CN107864625A - 含有取代的2,3‑二氢咪唑并[1,2‑c]喹唑啉的组合产品 - Google Patents
含有取代的2,3‑二氢咪唑并[1,2‑c]喹唑啉的组合产品 Download PDFInfo
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- CN107864625A CN107864625A CN201680026204.XA CN201680026204A CN107864625A CN 107864625 A CN107864625 A CN 107864625A CN 201680026204 A CN201680026204 A CN 201680026204A CN 107864625 A CN107864625 A CN 107864625A
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- Prior art keywords
- amino
- bases
- alkyl
- methyl
- benzothiophene
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- 229940127555 combination product Drugs 0.000 title claims abstract description 80
- 239000013066 combination product Substances 0.000 title claims abstract description 76
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title claims description 24
- -1 quinazoline compound Chemical class 0.000 claims abstract description 265
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- KGRPHHFLPMPUBB-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine Chemical compound C1=NC=NN2C=CC=C21 KGRPHHFLPMPUBB-UHFFFAOYSA-N 0.000 claims abstract description 85
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 31
- 239000012453 solvate Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 30
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims abstract description 28
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims abstract description 28
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 claims abstract description 27
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 claims abstract description 26
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 claims abstract description 26
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 claims abstract description 26
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 claims abstract description 20
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 claims abstract description 20
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 claims abstract description 20
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 claims abstract description 20
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 claims abstract description 20
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 claims abstract description 20
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 claims abstract description 20
- 101001120097 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit beta Proteins 0.000 claims abstract description 20
- 101001098116 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit gamma Proteins 0.000 claims abstract description 20
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 claims abstract description 20
- 101000595746 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Proteins 0.000 claims abstract description 20
- 101000595751 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 claims abstract description 20
- 101000692672 Homo sapiens Phosphoinositide 3-kinase regulatory subunit 4 Proteins 0.000 claims abstract description 20
- 101000692678 Homo sapiens Phosphoinositide 3-kinase regulatory subunit 5 Proteins 0.000 claims abstract description 20
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 claims abstract description 20
- 102100026177 Phosphatidylinositol 3-kinase regulatory subunit beta Human genes 0.000 claims abstract description 20
- 102100037553 Phosphatidylinositol 3-kinase regulatory subunit gamma Human genes 0.000 claims abstract description 20
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 claims abstract description 20
- 102100036056 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Human genes 0.000 claims abstract description 20
- 102100036052 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Human genes 0.000 claims abstract description 20
- 102100026481 Phosphoinositide 3-kinase regulatory subunit 4 Human genes 0.000 claims abstract description 20
- 102100026478 Phosphoinositide 3-kinase regulatory subunit 5 Human genes 0.000 claims abstract description 20
- 239000000463 material Substances 0.000 claims abstract description 20
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 20
- 230000008859 change Effects 0.000 claims abstract description 13
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 claims abstract description 11
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 claims abstract description 11
- 239000000090 biomarker Substances 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 230
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 218
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 147
- 229910052757 nitrogen Inorganic materials 0.000 claims description 107
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 84
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 56
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 45
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 125000005842 heteroatom Chemical group 0.000 claims description 37
- 238000006467 substitution reaction Methods 0.000 claims description 35
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 201000003914 endometrial carcinoma Diseases 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- 230000000306 recurrent effect Effects 0.000 claims description 26
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 22
- 150000003233 pyrroles Chemical class 0.000 claims description 22
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 claims description 20
- 201000009273 Endometriosis Diseases 0.000 claims description 20
- 108091007960 PI3Ks Proteins 0.000 claims description 20
- 230000004913 activation Effects 0.000 claims description 20
- 238000001994 activation Methods 0.000 claims description 20
- DFACNZQBZCMJFM-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-4-amine trihydrochloride Chemical class Cl.Cl.Cl.N=1N2C(C(=NC1)N)=CC=C2 DFACNZQBZCMJFM-UHFFFAOYSA-N 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 19
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- 230000035772 mutation Effects 0.000 claims description 16
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 235000005152 nicotinamide Nutrition 0.000 claims description 14
- 239000011570 nicotinamide Substances 0.000 claims description 14
- 229960003966 nicotinamide Drugs 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 12
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 12
- 150000003248 quinolines Chemical class 0.000 claims description 12
- 229940124530 sulfonamide Drugs 0.000 claims description 12
- 150000003456 sulfonamides Chemical class 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- VSPXQZSDPSOPRO-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical class NC1=NC=NN2C=CC=C12 VSPXQZSDPSOPRO-UHFFFAOYSA-N 0.000 claims description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- BOUIZPWBFIVJPD-UHFFFAOYSA-N 3h-1,2,4-triazin-4-amine Chemical compound NN1CN=NC=C1 BOUIZPWBFIVJPD-UHFFFAOYSA-N 0.000 claims description 10
- 206010011224 Cough Diseases 0.000 claims description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 10
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 10
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical class NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 230000037361 pathway Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 150000003851 azoles Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- QPPKRHQQQDCYFR-UHFFFAOYSA-N C(=O)O.N1=NCN(C=C1)N Chemical class C(=O)O.N1=NCN(C=C1)N QPPKRHQQQDCYFR-UHFFFAOYSA-N 0.000 claims description 6
- XLFDGCWUDNNHCY-UHFFFAOYSA-N C(=O)O.N=1N2C(C(=NC1)N)=CC=C2 Chemical class C(=O)O.N=1N2C(C(=NC1)N)=CC=C2 XLFDGCWUDNNHCY-UHFFFAOYSA-N 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical class NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- HQRJTOUXBJDGTF-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile Chemical compound C1=NC=NN2C(C#N)=CC=C21 HQRJTOUXBJDGTF-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 108020004999 messenger RNA Proteins 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- DUCOISOCHCDKOU-UHFFFAOYSA-N Cl.Cl.C(C)C(=O)CC Chemical compound Cl.Cl.C(C)C(=O)CC DUCOISOCHCDKOU-UHFFFAOYSA-N 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 claims description 4
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 claims description 4
- VLAZLCVSFAYIIL-UHFFFAOYSA-N morpholin-2-ylmethanol Chemical compound OCC1CNCCO1 VLAZLCVSFAYIIL-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000005545 phthalimidyl group Chemical group 0.000 claims description 4
- XHPFQFHVSHYIJJ-UHFFFAOYSA-N pyrrolidin-2-one;dihydrochloride Chemical compound Cl.Cl.O=C1CCCN1 XHPFQFHVSHYIJJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 229930003945 thebaine Natural products 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 3
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- QTHKLKYLNNEKFC-UHFFFAOYSA-N 3H-1,2,4-triazin-4-amine dihydrochloride Chemical class Cl.Cl.N1=NCN(C=C1)N QTHKLKYLNNEKFC-UHFFFAOYSA-N 0.000 claims description 2
- PWKCGMGBBJGUKV-UHFFFAOYSA-N 3H-1,2,4-triazin-4-amine trihydrochloride Chemical class Cl.Cl.Cl.N1=NCN(C=C1)N PWKCGMGBBJGUKV-UHFFFAOYSA-N 0.000 claims description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- CJHWGLBDSDKVIH-UHFFFAOYSA-N 5,7-dimethoxy-1-benzothiophene Chemical compound COC1=CC(OC)=C2SC=CC2=C1 CJHWGLBDSDKVIH-UHFFFAOYSA-N 0.000 claims description 2
- XEMKCLMWIJVFLP-UHFFFAOYSA-N C(=O)O.N1(CCNCC1)C=O Chemical class C(=O)O.N1(CCNCC1)C=O XEMKCLMWIJVFLP-UHFFFAOYSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- AAQLWZRNSJGQGC-UHFFFAOYSA-N acetamide;formic acid Chemical class OC=O.CC(N)=O AAQLWZRNSJGQGC-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 2
- GUDMZGLFZNLYEY-UHFFFAOYSA-N cyclopropylmethanol Chemical compound OCC1CC1 GUDMZGLFZNLYEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- XRZVNIXEBCWMJE-UHFFFAOYSA-N ethanol;trihydrochloride Chemical compound Cl.Cl.Cl.CCO XRZVNIXEBCWMJE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims description 2
- 229960005206 pyrazinamide Drugs 0.000 claims description 2
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 2
- OAYAAPBXCADBMP-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide Chemical class C1=NC=NN2C(C(=O)N)=CC=C21 OAYAAPBXCADBMP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 claims 1
- XSYKRKGTOHLJJI-UHFFFAOYSA-N pyrimidine-5-carboxamide;dihydrochloride Chemical class Cl.Cl.NC(=O)C1=CN=CN=C1 XSYKRKGTOHLJJI-UHFFFAOYSA-N 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 abstract description 15
- 238000007912 intraperitoneal administration Methods 0.000 abstract description 13
- 238000009434 installation Methods 0.000 abstract description 12
- 150000001412 amines Chemical class 0.000 abstract description 3
- 239000002585 base Substances 0.000 description 287
- 239000003795 chemical substances by application Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 27
- 238000011282 treatment Methods 0.000 description 25
- MWYDSXOGIBMAET-UHFFFAOYSA-N 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide Chemical compound NC1=NC=C(C=N1)C(=O)N=C1N=C2C(=C(C=CC2=C2N1CCN2)OCCCN1CCOCC1)OC MWYDSXOGIBMAET-UHFFFAOYSA-N 0.000 description 23
- 229950002550 copanlisib Drugs 0.000 description 23
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Abstract
本发明涉及*以下物质的组合产品:•组分A:一种或多种通式(A1)或(A2)的2,3‑二氢咪唑并[1,2‑c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或•立体异构体;•组分B:一种或多种通式(B)的取代的5‑(1‑苯并噻吩‑2‑基)吡咯并[2,1‑f][1,2,4]‑三嗪‑4‑胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;•其中任选地所述组分中的一些或全部呈即用于同时、共同、分开或依次给药的药物制剂的形式。•其彼此独立地通过经口、静脉内、外用、局部安装、•腹膜内或经鼻途径;*此类组合产品用于制备用于治疗或预防癌症的药物的用途;*包含此类组合产品的试剂盒;*作为肿瘤抑制因子PTEN或FBXW7的损失的生物标志物用于预测癌症患者对所述化合物的敏感性和/或耐受性和提供基于理论的剂量以增加敏感性和/或克服耐受性的用途;*确定肿瘤抑制因子PTEN或FBXW7的损失的方法;和用于确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的扰动、PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变的方法。
Description
本发明涉及:
- 以下物质的组合产品(combinations):
组分A:一种或多种通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;和任选地
组分C:一种或多种进一步药剂;
其中任选地任何上述组合产品中的组分A和B中的任一种或两种呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
本发明的另一个方面涉及如上所述的此类组合产品用于制备用于治疗或预防癌症、特别是子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的药物的用途。
进一步,本发明涉及:
试剂盒,其包含:
- 以下物质的组合产品:
组分A:一种或多种通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其中任选地任何上述组合产品中的所述组分(A)和(B)中的任一种或两种呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
进一步,本发明涉及:
- 单独或与另一种形式的PI3K途径活化组合的生物标志物诸如肿瘤抑制因子PTEN或FBXW7的损失用于预测具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的敏感性和/或耐受性、因此提供如本文所定义的基于理论的剂量以克服所述具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的耐受性(患者分层)的用途,所述另一种形式的PI3K途径活化选自任何以下单独或组合的扰动:PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的突变;PTEN-损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变,其可以在蛋白水平、mRNA水平或DNA水平上测量;
- 确定肿瘤抑制因子PTEN或FBXW7的损失的方法;和
- 用于确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的扰动、PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变的方法。
发明背景
癌症是具有获得性功能能力(如增强的存活/针对细胞凋亡的抗性和无限增殖潜力)的细胞的选择过程之后产生的复杂疾病。因此,优选开发用于解决确立肿瘤的显著特征的癌症疗法的药物。
PI3K信号传导途径是促进肿瘤细胞存活的突出途径之一。PI3K被许多癌症相关的受体酪氨酸激酶(例如PDGFR、EGFR、HER2/3或IGF-1R)、细胞粘附分子、GPCR和致癌蛋白(诸如Ras)活化。在许多肿瘤中经常发现通过PI3K的遗传改变(活化突变和/或扩增)和/或肿瘤抑制因子PTEN的功能丧失的PI3K途径活化。此外,PI3K的活化是引起肿瘤对放射性-、化学-和靶向治疗剂的耐受性的重要机制之一。
一旦PI3K被活化,其催化从PIP2生成PIP3。生物活性PIP3结合PDK-1、AKT和其它含有普列克底物蛋白同源(PH)-结构域的蛋白诸如Rho和PLC的PH结构域。作为结合PIP3的结果,这些蛋白被易位至细胞膜,并随后被活化以诱导肿瘤细胞增殖、存活、侵入和迁移。
成纤维细胞生长因子(FGFs)及其受体(FGFRs)驱动关键的发育信号传导途径,其通过由PLCγ/PKC、RAS/MAPK、PI3K/AKT和STATs介导的下游信号传导途径负责肿瘤细胞的许多功能,包括细胞增殖、存活和迁移。FGFR信号传导途径也调节肿瘤基质细胞以及肿瘤血管生成。存在几种类型的遗传证据支持FGFRs的致癌功能:基因扩增、活化突变、染色体易位和转录后水平的异常剪接。
子宫内膜癌(EC)是工业化国家中最常见的妇科恶性肿瘤,其中发病率为12.9/每100,000名妇女/每年。早期EC (I期或II期)可以用外科手术有效地治疗,而复发性或高级转移性疾病的治疗限于细胞毒性化学疗法,例如紫杉醇和卡铂。此外,对于复发性EC,尽管该患者子集的预后不佳,但仍然没有一致意见,也没有确定的选择药物。值得注意的是,可用的化学疗法没有提供长期的疾病控制,并且许多患者表明对这些疗法的内在的耐受性和显著的毒性。因此,仍然存在对于复发性EC的重要的未满足的医疗需求。这些患者的成功管理取决于基于生物学肿瘤概况鉴定和理解EC的起始和进展的基础分子机制以实现更加定制的疗法。
如本文中所述,PI3K抑制剂copanlisib的抗肿瘤效力在体外和体内临床前肿瘤模型中以组合进行研究。发现PI3K抑制剂copanlisib与FGFR抑制剂的组合是协同的,这导致在体内临床前肿瘤模型中与用每种药剂的单一疗法治疗的动物中的肿瘤进展或肿瘤停滞相比的肿瘤消退。
出乎意料地,且这代表了本发明的基础,当针对治疗子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症评估以下物质的组合产品时,用这些组合产品证明了与每种单一疗法相比的协同增加的抗肿瘤活性,为使用PI3K抑制剂-FGFR抑制剂的临床联合疗法提供了基本原理:
- 组分A:如本文描述和定义的通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;与
- 组分B:如本文描述和定义的通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
据申请人所知,现有技术中没有一般或具体公开或暗示已知以下物质的组合产品将会有效地治疗或预防癌症、特别是子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症:
组分A:一种或多种通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其中任选地任何上述组合产品的所述组分A和B中的任一种或两种呈即用于同时、共同、分开或依次给药的药物制剂的形式。
基于本发明中描述的测试化合物的作用,如本文描述和定义的本发明的组合产品在癌症、特别是子宫内膜癌(以下缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的治疗中显示有利的效果。
因此,根据第一个方面,本发明涉及以下物质的组合产品:
组分A:一种或多种通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其中任选地任何上述组合产品的所述组分A和B)中的任一种或两种呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据第二个方面,本发明涉及如上所述的任何此类组合产品用于制备用于治疗或预防癌症、特别是子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的药物的用途。
此外,根据第三个方面,本发明涉及涉及试剂盒,其包含:
以下物质的组合产品:
组分A:一种或多种通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其中任选地任何上述组合产品中的组分A和B中的任一种或两种呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
此外,根据第四个方面,本发明涉及:
- 单独或与另一种形式的PI3K途径活化组合的生物标志物诸如肿瘤抑制因子PTEN或FBXW7的损失用于预测具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的敏感性和/或耐受性、因此提供如本文所定义的基于理论的剂量以克服所述具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的耐受性(患者分层)的用途,所述另一种形式的PI3K途径活化选自任何以下单独或组合的扰动:PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的突变;PTEN-损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变,其可以在蛋白水平、mRNA水平或DNA水平上测量;
- 确定肿瘤抑制因子PTEN或FBXW7的损失的方法;和
- 确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的扰动、PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变的方法。
发明详述
根据本发明的上述方面的一个实施方案,所述组合产品是以下物质的组合产品:
组分A:其为一种或多种通式(A1)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物:
其中:
X代表CR5R6或NH;
Y1代表CR3或N;
Y2 ------ Y3之间的化学键代表单键或双键;
条件是当Y2 ------ Y3代表双键时,Y2和Y3 独立地代表CR4或N,且
当Y2 ------ Y3 代表单键时,Y2和Y3 独立地代表CR3R4或NR4;
Z1、Z2、Z3和Z4 独立地代表CH、CR2或N;
R1代表任选地具有1至3个选自R11的取代基的芳基,任选地具有1至3个选自R11的取代基的C3-8环烷基,
任选地被芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷基,
任选地被羧基、芳基、杂芳基、C1-6 烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷氧基,
或
3至15元单或双环杂环,其为饱和或不饱和的,且含有1至3个选自N、O和S的杂原子,其任选地具有1至3个选自R11的取代基,
其中
R11 代表卤素、硝基、羟基、氰基、羧基、氨基、N-(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、N-(甲酰基)-N-(C1-6烷基)氨基、N-(C1-6烷烃磺酰基)氨基、N-(羧基C1-6烷基)-N-(C1-6烷基)氨基、N-(C1-6烷氧基羰基)氨基、N-[N,N-二(C1-6烷基)氨基亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基(C1-6烷基)亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基C2-6烯基]氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、C3-8环烷基、C1-6烷硫基、C1-6烷烃磺酰基、氨磺酰、C1-6烷氧基羰基,
N-芳基氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,N-(芳基C1-6烷基)氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,芳基C1-6烷氧基羰基,其中所述芳基部分任选地具有1至3个选自R101的取代基,
任选地被单-、二-或三-卤素、氨基、N-(C1-6烷基)氨基或N,N-二(C1-6烷基)氨基取代的C1-6烷基,
任选地被单-、二-或三-卤素、N-(C1-6烷基)磺酰胺或N-(芳基)磺酰胺取代的C1-6烷氧基,
或
具有1至3个选自O、S和N的杂原子和任选地具有1至3个选自R101的取代基的5至7元饱和或不饱和环,
其中
R101 代表卤素、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、吡啶基,
任选地被氰基或单-、二-或三-卤素取代的C1-6 烷基,
或
任选地被氰基、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基或单-、二-或三-卤素取代的C1-6烷氧基;
R2代表羟基、卤素、硝基、氰基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N-(羟基C1-6烷基)-N-(C1-6烷基)氨基、C1-6 酰基氧基、氨基C1-6 酰基氧基、C2-6烯基、芳基,
具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:
羟基、C1-6烷基、C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、N-(C1-6烷基)羰基氨基、苯基、苯基C1-6 烷基、羧基、C1-6烷氧基羰基、氨基羰基、N-(C1-6烷基)氨基羰基或N,N-二(C1-6烷基)氨基、-C(O)- R20,
其中
R20代表C1-6烷基、C1-6烷氧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基或具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:C1-6烷基、C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、苯基或苄基,
任选地被R21取代的C1-6 烷基,
或
任选地被R21取代的C1-6烷氧基,
其中
R21代表氰基、单-、二-或三-卤素、羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6 烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、氨基 C2-6 烷基烯基(alkylenyl)、C1-6烷氧基、羟基C1-6烷氧基、-C(O)- R201、-NHC(O)- R201、C3-8环烷基、异吲哚啉基、苯邻二甲酰亚胺基、2-氧代-1,3-噁唑烷基、芳基或具有1至4个选自O、S和N的杂原子、任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基,
其中
R201 代表羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N- (卤代苯基C1-6 烷基)氨基、C1-6烷基、氨基C1-6 烷基、氨基C2-6 烷基烯基、C1-6 烷氧基、或具有1至4个选自O、S和N的杂原子、任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6 烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基;
R3代表氢、卤素、氨基羰基或任选地被芳基C1-6烷氧基或单-、二-或三-卤素取代的C1-6烷基;
R4代表氢或C1-6 烷基;
R5代表氢或C1-6 烷基;且
R6代表卤素、氢或C1-6 烷基;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
所述化合物在国际专利申请PCT/EP2003/010377(在2004年4月8日作为WO 04/029055A1公开,其以其整体通过引用并入本文)中作为通式I、I-a和I-b的化合物公开。在WO 04/029055中,所述通式I、I-a和I-b的化合物在第6页及其以后描述,它们可以根据在其中第26页及其以后给出的方法合成,并且在第47至106页被例举为具体化合物实施例1-1至1-210,在第107至204页被例举为具体化合物实施例2-1至2-368,在第205至207页被例举为具体化合物实施例3-1至3-2,并且在其中第208至210页被例举为具体化合物实施例4-1至4-2。
所述组分A可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据本发明的上述方面的另一个实施方案,所述组合产品是以下物质的组合产品:
组分A:其为上述一种或多种通式(A1)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物,
其选自国际专利申请PCT/EP2003/010377(在2004年4月8日作为WO 04/029055 A1公开,其以其整体通过引用并入本文)中第47至106页的具体化合物实施例1-1至1-210、第107至204页的具体化合物实施例2-1至2-368、第205至207页的具体化合物实施例3-1至3-2以及第208至210页的具体化合物实施例4-1至4-2,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体。
所述组分A可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
如上所述,所述具体化合物实施例可以根据WO 04/029055 A1的第26页及其以后中给出的方法合成。
根据本发明的上述方面的另一个实施方案,所述组合产品是以下物质的组合产品:
组分A:其为一种或多种通式(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物:
其中:
X代表CR5R6或NH;
Y1代表CR3或N;
Y2 ------ Y3之间的化学键代表单键或双键;
条件是当Y2 ------ Y3代表双键时,Y2和Y3 独立地代表CR4或N,且
当Y2 ------ Y3 代表单键时,Y2和Y3 独立地代表CR3R4或NR4;
Z1、Z2、Z3和Z4 独立地代表CH、CR2或N;
R1代表任选地具有1至3个选自R11的取代基的芳基,任选地具有1至3个选自R11的取代基的C3-8环烷基,
任选地被芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷基,
任选地被羧基、芳基、杂芳基、C1-6 烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷氧基,
或
3至15元单或双环杂环,其为饱和或不饱和的,任选地具有1至3个选自R11的取代基,且含有1至3个选自N、O和S的杂原子,
其中
R11 代表卤素、硝基、羟基、氰基、羧基、氨基、N-(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、N-(甲酰基)-N-(C1-6烷基)氨基、N-(C1-6烷烃磺酰基)氨基、N-(羧基C1-6烷基)-N-(C1-6烷基)氨基、N-(C1-6烷氧基羰基)氨基、N-[N,N-二(C1-6烷基)氨基亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基(C1-6烷基)亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基C2-6烯基]氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、C3-8环烷基、C1-6烷硫基、C1-6烷烃磺酰基、氨磺酰、C1-6烷氧基羰基,
N-芳基氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,N-(芳基C1-6烷基)氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,芳基C1-6烷氧基羰基,其中所述芳基部分任选地具有1至3个选自R101的取代基,
任选地被单-、二-或三-卤素、氨基、N-(C1-6烷基)氨基或N,N-二(C1-6烷基)氨基取代的C1-6烷基,
任选地被单-、二-或三-卤素、N-(C1-6烷基)磺酰胺或N-(芳基)磺酰胺取代的C1-6烷氧基,
或
具有1至3个选自O、S和N的杂原子和任选地具有1至3个选自R101的取代基的5至7元饱和或不饱和环,
其中
R101 代表卤素、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、吡啶基,
任选地被氰基或单-、二-或三-卤素取代的C1-6 烷基,
和
任选地被氰基、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基或单-、二-或三-卤素取代的C1-6烷氧基;
R2代表羟基、卤素、硝基、氰基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N-(羟基C1-6烷基)-N-(C1-6烷基)氨基、C1-6 酰基氧基、氨基C1-6 酰基氧基、C2-6烯基、芳基,
具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:
羟基、C1-6烷基、C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、N-(C1-6烷基)羰基氨基、苯基、苯基C1-6 烷基、羧基、C1-6烷氧基羰基、氨基羰基、N-(C1-6烷基)氨基羰基或N,N-二(C1-6烷基)氨基、-C(O)- R20,
其中
R20代表C1-6烷基、C1-6烷氧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基或具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:C1-6烷基、C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、苯基或苄基,
任选地被R21取代的C1-6 烷基,
或
任选地被R21取代的C1-6烷氧基,
其中
R21代表氰基、单-、二-或三-卤素、羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6 烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、氨基 C2-6 烷基烯基、C1-6烷氧基、羟基C1-6烷氧基、-C(O)- R201、-NHC(O)- R201、C3-8环烷基、异吲哚啉基、苯邻二甲酰亚胺基、2-氧代-1,3-噁唑烷基、芳基或具有1至4个选自O、S和N的杂原子和任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基,
其中
R201 代表羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N- (卤代苯基C1-6 烷基)氨基、C1-6烷基、氨基C1-6 烷基、氨基C2-6 烷基烯基、C1-6 烷氧基、或具有1至4个选自O、S和N的杂原子和任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6 烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基;
R3代表氢、卤素、氨基羰基或任选地被芳基C1-6烷氧基或单-、二-或三-卤素取代的C1-6烷基;
R4代表氢或C1-6 烷基;
R5代表氢或C1-6 烷基;且
R6代表卤素、氢或C1-6 烷基;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
所述化合物在国际专利申请PCT/US2007/024985(在2008年6月 12日作为WO 2008/070150 A1公开,其以其整体通过引用并入本文)中作为通式I、Ia、Ib、Ic、Id和Ie的化合物公开。在WO 2008/070150中,所述通式I、Ia、Ib、Ic、Id和Ie的化合物描述于第9页及其以后,它们可以根据在其中第42页及其以后给出的方法合成,并且在其中第65至101页被例举为的具体化合物实施例1至103。所述化合物的某些的生物测试数据在其中第101至107页给出。
与本文中的结构(A)相关使用的定义如下:
术语“烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,其仅含有碳和氢原子,不含不饱和度,具有一至八个碳原子,并且通过单键与分子的剩余部分连接,诸如说明性地,甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
术语“烯基”是指含有碳-碳双键的脂肪族烃基团,其可以是具有约2至约10个碳原子的直链或支链或支链,例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-I-丙烯基、1-丁烯基和2-丁烯基。
术语“炔基”是指具有至少一个碳-碳三键的直链或支链烃基,并且具有范围为约2至最高达12个碳原子(目前优选具有范围为约2至最高达10个碳原子的基团),例如乙炔基。
术语“烷氧基”表示经由氧连接与分子的剩余部分连接的本文定义的烷基基团。烷氧基的代表性实例是甲氧基和乙氧基。
术语“烷氧基烷基”表示经由氧连接与烷基连接的本文定义的烷氧基,其然后在来自烷基的任何碳原子处与主结构连接,导致产生分子剩余部分的稳定的结构。那些基团的代表性实例是-CH2OCH3、-CH2OC2H5。
术语“环烷基”表示约3至12个碳原子的非芳族单环或多环体系,诸如环丙基、环丁基、环戊基、环己基,和多环环烷基的实例包括全氢萘基(perhydronapththyl)、金刚烷基和降冰片基桥环基团或螺二环基团,例如螺(4,4)壬-2-基。
术语“环烷基烷基”是指含有与烷基直接连接的范围为约3至最高达8个碳原子的含环基团,其然后还在来自所述烷基的任何碳原子处与主结构连接,导致产生稳定的结构,诸如环丙基甲基、环丁基乙基、环戊基乙基。
术语“芳基”是指具有范围为6至最高达14个碳原子的芳族基团,诸如苯基、萘基、四氢萘基、茚满基、联苯基。
术语“芳基烷基”是指与如本文定义的烷基直接连接的如本文定义的芳基,其然后在来自烷基的任何碳原子处与主结构连接,导致产生分子剩余部分的稳定的结构,例如-CH2C6H5、-C2H5C6H5。
术语“杂环”是指由碳原子和一至五个选自氮、磷、氧和硫的杂原子组成的稳定的3-15元环基团。为了本发明的目的,所述杂环基可以是单环、双环或三环体系,其可包括稠环、桥环或螺环体系,并且所述杂环基中的氮、磷、碳、氧或硫原子可以任选地被氧化为各种氧化状态。此外,所述氮原子可以任选地被季铵化;并且所述环基可以部分或完全饱和(即杂芳环或杂芳基芳环)。这样的杂环基团的实例包括但不限于:氮杂环丁基、吖啶基、苯并间二氧杂环戊烯基、苯并二噁烷基、苯并呋喃基(benzofurnyl)、咔唑基、噌啉基、二氧戊环基、中氮茚基、萘啶基、全氢氮杂䓬基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基(phthalazil)、吡啶基、蝶啶基、嘌呤基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基、四唑基、咪唑基、四氢异喹啉基(tetrahydroisouinolyl)、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂䓬基、氮杂䓬基、吡咯基、4-哌啶酮基、吡咯烷基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑啉基、噁唑烷基(oxasolidinyl)、三唑基、茚满基、异噁唑基、异噁唑烷基(isoxasolidinyl)、吗啉基、噻唑基、噻唑啉基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、异吲哚基、二氢吲哚基、异二氢吲哚基、八氢吲哚基、八氢异吲哚基、喹啉基、异喹啉基、十氢异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基(tetrahydrofurtyl)、四氢吡喃基、噻吩基、苯并噻吩基、硫吗啉基、硫吗啉基亚砜(thiamorpholinyl sulfoxide)、硫吗啉基砜(thiamorpholinyl sulfone)、二氧杂磷杂环戊烷基(dioxaphospholanyl)、噁二唑基、色满基、异色满基。
术语“杂芳基”是指芳香的如本文定义的杂环基团。所述杂芳基环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
所述杂环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
术语“杂芳基烷基”是指与烷基直接键合的如本文定义的杂芳基环基团。所述杂芳基烷基可以在来自烷基的任何碳原子处与主结构连接,导致产生稳定的结构。
术语“杂环基”是指如本文定义的杂环基团。所述杂环基团可以在任何杂原子或碳原子处与主结构连接,导致产生稳定的结构。
术语“杂环基烷基”是指与烷基直接键合的如本文定义的杂环基团。所述杂环基烷基可以在所述烷基中的碳原子处与主结构连接,导致产生稳定的结构。
术语“羰基”是指通过双键与分子的碳原子键合的氧原子。
术语“卤素”是指氟、氯、溴和碘的基团。
所述组分A可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据本发明的上述方面的另一个实施方案,所述组合产品是以下物质的组合产品:
组分A:其为上述一种或多种通式(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物,其选自:
实施例1:N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺
实施例2:N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例3:N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-2,4-二甲基-1,3-噻唑-5-甲酰胺
实施例4:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-5-甲酰胺.
实施例5:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺
实施例6:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基-1,3-噻唑-5-甲酰胺
实施例7:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-丙基嘧啶-5-甲酰胺
实施例8:N-{8-[2-(4-乙基吗啉-2-基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺
实施例9:N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺
实施例10:N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例11:N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例12:N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺 1-氧化物
实施例13:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺。
实施例14:N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2-吡咯烷-1-基乙基)烟酰胺.
实施例15:6-(环戊基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺
1
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体,
所述化合物在国际专利申请PCT/US2007/024985(在2008年6月 12日作为WO 2008/070150 A1公开,其以其整体通过引用并入本文)中作为具体化合物实施例1至103公开。在WO 2008/070150中,所述具体化合物实施例可以根据实施例合成。所述化合物的某些的生物测试数据在其中第101至107页给出。
所述组分A可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据本发明的上述方面的一个实施方案,所述组合产品是以下物质的组合产品:
组分B:其为一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物:
其中
R1是氢、氯、甲基或甲氧基,
R2是氢或甲氧基,
条件是R1和R2中的至少一个不是氢,
G1代表氯、(C1-C4)-烷基、(C1-C4)-烷氧基羰基、5-元氮杂-杂芳基或基团-CH2-OR3、-CH2-NR4R5或-C(=O)-NR4R6,其中
R3是氢、(C1-C4)-烷基、(C3-C6)-环烷基或苯基,
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基、(C3-C6)-环烷基或最高达三个氟原子取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述苯基任选地被一个或两个独立地选自氟、氯、溴、氰基、三氟甲基、三氟甲氧基、(C1-C4)-烷基和(C1-C4)-烷氧基的取代基取代,
R4是氢或(C1-C4)-烷基,
R5是氢、(C1-C4)-烷基、(C1-C4)-烷基羰基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基或(C3-C6)-环烷基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
R6是氢、(C1-C4)-烷基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基或(C3-C6)-环烷基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
或
R4和R5或R4和R6分别与它们所连接的氮原子连接在一起,形成单环、饱和的4-至7-元杂环烷基环,其可以含有选自N(R7)和O的第二环杂原子,并且其可以在环碳原子上被一个或两个独立地选自以下的取代基取代:(C1-C4)-烷基、氧代、羟基、氨基和氨基羰基,且其中
R7是氢、(C1-C4)-烷基、甲酰基或(C1-C4)-烷基羰基,
且
G2代表氯、氰基、(C1-C4)-烷基或基团-CR8AR8B-OH、-CH2-NR9R10、-C(=O)-NR11R12或-CH2-OR15,其中
R8A和R8B独立地选自氢、(C1-C4)-烷基、环丙基和环丁基,
R9是氢或(C1-C4)-烷基,
R10是氢、(C1-C4)-烷基、(C1-C4)-烷基羰基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基或二-(C1-C4)-烷基氨基羰基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
R11是氢或(C1-C4)-烷基,
R12是氢、(C1-C4)-烷基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基或二-(C1-C4)-烷基氨基羰基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
或
R9和R10或R11和R12分别与它们所连接的氮原子连接在一起,形成单环、饱和的4-至7-元杂环烷基环,其可以含有选自N(R13)、O、S和S(O)2的第二环杂原子,并且其可以在环碳原子上被最高达三个独立地选自以下的取代基取代:氟、(C1-C4)-烷基、氧代、羟基、氨基和氨基羰基,且其中
R13是氢、(C1-C4)-烷基、(C3-C6)-环烷基、甲酰基或(C1-C4)-烷基羰基,
且
R15是(C1-C4)-烷基,
条件是当G2是氯或氰基时,G1不是氯,
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
所述化合物在国际专利申请PCT/EP2012/074977(在2013年6月 20日作为WO 2013/087578公开,其以其整体通过引用并入本文)中作为通式(I)的化合物公开。在WO 2013/087578中,所述通式(I)的化合物描述于第5页及其以后、第13页及其以后和第109页及其以后,它们可以根据其中第19页及其以后和第53页及其以后给出的方法合成,并且在其中第109至205页被例举为具体化合物实施例1至127。所述化合物的某些的生物测试数据在其中第206至226页给出。
与本文中的结构(B)相关使用的定义如下:
(C1-C4)-烷基在本发明的上下文中代表具有1至4个碳原子的直链或支链烷基。可以通过实例的方式且优选地提及:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。
(C1-C4)-烷氧基在本发明的上下文中代表具有1至4个碳原子的直链或支链烷氧基。可以通过实例的方式且优选地提及:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。
单-(C1-C4)-烷基氨基在本发明的上下文中代表具有含有1至4个碳原子的直链或支链烷基取代基的氨基。可以通过实例的方式且优选地提及:甲基氨基、乙基氨基、正丙基氨基、异丙基氨基、正丁基氨基和叔丁基氨基。
二-(C1-C4)-烷基氨基在本发明的上下文中代表具有各自含有1至4个碳原子的两个相同或不同的直链或支链烷基取代基的氨基。可以通过实例的方式且优选地提及:N,N-二甲基氨基、N,N-二乙基氨基、N-乙基-N-甲基氨基、N-甲基-N-正丙基氨基、N-异丙基-N-甲基氨基、N-异丙基-N-正丙基氨基、N,N-二异丙基氨基、N-正丁基-N-甲基氨基和N-叔丁基-N-甲基氨基。
(C1-C4)-烷基羰基在本发明的上下文中代表具有经由羰基[-C(=O)-]键合至分子的其余部分的1至4个碳原子的直链或支链烷基。可以通过实例的方式且优选地提及:乙酰基、丙酰基、正丁酰基、异丁酰基、正丁酰基和新戊酰基。
(C1-C4)-烷氧基羰基在本发明的上下文中代表具有经由羰基[-C(=O)-]键合至分子的其余部分的1至4个碳原子的直链或支链烷氧基。可以通过实例的方式且优选地提及:甲氧基羰基、乙氧基羰基、正丙氧基羰基、异丙氧基羰基、正丁氧基羰基和叔丁氧基羰基。
单-(C1-C4)-烷基氨基羰基在本发明的上下文中代表经由羰基[-C(=O)-]键合至分子的其余部分且具有带有1至4个碳原子的直链或支链烷基取代基的氨基。可以通过实例的方式且优选地提及:甲基氨基羰基、乙基氨基羰基、正丙基氨基羰基、异丙基氨基羰基、正丁基氨基羰基和叔丁基氨基羰基。
二-(C1-C4)-烷基氨基羰基在本发明的上下文中代表经由羰基[-C(=O)-]键合至分子的其余部分且具有在每种情况下具有1至4个碳原子的两个相同或不同的直链或支链烷基取代基的氨基。可以通过实例的方式且优选地提及:N,N-二甲基氨基羰基、N,N-二乙基氨基羰基、N-乙基-N-甲基氨基羰基、N-甲基-N-正丙基氨基羰基、N-异丙基-N-甲基氨基羰基、N,N-二异丙基氨基羰基、N-正丁基-N-甲基氨基羰基和N-叔丁基-N-甲基氨基羰基。
(C3-C6)-环烷基在本发明的上下文中代表具有3至6个环碳原子的单环、饱和碳环。可以通过实例的方式提及:环丙基、环丁基、环戊基和环己基。优选的是环丙基和环丁基。
4-至7-元杂环烷基和4-至6-元杂环烷基在本发明的上下文中代表总共具有分别4至7个或4至6个环原子的单环、饱和杂环,其含有一个或两个相同或不同的来自系列N、O、S和S(O)2的环杂原子,且可以经由环碳原子或经由环氮原子(如果存在)键合。优选含有一个环氮原子和任选另一个来自系列N、O或S(O)2的环杂原子的4-至6-元杂环烷基。特别优选含有一个环氮原子和任选另一个来自系列N或O的环杂原子的5-或6-元杂环烷基。可以通过实例的方式提及:氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、硫杂环戊烷基、1,1-二氧桥硫杂环戊烷基、1,2-噁唑烷基、1,3-噁唑烷基、1,3-噻唑烷基、哌啶基、哌嗪基、四氢吡喃基、四氢硫代吡喃基、1,3-二氧杂环己烷基、1,4-二氧杂环己烷基、1,2-噁嗪烷基、吗啉基、硫代吗啉基、1,1-二氧桥硫代吗啉基、氮杂环庚烷基、1,4-二氮杂环庚烷基和1,4-氧氮杂环庚烷基。优选的是氮杂环丁烷基、吡咯烷基、吡唑烷基、咪唑烷基、1,2-噁唑烷基、1,3-噁唑烷基、哌啶基、哌嗪基、1,2-噁嗪烷基、吗啉基和硫代吗啉基。特别优选的是吡咯烷基、哌啶基、哌嗪基和吗啉基。
5-元氮杂-杂芳基在本发明的上下文中代表总共具有5个环原子的芳族杂环基(杂芳族),其含有至少一个环氮原子和任选一个或两个来自系列N、O和/或S的其它环杂原子,并且其经由环碳原子或任选地经由环氮原子(当价态允许时)键合。优选含有一个环氮原子和一个或两个其它来自系列N和/或O的环杂原子的5-元氮杂-杂芳基。可以通过实例的方式提及:吡咯基、吡唑基、咪唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、三唑基、噁二唑基和噻二唑基。优选的是吡唑基、咪唑基、噁唑基、异噁唑基和噁二唑基。
氧代取代基在本发明的上下文中代表经由双键键合至碳原子的氧原子。
所述组分B可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据本发明的上述方面的另一个实施方案,所述组合产品是以下物质的组合产品:
组分B:其为上述一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物,其选自:
实施例1
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例2
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮二盐酸盐
实施例3
(3R)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮二盐酸盐
实施例4
(3R)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例5
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例6
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮二盐酸盐
实施例7
(3R)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮二盐酸盐
实施例8
(3R)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例9
N2-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}甘氨酰胺二盐酸盐
实施例10
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例11
1-(4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮二盐酸盐
实施例12
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇双(甲酸盐)
实施例13
4-{[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例14
7-{[(3S)-3-氨基-3-甲基吡咯烷-1-基]甲基}-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例15
7-{[(3S)-3-氨基-3-甲基吡咯烷-1-基]甲基}-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例16
1-(4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮二盐酸盐
实施例17
6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例18
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例19
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺二盐酸盐
实施例20
1-(4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例21
4-({4-氨基-6-[(2-羟基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基}甲基)哌嗪-2-酮甲酸盐
实施例22
2-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙醇二盐酸盐
实施例23
6-(丁氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例24
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-(丙氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例25
6-[(环丙基甲氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例26
6-[(环丁基氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例27
6-(异丙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例28
6-[(2-甲氧基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例29
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-[(2,2,2-三氟乙氧基)甲基]吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例30
6-[(2-氨基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例31
{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酸甲酯
实施例32
{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酸
实施例33
2-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酰胺
实施例34
2-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲氧基)乙酰胺
实施例35
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-(苯氧基甲基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例36
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(甲基氨基)甲基]-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例37
6-[(二甲基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例38
6-[(乙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例39
2-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)乙醇三盐酸盐
实施例40
外消旋-1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌啶-3-醇三盐酸盐
实施例41
1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌啶-4-醇三盐酸盐
实施例42
外消旋-1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}吡咯烷-3-醇三盐酸盐
实施例43
6-[(二乙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例44
6-[(环丁基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例45
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-(吡咯烷-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例46
6-[(环丙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例47
6-{[(环丙基甲基)氨基]甲基}-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例48
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}甘氨酸三盐酸盐
实施例49
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮三盐酸盐
实施例50
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例51
(3S)-3-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)吡咯烷-2-酮
实施例52
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例53
外消旋-1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)丙-2-醇
实施例54
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例55
1-(4-{[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例56
(3R)-3-[({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)氨基]吡咯烷-2-酮
实施例57
1-(4-{[4-氨基-6-{[(2-羟基-2-甲基丙基)氨基]甲基}-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例58
4-({4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-7-基}甲基)哌嗪-1-甲醛甲酸盐
实施例59
4-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)哌嗪-2-酮
实施例60
4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基羰基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酸甲酯双(甲酸盐)
实施例61
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-(1,3-噁唑-5-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例62
6-(氨基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例63
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}乙酰胺双(三氟乙酸盐)
实施例64
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}乙酰胺二盐酸盐
实施例65
N-({4-氨基-7-[(4-甲酰基哌嗪-1-基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺甲酸盐
实施例66
N-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺
实施例67
N-({4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺
实施例68
4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例69
4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例70
4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例71
4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例72
N,N'-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6,7-二基]双(亚甲基)}二乙酰胺
实施例73
2-[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]丙-2-醇
实施例74
4-{[4-氨基-7-(2-羟基丙-2-基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例75
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例76
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例77
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇甲酸盐
实施例78
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例79
[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例80
4-{[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例81
1-({[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇甲酸盐
实施例82
1-({[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例83
7-氯-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例84
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-甲基-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例85
6-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例86
[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲醇
实施例87
1-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}咪唑烷-2-酮
实施例88
4-{[4-氨基-5-(7-甲氧基-1-苯并噻吩-2-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例89
4-{[4-氨基-6-(甲氧基甲基)-5-(5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例90
1-[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]乙醇
实施例91
[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基](环丙基)甲醇
实施例92
(3S)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例93
(3S)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例106
4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-N-[(3R)-2-氧代吡咯烷-3-基]吡咯并[2,1-f][1,2,4]三嗪-7-甲酰胺
实施例107
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]羰基}哌嗪-2-酮
实施例124
4-{[4-氨基-5-(5,7-二甲氧基-1-苯并噻吩-2-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例125
4-{[4-氨基-7-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例126
4-{[4-氨基-7-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例127
4-{[4-氨基-7-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮。
根据本发明的上述方面的一个实施方案,所述组合产品是以下物质的组合产品:
组分A:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺;和
组分B:4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
所述组分B可以呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
根据一个实施方案,本发明涉及本文提及的任何组分A与本文提及的任何组分B的组合产品。
根据一个具体实施方案,本发明涉及如本文实施例部分中提及的组分A与组分B的组合产品。
本发明的组合产品的组分A和B的有用形式
如上所提及,本发明的任何组合产品的组分A和B的任一者或两者可以呈有用的形式,诸如所有实施例化合物的药学上可接受的盐、共沉淀物、代谢物、水合物、溶剂化物和前药。术语“药学上可接受的盐”是指本发明化合物的相对无毒、无机或有机酸加成盐。例如,参见S. M. Berge等人,“Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19。药学上可接受的盐包括通过使作为碱发挥功能的主要化合物与无机或有机酸反应以形成盐而获得的那些盐,例如盐酸、硫酸、磷酸、甲磺酸、樟脑磺酸、草酸、马来酸、琥珀酸和柠檬酸的盐。药学上可接受的盐还包括其中使作为酸发挥功能的主要化合物与适当的碱反应形成的那些盐,例如钠、钾、钙、镁、铵盐和氯盐。本领域技术人员将进一步认识到请求保护的化合物的酸加成盐可以经由任何多种已知方法使化合物与适当的无机或有机酸反应来制备。或者,本发明的酸性化合物的碱金属和碱土金属盐可以经由各种已知方法使本发明化合物与适当的碱反应来制备。
本发明化合物的代表性盐包括常规的无毒盐和季铵盐,其由例如通过本领域众所周知的方式从无机或有机酸或碱形成。例如,这样的酸加成盐包括乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、肉桂酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、反丁烯二酸盐、葡庚糖酸盐(glucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙烷磺酸盐、衣康酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、巴莫酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、磺酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。
碱式盐包括碱金属盐诸如钾盐和钠盐、碱土金属盐诸如钙盐和镁盐,以及与有机碱诸如二环己胺和N-甲基-D-葡萄糖胺形成的铵盐。此外,可以利用试剂将碱性含氮基团季铵化,所述试剂诸如低级烷基卤化物,诸如甲基、乙基、丙基或丁基氯化物、溴化物和碘化物;二烷基硫酸酯(或盐),例如二甲基、二乙基、二丁基硫酸酯(或盐)或二戊基硫酸酯(或盐),长链卤化物诸如癸基、月桂基、肉豆蔻基和硬脂酰基(strearyl)氯化物、溴化物和碘化物,芳烷基卤化物,例如苄基和苯乙基溴化物等。
用于本发明目的的溶剂化物是溶剂和固体状态的本发明化合物的络合物(complex)。示例性的溶剂化物将包括但不限于:本发明的化合物与乙醇或甲醇的络合物。水合物是其中溶剂为水的溶剂化物的具体形式。
本发明的组合产品的组分A和B的药物制剂
如上所述,所述组分A或B可以彼此独立地呈即用于同时、共同、分开或依次给药的药物制剂的形式。所述组分可以彼此独立地通过经口、静脉内、外用、局部安装、腹膜内或经鼻途径给药。
所述组合物可用于通过给药至有此需要的患者来实现所需的药理作用。出于本发明的目的,患者是需要治疗特定病况或疾病的哺乳动物,包括人类。因此,本发明包括下述组合产品,其中彼此独立的组分A和B是由药学上可接受的载体和药学有效量的所述组分构成的药物制剂组合物。药学上可接受的载体优选为对患者相对无毒且无害的载体,其浓度与活性成分的有效活性一致,使得归因于载体的任何副作用不会损害组分和/或组合产品的有益效果。组合产品的药学有效量优选为对所治疗的特定病况产生结果或发挥影响的量。本发明的组合产品可以使用任何有效的常规剂量单位形式(包括立即、缓慢和定时释放制备物、口服、肠胃外、局部、经鼻、眼睛、光学、舌下、直肠、阴道等)与本领域众所周知的药学上可接受的载体一起给药。
对于口服给药,所述组合产品可以配制成固体或液体制备物诸如胶囊、丸剂、片剂、糖锭剂、锭剂、熔剂、粉剂、溶液剂、混悬剂或乳剂,并且可以根据本领域已知用于制造药物组合物的方法进行制备。固体单位剂型可以是胶囊,其可以是含有例如表面活性剂、润滑剂和惰性填充剂诸如乳糖、蔗糖、磷酸钙和玉米淀粉的普通硬壳或软壳明胶类型。
在另一个实施方案中,本发明的组合产品可以用常规片剂基质诸如乳糖、蔗糖和玉米淀粉与如下组分的组合压片:粘合剂诸如阿拉伯胶、玉米淀粉或明胶,给药后意图帮助片剂崩解和溶解的崩解剂诸如马铃薯淀粉、藻酸、玉米淀粉和瓜尔胶、黄蓍胶、阿拉伯胶,意图改善片剂颗粒流动和防止片剂材料与片剂模具和冲床表面粘附的润滑剂例如滑石、硬脂酸或硬脂酸镁、硬脂酸钙或硬脂酸锌,意图增强片剂的美学品质和使它们更容易被患者接受的染料、着色剂和矫味剂诸如薄荷油、冬青油或樱桃香精。用于口服液体剂型的合适的赋形剂包括磷酸二钙和稀释剂诸如水和醇,例如乙醇、苯甲醇和聚乙二醇,加入或不加入药学上可接受的表面活性剂、助悬剂或乳化剂。各种其它材料可以作为包衣剂存在或以其它方式修饰剂量单位的物理形式。例如,可以用虫胶、糖或二者将片剂、丸剂或胶囊剂包衣。
可分散粉末和颗粒适于制备含水悬浮剂。它们提供活性成分和分散剂或湿润剂、助悬剂和一种或多种防腐剂的混合物。合适的分散剂或湿润剂和助悬剂通过上面已经提及的那些例举。也可存在额外的赋形剂,例如上述那些甜味剂、矫味剂和着色剂。
本发明的药物组合物也可以呈水包油乳液形式。油相可以是植物油,诸如液体石蜡或植物油的混合物。合适的乳化剂可以是(1)天然存在的树胶,诸如阿拉伯胶和黄蓍胶,(2)天然存在的磷脂,诸如大豆和卵磷脂,(3)由脂肪酸和己糖醇酐衍生的酯或偏酯,例如脱水山梨糖醇单油酸酯,(4)所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液也可以含有甜味剂和矫味剂。
可以通过将活性成分悬浮于植物油诸如例如落花生油、橄榄油、芝麻油或椰子油或矿物油诸如液体石蜡中而配制油性悬浮剂。油性悬浮剂可含有增稠剂,诸如例如蜂蜡、硬石蜡或鲸蜡醇。悬浮剂也可含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种矫味剂;和一种或多种甜味剂诸如蔗糖或糖精。
可以用甜味剂,诸如例如甘油、丙二醇、山梨糖醇或蔗糖配制糖浆剂和酏剂。这样的制剂也可以含有缓和剂和防腐剂,诸如尼泊金甲酯和尼泊金丙酯和矫味剂和着色剂。
本发明的组合产品也可以肠胃外给药,即皮下、静脉内、眼内、滑膜内、肌内或腹膜间,作为优选在生理学上可接受的稀释剂与药物载体中的化合物的可注射剂量给药,所述药物载体可以是无菌液体或液体的混合物,诸如水、盐水、右旋糖水溶液和相关糖溶液,醇诸如乙醇、异丙醇或十六醇,二醇类诸如丙二醇或聚乙二醇,甘油缩酮类诸如2,2-二甲基-1,1-二氧杂环戊烷-4-甲醇,醚类诸如聚(乙二醇)400、油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙酰化的脂肪酸甘油酯,加入或不加入药学上可接受的表面活性剂诸如皂或去污剂,助悬剂诸如果胶、卡波姆、甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素,或乳化剂和其它药物助剂。
可用于本发明的肠胃外制剂中的说明性油类为石油、动物、植物或合成来源的那些油,例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄榄油、矿脂和矿物油。合适的脂肪酸包括油酸、硬脂酸、异硬脂酸和肉豆蔻酸。合适的脂肪酸酯为例如油酸乙酯和肉豆蔻酸异丙酯。合适的皂类包括脂肪酸碱金属、铵和三乙醇胺盐,且合适的去污剂包括阳离子去污剂,例如二甲基二烷基卤化铵、卤化烷基吡啶鎓和烷基胺乙酸盐;阴离子去污剂,例如磺酸的烷基酯、芳基酯和烯烃酯,硫酸的烷基酯、烯烃酯、醚和甘油单酯,和磺基琥珀酸酯;非离子去污剂,例如脂肪胺氧化物、脂肪酸烷醇酰胺,和聚(氧乙烯-氧丙烯)或环氧乙烷或环氧丙烷共聚物;和两性去污剂,例如β-氨基丙酸烷基酯,和2-烷基咪唑啉季铵盐以及混合物。
本发明的肠胃外组合物通常在溶液中含有约0.5重量%至约25重量%的活性成分。也可以有利地使用防腐剂和缓冲剂。为了尽可能减少或消除在注射部位的刺激,这样的组合物可含有优选具有约12至约17的亲水-亲油平衡值(HLB)的非离子表面活性剂。这样的制剂中的表面活性剂的量优选范围为约5重量%至约15重量%。表面活性剂可以是具有以上HLB的单一组分,或可以是具有期望HLB的两种或更多种组分的混合物。
用于肠胃外制剂中的说明性表面活性剂是聚乙烯脱水山梨糖醇脂肪酸酯类表面活性剂,例如脱水山梨糖醇单油酸酯,和环氧乙烷与疏水性基质的高分子量加合物,其由环氧丙烷和丙二醇缩合形成。
药物组合物可以呈无菌可注射含水悬浮液的形式。这样的悬浮液可以根据已知方法,使用以下来配制:合适的分散剂或湿润剂和助悬剂诸如例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基-纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或湿润剂,其可以为天然存在的磷脂诸如卵磷脂、环氧烷与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯、环氧乙烷与长链脂肪醇的缩合产物例如十七-乙烯氧基鲸蜡醇(heptadeca-ethyleneoxycetanol)、环氧乙烷与由脂肪酸和己糖醇衍生的偏酯的缩合产物诸如聚氧乙烯山梨糖醇单油酸酯、或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物例如聚氧乙烯脱水山梨糖醇单油酸酯。
无菌可注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液。可以采用的稀释剂和溶剂是例如水、林格氏溶液、等渗氯化钠溶液和等渗葡萄糖溶液。此外,可方便地使用无菌非挥发油作为溶剂或悬浮介质。为此目的,可以使用包括合成的甘油单酯或甘油二酯的任何非刺激性非挥发油。此外,脂肪酸诸如油酸可用于制备注射剂。
本发明的组合物也可以栓剂形式给药而用于药物的直肠给药。这些组合物可以通过将药物与在常温下为固体但在直肠温度下为液体、因此在直肠中将熔化以释放药物的合适的非刺激性赋形剂混合来制备。这样的材料为例如可可脂和聚乙二醇。
本发明的方法中利用的另一种制剂利用透皮递送装置(“贴剂”)。这样的透皮贴剂可用于提供受控量的本发明化合物的连续或非连续输注。用于递送药剂的透皮贴剂的构建和用途是本领域众所周知的(参见例如1991年6月11 日公开的美国专利号5,023,252,其通过引用并入本文)。这样的贴剂可以构建用于连续地、脉动式或按需递送药剂。
用于肠胃外给药的控释制剂包括本领域已知的脂质体、聚合微球和聚合凝胶制剂。
可期望或必需经由机械递送装置将药物组合物引入患者。用于递送药剂的机械递送装置的构建和用途是本领域众所周知的。用于例如将药物直接给药至脑的直接技术通常涉及将药物递送导管置入患者的脑室系统以绕过血-脑屏障。用于将药剂转运至身体的特定解剖学区域的一种这样的可植入递送系统描述于1991年4月30日公开的美国专利号5,011,472。
本发明的组合物如必需或期望还可含有通常被称作载体或稀释剂的其它常规的药学上可接受的复合成分。可利用用于将这样的组合物制备成适合的剂型的常规程序。这样的成分和程序包括描述于以下参考文献中的那些,其各自通过引用并入本文:Powell,M.F.等人,"Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349;和Nema, S. 等人, "Excipients and Their Use in InjectableProducts" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4),166-171。
可以适当时用于配制组合物以用于其预定给药途径的常用药物成分包括:
酸化剂(实例包括但不限于乙酸、柠檬酸、富马酸、盐酸、硝酸);
碱化剂(实例包括但不限于氨水溶液、碳酸铵、二乙醇胺、一乙醇胺、氢氧化钾、硼酸钠、碳酸钠、氢氧化钠、三乙醇胺(triethanolamine)、三乙醇胺(trolamine));
吸附剂(实例包括但不限于粉状纤维素和活性碳);
气雾剂推进剂(实例包括但不限于二氧化碳、CCl2F2、F2ClC-CClF2和CClF3);
空气置换剂(实例包括但不限于氮气和氩气);
抗真菌防腐剂(实例包括但不限于苯甲酸、尼泊金丁酯、尼泊金乙酯、尼泊金甲酯、尼泊金丙酯、苯甲酸钠);
抗微生物防腐剂(实例包括但不限于苯扎氯铵、苄索氯铵、苯甲醇、西吡氯铵、氯丁醇、苯酚、苯乙醇、硝酸苯汞和硫柳汞);
抗氧化剂(实例包括但不限于抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、次磷酸、单硫代甘油、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、甲醛合次硫酸氢钠、焦亚硫酸氢钠);
粘合物质(实例包括但不限于嵌段聚合物、天然和合成橡胶、聚丙烯酸酯、聚氨酯、硅酮、聚硅氧烷和苯乙烯-丁二烯共聚物);
缓冲剂(实例包括但不限于偏磷酸钾、磷酸氢二钾、乙酸钠、无水柠檬酸钠和柠檬酸钠二水合物);
载体(实例包括但不限于阿拉伯胶糖浆、芳香糖浆、芳香酏剂、樱桃糖浆、可可糖浆、柑桔糖浆、糖浆、玉米油、矿物油、花生油、芝麻油、抑菌的氯化钠注射液和抑菌的注射用水);
螯合剂(实例包括但不限于依地酸二钠和依地酸);
着色剂(实例包括但不限于FD&C Red No. 3、FD&C Red No. 20、FD&C Yellow No. 6、FD&C Blue No. 2、D&C Green No. 5、D&C Orange No. 5、D&C Red No. 8、焦糖和氧化铁红);
澄清剂(实例包括但不限于皂土);
乳化剂(实例包括但不限于阿拉伯胶、聚西托醇(cetomacrogol)、鲸蜡醇、单硬脂酸甘油酯、卵磷脂、脱水山梨糖醇单油酸酯、聚氧乙烯50单硬脂酸酯);
包囊剂(实例包括但不限于明胶和邻苯二甲酸乙酸纤维素);
香料(实例包括但不限于茴芹油、肉桂油、可可、薄荷醇、橙油、薄荷油和香草醛);
保湿剂(实例包括但不限于甘油、丙二醇和山梨糖醇);
研磨剂(实例包括但不限于矿物油和甘油);
油(实例包括但不限于落花生油、矿物油、橄榄油、花生油、芝麻油和植物油);
软膏基质(实例包括但不限于羊毛脂、亲水性软膏、聚乙二醇软膏、矿脂、亲水性矿脂、白色软膏、黄色软膏和玫瑰水软膏);
渗透促进剂(透皮递送)(实例包括但不限于单羟基或多羟基醇、一价或多价醇、饱和或不饱和脂肪醇、饱和或不饱和脂肪酸酯、饱和或不饱和二羧酸、精油、磷脂酰衍生物、脑磷脂、萜烯、酰胺、醚、酮和脲);
增塑剂(实例包括但不限于邻苯二甲酸二乙酯和甘油);
溶剂(实例包括但不限于乙醇、玉米油、棉籽油、甘油、异丙醇、矿物油、油酸、花生油、纯净水、注射用水、无菌注射用水和无菌冲洗用水);
硬化剂(实例包括但不限于鲸蜡醇、十六烷基酯蜡、微晶蜡、石蜡、硬脂醇、白蜡和黄蜡);
栓剂基质(实例包括但不限于可可脂和聚乙二醇(混合物));
表面活性剂(实例包括但不限于苯扎氯铵、壬苯醇醚10、辛苯昔醇9、聚山梨酯80、十二烷基硫酸钠和脱水山梨糖醇单棕榈酸酯);
助悬剂(实例包括但不限于琼脂、皂土、卡波姆、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、高岭土、甲基纤维素、黄蓍胶和硅酸镁铝(veegum));
甜味剂(实例包括但不限于阿司帕坦、右旋糖、甘油、甘露醇、丙二醇、糖精钠、山梨糖醇和蔗糖);
片剂抗粘附剂(实例包括但不限于硬脂酸镁和滑石);
片剂粘合剂(实例包括但不限于阿拉伯胶、藻酸、羧甲基纤维素钠、可压缩糖、乙基纤维素、明胶、液体葡萄糖、甲基纤维素、非交联聚乙烯吡咯烷酮和预胶化淀粉);
片剂和胶囊剂稀释剂(实例包括但不限于磷酸氢钙、高岭土、乳糖、甘露醇、微晶纤维素、粉状纤维素、沉淀碳酸钙、碳酸钠、磷酸钠、山梨糖醇和淀粉);
片剂包衣剂(实例包括但不限于液体葡萄糖、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、邻苯二甲酸乙酸纤维素和虫胶);
直接压片赋形剂(实例包括但不限于磷酸氢钙);
片剂崩解剂(实例包括但不限于藻酸、羧甲基纤维素钙、微晶纤维素、聚克立林钾、交联聚乙烯吡咯烷酮、藻酸钠、淀粉羟乙酸钠和淀粉);
片剂助流剂(实例包括但不限于胶体二氧化硅、玉米淀粉和滑石);
片剂润滑剂(实例包括但不限于硬脂酸钙、硬脂酸镁、矿物油、硬脂酸和硬脂酸锌);
片剂/胶囊剂遮光剂(实例包括但不限于二氧化钛);
片剂抛光剂(实例包括但不限于巴西棕榈蜡和白蜡);
增稠剂(实例包括但不限于蜂蜡、鲸蜡醇和石蜡);
张度剂(实例包括但不限于右旋糖和氯化钠);
增粘剂(实例包括但不限于藻酸、皂土、卡波姆、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮、藻酸钠和黄蓍胶);和
湿润剂(实例包括但不限于十七乙烯氧基鲸蜡醇、卵磷脂、山梨糖醇单油酸酯、聚氧乙烯山梨糖醇单油酸酯和聚氧乙烯硬脂酸酯)。
根据本发明的药物组合物可举例如下:
无菌IV溶液剂:可使用无菌注射用水制备本发明的期望化合物的5 mg/mL溶液,根据需要调节pH。用无菌5%右旋糖将所述溶液稀释至1-2 mg/mL用于给药,并且在约60分钟内作为IV输注给药。
用于IV给药的冻干粉:可用(i)100-1000mg的作为冻干粉的本发明的期望化合物,(ii)32-327mg/mL柠檬酸钠,和(iii)300-3000mg Dextran 40制备无菌制剂。用无菌注射用盐水或右旋糖5%将该制剂重构至10-20 mg/mL的浓度,然后用盐水或右旋糖5%进一步稀释至0.2-0.4mg/mL,并且经15-60分钟IV推注或通过IV输注给药。
肌内悬浮剂:可制备以下溶液剂或悬浮剂用于肌内注射:
50mg/mL期望的水不溶性的本发明的化合物
5mg/mL羧甲基纤维素钠
4mg/mL TWEEN 80
9mg/mL氯化钠
9mg/mL苯甲醇。
硬壳胶囊剂:通过各自用100mg粉状活性成分、150mg乳糖、50mg纤维素和6mg硬脂酸镁填充标准的两片式硬明胶胶囊来制备大量的单位胶囊剂。
软明胶胶囊剂:制备活性成分在可消化的油(诸如大豆油、棉籽油或橄榄油)中的混合物并且通过正置换型泵(positive displacement pump)注入熔化的明胶中以形成含有100mg活性成分的软明胶胶囊。将胶囊洗涤并干燥。可将所述活性成分溶解于聚乙二醇、甘油和山梨糖醇的混合物中以制备水混溶性药物混合物。
片剂:通过常规程序制备大量片剂,使得剂量单位为100mg活性成分、0.2mg胶体二氧化硅、5mg硬脂酸镁、275mg微晶纤维素、11mg淀粉和98.8mg乳糖。可应用适当的水性和非水性包衣以增加适口性、改善精致(elegance)和稳定性或延迟吸收。
速释片剂/胶囊剂:这些是通过常规方法和新颖方法制备的固体口服剂型。将这些单位口服,而不用水进行药物的即刻溶出和递送。将活性成分混合在含有成分诸如糖、明胶、果胶和甜味剂的液体中。通过冷冻干燥和固态萃取技术使这些液体固化成固体片剂或囊片。可将药物化合物与粘弹性和热塑性的糖和聚合物或泡腾组分一起压缩以产生旨在不需要水的情况下速释的多孔基质。
治疗癌症的方法
在本发明的上下文内,术语“癌症”包括但不限于子宫内膜癌、乳腺癌、肺癌、脑癌、生殖器官癌、消化道癌、泌尿道癌、肝癌、眼癌、皮肤癌、头颈癌、甲状腺癌、甲状旁腺癌、及其远端转移。那些病症还包括多发性骨髓瘤、淋巴瘤、肉瘤和白血病。
子宫内膜癌的实例包括但不限于I型EC(雌激素依赖性和/或孕酮依赖性的,其具有子宫内膜样组织学)和II型EC或子宫内膜异位症(激素非依赖性的分化不良的子宫内膜样、透明细胞和浆液性癌)。
乳腺癌的实例包括,但不限于侵入性导管癌、侵入性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌症的实例包括,但不限于小细胞和非小细胞肺癌,以及支气管腺瘤和胸膜肺母细胞瘤。
脑癌的实例包括,但不限于脑干和hypophtalmic胶质瘤、小脑和大脑星形细胞瘤、成神经管细胞瘤、室管膜瘤及神经外胚层瘤和松果体瘤。
雄性生殖器官肿瘤包括,但不限于前列腺癌和睾丸癌。雌性生殖器官肿瘤包括,但不限于子宫内膜癌、子宫颈癌、卵巢癌、阴道癌和外阴癌,以及子宫肉瘤。
消化道肿瘤包括,但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道肿瘤包括,但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括,但不限于眼内黑色素瘤和视网膜母细胞瘤。
肝癌的实例包括,但不限于肝细胞癌(具有或不具有羽层状变体(fibrolamellarvariant)的肝细胞癌)、胆管癌(肝内胆管癌)和混合型肝细胞胆管癌。
皮肤癌包括,但不限于鳞状细胞癌、卡波济氏肉瘤、恶性黑素瘤、Merkel细胞皮肤癌和非黑素瘤皮肤癌。
头颈癌包括,但不限于喉、下咽部、鼻咽部、口咽部癌症,唇和口腔癌以及鳞状细胞癌。
淋巴瘤包括,但不限于AIDS相关淋巴瘤、非霍奇金淋巴瘤、皮肤T-细胞淋巴瘤、伯基特淋巴瘤、霍奇金病、和中枢神经系统的淋巴瘤。
肉瘤包括,但不限于软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括,但不限于急性髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性粒性白血病和毛细胞白血病。
本发明涉及用于使用本发明的组合产品来治疗或预防癌症、特别是子宫内膜癌(以下缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的方法。在癌症、特别是EC(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的治疗或预防中,本发明的组合产品可用于抑制、阻断、降低、减少等细胞增殖和/或细胞分裂,和/或产生细胞凋亡。该方法包括向有此需要的哺乳动物(包括人类)给药一定量的本发明的组合产品或其药学上可接受的盐、异构体、多晶型物、代谢物、水合物、溶剂化物或酯;等,所述量对于治疗或预防癌症、特别是EC、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症是有效的。
本文件通篇提及的术语“治疗(treating)”或“治疗(treatment)”是常规使用的,例如为了抵抗、减轻、减少、缓解、改善疾病或病症诸如癌的状况等的目的来控制或护理受试者。
剂量和给药
基于已知评估可用于治疗或预防癌症、特别是子宫内膜癌(EC)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的化合物的标准实验室技术,通过标准毒性测试和通过用于确定对哺乳动物中上述状况的治疗的标准药理学测定,并且通过将这些结果与用于治疗这些状况的已知药物的结果进行比较,可以容易地确定本发明的组合产品用于治疗适应症的有效剂量。在所述状况的治疗中待给药的活性成分的量可以根据诸如以下的考量而在很大程度上变化:所采用的具体组合产品和剂量单位、给药模式、疗程、所治疗患者的年龄和性别、以及所治疗状况的性质和程度。
待给药的活性成分的总量通常范围为约0.001mg/kg-约200mg/kg体重/天,并且优选约0.01mg/kg-约20mg/kg体重/天。临床上有用的给药方案的范围将为每日一次至三次的给药至每四周一次的给药。此外,“停药期”(其中在特定时间段内不给予患者药物)对于药理学效应和耐受性之间的整体平衡可能是有利的。单位剂量可含有约0.5mg-约1,500mg活性成分,并且可每日一次或多次地给药,或者少于每日一次地给药。通过注射(包括静脉内、肌内、皮下和肠胃外注射)以及使用输注技术给药的平均每日剂量优选为0.01-200 mg/kg总体重。平均每日直肠剂量方案将优选为0.01-200mg/kg 总体重。平均每日阴道剂量方案将优选为0.01-200mg/kg总体重。平均每日局部剂量方案将优选为每日一次至四次给药0.1-200mg。透皮浓度将优选为维持0.01-200mg/kg的每日剂量所需的浓度。平均每日吸入剂量方案将优选为0.01-100mg/kg总体重。
当然对于每个患者的具体起始和持续剂量方案将根据以下因素而变化:如临床诊断医生所确定的状况的性质和严重度、所使用的具体组合产品的活性、患者的年龄和整体状况、给药时间、给药途径、药物的排泄速率、药物组合等。本发明的组合产品或其药学上可接受的盐或酯或其组合物的期望的治疗模式和剂量的数量可由本领域技术人员使用常规的治疗测试来确定。
使用如上所述的组分A、如上所述的组分B和组分C(一种或多种其它药剂)的组合
产品的疗法。
本发明的组分A和组分B的组合产品可以作为唯一的药剂或与一种或多种其它药剂组合(其中所得的组分A、B和C的组合不会引起不可接受的副作用)给药。例如,本发明的组分A和B的组合产品可以与组分C、即一种或多种其它药剂、诸如已知的抗血管生成剂、抗过度增殖剂、抗炎剂、镇痛剂、免疫调节剂、利尿剂、抗心律失常剂、抗高胆固醇血症剂、抗血脂障碍剂、抗糖尿病剂或抗病毒剂等,以及与其混合物和组合进行组合。
组分C可以是一种或多种药剂,诸如131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、赤式-羟基壬基腺嘌呤(ado-trastuzumab emtansine)、阿法替尼、阿柏西普、阿地白介素、阿仑珠单抗、阿仑膦酸、阿利维A酸、六甲蜜胺、氨磷汀、氨鲁米特、氨基酮戊酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴香脑二硫杂环戊二烯硫酮(anetholedithiolethione)、血管紧张素II、抗凝血酶III、阿瑞匹坦、阿西莫单抗、阿格拉宾、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗、贝洛替康、苯达莫司汀、贝利司他、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼(bosutinib)、brentuximab vedotin、白消安、卡巴他赛(cabazitaxel)、卡博替尼、亚叶酸钙、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡非佐米、卡莫氟、卡莫司汀、卡妥索单抗、塞来考昔、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨、克立他酶(crisantaspase)、环磷酰胺、环丙特龙、阿糖胞苷、达卡巴嗪、放线菌素D、达促红素α、达拉菲尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素、地舒单抗、地普奥肽、地洛瑞林、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依库珠单抗、依屈洛单抗、依利醋铵、艾曲泊帕、内皮他丁、依诺他滨、恩杂鲁胺、表柔比星、环硫雄醇、促红素α、倍他铂、泽塔铂、依他铂、艾立布林、厄洛替尼、埃索美拉唑、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟甲睾酮、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、钆特醇、钆特酸葡甲胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、羧肽酶、氧化型谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格拉司琼、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林、羟基脲、I-125种子(I-125 seeds)、兰索拉唑、伊班膦酸、替伊莫单抗、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、吡地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、伊匹木单抗、伊立替康、伊曲康唑、伊沙匹隆、兰瑞肽、拉帕替尼、lasocholine、来那度胺、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、左炔诺孕酮、左甲状腺素钠、利舒脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯嘌呤、美司钠、美沙酮、甲氨蝶呤、甲氧沙林、氨基酮戊酸甲酯、甲基泼尼松龙、甲睾酮、甲酪氨酸、米法莫肽、米替福新、米立铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫派达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮 + 喷他佐辛、纳曲酮、那托司亭、奈达铂、奈拉滨、奈立膦酸、nivolumabpentetreotide、尼洛替尼、尼鲁米特、尼莫拉唑、尼妥珠单抗、尼莫司汀、尼曲吖啶、nivolumab、obinutuzumab、奥曲肽、奥法木单抗、高三尖杉酯碱(omacetaxinemepesuccinate)、奥美拉唑、昂丹司琼、奥普瑞白介素、奥古蛋白(orgotein)、orilotimod、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因疗法、紫杉醇、帕利夫明、钯-103种子(palladium-103 seed)、帕洛诺司琼、帕米膦酸、帕尼单抗、泮托拉唑、帕唑帕尼、培门冬酶、PEG-倍他铂(甲氧基PEG-倍他铂)、派姆单抗、培非司亭、培干扰素α-2b、培美曲塞、喷他佐辛、喷司他丁、培洛霉素、全氟正丁烷、培磷酰胺、帕妥珠单抗、毕西巴尼、匹鲁卡品、吡柔比星、匹克生琼、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、聚乙烯吡咯烷酮 + 透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙、泼尼莫司汀、强的松、丙卡巴肼、丙考达唑、普萘洛尔、喹高利特、雷贝拉唑、racotumomab、镭-223氯化物、雷多替尼、雷洛昔芬、雷替曲塞、雷莫司琼、雷莫芦单抗、雷莫司汀、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、依替膦酸铼-186、利妥昔单抗、罗米地新、罗米司亭、罗莫肽、roniciclib、钐(153Sm) lexidronam、沙格司亭、沙妥莫单抗、胰泌素、西普鲁塞-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼、司坦唑醇、链佐星、舒尼替尼、他拉泊芬、他米巴罗汀、他莫昔芬、他喷他多、他索纳明、替西白介素、锝(99mTc)nofetumomab merpentan、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、替曲膦、沙立度胺、塞替派、胸腺法新、促甲状腺素α、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲马多、曲妥珠单抗、曲妥珠单抗-emtansine、曲奥舒凡、维甲酸、三氟尿苷 + tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、戊柔比星、凡他尼布、伐普肽、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、维莫德吉、伏林司他、伏罗唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星或其组合。
或者,所述组分C可以是一种或多种选自以下的其它药剂:吉西他滨、紫杉醇(当组分B本身不是紫杉醇时)、顺铂、卡铂、丁酸钠、5-FU、多柔比星、他莫昔芬、依托泊苷、曲妥珠单抗、吉非替尼、intron A、雷帕霉素、17-AAG、U0126、胰岛素、胰岛素衍生物、PPAR配体、磺酰脲类药物、α-葡萄糖苷酶抑制剂、双胍类、PTP-1B抑制剂、DPP-IV抑制剂、11-β-HSD抑制剂、GLP-1、GLP-1衍生物、GIP、GIP衍生物、PACAP、PACAP衍生物、胰泌素或胰泌素衍生物。
可以作为组分C添加至本发明的组分A和B的组合产品的任选的抗过度增殖剂包括但不限于Merck Index, (1996) 第11版中的癌症化疗药物方案上列出的化合物,其在此通过引用并入,所述化合物诸如门冬酰胺酶、博来霉素、卡铂、卡莫司汀、苯丁酸氮芥、顺铂、门冬酰胺酶、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素、多柔比星(阿霉素)、表柔比星、依托泊苷、5-氟尿嘧啶、六甲蜜胺、羟基脲、异环磷酰胺、伊立替康、亚叶酸、洛莫司汀、双氯乙基甲胺、6-巯基嘌呤、美司钠、甲氨蝶呤、丝裂霉素C、米托蒽醌、泼尼松龙、泼尼松、丙卡巴肼、雷洛昔芬、链佐星、他莫昔芬、硫鸟嘌呤、托泊替康、长春碱、长春新碱和长春地辛。
适合作为组分C与本发明的组分A和B的组合产品一起使用的其它抗过度增殖剂包括但不限于Goodman和Gilman的 The Pharmacological Basis of Therapeutics(第九版), 编辑Molinoff等人, 由McGraw-Hill公开, 第1225-1287页,(1996)中的认可用于治疗肿瘤性疾病的那些化合物,其在此通过引用并入,所述化合物诸如氨鲁米特、L-门冬酰胺酶、硫唑嘌呤、5-氮杂胞苷克拉屈滨(5-azacytidine cladribine)、白消安、己烯雌酚、2',2'-双氟脱氧胞啶(2',2'-difluorodeoxycytidine)、多西他赛、赤式-羟基壬基腺嘌呤、乙炔雌二醇、5-氟脱氧尿苷、单磷酸5-氟脱氧尿苷、磷酸氟达拉滨、氟甲睾酮、氟他胺、己酸羟孕酮、伊达比星、干扰素、醋酸甲羟孕酮、醋酸甲地孕酮、美法仑、米托坦、紫杉醇(当组分B本身不是紫杉醇时)、喷司他丁、N-膦酰基乙酰基-L-天冬氨酸(PALA)、普卡霉素、司莫司汀、替尼泊苷、丙酸睾酮、塞替派、三甲基三聚氰胺、尿核苷和长春瑞滨。
适合作为组分C与本发明的组分A和B的组合产品一起使用的其它抗过度增殖剂包括但不限于其它抗癌剂,诸如埃坡霉素及其衍生物、伊立替康、雷洛昔芬和托泊替康。
通常,细胞毒性剂和/或细胞抑制剂作为组分C与本发明的组分A和B的组合产品的组合使用将起到以下作用:
(1) 与给药单独任一种药剂相比在减少肿瘤生长或者甚至消除肿瘤方面产生更好的效力,
(2) 提供给药更少量的所给药的化疗剂,
(3) 提供化疗治疗,其在患者中被很好地耐受并且有害药理学并发症比在单一药剂化疗和某些其它组合疗法中所观察到的更少,
(4) 提供治疗更广范围的哺乳动物(特别是人)中的不同癌症类型,
(5) 提供受治疗患者中更高的响应率,
(6) 与标准的化疗治疗相比提供受治疗患者中更长的存活时间,
(7) 提供更长的肿瘤进展时间,和/或
(8) 与其它癌症药剂组合产生拮抗效应的已知情况相比,得到至少与单独使用的药剂一样好的效力和耐受性结果。
生物标志物:
用于患者分层的生物标志物是例如单独或与另一种形式的PI3K途径活化组合的肿瘤抑制因子PTEN或FBXW7的损失,其用于预测具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的敏感性和/或耐受性、因此提供如本文所定义的基于理论的剂量以克服所述具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的组分A和组分B的组合产品的耐受性(患者分层),所述另一种形式的PI3K途径活化选自任何以下单独或组合的扰动:PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的突变;PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变,其可以在蛋白水平、mRNA水平或DNA水平上测量。
实施例
在实施例中使用以下缩写:
•组分A:
◦“copanlisib”或“化合物A”意指如本文所示的WO 2008/070150 A1的化合物实施例13(其为如本文描述和定义的组分A的实例);
◦“copanlisib二盐酸盐”或“化合物A*” 意指欧洲专利申请号EP 11 161 111.7和以WO2012/136553公开的PCT申请号PCT/EP2012/055600(其两者在此以其整体通过引用并入本文)中的化合物实施例1(其为如本文描述和定义的组分A的实例)。
•组分B:
“FGFRi”或“化合物B”意指WO 2013/087578的化合物实施例1,即以下结构的化合物:
(其为如本文描述和定义的组分B的实例)。
材料和方法:
体外组合评价:使用组合指数等效线分析评估本发明的组合产品的效果,用于体外评价。效力参数是48小时胱天蛋白酶3/7活化测定中的作用。简言之,将细胞铺板在含有25μL培养基的384孔板中。在24小时之后,5μL含有以下的实验培养基以不同比率(***)用于进行连续3倍稀释以生成具有7个浓度的响应曲线:
•单独的A,或
•单独的B,或
•A(作为组分A)加B(作为组分B)的组合。一式三份进行实验。在化合物暴露后48小时进行胱天蛋白酶3/7测定。
在具有建立的人肿瘤细胞系的裸小鼠中的肿瘤异种移植模型中以MTD和亚-MTD剂量评估体内效力。根据ATCC方案在含有10% FCS的推荐培养基中培养肿瘤细胞。在亚汇合(70%)状态下收获细胞用于移植。用于接种的细胞数显示于表1中。对于小鼠,植入体积为100μl。当肿瘤大小为约25 – 50 mm2时,将动物随机化至治疗和对照组,并开始治疗。每只动物的治疗基于个体体重。对于每种化合物使用最佳制剂、应用途径和时间表(参见表2)。经口给药(p.o.)通过胃管进行。经口应用体积为10 ml/kg,且静脉内应用体积为10 ml/kg。使用卡尺测定肿瘤面积(最长直径和其垂直线的乘积)。监测动物体重作为治疗相关毒性的量度。肿瘤面积和体重的测量每周进行2-3次。用最终肿瘤面积计算T/C比率(治疗/对照)。通过临床使用的RECIST标准(完全反应、部分反应、疾病稳定和疾病进展)评估治疗反应,并且相应计算反应率(RR =具有完全和部分反应的动物数目)。
表1. 用于在体内子宫内膜肿瘤模型中评价化合物A (copanlisib)和化合物B(FGFRi)的肿瘤模型。
肿瘤模型 | 植入模式 |
MFE 280 | 悬浮于50% Matrigel中的1 x 106个细胞s.c.植入雌性小鼠的腹股沟区域 |
表2. 体内研究中使用的制剂、应用途径和时间表。
药物 | 制剂 | 应用途径 | 应用时间表 |
化合物A | 5%甘露醇/0.9% NaCl | i.v. | Q2D |
多柔比星 | 0.9% NaCl | i.p. | Q14D |
化合物B | 10%EtOH, 40%Solutol, 50%水(~2% HCl [2M]) | p.o. | QD |
本发明在以下实施例中证明,以下实施例并不意味着以任何方式限制本发明:
实施例1. 在MFE 280子宫内膜肿瘤模型中PI3K抑制剂化合物A (copanlisib)和FGFR抑制剂化合物B的协同组合产品。
如表1和Cosmic数据库中所示,子宫内膜癌是具有不同分子特征的异质性疾病。最常见的异常是PI3K的活化和PTEN的功能损失。据报道,FGFR2的活化突变存在于I型和II型子宫内膜癌中(Pollock等人)。在约10%的人子宫内膜癌中已经鉴定到FGFR2中的活化突变。体外测试的11种细胞系中的3种具有活化FGFR2突变(MFE 280、MFE296和AN3CA)。令人惊讶地,这3种细胞系都具有共存的PIK3CA突变或PTEN的功能损失,但没有KRAS突变。
图1. 在MFE-280细胞(PIK3CAG1047Y,FGFR2S252W)中PI3K抑制剂化合物A(Copanlisib)和FGFR抑制剂化合物B的协同组合产品。测试PI3K抑制剂化合物A(copanlisib)和FGFR抑制剂化合物B的组合产品,并将其与MFE 280中的单一药剂活性进行比较,以解决使用切割的胱天蛋白酶3/7测定的凋亡诱导中的活性。MFE 280细胞同时具有活化PIK3CA和FGFR2突变。作为单一药剂,化合物A和化合物B都没有分别显示最高达5和10μM的凋亡诱导。然而,当组合化合物A和化合物B时,在亚-μM浓度下诱导显著的凋亡,例如0.33 µM化合物A +0.44μM化合物B(图1(A)),0.22μM化合物A +0.66μM化合物B(图1(B))。
图2. 在MFE-296细胞(PTENdel,FGFR2N549K)中PI3K抑制剂化合物A (Copanlisib)和FGFR抑制剂化合物B的协同组合产品。测试PI3K抑制剂化合物A (copanlisib)和FGFR抑制剂化合物B的组合产品,并将其与MFE 296中的单一药剂活性进行比较,以解决使用切割的胱天蛋白酶3/7测定的凋亡诱导中的活性。MFE 296细胞具有活化FGFR2突变和PTEN的损失。作为单一药剂,化合物A和化合物B都没有分别显示最高达5和10μM的凋亡诱导。然而,当组合化合物A和化合物B时,通过测量活化的胱天蛋白酶3/7来检测剂量-依赖性凋亡。
图3. 在MFE-280异种移植肿瘤模型中PI3K抑制剂化合物A (Copanlisib)与FGFR抑制剂化合物B的协同组合产品。测试PI3K抑制剂化合物A (copanlisib)和FGFR抑制剂化合物B的组合,并将其与MFE 280(携带活化PIK3CA和FGFR2突变两者的子宫内膜肿瘤模型)中的单一药剂活性和SoC多柔比星进行比较。在约40 mm2的肿瘤大小的情况下,皮下生长的MFE-280肿瘤用两种不同剂量的化合物A (copanlisib)、14(实心三角形)/10(空心三角形)mg/kg和7mg/kg)以及化合物A和化合物B的组合静脉内治疗。化合物A的给药方案在图3A中用三角形表示。在两种单一疗法和与7mg/kg化合物A的组合疗法中观察到与起始体重相比没有体重减轻。在两种单一疗法和组合组中将化合物A的14mg/kg的剂量(实心三角形)减少至10mg/kg(空心三角形),这是由于个体动物在组合组中显示体重减轻。作为SoC参考,将多柔比星每14天静脉内应用1次。
PI3K抑制剂化合物A(copanlisib)的治疗导致肿瘤重量减少约84% ((14)10 mg/kg)和76% (7 mg/kg)。在研究结束时,FGFR抑制剂化合物B也达到78%肿瘤生长抑制。与SoC多柔比星相比,两种抑制剂都更有效(通过肿瘤重量评价,61%肿瘤生长抑制)。化合物B与(14)10 mg/kg和7 mg/kg化合物A(copanlisib)的组合将肿瘤生长抑制分别进一步增强至99%和96%。更重要地,组合疗法导致100%反应率,相比之下,在用每种单一药剂治疗的动物组中,反应率为12.5%至37.5%。值得注意的是,组合疗法组中57%和25%的动物甚至达到了完全的肿瘤缓解(表3)。此外,化合物A (copanlisib 7mg/kg)和化合物B (FGFRi 75mg/kg)的组合在整个治疗期间被良好耐受,没有体重减轻,仅用化合物A (copanlisib 14mg/kg)和化合物B (FGFRi 75mg/kg)观察到单独的体重减轻,其在第四次治疗剂量后引发将化合物A的剂量降低至10mk/kg(图4)。
表 3:在MFE 280异种移植肿瘤模型中PI3K抑制剂化合物A (copanlisib)和FGFR抑制剂化合物B的效力
a) T/C =治疗/对照比率,从研究结束时的平均肿瘤面积或最终肿瘤重量计算。
b) 反应:PD =疾病进展,肿瘤数目表现出>20%肿瘤增加;SD =疾病稳定,肿瘤数目表现出<30%肿瘤缩小和<20%肿瘤增加;PR =部分反应,肿瘤数目表现出>30%肿瘤缩小;CR=完全反应,不可测量肿瘤的数目。
实施例2. PI3K抑制剂化合物A (copanlisib)在子宫内膜癌患者中的临床益处。
在I期剂量递增研究中,在每28天周期的第1天、第8天和第15天用经60分钟静脉内给药的化合物A (copanlisib)治疗受试者。17个受试者在5个剂量递增组群(0.1、0.2、0.4、0.8和1.2 mg/kg)中治疗,并且最大耐受剂量(MTD)被确定为0.8 mg/kg。将额外患者招募至在MTD治疗的3个扩展组群中的研究中,以评价所选患者群体(包括实体瘤(n=25)、非霍奇金淋巴瘤(NHL;n=9)和糖尿病实体瘤患者(n=6;以0.4 mg/kg治疗))中的安全性、药代动力学、生物标志物和临床益处。在本研究中治疗的4/5 (80%)子宫内膜癌患者中观察到临床益处(经历完全反应的患者[CR]、部分反应[PR]或疾病稳定[SD]的患者)(表4),其中包括1个患者具有CR,且2个患者具有持续多于8个周期(多于224天)的延长SD。
使用数字PCR对归档肿瘤样品和从血浆分离的无细胞DNA测试PIK3CA、BRAF和KRAS突变。还对归档肿瘤样品进行一组肿瘤基因的下一代测序(NGS)和PTEN蛋白的免疫组织化学(IHC)。值得注意的是,研究中具有CR的唯一患者具有通过IHC的PTEN损失和PTEN和PIK3CA基因两者中的突变的子宫内膜癌(表4)。在具有持续多于8个周期的延长SD的2个子宫内膜癌患者中,仅可对1个(患者# 2117)生成PTEN数据,并且该肿瘤通过IHC也是PTEN-阴性的(表4)。具有延长SD的其它子宫内膜癌患者(具有24.3%肿瘤缩小)具有KRAS肿瘤突变(表4)。该数据显示,化合物A (copanlisib)可以为具有有或无PIK3CA突变、有或无PTEN损失或突变且KRAS中有或无突变的子宫内膜癌的患者提供临床益处。经由单独或组合的多种机制(诸如PTEN损失和/或突变、PIK3CA突变和/或KRAS突变)活化PI3K途径信号传导可以富集该群体中的化合物A (copanlisib)活性。
表4. 化合物A (copanlisib)的I期研究中所治疗的子宫内膜癌患者间的临床结果和生物标志物数据。
Pt,患者;WT,野生型;MUT,突变体;nd,没有进行
*仅外科手术,患者拒绝辅助化疗和放射
#在周期2结束时PR,直到周期8结束,然后CR,直到周期14结束
°由于不良事件,在周期5时剂量减少。
这些发现提供了开发用于治疗子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的个体化疗法的理论。
因此,如上所提及,本发明涉及生物标志物(其为单独或与另一种形式的PI3K途径活化(如下一段中所述)组合的肿瘤抑制因子PTEN或FBXW7的损失)用于预测具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对如本文所定义的2,3-二氢咪唑并[1,2-c]喹唑啉化合物的敏感性和/或耐受性、因此提供如本文定义的基于理论的剂量以克服耐受性(患者选择或分层)的用途。PI3K途径活化的其它形式包括但不限于任何以下单独或组合的扰动:PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的突变。PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变可以在蛋白水平、mRNA水平或DNA水平上测量。
根据一个实施方案,本发明涉及确定肿瘤抑制因子PTEN或FBXW7的损失的方法。
根据另一个实施方案,本发明涉及用于确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的扰动、PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变的方法。
Claims (21)
1.以下物质的组合产品:
组分A:一种或多种通式(A1)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物:
其中
X代表CR5R6或NH;
Y1代表CR3或N;
Y2 ------ Y3之间的化学键代表单键或双键,
条件是当Y2 ------ Y3代表双键时,Y2和Y3 独立地代表CR4或N,且
当Y2 ------ Y3代表单键时,Y2和Y3 独立地代表CR3R4或NR4;
Z1、Z2、Z3和Z4 独立地代表CH、CR2或N;
R1代表任选地具有1至3个选自R11的取代基的芳基,任选地具有1至3个选自R11的取代基的C3-8环烷基,
任选地被芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷基,
任选地被羧基、芳基、杂芳基、C1-6 烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷氧基,
或
3至15元单或双环杂环,其为饱和或不饱和的,且含有1至3个选自N、O和S的杂原子,且任选地具有1至3个选自R11的取代基,
其中
R11 代表卤素、硝基、羟基、氰基、羧基、氨基、N-(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、N-(甲酰基)-N-(C1-6烷基)氨基、N-(C1-6烷烃磺酰基)氨基、N-(羧基C1-6烷基)-N-(C1-6烷基)氨基、N-(C1-6烷氧基羰基)氨基、N-[N,N-二(C1-6烷基)氨基亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基(C1-6烷基)亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基C2-6烯基]氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、C3-8环烷基、C1-6烷硫基、C1-6烷烃磺酰基、氨磺酰、C1-6烷氧基羰基,
N-芳基氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,N-(芳基C1-6烷基)氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,芳基C1-6烷氧基羰基,其中所述芳基部分任选地具有1至3个选自R101的取代基,
任选地被单-、二-或三-卤素、氨基、N-(C1-6烷基)氨基或N,N-二(C1-6烷基)氨基取代的C1-6烷基,
任选地被单-、二-或三-卤素、N-(C1-6烷基)磺酰胺或N-(芳基)磺酰胺取代的C1-6烷氧基,
或
具有1至3个选自O、S和N的杂原子和任选地具有1至3个选自R101的取代基的5至7元饱和或不饱和环,
其中
R101 代表卤素、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、吡啶基,
任选地被氰基或单-、二-或三-卤素取代的C1-6 烷基,
或
任选地被氰基、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基或单-、二-或三-卤素取代的C1-6烷氧基;
R2代表羟基、卤素、硝基、氰基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N-(羟基C1-6烷基)-N-(C1-6烷基)氨基、C1-6 酰基氧基、氨基C1-6 酰基氧基、C2-6烯基、芳基,
具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:
羟基、C1-6烷基、C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、N-(C1-6烷基)羰基氨基、苯基、苯基C1-6 烷基、羧基、C1-6烷氧基羰基、氨基羰基、N-(C1-6烷基)氨基羰基或N,N-二(C1-6烷基)氨基、-C(O)- R20,
其中
R20代表C1-6烷基、C1-6烷氧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基或具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:
C1-6烷基、C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、苯基或苄基,
任选地被R21取代的C1-6 烷基,
或
任选地被R21取代的C1-6烷氧基,
其中
R21代表氰基、单-、二-或三-卤素、羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6 烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、氨基 C2-6 烷基烯基、C1-6烷氧基、羟基C1-6烷氧基、-C(O)- R201、-NHC(O)- R201、C3-8环烷基、异吲哚啉基、苯邻二甲酰亚胺基、2-氧代-1,3-噁唑烷基、芳基或具有1至4个选自O、S和N的杂原子且任选地被以下取代的5或6元饱和或不饱和杂环:
羟基、C1-6烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基,
其中
R201 代表羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、C1-6烷基、氨基C1-6 烷基、氨基C2-6 烷基烯基、C1-6 烷氧基、或具有1至4个选自O、S和N的杂原子且任选地被以下取代的5或6元饱和或不饱和杂环:
羟基、C1-6 烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基;
R3代表氢、卤素、氨基羰基或任选地被芳基C1-6烷氧基或单-、二-或三-卤素取代的C1-6烷基;
R4代表氢或C1-6 烷基;
R5代表氢或C1-6 烷基;且
R6代表卤素、氢或C1-6 烷基;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其任选地呈即用于同时、共同、分开或依次给药的药物制剂的形式;
和
组分B:一种或多种通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物:
其中
R1是氢、氯、甲基或甲氧基,
R2是氢或甲氧基,
条件是R1和R2中的至少一个不是氢,
G1代表氯、(C1-C4)-烷基、(C1-C4)-烷氧基羰基、5-元氮杂-杂芳基或基团-CH2-OR3、-CH2-NR4R5或-C(=O)-NR4R6,其中
R3是氢、(C1-C4)-烷基、(C3-C6)-环烷基或苯基,
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基、(C3-C6)-环烷基或最高达三个氟原子取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述苯基任选地被一个或两个独立地选自氟、氯、溴、氰基、三氟甲基、三氟甲氧基、(C1-C4)-烷基和(C1-C4)-烷氧基的取代基取代,
R4是氢或(C1-C4)-烷基,
R5是氢、(C1-C4)-烷基、(C1-C4)-烷基羰基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基或(C3-C6)-环烷基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
R6是氢、(C1-C4)-烷基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、(C1-C4)-烷氧基、羟基羰基、(C1-C4)-烷氧基羰基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基、二-(C1-C4)-烷基氨基羰基或(C3-C6)-环烷基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
或
R4和R5或R4和R6分别与它们所连接的氮原子连接在一起,形成单环、饱和的4-至7-元杂环烷基环,其可以含有选自N(R7)和O的第二环杂原子,并且其可以在环碳原子上被一个或两个独立地选自以下的取代基取代:(C1-C4)-烷基、氧代、羟基、氨基和氨基羰基,且其中
R7是氢、(C1-C4)-烷基、甲酰基或(C1-C4)-烷基羰基,
且
G2代表氯、氰基、(C1-C4)-烷基或基团-CR8AR8B-OH、-CH2-NR9R10、-C(=O)-NR11R12或-CH2-OR15,其中
R8A和R8B独立地选自氢、(C1-C4)-烷基、环丙基和环丁基,
R9是氢或(C1-C4)-烷基,
R10是氢、(C1-C4)-烷基、(C1-C4)-烷基羰基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基或二-(C1-C4)-烷基氨基羰基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
R11是氢或(C1-C4)-烷基,
R12是氢、(C1-C4)-烷基、(C3-C6)-环烷基或4-至6-元杂环烷基,其中
(i)所述(C1-C4)-烷基任选地被羟基、氨基、氨基羰基、单-(C1-C4)-烷基氨基羰基或二-(C1-C4)-烷基氨基羰基取代,
且
(ii)所述(C3-C6)-环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基和氨基的取代基取代,
且
(iii)所述4-至6-元杂环烷基任选地被一个或两个独立地选自(C1-C4)-烷基、羟基、氧代和氨基的取代基取代,
或
R9和R10或R11和R12分别与它们所连接的氮原子连接在一起,形成单环、饱和的4-至7-元杂环烷基环,其可以含有选自N(R13)、O、S和S(O)2的第二环杂原子,并且其可以在环碳原子上被最高达三个独立地选自以下的取代基取代:氟、(C1-C4)-烷基、氧代、羟基、氨基和氨基羰基,且其中
R13是氢、(C1-C4)-烷基、(C3-C6)-环烷基、甲酰基或(C1-C4)-烷基羰基,
且
R15是(C1-C4)-烷基,
条件是当G2是氯或氰基时,G1不是氯。
2.根据权利要求1所述的组合产品,其中:
所述组分A是一种或多种通式(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物:
其中:
X代表CR5R6或NH;
Y1代表CR3或N;
Y2 ------ Y3之间的化学键代表单键或双键,
条件是当Y2 ------ Y3代表双键时,Y2和Y3 独立地代表CR4或N,且
当Y2 ------ Y3代表单键时,Y2和Y3 独立地代表CR3R4或NR4;
Z1、Z2、Z3和Z4 独立地代表CH、CR2或N;
R1代表任选地具有1至3个选自R11的取代基的芳基,任选地具有1至3个选自R11的取代基的C3-8环烷基,
任选地被芳基、杂芳基、C1-6烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷基,
任选地被羧基、芳基、杂芳基、C1-6 烷氧基芳基、芳基氧基、杂芳基氧基或一个或多个卤素取代的C1-6烷氧基,
或
3至15元单或双环杂环,其为饱和或不饱和的,其任选地具有1至3个选自R11的取代基,且含有1至3个选自N、O和S的杂原子,
其中
R11 代表卤素、硝基、羟基、氰基、羧基、氨基、N-(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基、N-(甲酰基)-N-(C1-6烷基)氨基、N-(C1-6烷烃磺酰基)氨基、N-(羧基C1-6烷基)-N-(C1-6烷基)氨基、N-(C1-6烷氧基羰基)氨基、N-[N,N-二(C1-6烷基)氨基亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基(C1-6烷基)亚甲基]氨基、N-[N,N-二(C1-6烷基)氨基C2-6烯基]氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、C3-8环烷基、C1-6烷硫基、C1-6烷烃磺酰基、氨磺酰、C1-6烷氧基羰基,
N-芳基氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,N-(芳基C1-6烷基)氨基,其中所述芳基部分任选地具有1至3个选自R101的取代基,芳基C1-6烷氧基羰基,其中所述芳基部分任选地具有1至3个选自R101的取代基,
任选地被单-、二-或三-卤素、氨基、N-(C1-6烷基)氨基或N,N-二(C1-6烷基)氨基取代的C1-6烷基,
任选地被单-、二-或三-卤素、N-(C1-6烷基)磺酰胺或N-(芳基)磺酰胺取代的C1-6烷氧基,
或
具有1至3个选自O、S和N的杂原子和任选地具有1至3个选自R101的取代基的5至7元饱和或不饱和环,
其中
R101 代表卤素、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基、吡啶基,
任选地被氰基或单-、二-或三-卤素取代的C1-6 烷基,
和
任选地被氰基、羧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、氨基羰基、N-(C1-6烷基)氨基羰基、N,N-二(C1-6烷基)氨基羰基或单-、二-或三-卤素取代的C1-6烷氧基;
R2代表羟基、卤素、硝基、氰基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6烷基)氨基、N-(羟基C1-6烷基)-N-(C1-6烷基)氨基、C1-6 酰基氧基、氨基C1-6 酰基氧基、C2-6烯基、芳基,
具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:
羟基、C1-6烷基、C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、N-(C1-6烷基)羰基氨基、苯基、苯基C1-6 烷基、羧基、C1-6烷氧基羰基、氨基羰基、N-(C1-6烷基)氨基羰基或N,N-二(C1-6烷基)氨基、-C(O)- R20,
其中
R20代表C1-6烷基、C1-6烷氧基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6酰基)氨基或具有1至3个选自O、S和N的杂原子和任选地被以下取代的5-7元饱和或不饱和杂环:C1-6烷基、C1-6烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基、苯基或苄基,
任选地被R21取代的C1-6 烷基,
或
任选地被R21取代的C1-6烷氧基,
其中
R21代表氰基、单-、二-或三-卤素、羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(羟基C1-6 烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、氨基 C2-6 烷基烯基、C1-6烷氧基、羟基C1-6烷氧基、-C(O)- R201、-NHC(O)- R201、C3-8环烷基、异吲哚啉基、苯邻二甲酰亚胺基、2-氧代-1,3-噁唑烷基、芳基或具有1至4个选自O、S和N的杂原子且任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、氨基C1-6烷基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基,
其中
R201 代表羟基、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(卤代苯基C1-6 烷基)氨基、C1-6烷基、氨基C1-6 烷基、氨基C2-6 烷基烯基、C1-6 烷氧基、或具有1至4个选自O、S和N的杂原子且任选地被以下取代的5或6元饱和或不饱和杂环:羟基、C1-6 烷基、C1-6 烷氧基、C1-6 烷氧基羰基、羟基C1-6 烷氧基、氧代、氨基、N-(C1-6烷基)氨基、N,N-二(C1-6烷基)氨基、N-(C1-6 酰基)氨基或苄基;
R3代表氢、卤素、氨基羰基或任选地被芳基C1-6烷氧基或单-、二-或三-卤素取代的C1-6烷基;
R4代表氢或C1-6 烷基;
R5代表氢或C1-6 烷基;且
R6代表卤素、氢或C1-6 烷基;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其任选地呈即用于同时、共同、分开或依次给药的药物制剂的形式。
3.根据权利要求1所述的组合产品,其中:
所述组分A是一种或多种根据权利要求1所述的通式(A1)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物,其选自在2004年4月8日作为WO 04/029055 A1公开的国际专利申请PCT/EP2003/010377中第47至106页的具体化合物实施例1-1至1-210、第107至204页的具体化合物实施例2-1至2-368、第205至207页的具体化合物实施例3-1至3-2以及第208至210页的具体化合物实施例4-1至4-2;
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其任选地呈即用于同时、共同、分开或依次给药的药物制剂的形式。
4.根据权利要求2所述的组合产品,其中:
所述组分A是一种或多种根据权利要求2所述的通式(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物,其选自:
实施例1:N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺
实施例2:N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例3:N-(8-{3-[(2R,6S)-2,6-二甲基吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)-2,4-二甲基-1,3-噻唑-5-甲酰胺
实施例4:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-1,3-噻唑-5-甲酰胺
实施例5:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]异烟酰胺
实施例6:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-甲基-1,3-噻唑-5-甲酰胺
实施例7:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-4-丙基嘧啶-5-甲酰胺
实施例8:N-{8-[2-(4-乙基吗啉-2-基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺
实施例9:N-{8-[2-(二甲基氨基)乙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}嘧啶-5-甲酰胺
实施例10:N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例11:N-(8-{3-[2-(羟基甲基)吗啉-4-基]丙氧基}-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基)烟酰胺
实施例12:N-{8-[3-(二甲基氨基)丙氧基]-7-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基}烟酰胺 1-氧化物
实施例13:2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺
实施例14:N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]-6-(2-吡咯烷-1-基乙基)烟酰胺.
实施例15:6-(环戊基氨基)-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]烟酰胺
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其任选地呈即用于同时、共同、分开或依次给药的药物制剂的形式.
5.根据权利要求1至3中任一项所述的组分产品,其中:
所述组分B是一种或多种根据权利要求1所述的通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物,其选自:
实施例1
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例2
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮二盐酸盐
实施例3
(3R)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮二盐酸盐
实施例4
(3R)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例5
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例6
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮二盐酸盐
实施例7
(3R)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮二盐酸盐
实施例8
(3R)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例9
N2-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}甘氨酰胺二盐酸盐
实施例10
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例11
1-(4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮二盐酸盐
实施例12
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇双(甲酸盐)
实施例13
4-{[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例14
7-{[(3S)-3-氨基-3-甲基吡咯烷-1-基]甲基}-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例15
7-{[(3S)-3-氨基-3-甲基吡咯烷-1-基]甲基}-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例16
1-(4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮二盐酸盐
实施例17
6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例18
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例19
6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺二盐酸盐
实施例20
1-(4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例21
4-({4-氨基-6-[(2-羟基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基}甲基)哌嗪-2-酮甲酸盐
实施例22
2-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙醇二盐酸盐
实施例23
6-(丁氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例24
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-(丙氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例25
6-[(环丙基甲氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例26
6-[(环丁基氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例27
6-(异丙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例28
6-[(2-甲氧基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例29
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-[(2,2,2-三氟乙氧基)甲基]吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例30
6-[(2-氨基乙氧基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例31
{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酸甲酯
实施例32
{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酸
实施例33
2-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲氧基}乙酰胺
实施例34
2-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲氧基)乙酰胺
实施例35
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-(苯氧基甲基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺双(甲酸盐)
实施例36
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(甲基氨基)甲基]-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例37
6-[(二甲基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例38
6-[(乙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例39
2-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)乙醇三盐酸盐
实施例40
外消旋-1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌啶-3-醇三盐酸盐
实施例41
1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌啶-4-醇三盐酸盐
实施例42
外消旋-1-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}吡咯烷-3-醇三盐酸盐
实施例43
6-[(二乙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例44
6-[(环丁基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例45
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)-6-(吡咯烷-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例46
6-[(环丙基氨基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例47
6-{[(环丙基甲基)氨基]甲基}-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例48
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}甘氨酸三盐酸盐
实施例49
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮三盐酸盐
实施例50
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例51
(3S)-3-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)吡咯烷-2-酮
实施例52
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例53
外消旋-1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)丙-2-醇
实施例54
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(吗啉-4-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例55
1-(4-{[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例56
(3R)-3-[({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)氨基]吡咯烷-2-酮
实施例57
1-(4-{[4-氨基-6-{[(2-羟基-2-甲基丙基)氨基]甲基}-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-1-基)乙酮
实施例58
4-({4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-7-基}甲基)哌嗪-1-甲醛甲酸盐
实施例59
4-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)哌嗪-2-酮
实施例60
4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基羰基)吡咯并[2,1-f][1,2,4]三嗪-6-甲酸甲酯双(甲酸盐)
实施例61
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-(1,3-噁唑-5-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例62
6-(氨基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例63
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}乙酰胺双(三氟乙酸盐)
实施例64
N-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}乙酰胺二盐酸盐
实施例65
N-({4-氨基-7-[(4-甲酰基哌嗪-1-基)甲基]-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺甲酸盐
实施例66
N-({7-[(4-乙酰基哌嗪-1-基)甲基]-4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺
实施例67
N-({4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-6-基}甲基)乙酰胺
实施例68
4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例69
4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例70
4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例71
4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-[(3-氧代哌嗪-1-基)甲基]吡咯并[2,1-f][1,2,4]三嗪-7-甲腈
实施例72
N,N'-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6,7-二基]双(亚甲基)}二乙酰胺
实施例73
2-[4-氨基-6-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]丙-2-醇
实施例74
4-{[4-氨基-7-(2-羟基丙-2-基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例75
[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例76
4-{[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例77
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇甲酸盐
实施例78
1-({[4-氨基-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例79
[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲醇
实施例80
4-{[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例81
1-({[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇甲酸盐
实施例82
1-({[4-氨基-7-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}氨基)-2-甲基丙-2-醇
实施例83
7-氯-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺
实施例84
5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-6-甲基-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺甲酸盐
实施例85
6-氯-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-7-(哌嗪-1-基甲基)吡咯并[2,1-f][1,2,4]三嗪-4-胺三盐酸盐
实施例86
[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲醇
实施例87
1-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}咪唑烷-2-酮
实施例88
4-{[4-氨基-5-(7-甲氧基-1-苯并噻吩-2-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例89
4-{[4-氨基-6-(甲氧基甲基)-5-(5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例90
1-[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]乙醇
实施例91
[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基](环丙基)甲醇
实施例92
(3S)-3-({[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例93
(3S)-3-({[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}氨基)吡咯烷-2-酮
实施例106
4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)-N-[(3R)-2-氧代吡咯烷-3-基]吡咯并[2,1-f][1,2,4]三嗪-7-甲酰胺
实施例107
4-{[4-氨基-6-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]羰基}哌嗪-2-酮
实施例124
4-{[4-氨基-5-(5,7-二甲氧基-1-苯并噻吩-2-基)-6-(甲氧基甲基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮
实施例125
4-{[4-氨基-7-(羟基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例126
4-{[4-氨基-7-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
实施例127
4-{[4-氨基-7-(乙氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-6-基]甲基}哌嗪-2-酮
或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其任选地呈即用于同时、共同、分开或依次给药的药物制剂的形式。
6.根据权利要求1至4中任一项所述的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺。
7.根据权利要求1至4中任一项所述的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐。
8.根据权利要求1至6中任一项所述的组合产品,其中所述组分B是
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
9.根据权利要求1至7中任一项所述的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺且所述组分B是
4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
10.根据权利要求1至7中任一项所述的组合产品,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐且所述组分B是4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
11.根据权利要求1至9中任一项所述的组合产品用于制备用于治疗或预防癌症、特别是子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的药物的用途。
12.根据权利要求10所述的用途,其中所述癌症是子宫内膜癌(下文缩写为“EC”)。
13.根据权利要求10或11所述的用途,其中所述癌症是第1线、第2线、复发性、难治性、I型EC。
14.根据权利要求10或11所述的用途,其中所述癌症是第1线、第2线、复发性、难治性、II型EC或子宫内膜异位症。
15.治疗或预防受试者中的癌症、特别是子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的方法,其包括向所述受试者给药治疗有效量的根据权利要求1至9中任一项所述的组合产品。
16.试剂盒,其包含以下物质的组合产品:
组分A:一种或多种根据权利要求1至9中任一项所述的通式(A1)或(A2)的2,3-二氢咪唑并[1,2-c]喹唑啉化合物,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
组分B:一种或多种根据权利要求1至9中任一项所述的通式(B)的取代的5-(1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]-三嗪-4-胺化合物,或其生理学上可接受的盐、溶剂化物、水合物或立体异构体;
其中任选地所述组分A)和B)中的任一种或两种呈即用于同时、共同、分开或依次施用的药物制剂的形式。
17.根据权利要求15所述的试剂盒,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺且所述组分B是4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
18.根据权利要求15所述的试剂盒,其中所述组分A是2-氨基-N-[7-甲氧基-8-(3-吗啉-4-基丙氧基)-2,3-二氢咪唑并[1,2-c]喹唑啉-5-基]嘧啶-5-甲酰胺二盐酸盐且所述组分B是4-{[4-氨基-6-(甲氧基甲基)-5-(7-甲氧基-5-甲基-1-苯并噻吩-2-基)吡咯并[2,1-f][1,2,4]三嗪-7-基]甲基}哌嗪-2-酮。
19.单独或与另一种形式的PI3K途径活化组合的生物标志物诸如肿瘤抑制因子PTEN或FBXW7的损失用于预测具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对权利要求1至9中任一项的组分A和组分B的组合产品的敏感性和/或耐受性、因此提供如本文所定义的基于理论的剂量以克服所述具有子宫内膜癌(下文缩写为“EC”)、特别是第1线、第2线、复发性、难治性、I型或II型EC或子宫内膜异位症的患者对权利要求1至9中任一项的组分A和组分B的组合产品的耐受性(患者选择或分层)的用途,所述另一种形式的PI3K途径活化选自任何以下单独或组合的扰动:PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的突变;PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变,其可以在蛋白水平、mRNA水平或DNA水平上测量。
20.确定肿瘤抑制因子PTEN或FBXW7的损失的方法。
21.用于确定PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4中的扰动、PTEN损失和PIK3CA、PIK3CB、PIK3CD、PIK3CG、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5、FGFR1、FGFR2、FGFR3和/或FGFR4的改变的方法。
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MX2017011635A (es) | 2018-02-09 |
JP6867295B2 (ja) | 2021-04-28 |
SG11201707240SA (en) | 2017-10-30 |
IL254167A0 (en) | 2017-10-31 |
WO2016142312A1 (en) | 2016-09-15 |
KR20180013851A (ko) | 2018-02-07 |
CA2978830A1 (en) | 2016-09-15 |
BR112017019188A2 (pt) | 2018-04-24 |
PH12017501643A1 (en) | 2018-03-12 |
CN107864625B (zh) | 2021-05-28 |
EP3268490B1 (en) | 2020-07-08 |
SV2017005530A (es) | 2018-10-02 |
EP3268490A1 (en) | 2018-01-17 |
EA201791974A1 (ru) | 2018-05-31 |
US20180055851A1 (en) | 2018-03-01 |
US10406162B2 (en) | 2019-09-10 |
AU2016231259A1 (en) | 2017-09-21 |
JP2018510869A (ja) | 2018-04-19 |
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