HRP20220227T1 - Postupak priprave tricikličnih spojeva inhibitora p13k i postupci upotrebe navedenih spojeva u liječenju raka - Google Patents
Postupak priprave tricikličnih spojeva inhibitora p13k i postupci upotrebe navedenih spojeva u liječenju raka Download PDFInfo
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- HRP20220227T1 HRP20220227T1 HRP20220227TT HRP20220227T HRP20220227T1 HR P20220227 T1 HRP20220227 T1 HR P20220227T1 HR P20220227T T HRP20220227T T HR P20220227TT HR P20220227 T HRP20220227 T HR P20220227T HR P20220227 T1 HRP20220227 T1 HR P20220227T1
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- Prior art keywords
- palladium
- compound
- alkylene
- ch2ch3
- process according
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- 238000000034 method Methods 0.000 title claims 19
- 150000001875 compounds Chemical class 0.000 title claims 11
- 206010028980 Neoplasm Diseases 0.000 title 1
- 239000012828 PI3K inhibitor Substances 0.000 title 1
- 201000011510 cancer Diseases 0.000 title 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 title 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 10
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 8
- 239000003054 catalyst Substances 0.000 claims 7
- 239000000203 mixture Substances 0.000 claims 7
- -1 1,1-dioxothiopyran-4-yl Chemical group 0.000 claims 6
- 229910052794 bromium Inorganic materials 0.000 claims 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 5
- 229910052801 chlorine Inorganic materials 0.000 claims 5
- 229910052731 fluorine Inorganic materials 0.000 claims 5
- 229910052740 iodine Inorganic materials 0.000 claims 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 5
- 229910052763 palladium Inorganic materials 0.000 claims 5
- 239000002904 solvent Substances 0.000 claims 5
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 claims 4
- 125000004452 carbocyclyl group Chemical group 0.000 claims 4
- 239000007795 chemical reaction product Substances 0.000 claims 4
- 239000013078 crystal Substances 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims 4
- 239000011541 reaction mixture Substances 0.000 claims 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 4
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- 229920002396 Polyurea Polymers 0.000 claims 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) Substances [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims 3
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 claims 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 239000000706 filtrate Substances 0.000 claims 3
- 239000011159 matrix material Substances 0.000 claims 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 3
- 125000003566 oxetanyl group Chemical group 0.000 claims 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 3
- 239000003880 polar aprotic solvent Substances 0.000 claims 3
- 239000003586 protic polar solvent Substances 0.000 claims 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 2
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- NMMPMZWIIQCZBA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylethanamine Chemical group [Pd+]Cl.NCCC1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 NMMPMZWIIQCZBA-UHFFFAOYSA-M 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 2
- 230000008025 crystallization Effects 0.000 claims 2
- JCWIWBWXCVGEAN-UHFFFAOYSA-L cyclopentyl(diphenyl)phosphane;dichloropalladium;iron Chemical compound [Fe].Cl[Pd]Cl.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1.[CH]1[CH][CH][CH][C]1P(C=1C=CC=CC=1)C1=CC=CC=C1 JCWIWBWXCVGEAN-UHFFFAOYSA-L 0.000 claims 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 229910052751 metal Inorganic materials 0.000 claims 2
- 239000002184 metal Substances 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- 238000010899 nucleation Methods 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000002516 radical scavenger Substances 0.000 claims 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tri(ortho-tolyl)phosphine Substances CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims 2
- 125000006736 (C6-C20) aryl group Chemical group 0.000 claims 1
- FAFGMAGIYHHRKN-UHFFFAOYSA-N 2-diphenylphosphanylethyl(diphenyl)phosphane;palladium Chemical compound [Pd].C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 FAFGMAGIYHHRKN-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims 1
- 101150003085 Pdcl gene Proteins 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- XOJNEFQLMRCOMS-UHFFFAOYSA-N ditert-butyl(phenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1 XOJNEFQLMRCOMS-UHFFFAOYSA-N 0.000 claims 1
- 229940093499 ethyl acetate Drugs 0.000 claims 1
- 235000019439 ethyl acetate Nutrition 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000011874 heated mixture Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims 1
- 229940032007 methylethyl ketone Drugs 0.000 claims 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims 1
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—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
- A61K31/495—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
-
- 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
- A61K31/535—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
- A61K31/5383—1,4-Oxazines, e.g. morpholine 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
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Physiology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Claims (15)
1. Postupak priprave spoja Formule III iz spoja Formule II u reakcijskoj smjesi prema sljedećoj reakcijskoj shemi:
[image]
gdje se postupak sastoji u:
(i) pripravi reakcijske smjese koja sadrži spoj Formule II, organobor-R4, sustav otapala koji sadrži najmanje 5 vol./vol.% vode, bazu i katalizator;
(ii) reagiranju reakcijske smjese na temperaturi ispod 100 °C kako bi se dobilo smjesu produkata reakcije koja sadrži spoj Formule III; i
(iii) izdvajanju spoja Formule III, njegovog stereoizomera, geometrijskog izomera, tautomera ili farmaceutski prihvatljive soli, iz smjese produkata reakcije,
gdje postupak dodatno uključuje korake pročišćavanja, gdje se navedeni koraci sastoje u:
(I) miješanju spoja Formule III s hvatačem metala u sustavu otapala koji sadrži najmanje jedno polarno protonsko otapalo;
(II) grijanju smjese kako bi se otopilo spoj Formule III;
(III) filtriranju zagrijane smjese;
(IV) snižavanju temperature filtrata i miješanju kristala spoja Formule III za zasijavanje s ohlađenim filtratom;
(V) snižavanju temperature smjese filtrata i kristala za zasijavanje kako bi se potaklo kristalizaciju pročišćenog spoja Formule III; i
(VI) prikupljanju kristala pročišćenog spoja Formule III,
pri čemu:
(a) sustav otapala sadrži vodu i octenu kiselinu ili uglavnom se sastoji od vode i octene kiseline, pri čemu se volumni omjer između octene kiseline i vode kreće od 1:1 do 10:1;
(b) hvatač metala je silika-tiol; i
(c) temperatura otapanja se kreće od 80 °C do 100 °C, kristale za zasijavanje se kombinira s filtratom na temperaturi od 70 °C do 80 °C, a temperatura kristalizacije se kreće od 0 °C do 10 °C,
te pri čemu:
katalizator sadrži paladij, a reakcijska smjesa sadrži manje od 0,05 ekvivalenata katalizatora po ekvivalentu spoja Formule II;
X1 je S, O, N, NR6, CR1, C(R1)2 ili -C(R1)2O-;
X2 je C, CR2 ili N;
X3 je C, CR3 ili N;
X4 je halogen;
A je 5, 6 ili 7-eročlani karbociklilni ili heterociklilni prsten kondenziran s X2 i X3, koji može biti supstituiran s jednom ili više skupina R5, R10 ili R15;
R6 je H, C1-C12 alkil, C2-C8 alkenil, C2-C8 alkinil, -(C1-C12 alkilen)-(C3-C12 karbociklil), -(C1-C12 alkilen)(-C2-C20 heterociklil), -(C1-C12 alkilen)-C(=O)-(C2-C20 heterociklil), (C1-C12 alkilen)-(C6-C20 aril), te -(C1-C12 alkilen)-(C1-C20 heteroaril), gdje alkil, alkenil, alkinil, alkilen, karbociklil, heterociklil, aril, te heteroaril mogu biti supstituirani s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -(CH3)2OH, -CH2OCH3, -CN, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila;
R1, R2, te R3 se neovisno bira između H, F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2OCH3, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2, -CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila;
R4 se bira između C6-C20 arila, C2-C20 heterociklila i C1-C20 heteroarila, od kojih svaki može biti supstituiran s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH3, -CH2CN, -CN, -CF3, -CH2OH, -CO2H, -CONH2, CONH(CH3), -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -NHS(O)2CH3, -N(CH3)C(O)OC(CH3)3, -S(O)2CH3, benzila, benziloksi, morfolinila, morfolinometila, te 4-metilpiperazin-1-ila;
svakog R5, R10 i R15 se neovisno bira između C1-C12 alkila, C2-C8 alkenila, C2-C8 alkinila, -(C1-C12 alkilen)-(C3-C12 karbociklila), -(C1-C12 alkilen)-(C2-C20 heterociklila), -(C1-C12 alkilen)-C(O)-(C2-C20 heterociklila), -(C1-C12 alkilen)-(C6-C20 arila), te -(C1-C12 alkilen)-(C1-C20 heteroarila); ili dvije geminalne skupine R5, R10 i/ili R15 tvore 3, 4, 5, ili 6-eročlani karbociklilni ili heterociklilni prsten, gdje alkil, alkenil, alkinil, alkilen, karbociklil, heterociklil, aril, te heteroaril mogu biti supstituirani s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2OCH3, -CN, -CH2F, -CHF2, -CF3, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NH-COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila; i
mor se bira između:
[image]
[image]
,
pri čemu mor može biti supstituiran s jednom ili više skupina R7 koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, te -CH2S(O)2CH3.
2. Postupak u skladu s patentnim zahtjevom 1, pri čemu sustav otapala dodatno sadrži najmanje jedno polarno neprotonsko otapalo kojeg se bira između N-metilpirolidona, metil-izobutil-ketona, metil-etil-ketona, tetrahidrofurana, diklormetana, etil-acetata, acetona, N,N-dimetilformamida, acetonitrila i dimetil-sulfoksida.
3. Postupak u skladu s patentnim zahtjevom 2, pri čemu se omjer između vode i najmanje jednog polarnog neprotonskog otapala kreće od 1:10 vol./vol. i 5:1 vol./vol.
4. Postupak u skladu s patentnim zahtjevom 2 ili patentnim zahtjevom 3, pri čemu se sustav otapala uglavnom sastoji od vode i najmanje jednog polarnog neprotonskog otapala.
5. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 4, pri čemu je organobor-R4 5-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2 il)-R4.
6. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 5, pri čemu se bazu bira između K3PO4, Cs2CO3 i KOH.
7. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 6, pri čemu se katalizator koji sadrži paladij bira između klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-aminoetil)fenil)]paladija(II) ("Pd Xphos"); kompleksa 1,1′-bis(difenilfosfino)ferocen]dikloropaladija(II) s diklormetanom ("PdCl2 dppf CH2Cl2"); bis(di-tert-butil(4-dimetilaminofenil)fosfin)dikloropaladija(II) ("Pd(amphos)Cl2"); diklorbis(di-tert-butilfenilfosfin)paladija(II) ("Pd 122"); PdCl2(PPh3)2; Pd(t-Bu)3; Pd(PPh3)4; Pd(Oac)/PPh3; Cl2Pd[(Pet3)]2; Pd(DIPHOS)2; Cl2Pd(Bipy); [PdCl(Ph2PCH2PPh2)]2; Cl2Pd[P(o-tol)3]2; Pd2(dba)3/P(o-tol)3; Pd2(dba)/P(furil)3; Cl2Pd[P(furil)3]2; Cl2Pd(PmePh2)2; Cl2Pd[P(4-F-Ph)3]2; Cl2Pd[P(C6F6)3]2; Cl2Pd[P(2-COOH-Ph)(Ph)2]2; Cl2Pd[P(4-COOH-Ph)(Ph)2]2; paladijevog acetata, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd; paladijevog acetata i trifenilfosfina, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd i 0,3 mmol/g fosfora; paladijevog acetata i BINAP, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd; i klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladija(II) ("XPhos PdG2").
8. Postupak u skladu s patentnim zahtjevom 7, pri čemu se katalizator koji sadrži paladij bira između:
klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-aminoetil)fenil)]paladij(II), kompleks 1,1′-bis(difenilfosfino)ferocen]dikloropaladija(II) s diklormetanom, te
klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladij(II) ("XPhos PdG2").
9. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 8, pri čemu je ekvivalentni omjer između katalizatora koji sadrži paladij i spoja Formule II između 0,003:1 i 0,05:1.
10. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 9, pri čemu je temperatura reakcije između 40 °C i 100 °C.
11. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 10, koji se dodatno sastoji u dodavanju polarnog protonskog otapala u smjesu produkata reakcije kako bi se dobilo smjesu koja sadrži više od 25 vol./vol.% vode i izdvajanju spoja Formule III iz smjese produkata reakcije odvajanjem krutine od tekućine.
12. Postupak u skladu s patentnim zahtjevom 11, pri čemu se polarno protonsko otapalo bira između vode, metanola, etanola, izopropanola, n-propanola, te octene kiseline.
13. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 12, pri čemu se volumni omjer između octene kiseline i vode kreće (i) od 1:1 do 5:1 ili (ii) od 1:1 do 3:1, ili (iii) 3:1.
14. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 13, pri čemu je spoj Formule III:
[image]
.
15. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 14, pri čemu je katalizator koji sadrži paladij klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladij(II) ("Xphos PdG2").
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EP16876773.9A EP3389662B1 (en) | 2015-12-16 | 2016-12-16 | Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer |
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EP3978500C0 (en) | 2023-11-22 |
AU2021204704A1 (en) | 2021-08-05 |
ES2907574T3 (es) | 2022-04-25 |
AU2016369528A1 (en) | 2018-06-07 |
US10906918B2 (en) | 2021-02-02 |
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