H-purin-6-ilamino)etil)fenol;
2-kloro-4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
3-fluoro-4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)fenol;
N-(2-(5-kloro-1H-indol-3-il)etil)-9-izopropil-2-(piridin-3-il)-9H-purin-6-amin;
N-(2-(5-fluoro-1H-indol-3-il)etil)-9-izopropil-2-(piridin-3-il)-9H-purin-6-amin;
4-(2-(9-izopropil-2-(piridin-3-il)-9H-purin-6-ilamino)etil)-2-metilfenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-(oksetan-3-il)-9H-purin-6-ilamino)etil)fenol;
(S)-4-(2-(2-(benzo[b]tiofen-3-il)-9-(tetrahidrofuran-3-il)-9H-purin-6-ilamino)etil)fenol;
(R)-4-(2-(2-(benzo[b]tiofen-3-il)-9-(tetrahidrofuran-3-il)-9H-purin-6-ilamino)etil)fenol;
2-(6-(2-(1H-indol-3-il)etilamino)-2-(5-fluoropiridin-3-il)-9H-purin-9-il)propan-1-ol;
(R)-2-(6-(2-(1H-indol-3-il)etilamino)-2-(5-fluoropiridin-3-il)-9H-purin-9-il)propan-1-ol;
(S)-2-(6-(2-(1H-indol-3-il)etilamino)-2-(5-fluoropiridin-3-il)-9H-purin-9-il)propan-1-ol;
(R)-N-(2-(1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-(tetrahidrofuran-3-il)-9H-purin-6-amin;
4-(2-(2-(3H-imidazo[4,5-b]piridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(2-(1H-imidazo[4,5-b]piridin-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(6-(5-fluoropiridin-3-il)-1-izopropil-1H-imidazo[4,5-c]piridin-4-ilamino)etil)fenol;
4-(2-(2-(4,5-dimetil-1H-imidazol-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(piridin-3-il)etil)-9H-purin-6-amin;
4-(2-(2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)-1-hidroksietil)fenol;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(6-metoksi-1H-indol-3-il)etil)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(5-metoksi-1H-indol-3-il)etil)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-(prop-1-en-2-il)-9H-purin-6-amin;
5-(2-(2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)piridin-2-ol;
N-(2-(1H-pirolo[2,3-b]piridin-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
N-(2-(6-(2-(dietilamino)etoksi)-1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
4-(2-(5-(5-fluoropiridin-3-il)-3-izopropil-3H-imidazo[4,5-b]piridin-7-ilamino)etil)fenol;
N-(2-(1H-indol-3-il)etil)-9-sek-butil-2-(2-metil-1H-imidazol-1-il)-9H-purin-6-amin;
4-(2-(2-(2-etil-1H-imidazol-1-il)-9-izopropil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(2-propil-1H-imidazol-1-il)-9H-purin-6-ilamino)etil)fenol;
3-(2-(2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-ilamino)etil)-1H-indol-6-ol;
N-(2-(1H-indol-3-il)etil)-9-izopropil-2-(5-metilpiridin-3-il)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-9-izopropil-2-(2-metil-1H-imidazol-1-il)-9H-purin-6-amin;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(7-metil-1H-indol-3-il)etil)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-(oksetan-3-il)-9H-purin-6-amin;
N-(2-(1H-indol-3-il)etil)-2-(5-metilpiridin-3-il)-9-(oksetan-3-il)-9H-purin-6-amin;
N-(2-(6-fluoro-1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(6-metil-1H-indol-3-il)etil)-9H-purin-6-amin;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(2-metil-1H-indol-3-il)etil)-9H-purin-6-amin;
N-(2-(4-fluoro-1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
N-(2-(7-fluoro-1H-indol-3-il)etil)-2-(5-fluoropiridin-3-il)-9-izopropil-9H-purin-6-amin;
2-(5-fluoropiridin-3-il)-9-izopropil-N-(2-(4-metil-1H-indol-3-il)etil)-9H-purin-6-amin;
4-(2-(2-(benzo[b]tiofen-3-il)-7-izopropil-7H-pirolo[2,3-d]pirimidin-4-ilamino)etil)fenol;
4-(2-(2-(5-fluoropiridin-3-il)-9-(1-hidroksipropan-2-il)-9H-purin-6-ilamino)etil)-2-metilfenol;
4-(2-(2-(benzo[b]tiofen-3-il)-9-cikloheksil-9H-purin-6-ilamino)etil)fenol;
4-(2-(9-izopropil-2-(tiofen-3-il)-9H-purin-6-ilamino)etil)fenol; i
1-(2-(2-(benzo[b]tiofen-3-il)-6-(4-hidroksifenetilamino)-9H-purin-9-il)etil)pirolidin-2-on;
ili njihova sol.
9. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj predstavljen formulom:
ili njegova sol; ili
formulom:
ili njegova sol; ili
formulom:
ili njegova sol; ili
formulom:
ili njegova sol; ili
formulom:
ili njegova sol.
10. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj predstavljen formulom:
ili njegova sol.
11. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj predstavljen formulom:
ili njegova sol.
12. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj predstavljen formulom:
ili njegova sol.
13. Spoj prema patentnom zahtjevu 1, naznačen time, što je spoj predstavljen formulom:
ili njegova sol.
14. Pripravak, naznačen time, što obuhvaća spoj prema bilo kojem od zahtjeva 1 do 13.
15. Postupak in vitro ili ex vivo povećanja broja matičnih i progenitorskih stanica; naznačen time, što navedeni postupak obuhvaća dovođenje u kontakt matičnih stanica sa spojem prema bilo kojem od patentnih zahtjeva 1 do 13, pri čemu je spoj sposoban antagonizirati aktivnost i/ili ekspresiju aril ugljikovodičnog receptora i/ili efektora silaznog puta aril ugljikovodičnog receptora.
16. Spoj prema bilo kojem od zahtjeva 1 do 13, naznačen time, što se upotrebljava u postupku liječenja pomoću povećanja broja matičnih i progenitorskih stanica; pri čemu je spoj sposoban antagonizirati i/ili ekspresiju aril ugljikovodičnog receptora i/ili efektora silaznog puta aril ugljikovodičnog receptora.
17. Postupak prema patentnom zahtjevu 15 ili spoj za uporabu u postupku liječenja prema zahtjevu 16, naznačen time, što: (i) matične stanice su ljudske; i/ili (ii) matične stanice su izvedene iz koštane srži, matične stanice su izvedene iz krvi pupkovine i/ili matične stanice su hematopoietske matične stanice.
18. Postupak ex vivo ekspandiranja hematopoietskih matičnih stanica, naznačen time, što postupak sadrži (a) osiguravanje početne stanične populacije koja sadrži hematopoietske matične stanice i (b) kultiviranje navedene početne populacije stanica ex vivo u prisutnosti spoja prema bilo kojem od zahtjeva 1 do 13, pod pogodnim uvjetima za ekspandiranje hematopoietskih matičnih stanica, pri čemu je spoj sposoban antagonizirati aktivnost i/ili ekspresiju aril ugljikovodičnog receptora i/ili efektora silaznog puta aril ugljikovodičnog receptora; i proizvoljno gdje je silazni put aril ugljikovodičnog receptora odabran od Cyp1B1, Cyp1A1, Beta katenina, AHRR, STAT5 i STAT1.
19. Postupak prema patentnom zahtjevu 18, naznačen time, što:
(a) navedena početna populacija stanica je obogaćena sa CD34+ stanicama;; ili
(b) navedena početna populacija stanica je izvedena iz krvnih stanica pupkovine; ili
(c) navedena početna populacija stanica je izvedena iz jedne ili dvije jedinice krvi iz pupkovine, poželjno jedne jedinice krvi iz pupkovine; ili
(d) navedena početna populacija stanica je izvedena iz mobiliziranih stanica periferne krvi, po izboru gdje su mobilizirane stanice periferne krvi dobivene od samo jednog sisavca.
20. Postupak prema zahtjevu 18 ili zahtjevu 19, naznačen time, što:
(a) navedena početna populacija stanica se uglavnom sastoji od CD34+ stanica pročišćenih iz jedne ili dvije jedinice krvi iz pupkovine, poželjno iz jedne jedinice krvi iz pupkovine; ili
(b) navedeni uvjeti za ekspandiranje hematopoietskih matičnih stanica uključuju kultivaciju navedene početne populacije stanica u prisutnosti dovoljne količine IL6, Flt3-L, TPO i SCF; ili
(c) navedeni spoj je dodan u medij za kultiviranje stanica u koncentraciji između 1pM i 10µM; ili
(d) navedena početna populacija stanica se uglavnom sastoji od CD34+ stanica pročišćenih iz jedne ili dvije jedinice krvi iz pupkovine, poželjno iz jedne jedinice krvi iz pupkovine; ili
(e) navedena početna populacija stanica se kultivira u prisutnosti navedenog spoja tijekom vremena dovoljnog za deseterostruku do 50000-struku ekspanziju CD34+ stanica; ili
(f) postupak obuhvaća ponovno suspendiranje ekspandiranih stanica u farmaceutski prihvatljivom mediju prikladnom za primjenu na domaćinu sisavcu.
21. Komplet za ekspandiranje hematopoietskih matičnih stanica, naznačen time, što obuhvaća spoj prema bilo kojem od zahtjeva 1 do 13 i upute za uporabu u postupku prema bilo kojem od zahtjeva 18 do 20, te po izboru, jedan ili više od slijedećih: citokine, faktore rasta i medij za rast stanica, pri čemu su navedeni jedan ili više citokina ili jedan ili više faktora rasta poželjno izabrani iz skupine koja se sastoji od IL6, Flt3-L, SCF i TPO.
22. Pripravak, naznačen time, što obuhvaća staničnu populaciju s ekspandiranim hematopoietskim matičnim stanicama i spoj prema bilo kojem od zahtjeva 1 do 13.
23. Pripravak prema patentnom zahtjevu 22, naznačen time, što:
(a) navedena populacija stanica s ekspandiranim hematopoietskim matičnim stanicama izvedena je iz jedne ili dvije jedinice krvi iz pupkovine, poželjno iz jedne jedinice krvi iz pupkovine, pri čemu navedeni pripravak sadrži ukupnu količinu stanica od najmanje 105 stanica, 107 stanica, 108 stanica ili 109 stanica, i pri čemu između 20-100% ukupnih stanica su CD34+ stanice; ili
(b) navedeni pripravak sadrži između 0,1%-40% ukupnih stanica koje eksprimiraju CD34 i Thy1 markere; 20-80% ukupnih stanica koje eksprimiraju CD34 i CD45RA markere; 10-95% stanica su CD38+; i 5-70% stanica su CD133+; ili
(c) navedeni pripravak je prikladan za intravensku infuziju i navedeni pripravak sadrži najmanje 104 stanica/kg danih transfuzijom pacijentu, poželjno između 105 stanica / kg i 109 stanica / kg.
24. Pripravak prema patentnom zahtjevu 22 ili patentnom zahtjevu 23, naznačen time, što se upotrebljava u postupku alogene transplantacije hematopoietskih matičnih stanica kod pojedinca koji je sisavac.
25. Spoj prema bilo kojem od zahtjeva 1 do 13 ili pripravak prema patentnom zahtjevu 22 ili patentnom zahtjevu 23, naznačen time, što se upotrebljava u postupku liječenja ekspandiranjem hematopoietskih matičnih stanica koje se koriste u liječenju nasljedne bolesti imunodeficijencije, autoimune bolesti i ili hematopoietskog poremećaja.
26. Spoj ili pripravak za uporabu u postupku liječenja prema patentnom zahtjevu 25, naznačen time, što:
(a) primjena je autologna transplantacija, te je hematopoietski poremećaj odabran od multiplog mijeloma, ne-Hodgkinovog limfoma, Hodgkinove bolesti, akutne mijeloidne leukemije, neuroblastoma, tumora zametnih stanica, autoimunih poremećaja i amiloidoze; ili
(b) autoimuni poremećaji su odabrani od sistemskog eritemskog lupusa i sistemske skleroze; ili
(c) hematopoietski poremećaj je odabran od akutne mijeloidne leukemije, akutne limfoblastične leukemije, kronične mijeloidne leukemije, kronične limfocitne leukemije, mijeloproliferativnih poremećaja, mijelodisplastičnih sindroma, multiplog mijeloma, ne-Hodgkinovog limfoma, Hodgkinove bolesti, aplastične anemije, čiste aplazije crvenih krvnih stanica, paroksizmalne noćne hemoglobinurije, Fanconijeve anemije, talasemije major, anemije srpastih stanica, teške kombinirane imunodeficijencije, Wiskott-Aldrichovog sindroma, hemofagocitne limfohistiocitoze i urođenih pogrešaka u metabolizmu, kao što su mukopolisaharidoza, Gaucherova bolest, metakromatske leukodistrofije i adrenoleukodistrofije.
27. Postupak prema patentnom zahtjevu 18, naznačen time, što se navedena početna stanična populacija uglavnom sastoji od CD34+ stanica pročišćenih iz jedne ili dvije jedinice krvi iz pupkovine, poželjno iz jedne jedinice krvi iz pupkovine, i
(i) navedena početna stanična populacija se kultivira u prisutnosti spoja iz bilo kojeg od patentnih zahtjeva 1 do 13, od oko 3 dana do oko 90 dana, poželjno između 7 do 35 dana; i/ili
(ii) navedena početna stanična populacija se kultivira u prisutnosti spoja iz bilo kojeg od patentnih zahtjeva 1 do 13, tijekom vremena dovoljnog za ekspanziju CD34 + stanica od 100 do 10000 puta.
28. Postupak prema patentnom zahtjevu 27, naznačen time, što se navedena početna populacija stanica uzgaja u prisutnosti spoja prema bilo kojem od patentnih zahtjeva 1 do 13, ne dulje od 21 dana, 14 dana ili 7 dana i/ili sve dok se ne dobije pokrenuta višestruka ekspanzija i karakteristične populacije stanica.
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| EP09748626.0A EP2350078B1 (en) | 2008-10-30 | 2009-10-29 | Compounds that expand hematopoietic stem cells |
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