HRP20220255T1 - Derivati 6,7,8,9-tetrahidro-3h-pirazolo[4,3-f]izokinolina koji su korisni u liječenju raka - Google Patents
Derivati 6,7,8,9-tetrahidro-3h-pirazolo[4,3-f]izokinolina koji su korisni u liječenju raka Download PDFInfo
- Publication number
- HRP20220255T1 HRP20220255T1 HRP20220255TT HRP20220255T HRP20220255T1 HR P20220255 T1 HRP20220255 T1 HR P20220255T1 HR P20220255T T HRP20220255T T HR P20220255TT HR P20220255 T HRP20220255 T HR P20220255T HR P20220255 T1 HRP20220255 T1 HR P20220255T1
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- pyrazolo
- tetrahydro
- fluoropropyl
- azetidin
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims 7
- 201000011510 cancer Diseases 0.000 title claims 7
- RMHAAZORBZSYHX-UHFFFAOYSA-N 6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline Chemical class C1=NNC=2C1=C1CCNCC1=CC=2 RMHAAZORBZSYHX-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 14
- 150000003839 salts Chemical class 0.000 claims 12
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 claims 2
- HZEJTMIZKGGUNU-TYYICDPESA-N (2S)-3-[(6S,8R)-6-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-7-yl]-2-fluoro-2-methylpropan-1-ol Chemical compound C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@H](N1C[C@](C)(F)CO)c1c(F)cc(NC2CN(CCCF)C2)cc1F HZEJTMIZKGGUNU-TYYICDPESA-N 0.000 claims 1
- UEPQDBDTOSJGSX-DXPJPUQTSA-N (6S,8R)-7-(2,2-difluoroethyl)-6-[4-[1-(3-fluoropropyl)azetidin-3-yl]oxy-2-methoxyphenyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinoline Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=C(C=C(C=C1)OC1CN(C1)CCCF)OC)F UEPQDBDTOSJGSX-DXPJPUQTSA-N 0.000 claims 1
- MULJMOFCKZZSRK-MYYSRTQBSA-N (6S,8R)-7-(2,2-difluoroethyl)-6-[5-[1-(3-fluoropropyl)azetidin-3-yl]oxypyridin-2-yl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinoline Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=NC=C(C=C1)OC1CN(C1)CCCF)F MULJMOFCKZZSRK-MYYSRTQBSA-N 0.000 claims 1
- ZGUXYASZYGTIJK-LKQXKPBUSA-N (6S,8R)-7-[(1-fluorocyclopropyl)methyl]-6-[4-[1-(3-fluoropropyl)azetidin-3-yl]oxy-2-methoxyphenyl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinoline Chemical compound COc1cc(OC2CN(CCCF)C2)ccc1[C@@H]1C2CCC3NNCC3C2C[C@@H](C)N1CC1(F)CC1 ZGUXYASZYGTIJK-LKQXKPBUSA-N 0.000 claims 1
- QRMYMYMDWPWRLR-NFXMZALSSA-N (6S,8R)-7-[(2R)-2-fluoro-3-methoxy-2-methylpropyl]-6-[4-[1-(3-fluoropropyl)azetidin-3-yl]oxy-2-methoxyphenyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinoline Chemical compound COC[C@](C)(F)CN1[C@H](C)CC2=C3C=NNC3=CC=C2[C@H]1C1=CC=C(OC2CN(CCCF)C2)C=C1OC QRMYMYMDWPWRLR-NFXMZALSSA-N 0.000 claims 1
- JUMJODAYGHYIAH-CPJLOUKISA-N 1-(3-fluoropropyl)-N-[3-methoxy-4-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]azetidin-3-amine Chemical compound FCCCN1CC(C1)NC1=CC(=C(C=C1)[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC(F)(F)F)OC JUMJODAYGHYIAH-CPJLOUKISA-N 0.000 claims 1
- RDIWNJDCZLGDOS-VOIUYBSRSA-N 1-(3-fluoropropyl)-N-[4-[(6R,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]azetidin-3-amine Chemical compound FCCCN1CC(C1)NC1=CC=C(C=C1)[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC(F)(F)F RDIWNJDCZLGDOS-VOIUYBSRSA-N 0.000 claims 1
- MDPDWODDUWCPLL-GFWZQFBZSA-N 2,2-difluoro-3-[(6S,8R)-6-[3-fluoro-5-[1-(3-fluoropropyl)azetidin-3-yl]oxypyridin-2-yl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-7-yl]propan-1-ol Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)CO)c1ncc(OC2CN(CCCF)C2)cc1F MDPDWODDUWCPLL-GFWZQFBZSA-N 0.000 claims 1
- JOMLMASVVZANDG-GFWZQFBZSA-N 2,2-difluoro-3-[(6S,8R)-6-[3-fluoro-5-[[1-(3-fluoropropyl)azetidin-3-yl]amino]pyridin-2-yl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-7-yl]propan-1-ol Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)CO)c1ncc(NC2CN(CCCF)C2)cc1F JOMLMASVVZANDG-GFWZQFBZSA-N 0.000 claims 1
- ABIUMPAAHDKRAH-XJJSMDPLSA-N 2,2-difluoro-3-[(6S,8R)-6-[5-[1-(3-fluoropropyl)azetidin-3-yl]oxypyridin-2-yl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-7-yl]propan-1-ol Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)CO)c1ccc(OC2CN(CCCF)C2)cn1 ABIUMPAAHDKRAH-XJJSMDPLSA-N 0.000 claims 1
- MKAPFCBLWCECBI-GYCJOSAFSA-N 2,2-difluoro-3-[(6S,8R)-6-[5-[[1-(3-fluoropropyl)azetidin-3-yl]amino]pyridin-2-yl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-7-yl]propan-1-ol Chemical compound FC(CO)(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=NC=C(C=C1)NC1CN(C1)CCCF)F MKAPFCBLWCECBI-GYCJOSAFSA-N 0.000 claims 1
- AAGZIXXYNUTCQC-PLNGFPJTSA-N 3-[(6S,8R)-6-[2,6-difluoro-4-[[1-(3-fluoropropyl)azetidin-3-yl]amino]phenyl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-7-yl]-2,2-difluoropropan-1-ol Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)CO)c1c(F)cc(NC2CN(CCCF)C2)cc1F AAGZIXXYNUTCQC-PLNGFPJTSA-N 0.000 claims 1
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 claims 1
- ZMANQSXBZZYBCV-ASSNKEHSSA-N 5-[(6S,8R)-1-fluoro-8-methyl-7-(2,2,2-trifluoroethyl)-2,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyrazin-2-amine Chemical compound FC1=NNC=2C1=C1C[C@H](N([C@@H](C1=CC=2)C=1N=CC(=NC=1)NC1CN(C1)CCCF)CC(F)(F)F)C ZMANQSXBZZYBCV-ASSNKEHSSA-N 0.000 claims 1
- VMYIWPNMBCKTFR-QUGAMOGWSA-N 5-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]-4-methoxypyridin-2-amine Chemical compound FC1(CC1)CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C=1C(=CC(=NC=1)NC1CN(C1)CCCF)OC VMYIWPNMBCKTFR-QUGAMOGWSA-N 0.000 claims 1
- CZXRKQNLGWTZPP-CPJLOUKISA-N 5-fluoro-6-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine Chemical compound FC=1C=C(C=NC=1[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC1(CC1)F)NC1CN(C1)CCCF CZXRKQNLGWTZPP-CPJLOUKISA-N 0.000 claims 1
- UIBIHIYPROZZQP-KLKUMWAYSA-N 5-fluoro-N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)F)c1ncc(NC2CN(CCCF)C2)cc1F UIBIHIYPROZZQP-KLKUMWAYSA-N 0.000 claims 1
- BFXKWHZHXIVGOE-NSYGIPOTSA-N 6-[(6S,8R)-7-(2,2-difluoro-3-methoxypropyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=CC=C(C=N1)NC1CN(C1)CCCF)(COC)F BFXKWHZHXIVGOE-NSYGIPOTSA-N 0.000 claims 1
- HFVTZOGVWNKQPA-IDGYJWEWSA-N 6-[(6S,8R)-7-(2,2-difluoroethyl)-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-6-yl]-5-fluoro-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)F)c1ncc(NC2CN(CCCF)C2)cc1F HFVTZOGVWNKQPA-IDGYJWEWSA-N 0.000 claims 1
- LCCYGLSQPCXNFG-MYYSRTQBSA-N 6-[(6S,8R)-7-(2,2-difluoroethyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=CC=C(C=N1)NC1CN(C1)CCCF)F LCCYGLSQPCXNFG-MYYSRTQBSA-N 0.000 claims 1
- BZBLOXMQJGZOMI-VVQHYOOQSA-N 6-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-6-yl]-N-[1-(3-fluoropropyl)azetidin-3-yl]pyridin-3-amine Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC1(F)CC1)c1ccc(NC2CN(CCCF)C2)cn1 BZBLOXMQJGZOMI-VVQHYOOQSA-N 0.000 claims 1
- UBVSHUDCODGPFI-QCPISGCTSA-N C[C@@H]1CC2C(CCC3C2CNN3)[C@H](N1CC(CO)(F)F)C4=C(C=C(C=C4)OC5CN(C5)CCCF)OC Chemical compound C[C@@H]1CC2C(CCC3C2CNN3)[C@H](N1CC(CO)(F)F)C4=C(C=C(C=C4)OC5CN(C5)CCCF)OC UBVSHUDCODGPFI-QCPISGCTSA-N 0.000 claims 1
- QDHOYARHGFHPMY-RUOVOVAZSA-N N-[1-(3-fluoropropyl)azetidin-3-yl]-5-methoxy-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine Chemical compound COc1cc(NC2CN(CCCF)C2)cnc1[C@@H]1C2CCC3NNCC3C2C[C@@H](C)N1CC(F)(F)F QDHOYARHGFHPMY-RUOVOVAZSA-N 0.000 claims 1
- CSFQQUFMSRHZQI-CXQTVSNQSA-N N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-1,2,3,3a,4,5,5a,6,8,9,9a,9b-dodecahydropyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine Chemical compound C[C@@H]1CC2C3CNNC3CCC2[C@H](N1CC(F)(F)F)c1ccc(NC2CN(CCCF)C2)cn1 CSFQQUFMSRHZQI-CXQTVSNQSA-N 0.000 claims 1
- ITLZCAFYUUBRFV-DXPJPUQTSA-N N-[3,5-difluoro-4-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]-1-(3-fluoropropyl)azetidin-3-amine Chemical compound FC=1C=C(C=C(C=1[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC1(CC1)F)F)NC1CN(C1)CCCF ITLZCAFYUUBRFV-DXPJPUQTSA-N 0.000 claims 1
- MTFGAWDMZPCQKM-GDJIYFAZSA-N N-[3-ethoxy-4-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]-1-(3-fluoropropyl)azetidin-3-amine Chemical compound C(C)OC=1C=C(C=CC=1[C@H]1N([C@@H](CC2=C3C(=CC=C12)NN=C3)C)CC1(CC1)F)NC1CN(C1)CCCF MTFGAWDMZPCQKM-GDJIYFAZSA-N 0.000 claims 1
- FDUQYLYBWZAWAD-CLYVBNDRSA-N N-[4-[(6S,8R)-7-(2,2-difluoro-3-methoxypropyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-3-methoxyphenyl]-1-(3-fluoropropyl)azetidin-3-amine Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=C(C=C(C=C1)NC1CN(C1)CCCF)OC)(COC)F FDUQYLYBWZAWAD-CLYVBNDRSA-N 0.000 claims 1
- IVBCTFVBWGUGKC-DXPJPUQTSA-N N-[4-[(6S,8R)-7-(2,2-difluoroethyl)-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-3-methoxyphenyl]-1-(3-fluoropropyl)azetidin-3-amine Chemical compound FC(CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=C(C=C(C=C1)NC1CN(C1)CCCF)OC)F IVBCTFVBWGUGKC-DXPJPUQTSA-N 0.000 claims 1
- YZMMWVWLDOCLCK-CLYVBNDRSA-N N-[4-[(6S,8R)-7-[(1-fluorocyclopropyl)methyl]-8-methyl-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-3-methoxyphenyl]-1-(3-fluoropropyl)azetidin-3-amine Chemical compound FC1(CC1)CN1[C@@H](C2=CC=C3C(=C2C[C@H]1C)C=NN3)C1=C(C=C(C=C1)NC1CN(C1)CCCF)OC YZMMWVWLDOCLCK-CLYVBNDRSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical group N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 claims 1
- 229960004390 palbociclib Drugs 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662411799P | 2016-10-24 | 2016-10-24 | |
| US201662435159P | 2016-12-16 | 2016-12-16 | |
| EP19189010.2A EP3640251B1 (en) | 2016-10-24 | 2017-10-13 | 6,7,8,9-tetrahydro-3h-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20220255T1 true HRP20220255T1 (hr) | 2022-04-29 |
Family
ID=60083331
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20220255TT HRP20220255T1 (hr) | 2016-10-24 | 2017-10-13 | Derivati 6,7,8,9-tetrahidro-3h-pirazolo[4,3-f]izokinolina koji su korisni u liječenju raka |
Country Status (37)
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3355884B1 (en) | 2015-10-01 | 2021-04-28 | Olema Pharmaceuticals, Inc. | TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS |
| JP7241542B2 (ja) * | 2016-04-08 | 2023-03-17 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | テトラヒドロイソキノリン エストロゲン受容体モジュレーター及びその使用 |
| WO2017182493A1 (en) | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Indazole derivatives for use in down-regulation of the estrogen receptor for the treatment of cancer |
| US10149839B2 (en) | 2016-07-25 | 2018-12-11 | Astrazeneca Ab | Chemical compounds |
| AU2017349797B2 (en) * | 2016-10-24 | 2020-05-21 | Astrazeneca Ab | 6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer |
| TWI831738B (zh) | 2016-12-16 | 2024-02-11 | 美商瑞塔醫藥有限責任公司 | 用於抑制ＲＯＲγ及其他用途的嘧啶三環烯酮衍生物 |
| DK3555097T3 (da) | 2016-12-16 | 2022-07-25 | Janssen Pharmaceutica Nv | Imidazo[4,5-d]pyrrolo[2,3-b]pyridinforbindelser som inhibitorer af janus-kinaser |
| JOP20190144A1 (ar) | 2016-12-16 | 2019-06-16 | Janssen Pharmaceutica Nv | إيميدازو بيرولو بيريدين كمثبطات لعائلة jak الخاصة بإنزيمات الكيناز |
| UA125043C2 (uk) | 2017-01-30 | 2021-12-29 | Астразенека Аб | Модулятори рецептора естрогену |
| WO2019002441A1 (en) * | 2017-06-29 | 2019-01-03 | Astrazeneca Ab | CHEMICAL COMPOUNDS |
| WO2019002442A1 (en) * | 2017-06-29 | 2019-01-03 | Astrazeneca Ab | CHEMICAL COMPOUNDS |
| EP3696178B1 (en) * | 2017-11-14 | 2022-04-06 | Kind Pharmaceutical | Heterocyclic compound and application thereof in medicine |
| TW202016110A (zh) | 2018-06-15 | 2020-05-01 | 比利時商健生藥品公司 | Ｊａｋ激酶家族之小分子抑制劑 |
| US11993574B2 (en) | 2018-06-15 | 2024-05-28 | Reata Pharmaceuticals, Inc | Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma |
| WO2019246461A1 (en) | 2018-06-20 | 2019-12-26 | Reata Pharmaceuticals, Inc. | Cysteine-dependent inverse agonists of nuclear receptors ror-gamma/ror-gamma-t and methods of treating diseases or disorders therewith |
| CN113490850B (zh) | 2018-08-17 | 2024-12-06 | 基因泰克公司 | 用于治疗乳腺癌的诊断和治疗方法 |
| CN109053524A (zh) * | 2018-09-11 | 2018-12-21 | 山东谛爱生物技术有限公司 | 一种N-Boc-3-羟基氮杂环丁烷的制备方法 |
| WO2021007146A1 (en) | 2019-07-07 | 2021-01-14 | Olema Pharmaceuticals, Inc. | Regimens of estrogen receptor antagonists |
| AU2020407514A1 (en) * | 2019-12-20 | 2022-07-14 | Recurium Ip Holdings, Llc | Combinations |
| US12428428B2 (en) | 2020-01-10 | 2025-09-30 | Jiangsu Hengrui Medicine Co., Ltd. | Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine |
| MX2022013258A (es) | 2020-04-24 | 2022-11-14 | Astrazeneca Ab | Formulaciones farmaceuticas. |
| WO2021214253A1 (en) * | 2020-04-24 | 2021-10-28 | Astrazeneca Ab | Dosage regimen for the treatment of cancer |
| EP4151636A4 (en) * | 2020-05-15 | 2024-02-28 | Simcere Pharmaceutical Co. Ltd. | PYRROLIDINE COMPOUND AND ITS USE |
| TW202214626A (zh) * | 2020-06-12 | 2022-04-16 | 大陸商江蘇先聲藥業有限公司 | 雌激素受體調節劑化合物及其用途 |
| EP4174059A4 (en) | 2020-06-28 | 2024-07-03 | Medshine Discovery Inc. | INDAZOLE FUSED CYCLIC COMPOUND |
| CN114105977B (zh) * | 2020-08-28 | 2023-09-01 | 先声再明医药有限公司 | 雌激素受体调节剂化合物及其用途 |
| KR20220107752A (ko) | 2021-01-26 | 2022-08-02 | 충북대학교 산학협력단 | 피라졸로퀴놀린 유도체 및 이의 항암제로서의 용도 |
| WO2022166980A1 (zh) * | 2021-02-08 | 2022-08-11 | 贝达药业股份有限公司 | 杂芳基并哌啶类衍生物及其药物组合物和应用 |
| MX2023010642A (es) | 2021-03-11 | 2023-11-28 | Janssen Pharmaceutica Nv | Lorpucitinib para uso en el tratamiento de trastornos mediados por jak. |
| WO2023125700A1 (zh) * | 2021-12-28 | 2023-07-06 | 南京明德新药研发有限公司 | 四氢环庚吲唑化合物的盐型、晶型 |
| EP4604957A1 (en) | 2022-10-17 | 2025-08-27 | Astrazeneca AB | Combinations of a serd for the treatment of cancer |
| EP4615431A1 (en) | 2022-11-11 | 2025-09-17 | Astrazeneca AB | Combination therapies for the treatment of cancer |
| US20240180893A1 (en) | 2022-11-17 | 2024-06-06 | Astrazeneca Ab | Methods of treatment of breast cancer |
| WO2024231548A1 (en) | 2023-05-11 | 2024-11-14 | Astrazeneca Ab | Combination of a parp1 inhibitor and a selective estrogen degrader for treating cancer |
| WO2025175249A1 (en) * | 2024-02-14 | 2025-08-21 | Olema Pharmaceuticals, Inc. | Estrogen receptor modulators and uses thereof |
Family Cites Families (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
| US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
| EE05405B1 (et) | 2000-08-10 | 2011-04-15 | Pharmacia Italia S.P.A. | Kinaasi inhibiitoritena toimivad bitskloprasoolid, nende valmistamismeetod, kasutamine ja neid sisaldavad farmatseutilised kompositsioonid |
| EP1863810A4 (en) | 2005-03-22 | 2010-03-31 | Astrazeneca Ab | NEW TETRAHYDRO-1H-PYRIDO [4,3-B] INDOLDERIVATE AS CB1 'RECEPTOR LIGANDS |
| FR2884252B1 (fr) | 2005-04-08 | 2007-05-18 | Aventis Pharma Sa | Nouveaux derives d'isoindoles, compositions les contenant, leur preparation et leurs utilisations pharmaceutiques notamment en tant qu'inhibiteurs d'activites de la proteine chaperone hsp90 |
| AR058223A1 (es) | 2005-11-25 | 2008-01-23 | Palau Pharma Sa | Un comuesto de derivados de pirazoloisoquinolina, un procedimiento para l a preparacion de dicho compuesto y una composicion farmaceutica que comprende dicho compuesto |
| JP2010505961A (ja) | 2006-10-09 | 2010-02-25 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
| EP2434891B9 (en) | 2009-05-27 | 2021-05-05 | PTC Therapeutics, Inc. | Methods for treating cancer and non-neoplastic conditions |
| WO2010138659A1 (en) | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Methods for treating brain tumors |
| WO2010138695A1 (en) | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Methods for treating neurofibromatosis |
| DK2580210T5 (en) | 2010-06-10 | 2017-06-19 | Seragon Pharmaceuticals Inc | ESTROGEN RECEPTOR MODULATORS AND APPLICATIONS THEREOF |
| WO2011159769A2 (en) | 2010-06-17 | 2011-12-22 | Aragon Pharmaceuticals, Inc. | Indane estrogen receptor modulators and uses thereof |
| ES2586908T3 (es) * | 2010-12-24 | 2016-10-19 | Merck Sharp & Dohme B.V. | Derivados de azetidina N-sustituidos |
| EP2791133B1 (en) | 2011-12-14 | 2019-04-17 | Seragon Pharmaceuticals, Inc. | Fluorinated estrogen receptor modulators and uses thereof |
| PE20160874A1 (es) | 2013-05-28 | 2016-09-04 | Astrazeneca Ab | Compuestos quimicos |
| EA031077B1 (ru) | 2013-06-19 | 2018-11-30 | Серагон Фармасьютикалз, Инк. | Модулятор рецептора эстрогена и его применения |
| CA2915534A1 (en) | 2013-06-19 | 2014-12-24 | Seragon Pharmaceuticals, Inc. | Azetidine estrogen receptor modulators and uses thereof |
| WO2015092634A1 (en) | 2013-12-16 | 2015-06-25 | Novartis Ag | 1,2,3,4-tetrahydroisoquinoline compounds and compositions as selective estrogen receptor antagonists and degraders |
| JP6807841B2 (ja) | 2014-12-18 | 2021-01-06 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | エストロゲン受容体モジュレーター及びその使用 |
| US20160175284A1 (en) | 2014-12-18 | 2016-06-23 | Genentech, Inc. | Estrogen receptor modulators and uses thereof |
| PE20171330A1 (es) | 2014-12-18 | 2017-09-13 | Hoffmann La Roche | Tetrahidro-pirido[3,4-b]indoles moduladores de receptores de estrogenos y usos de los mismos |
| WO2016174551A1 (en) | 2015-04-27 | 2016-11-03 | Pfizer Inc. | Anti-estrogenic compounds |
| CN107531722B (zh) | 2015-05-26 | 2020-07-17 | 豪夫迈·罗氏有限公司 | 杂环雌激素受体调节剂及其用途 |
| AU2016279330B2 (en) * | 2015-06-16 | 2020-05-14 | Jiangsu Hengrui Medicine Co., Ltd. | Piperidine derivative and preparation method and pharmaceutical use thereof |
| CN106518768B (zh) | 2015-09-15 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | 丙烯酸类衍生物、其制备方法及其在医药上的应用 |
| EP3355884B1 (en) | 2015-10-01 | 2021-04-28 | Olema Pharmaceuticals, Inc. | TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS |
| JP6920295B2 (ja) | 2015-11-09 | 2021-08-18 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | テトラヒドロナフタレンエストロゲン受容体モジュレーター及びその使用 |
| CA3011391C (en) | 2015-11-12 | 2021-02-09 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Acrylic acid derivative, preparation method and use in medicine thereof |
| MX2018007844A (es) | 2015-12-22 | 2019-01-21 | Jiangsu Hengrui Medicine Co | Derivado de benzopiperidina, metodo de preparacion del mismo y su uso medico del mismo. |
| JP7241542B2 (ja) * | 2016-04-08 | 2023-03-17 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | テトラヒドロイソキノリン エストロゲン受容体モジュレーター及びその使用 |
| WO2017182495A1 (en) * | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Indazole derivatives that down-regulate the estrogen receptor and possess anti-cancer activity |
| WO2017182493A1 (en) | 2016-04-20 | 2017-10-26 | Astrazeneca Ab | Indazole derivatives for use in down-regulation of the estrogen receptor for the treatment of cancer |
| CN109415388A (zh) | 2016-05-06 | 2019-03-01 | 路易斯安那泽维尔大学 | 选择性雌激素受体下调剂(serds) |
| WO2018001232A1 (zh) | 2016-06-29 | 2018-01-04 | 浙江海正药业股份有限公司 | 丙烯酸类衍生物及其制备方法和其在医药上的用途 |
| US10149839B2 (en) | 2016-07-25 | 2018-12-11 | Astrazeneca Ab | Chemical compounds |
| CN107814798B (zh) | 2016-09-14 | 2020-11-03 | 四川科伦博泰生物医药股份有限公司 | 3-取代丙烯酸类化合物及其制备方法和用途 |
| ES2975558T3 (es) | 2016-09-15 | 2024-07-09 | Arvinas Inc | Derivados de indol como degradantes de receptor de estrógeno |
| BR102016024814A2 (pt) | 2016-10-24 | 2018-05-08 | Aché Laboratórios Farmacêuticos S.A. | composto, processo de obtenção do composto, composição farmacêutica, uso do composto e método de tratamento de desordens psiquiátricas e/ou distúrbios do sono |
| AU2017349797B2 (en) * | 2016-10-24 | 2020-05-21 | Astrazeneca Ab | 6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer |
| WO2018108671A1 (en) | 2016-12-16 | 2018-06-21 | Basf Se | Pesticidal compounds |
| TN2019000158A1 (en) | 2016-12-16 | 2020-10-05 | Lilly Co Eli | 7-phenylethylamino-4h-pyrimido[4,5-d][1,3]oxazin-2-one compounds as mutant idh1 and idh2 inhibitors |
| EA037318B1 (ru) | 2016-12-16 | 2021-03-11 | Пфайзер Инк. | Агонисты рецептора glp-1 и их применение |
| JOP20190144A1 (ar) | 2016-12-16 | 2019-06-16 | Janssen Pharmaceutica Nv | إيميدازو بيرولو بيريدين كمثبطات لعائلة jak الخاصة بإنزيمات الكيناز |
| DK3555097T3 (da) | 2016-12-16 | 2022-07-25 | Janssen Pharmaceutica Nv | Imidazo[4,5-d]pyrrolo[2,3-b]pyridinforbindelser som inhibitorer af janus-kinaser |
| TWI831738B (zh) | 2016-12-16 | 2024-02-11 | 美商瑞塔醫藥有限責任公司 | 用於抑制ＲＯＲγ及其他用途的嘧啶三環烯酮衍生物 |
| WO2018138293A1 (en) | 2017-01-30 | 2018-08-02 | Chiesi Farmaceutici S.P.A. | Tyrosine amide derivatives as rho- kinase inhibitors |
-
2017
- 2017-10-13 AU AU2017349797A patent/AU2017349797B2/en active Active
- 2017-10-13 MX MX2019004685A patent/MX382331B/es unknown
- 2017-10-13 PT PT191890102T patent/PT3640251T/pt unknown
- 2017-10-13 DK DK19189010.2T patent/DK3640251T3/da active
- 2017-10-13 CA CA3040040A patent/CA3040040A1/en active Pending
- 2017-10-13 CN CN202210381693.8A patent/CN114656464B/zh active Active
- 2017-10-13 EP EP17783857.0A patent/EP3433256B1/en active Active
- 2017-10-13 PT PT177838570T patent/PT3433256T/pt unknown
- 2017-10-13 SG SG11201903182XA patent/SG11201903182XA/en unknown
- 2017-10-13 JP JP2019520525A patent/JP6744489B2/ja active Active
- 2017-10-13 PL PL17783857T patent/PL3433256T3/pl unknown
- 2017-10-13 PE PE2019000845A patent/PE20191078A1/es unknown
- 2017-10-13 US US15/782,904 patent/US10131663B2/en active Active
- 2017-10-13 EP EP19189010.2A patent/EP3640251B1/en active Active
- 2017-10-13 ME MEP-2019-306A patent/ME03547B/me unknown
- 2017-10-13 SM SM20220098T patent/SMT202200098T1/it unknown
- 2017-10-13 RS RSP20191371 patent/RS59445B1/sr unknown
- 2017-10-13 SI SI201731087T patent/SI3640251T1/sl unknown
- 2017-10-13 SI SI201730111T patent/SI3433256T1/sl unknown
- 2017-10-13 PL PL19189010T patent/PL3640251T3/pl unknown
- 2017-10-13 ES ES19189010T patent/ES2907759T3/es active Active
- 2017-10-13 WO PCT/EP2017/076191 patent/WO2018077630A1/en not_active Ceased
- 2017-10-13 HU HUE19189010A patent/HUE057524T2/hu unknown
- 2017-10-13 ES ES17783857T patent/ES2751902T3/es active Active
- 2017-10-13 UA UAA201905126A patent/UA125824C2/uk unknown
- 2017-10-13 TW TW106135012A patent/TWI735681B/zh active
- 2017-10-13 LT LT17783857T patent/LT3433256T/lt unknown
- 2017-10-13 KR KR1020197014062A patent/KR102178692B1/ko active Active
- 2017-10-13 MY MYPI2019002161A patent/MY205300A/en unknown
- 2017-10-13 SM SM20190602T patent/SMT201900602T1/it unknown
- 2017-10-13 HU HUE17783857A patent/HUE045714T2/hu unknown
- 2017-10-13 DK DK17783857T patent/DK3433256T3/da active
- 2017-10-13 HR HRP20220255TT patent/HRP20220255T1/hr unknown
- 2017-10-13 CR CR20190204A patent/CR20190204A/es unknown
- 2017-10-13 JO JOP/2019/0090A patent/JOP20190090B1/ar active
- 2017-10-13 CN CN201780064567.7A patent/CN109843888B/zh active Active
- 2017-10-13 LT LTEP19189010.2T patent/LT3640251T/lt unknown
- 2017-10-13 NZ NZ753459A patent/NZ753459A/en unknown
-
2018
- 2018-10-09 US US16/155,041 patent/US10590130B2/en active Active
-
2019
- 2019-02-01 ZA ZA2019/00694A patent/ZA201900694B/en unknown
- 2019-04-16 PH PH12019500830A patent/PH12019500830A1/en unknown
- 2019-04-18 CO CONC2019/0003950A patent/CO2019003950A2/es unknown
- 2019-04-18 CL CL2019001077A patent/CL2019001077A1/es unknown
- 2019-04-22 IL IL266245A patent/IL266245B/en active IP Right Grant
- 2019-04-23 EC ECSENADI201928657A patent/ECSP19028657A/es unknown
- 2019-04-23 DO DO2019000104A patent/DOP2019000104A/es unknown
- 2019-04-24 NI NI201900039A patent/NI201900039A/es unknown
- 2019-10-24 CY CY20191101110T patent/CY1122566T1/el unknown
-
2020
- 2020-01-28 US US16/774,268 patent/US10961241B2/en active Active
- 2020-07-30 JP JP2020129457A patent/JP6993477B2/ja active Active
-
2021
- 2021-02-17 US US17/177,617 patent/US12077530B2/en active Active
-
2022
- 2022-02-23 CY CY20221100160T patent/CY1125292T1/el unknown
-
2024
- 2024-07-17 US US18/775,391 patent/US20240383895A1/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HRP20220255T1 (hr) | Derivati 6,7,8,9-tetrahidro-3h-pirazolo[4,3-f]izokinolina koji su korisni u liječenju raka | |
| HRP20171999T1 (hr) | Novi derivati aminopirimidina | |
| HRP20200624T1 (hr) | Derivati 2-(2,4,5-supstituiranog-anilino)pirimidina kao modulatori egfr korisni za liječenje raka | |
| MD20140130A2 (ro) | 4-(amino-substituite)-7H-pirolo[2,3-d]pirimidine noi ca inhibitori de LRRK2 | |
| HRP20171696T1 (hr) | 3,4-dihidroizokinolin-2(1h)-ilni spojevi | |
| HRP20171028T1 (hr) | Indolski i indazolski spojevi koji aktiviraju ampk | |
| HRP20140481T1 (hr) | SUPSTITUIRANI SPOJEVI IMIDAZO[1,2-b]PIRIDAZINA KAO INHIBITORI TRK KINAZE | |
| HRP20240293T1 (hr) | Derivati kinazolina kao protutumorska sredstva | |
| NZ629442A (en) | Heterocyclyl compounds as mek inhibitors | |
| RU2014107486A (ru) | Бициклические пиримидоновые соединения | |
| NZ604345A (en) | Pyrazolo[1,5-a]pyrimidines as antiviral agents | |
| RU2015151502A (ru) | Химические соединения | |
| HRP20220886T1 (hr) | Pripravci i postupci za proizvodnju pirimidina i spojeva piridina s btk inhibicijskom aktivnošću | |
| SI2935248T1 (en) | Compounds and procedures for kinase modulation and indications for the latter | |
| CA2918938C (en) | Substituted aminopyrimidine compounds and methods of use | |
| RU2018121499A (ru) | Гипоксантины в качестве ингибиторов убиквитин-специфической протеазы 1 | |
| HRP20200342T1 (hr) | Derivati dihidroimidazopirazinona korisni u liječenju raka | |
| WO2015132799A3 (en) | Heterocyclic compounds | |
| PH12012502438A1 (en) | Morpholino pyrimidines and their use in therapy | |
| HRP20170311T1 (hr) | Novi spojevi pirolopirimidina kao inhibitori protein kinaza | |
| JP2017521394A5 (enExample) | ||
| ME02452B (me) | Sredstva za induciranje apoptoze namijenjena liječenju raka i imunih i autoimunih bolesti | |
| BR112016013714A8 (pt) | compostos cristalinos de análogos de sofosbuvir antivirais, uso dos mesmos e composição farmacêutica | |
| HRP20191826T4 (hr) | Derivati n-piridinil acetamida kao inhibitori wnt signalnog puta | |
| RU2018133391A (ru) | 1,5-дигидро-4н-пиразоло[3,4-d]пиримидин-4-оны и 1,5-дигидро-4н-пиразоло[4,3-c]пиридин-4-оны в качестве ингибиторов pde1 |