SI3027602T1 - Novi derivati indola in pirola, postopek za njihovo pripravo in farmacevtski sestavki, ki jih vsebujejo - Google Patents
Novi derivati indola in pirola, postopek za njihovo pripravo in farmacevtski sestavki, ki jih vsebujejo Download PDFInfo
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- SI3027602T1 SI3027602T1 SI201430784T SI201430784T SI3027602T1 SI 3027602 T1 SI3027602 T1 SI 3027602T1 SI 201430784 T SI201430784 T SI 201430784T SI 201430784 T SI201430784 T SI 201430784T SI 3027602 T1 SI3027602 T1 SI 3027602T1
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- 238000000034 method Methods 0.000 title claims 7
- 239000008194 pharmaceutical composition Substances 0.000 title claims 7
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims 4
- 150000002475 indoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 33
- 206010028980 Neoplasm Diseases 0.000 claims abstract 5
- 201000011510 cancer Diseases 0.000 claims abstract 5
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract 2
- -1 (C1-C6) alkyl-S- Chemical group 0.000 claims 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 10
- 239000002253 acid Substances 0.000 claims 10
- 125000005843 halogen group Chemical group 0.000 claims 9
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- 125000003118 aryl group Chemical group 0.000 claims 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 8
- 150000003839 salts Chemical class 0.000 claims 8
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 5
- 230000015572 biosynthetic process Effects 0.000 claims 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 4
- 150000001768 cations Chemical class 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 238000002360 preparation method Methods 0.000 claims 4
- 238000000926 separation method Methods 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 3
- 125000000217 alkyl group Chemical group 0.000 claims 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 3
- 125000002619 bicyclic group Chemical group 0.000 claims 3
- 125000005842 heteroatom Chemical group 0.000 claims 3
- 125000002950 monocyclic group Chemical group 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 239000001301 oxygen Substances 0.000 claims 3
- 125000001424 substituent group Chemical group 0.000 claims 3
- 229910052717 sulfur Inorganic materials 0.000 claims 3
- 239000011593 sulfur Substances 0.000 claims 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims 2
- 206010005003 Bladder cancer Diseases 0.000 claims 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical class C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 2
- 206010033128 Ovarian cancer Diseases 0.000 claims 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 2
- 206010060862 Prostate cancer Diseases 0.000 claims 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- 210000004556 brain Anatomy 0.000 claims 2
- 210000000481 breast Anatomy 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims 2
- 230000008878 coupling Effects 0.000 claims 2
- 238000010168 coupling process Methods 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims 2
- 235000011180 diphosphates Nutrition 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 239000000543 intermediate Substances 0.000 claims 2
- 208000003747 lymphoid leukemia Diseases 0.000 claims 2
- 230000003211 malignant effect Effects 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 2
- 238000005897 peptide coupling reaction Methods 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 2
- 239000007858 starting material Substances 0.000 claims 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 2
- 210000003932 urinary bladder Anatomy 0.000 claims 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims 2
- 206010046766 uterine cancer Diseases 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical class C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- 150000000094 1,4-dioxanes Chemical class 0.000 claims 1
- FNFWTFIBKLZHSU-UHFFFAOYSA-N 1-amino-2-methoxy-3-phenoxyazetidin-2-ol Chemical compound OC1(N(CC1OC1=CC=CC=C1)N)OC FNFWTFIBKLZHSU-UHFFFAOYSA-N 0.000 claims 1
- BNGITRCRSAWPSZ-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2N[C]=CC2=C1 BNGITRCRSAWPSZ-UHFFFAOYSA-N 0.000 claims 1
- ZFFYPGZDXUPKNK-UHFFFAOYSA-N 2,3-dihydro-1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NCCC2=C1 ZFFYPGZDXUPKNK-UHFFFAOYSA-N 0.000 claims 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical class C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims 1
- AOPRXJXHLWYPQR-UHFFFAOYSA-N 2-phenoxyacetamide Chemical compound NC(=O)COC1=CC=CC=C1 AOPRXJXHLWYPQR-UHFFFAOYSA-N 0.000 claims 1
- KBRJQEVSKVOLNR-UHFFFAOYSA-N 2-phenylsulfanylacetamide Chemical compound NC(=O)CSC1=CC=CC=C1 KBRJQEVSKVOLNR-UHFFFAOYSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- 230000000340 anti-metabolite Effects 0.000 claims 1
- 239000003005 anticarcinogenic agent Substances 0.000 claims 1
- 229940100197 antimetabolite Drugs 0.000 claims 1
- 239000002256 antimetabolite Substances 0.000 claims 1
- 125000005110 aryl thio group Chemical group 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- MVXVYAKCVDQRLW-UHFFFAOYSA-N azain Natural products C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 150000007942 carboxylates Chemical class 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims 1
- 201000004101 esophageal cancer Diseases 0.000 claims 1
- 210000003238 esophagus Anatomy 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 231100000024 genotoxic Toxicity 0.000 claims 1
- 230000001738 genotoxic effect Effects 0.000 claims 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Chemical class C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims 1
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims 1
- 229940043355 kinase inhibitor Drugs 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 201000007270 liver cancer Diseases 0.000 claims 1
- 208000014018 liver neoplasm Diseases 0.000 claims 1
- 230000000394 mitotic effect Effects 0.000 claims 1
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims 1
- 239000002574 poison Substances 0.000 claims 1
- 231100000614 poison Toxicity 0.000 claims 1
- 230000000861 pro-apoptotic effect Effects 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 125000003003 spiro group Chemical group 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 230000006907 apoptotic process Effects 0.000 abstract 1
- 230000006735 deficit Effects 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 210000000987 immune system Anatomy 0.000 abstract 1
- 229940126601 medicinal product Drugs 0.000 abstract 1
- 230000007170 pathology Effects 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
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- 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
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
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- NOVI DERIVATI INDOLA IN PIROLA, POSTOPEK ZA NJIHOVO PRIPRAVO IN FARMACEVTSKI SESTAVKI, KI JIH VSEBUJEJO Patentni zahtevki1. Spojina s formulo (I):0) pri čemer: ♦ W predstavlja skupino C-H, medtem ko Ai in A2 predstavljata atom vodika in metilno skupino, oziroma W predstavlja skupino C-H, medtem ko A1 in A2 oblikujeta z atomi ogljika, ki ju nosijo, cikloheksenilni ali benzo obroč, ki je poljubno substituiran z atomom halogena,♦ T predstavlja atom vodika, linearni ali razvejani (C1-C6) alkil, ki je poljubno substituiran z od enim do tremi atomi halogena, skupino (Ci-C4)alkil-NRiR2, ali skupino (CrC4)alkil-OR6, ♦ R1 in R2 neodvisno drug od drugega predstavljata atom vodika ali linearno ali razvejano (Οι-Οθ) alkilno skupino, oziroma R1 in R2 oblikujeta z atomom dušika, ki ju nosi, heterocikloalkil, ♦ R3 predstavlja arilno ali heteroarilno skupino, pri čemer se razume, da je lahko eden ali več atomov ogljika predhodnih skupin, ali, kjer je primerno, njihovih substituentov, devteriran, ♦ R4 predstavlja arilno ali heteroarilno skupino, pri čemer se razume, da je lahko eden ali več atomov ogljika predhodnih skupin, ali, kjer je primerno, njihovih substituentov, devteriran, ♦ R5 predstavlja atom vodika ali halogena, linearno ali razvejano (C1-C6) alkilno skupino ali linearno ali razvejano (C1-C6) alkoksi skupino, ♦ R6 predstavlja atom vodika ali linearno ali razvejano (C1-C6) alkilno skupino, ♦ Ra, Rb, Rc in Ra, vsak neodvisno drug od drugega, predstavlja R7, atom halogena, linearno ali razvejano (Ο-ι-Οβ) alkoksi skupino, hidroksi skupino, linearno ali razvejano (C1-C6) polihalo-(CrC6)alkilno skupino, trifluorometoksi skupino, -NR7R7’, nitro oziroma substituenti enega izmed parov (Ra,Rb), (Rb,Rc) ali (Rc,Rd) oblikujejo skupaj z atomi ogljika, ki jih nosijo, obroč, ki je sestavljen iz od 5 do 7 obročnih členov, ki lahko vsebujejo od enega do dva hetero atoma, izbranega izmed kisika in žvepla, pri čemer se prav tako razume, da je lahko eden ali več atomov ogljika obroča, ki je opredeljen zgoraj, devteriran ali substituiran z od eno do tremi skupinami, ki so izbrane izmed halogena in linearnega ali razvejanega (Ci-Ce) alkila, oziroma Ra in Rd vsak predstavlja atom vodika, Rb predstavlja atom vodika, atom halogena, hidroksi ali metoksi skupino, Rc pa je izbran izmed ene izmed naslednjih skupin: hidroksi, metoksi, amino, 3-fenoksiazetidin, 2-(fenilsulfanil)acetamid ali 2-(fenoksi)acetamid, ♦ R? in R7’, vsak neodvisno drug od drugega, predstavlja atom vodika, linearno ali razvejano (Ο-ι-Οθ) alkilno skupino, linearno ali razvejano (C2-C6) alkenilno skupino, linearno ali razvejano (Ο2-Οθ) alkinilno skupino, arilno skupino ali heteroarilno skupino, oziroma R7 in R7’ oblikujeta skupaj z atomom dušika, ki ju nosi, heterocikel, ki je sestavljen iz od 5 do 7 obročnih členov, pri čemer se razume, da kadar spojina s formulo (I) vsebuje hidroksi skupino, se lahko ta poljubno substituira z eno izmed naslednjih skupin: PO(OM)(OM’), -PO(OM)(O-M-i+), -PO(O-Mi+)(O-M2+), -PO(O-)(O-)M32+, -PO(OM)(O[CH2CH2O]nCH3) ali PO(O-Mi+)(O[CH2CH2O]nCH3), pri čemer M in M’ neodvisno drug od drugega predstavljata atom vodika, linearno ali razvejano (Ci-C6) alkilno skupino, linearno ali razvejano (Ο2-Οθ) alkenilno skupino, linearno ali razvejano (Ο2-Οθ) alkinilno skupino, cikloalkil ali heterocikloalkil, pri čemer sta oba sestavljena iz od 5 do 6 obročnih členov, pri čemer M? in M2+ neodvisno drug od drugega predstavljata farmacevtsko sprejemljiv monovalentni kation, M32+ predstavlja farmacevtsko sprejemljiv dvovalentni kation, n pa je celo število od 1 do 5, pri čemer se prav tako razume naslednje: - „aril“ pomeni fenilno, naftilno, bifenilno ali indenilno skupino, - „heteroaril“ pomeni vsako mono- ali biciklično skupino, ki je sestavljena iz od 5 do 10 obročnih členov, ki imajo vsaj en aromatski del in vsebujejo od enega do štiri hetero atome, ki so izbrani izmed kisika, žvepla in dušika (vključno s kvarternimi dušiki), - „cikloalkil“ pomeni vsako mono- ali biciklično, nearomatsko, karbociklično skupino, ki vsebuje od 3 do 10 obročnih členov, - „heterocikloalkil“ pomeni vsako mono ali biciklično, nearomatsko skupino, ki je sestavljena iz od 3 do 10 obročnih členov in vsebuje od enega do tri hetero atome, ki so izbrani izmed kisika, žvepla, SO, SO2 in dušika, pri čemer je mogoče za na tak način opredeljeno arilno, heteroarilno, cikloalkilno in heterocikloalkilno skupino ter skupine alkila, alkenila, alkinila in alkoksija substituirati z od eno do tremi skupinami, ki so izbrane izmed linearnega ali razvejanega (Οι-Οβ) alkila, (C3-C6) spiro, linearnega ali razvejanega (Ο-ι-Οβ) alkoksija, (Ci-Ce)alkil-S-, hidroksija, okso (ali /V-oksida, kjer je to primerno), nitro, ciano, -COOR’, -OCOR’, NR’R", linearnega ali razvejanega polihalo-(Ci-C6) alkila, trifluorometoksija, (Ci-C6) alkilsulfonila, halogena, arila, heteroarila, ariloksija, ariltio, cikloalkila, heterocikloalkila, ki je poljubno substituiran z enim ali več atomi halogena ali alkilnimi skupinami, pri čemer se razume, da R’ and R" neodvisno drug od drugega predstavljata atom vodika oziroma linearno ali razvejano (C1-C6) alkilno skupino, njihovi enantiomeri in diastereoizomeri ter prav tako njihove dodatne soli s farmacevtsko sprejemljivo kislino ali bazo.
- 2. Spojina s formulo (I) po zahtevku 1, pri čemer R4 predstavlja fenil, k ije substituiran v para položaju s skupino s formulo -OPO(OM)(OM’), -OPO(OM)(O-Mi+), -OPO(O-Mi+)(O-M2+), -OPO(O-)(O-)M32+, -OPO(OM)(O[CH2CH2O]nCH3) ali -OPO(O-Mi+)(O[CH2-CH2O]nCH3), pri čemer M in M’ neodvisno drug od drugega predstavljata atom vodika, linearno ali razvejano (C1-C6) alkilno skupino, linearno ali razvejano (C2-Ce) alkenilno skupino, linearno ali razvejano (C2-Ce) alkinilno skupino, cikloalkil ali heterocikloalkil, ki sta oba sestavljena iz od 5 do 6 obročnih členov, pri čemer Mi+ in M2+ neodvisno drug od drugega predstavljata farmacevtsko sprejemljiv monovalentni kation, M32+ predstavlja farmacevtsko sprejemljiv dvovalentni kation, n pa je celo število od 1 do 5, pri čemer se razume, da je lahko fenilna skupina poljubno substituirana z enim ali več atomi halogena.
- 3. Spojina s formulo (I) po katerem koli izmed zahtevkov 1 ali 2, pri čemer T predstavlja skupino, ki je izbrana izmed metila, aminometila, dimetilaminometila, morfolinilmetila, (4-metil-1-piperazinil)metila, (3aR,6aS)- heksahidrociklopenta[c]pirol-2(1H)-ilmetila, (4,4-difluoropiperidin-1-il)metila, (4-ciklopentilpiperazin-1-il)metila, (4-ciklobutilpiperazin-1-il)metila, pirolidin-1-ilmetila, piperidin-1-ilmetila in 2-(morfolin-4-il)etila.
- 4. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 3, pri čemer Ra in Rd vsak predstavljata atom vodika in (Rb, Rc), skupaj z atomi ogljika, ki jih nosijo, oblikujeta eno izmed naslednjih skupin: poljubno substituirani 1,3-dioksolan; poljubno substituirani 1,4-dioksan; ciklopentan; tetrahidrofuran; 2,3-dihidrofuran; oziroma Ra, Rc in Rd vsak predstavljajo atom vodika, Rb pa predstavlja hidroksi ali metoksi skupino, atom halogena, trifuorometilno ali trifluorometoksi skupino.
- 5. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 3, pri čemer ena ali dve izmed skupin Ra, Rb, Rc, Rd predstavljata atom halogena, medtem ko druge predstavljajo atom vodika.
- 6. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 5, pri čemer R4 predstavlja fenil, 4-hidroksifenil, 4-metoksifenil, 4-metilfenil, 3-kloro-4-hidroksifenil ali 3-fluoro-4-hidroksifenilno skupino.
- 7. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 6, pri čemer R3 predstavlja skupino, ki je izbrana izmed fenila, 1/-/-indola, benzotiofena, benzofurana, 2,3-dihidro-1H-indola, 1/-/-indazola, 2,3-dihidro-1H-izoindola, 1/-/-pirolo[2,3-b]piridina, fenoksifenila, 2,3-dihidro-1H-pirolo[2,3-b]piridina, 1H-pirola, pri čemer te skupine poljubno vsebujejo enega ali več substituentov, ki so izbrani izmed atoma halogena, linearnega ali razvejanega (C1-C6) alkila, trifluorometoksija, 4-metilpiperazinila, linearnega ali razvejanega (C1-C6) alkoksija in ciana.
- 8. Spojina s formulo (I) po zahtevku 1, ki je izbrana izmed naslednje skupine: - A/-(4-hidroksifenil)-1 -{6-[(3S)-3-(morfolin-4-ilmetil)-1,2,3,4-tetrahidroizokinolin-2-karbonil]-2B-1,3-benzodioksol-5-il}-/\/-fenil-1 H indol-3-karboksamid, /V-(4-hidroksifenil)-/V-(1 -metil-1 H-pi rolo[2,3-b]pi rid in-5-il)-1 -(6-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}-1,3-benzodioksol-5-il)-4,5,6,7-tetrahidro-1/-/-indol-3-karboksamid, - /V-(4-hidroksifenil)-/V-(4-metilfenil)-1 -(6-{[(3S)-3-[(4-metilpiperazin-1 -il)metil]-3,4-dihidroizokinolin-2(1 H)-il]karbonil}-1,3-benzodioksol-5-il)-1 H-indol-3-karboksamid, - /V-(4-hidroksifenil)-A/-(1W-indol-5-il)-1-(6-{[(3S)-3-[(4-metilpiperazin-1-il)metil]-3,4-dihidroizokinolin-2(1 /-/)-il]karbonil}-1,3-benzodioksol-5-il)-1 H-indol-3-karboksamid, - /V-(4-hidroksifenil)-/V-(1-metil-1/-/-indol-5-il)-1-(6-{[(3S)-3-[(4-metilpiperazin-1-il)methyl]-3,4-dihidroizokinolin-2(1 H)-il]karbonil}-1,3-benzodioksol-5-il)-1 H-indol-3-karboksamid, - 1 -(5-kloro-2-{[(3S)-3-[(4-metilpiperazin-1 -il)metil]-3,4-d ih id roizokinolin-2( 1H)-il]karbonil}fenil)-N-(4-klorofenil)-N-(4-hidroksifenil)-5-metil-1/-/-pirol-3-karboksamid, - 1 -(5-kloro-2-{[(3S)-3-[(4-metilpiperazin-1 -il) metil]-3,4-d ihid roizokinol i n-2( 1H)-il]karbonil}fenil)-N-(4-hidroksifenil)-N-(1/-/-indol-5-il)-1/-/-indol-3-karboksamid, /V-(4-hid roksifeni I)-1 -{6-[(3S)-3-[(4-metilpiperazin-1 -il) metil]-1,2,3,4-tetrahidroizokinolin-2-karbonil]-2/-/-1,3-benzodioksol-5-il}-/V-fenil-1/-/-indol-3-karboksamid, ter njihove dodatne soli s farmacevtsko sprejemljivo kislino ali bazo.
- 9. Spojine, izbrane izmed naslednje skupine: 1 -(5-kloro-2-{[(3 S)-3-(morfolin-4-ilmetil)-3,4-d ih id roizokinolin-2( 1H)-il]karbonil}fenil)-/V-(4-hidroksifenil)-4,5-dimetil-/V-(1-metil-2,3-dihidro-1H-pirolo[2,3-b]piridin-5-il)-1/-/-pirol-3-karboksamid, 1-(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidroizokinolin-2(1H)-il]karbonil}fenil)-/V-(5-ciano-1,2-dimetil-1 H-pirol-3-il)-/V-(4-hidroksifenil)-4,5-dimetil-1H-pirole-3-karboksamid, 1 -(5-kloro-2-{[(3S)-3-(morfolin-4-ilmetil)-3,4-dihidrozokinolin-2(1 /-/)-il]karbonil}fenil)-/V-(4-hidroksifenil)-4,5-dimetil-A/-(1-metil-1 /-/-pirolo[2,3-b]piridin-5-il)-1/-/-pirol-3-karboksamid, 1 -[(2S)-2-[(benziloksi)metil]-7-[(3S)-3[(4-metilpiperazin-1 -il)metil]-1,2,3,4-tetrahidroizokinolin-2-karbonil]-2,3-dihidro-1,4-benzodioksin-6-il]-/V-(4-hidroksifenil)-/V-fenil-1/-/-indol-3-karboksamid, ter njihove dodatne soli s farmacevtsko sprejemljivo kislino ali bazo.
- 10. Postopek za pripravo spojine s formulo (I) po zahtevku 1, označen s tem, da je kot vhodna snov uporabljena spojina s formulo (II):(»)pri čemer Alk predstavlja (Ci-C6) alkilno skupino, W, Ai, A2, Ra, Rb, Rc, Ra pa so, kot so opredeljeni s formulo (I), pri čemer je spojina s formulo (II) nato izpostavljena peptidni sklopitvi s spojino s formulo (III):(Ml) pri čemer sta T in R5, kot sta opredeljena s formulo (I), da se tvori spojina s formulo (IV):(IV) pri čemer je Alk, kot je opredeljen zgoraj, W, Ai, A2, Ra, Rb, Rc, Rd, Rs and T pa so, kot so opredeljeni s formulo (I),pri čemer je esterska funkcija spojine s formulo (IV) hidrolizirana, da se tvori ustrezna karboksilna kislina ali karboksilat, ki se lahko pretvori v kisli derivat, kot je ustrezni acilni klorid ali anhidrid, preden se izvede sklopitev z aminom NHR3R4, pri čemer imata R3 in R4 enak pomen kot v formuli (I), ki se lahko poljudno izpostavi delovanju spojine pirofosfata ali fosfonata pod osnovnimi pogoji, da se tvori spojina s formulo (I), pri čemer se lahko spojina s formulo (I) nato prečisti v skladu s konvencionalnim postopkom separacije, ki se pretvori, poljubno, v svoje dodatne soli s farmacevtsko sprejemljivo kislino ali bazo ter se poljubno separira v svoje izomere v skladu s konvencionalnim postopkom separacije, pri čemer se razume, da so lahko, kadar koli se šteje za primerno v okviru zgoraj navedenega postopka, določene skupine (hidroksi, amino, ...) reagentov ali intermediatov sinteze zaščitene, nato pa odstranjene od zaščitne skupine v skladu z zahtevami sinteze.
- 11. Postopek po zahtevku 10 za pripravo spojine s formulo (I), pri čemer je ena izmed skupin R3 ali R4 substituirana s funkcijo hidroksi, označen s tem, da je amin NHR3R4 predhodno izpostavljen reakciji zaščite funkcije hidroksi pred kakršno koli sklopitvijo s karboksilno kislino, ki se tvori iz spojine s formulo (IV), oziroma z njenim ustreznim derivatom kisline, pri čemer je pridobljena zaščitena spojina s formulo (I) nato izpostavljena reakciji deprotekcije in se nato poljubno pretvori v eno izmed njenih dodatnih soli s farmacevtsko sprejemljivo kislino ali bazo.
- 12. Postopek za pripravo spojine s formulo (I) po zahtevku 1, označen s tem, da je kot vhodna snov uporabljena spojina s formulo (V):(V) pri čemer so W, Ai, A2, Ra, Rb, Rc, Ra, R3 in R4, kot so opredeljeni s formulo (I), pri čemer je spojina s formulo (V) nato izpostavljena peptidni sklopitvi s spojino s formulo (III):(lil) pri čemer sta T in R5, kot sta opredeljena v formuli (I), pri čemer je tako pridobljena spojina poljubno izpostavljena delovanju spojine pirofosfata ali fosfonata pod osnovnimi pogoji, da se tvori spojina s formulo (I), pri čemer se lahko spojina s formulo (I) nato prečisti v skladu s konvencionalnim postopkom separacije, ki se pretvori, poljubno, v svoje dodatne soli s farmacevtsko sprejemljivo kislino ali bazo ter poljubno separira v svoje izomere v skladu s konvencionalnim postopkom separacije,pri čemer se razume, da so lahko, kadar koli se šteje za primerno v okviru zgoraj navedenega postopka, določene skupine (hidroksi, amino, ...) reagentov ali intermediatov sinteze zaščitene, nato pa odstranjene od zaščitne skupine v skladu z zahtevami sinteze.
- 13. Farmacevtski sestavek, ki obsega spojino s formulo (I) po katerem koli izmed zahtevkov od 1 do 9 ali njeno dodatno sol s farmacevtsko sprejemljivo kislino ali bazo, v kombinaciji z eno ali več farmacevtsko sprejemljivimi pomožnimi snovmi.
- 14. Farmacevtski sestavek po zahtevku 13 za uporabo kot proapoptotsko sredstvo.
- 15. Farmacevtski sestavek po zahtevku 13 za uporabo pri zdravljenju različnih vrst raka, avtoimunskih bolezni in bolezni imunskega sistema.
- 16. Farmacevtski sestavek po zahtevku 15 za uporabo pri zdravljenju raka mehurja, možganov, dojke in maternice, kroničnih limfoidnih levkemij, kolorektalnega raka, raka požiralnika in jeter, limfoblastnih levkemij, ne-Hodgkinovega limfoma, melanomov, malignih hemopatij, mielomov, raka jajčnikov, nedrobnoceličnega raka pljuč, raka prostate in drobnoceličnega raka pljuč.
- 17. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 9, ali njena dodatna sol s farmacevtsko sprejemljivo kislino ali bazo, za uporabo pri zdravljenju raka mehurja, možganov, dojke in maternice, kroničnih limfoidnih levkemij, kolorektalnega raka, raka požiralnika in jeter, limfoblastnih levkemij, ne-Hodgkinovega limfoma, melanomov, malignih hemopatij, mielomov, raka jajčnikov, nedrobnoceličnega raka pljuč, raka prostate in drobnoceličnega raka pljuč.
- 18. Sestavek spojine s formulo (I) po katerem koli izmed zahtevkov od 1 do 9 z antikarcenogenim sredstvom, ki je izbrano izmed genotoksičnih snovi, mitotskih strupov, antimetabolitov, inhibitorjev proteazomov, inhibitorjev kinaze in protiteles. ♦ · 9 9 9 9 » w w — —
- 19. Farmacevtski sestavek, ki obsega sestavek po zahtevku 18, v kombinaciji z eno ali več farmacevtsko sprejemljivimi pomožnimi snovmi.
- 20. Kombinacija po zahtevku 18 za uporabo pri zdravljenju različnih vrst raka.
- 21. Spojina s formulo (I) po katerem koli izmed zahtevkov od 1 do 9 za uporabo v povezavi z radioterapijo pri zdravljenju različnih vrst raka.
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| Application Number | Priority Date | Filing Date | Title |
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| FR1357277A FR3008978A1 (fr) | 2013-07-23 | 2013-07-23 | "nouveaux derives d'indole et de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent" |
| PCT/FR2014/051884 WO2015011396A1 (fr) | 2013-07-23 | 2014-07-22 | Nouveaux derives d'indole et de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| EP14758604.4A EP3027602B1 (fr) | 2013-07-23 | 2014-07-22 | Nouveaux derives d'indole et de pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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| WO (1) | WO2015011396A1 (sl) |
| ZA (1) | ZA201600415B (sl) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237509A (zh) * | 2015-11-20 | 2016-01-13 | 江苏瑞邦农药厂有限公司 | 一种2,2-二氟-1,3-苯并二恶茂的合成方法 |
| WO2017197046A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
| WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
| EP3454856A4 (en) | 2016-05-10 | 2019-12-25 | C4 Therapeutics, Inc. | HETEROCYCLIC DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
| CN116462666A (zh) * | 2017-01-10 | 2023-07-21 | 瑞士苏黎世联邦理工学院 | 细胞保护性化合物及其用途 |
| EP3604540A4 (en) | 2017-03-31 | 2020-12-23 | The University of Tokyo | NOROVIRUS ANTIBODIES |
| CN108409580A (zh) * | 2018-02-01 | 2018-08-17 | 浙江工业大学 | 一种苄胺类化合物的合成方法 |
| WO2020132561A1 (en) | 2018-12-20 | 2020-06-25 | C4 Therapeutics, Inc. | Targeted protein degradation |
| TW202408588A (zh) | 2022-05-20 | 2024-03-01 | 瑞士商諾華公司 | 抗體-藥物結合物抗腫瘤化合物及其使用方法 |
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| US20070060596A1 (en) | 2003-10-24 | 2007-03-15 | Giblin Gerard M P | Heterocyclyl compounds |
| TW200533398A (en) * | 2004-03-29 | 2005-10-16 | Bristol Myers Squibb Co | Novel therapeutic agents for the treatment of migraine |
| WO2006023778A2 (en) * | 2004-08-20 | 2006-03-02 | The Regents Of The University Of Michigan | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| GB0522908D0 (en) | 2005-11-10 | 2005-12-21 | Merck Sharp & Dohme | Therapeutic agents |
| EP2714681B1 (en) * | 2011-05-25 | 2015-06-24 | Bristol-Myers Squibb Company | Substituted sulfonamides useful as antiapoptotic bcl inhibitors |
| US9126980B2 (en) * | 2011-12-23 | 2015-09-08 | Novartis Ag | Compounds for inhibiting the interaction of BCL2 with binding partners |
| EA201491259A1 (ru) * | 2011-12-23 | 2014-11-28 | Новартис Аг | Соединения и композиции для ингибирования взаимодействия bcl2 с партнерами связывания |
| MX2014007731A (es) * | 2011-12-23 | 2015-01-12 | Novartis Ag | Compuestos para inhibir la interaccion de bcl2 con los componentes de enlace. |
| BR112014015308A2 (pt) * | 2011-12-23 | 2017-06-13 | Novartis Ag | compostos para inibição da interação de bcl2 com contrapartes de ligação |
| CA2859869A1 (en) * | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
| FR2986002B1 (fr) * | 2012-01-24 | 2014-02-21 | Servier Lab | Nouveaux derives d'indolizine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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2013
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- 2014-07-22 EP EP14758604.4A patent/EP3027602B1/fr active Active
- 2014-07-22 DK DK14758604.4T patent/DK3027602T3/en active
- 2014-07-22 ES ES14758604.4T patent/ES2687475T3/es active Active
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- 2014-07-22 EP EP16201228.0A patent/EP3168217A1/fr not_active Withdrawn
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