HRP20200395T1 - Derivat izoksazola kao inhibitor mutirane izocitratne dehidrogenaze 1 - Google Patents
Derivat izoksazola kao inhibitor mutirane izocitratne dehidrogenaze 1 Download PDFInfo
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- HRP20200395T1 HRP20200395T1 HRP20200395TT HRP20200395T HRP20200395T1 HR P20200395 T1 HRP20200395 T1 HR P20200395T1 HR P20200395T T HRP20200395T T HR P20200395TT HR P20200395 T HRP20200395 T HR P20200395T HR P20200395 T1 HRP20200395 T1 HR P20200395T1
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- 229940123392 Isocitrate dehydrogenase 1 inhibitor Drugs 0.000 title 1
- 150000002545 isoxazoles Chemical class 0.000 title 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 19
- 150000001875 compounds Chemical class 0.000 claims 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 18
- 150000003839 salts Chemical class 0.000 claims 17
- 125000005843 halogen group Chemical group 0.000 claims 10
- 125000001424 substituent group Chemical group 0.000 claims 9
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 claims 4
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 claims 4
- 206010028980 Neoplasm Diseases 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 4
- 101150084750 1 gene Proteins 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 3
- 125000003282 alkyl amino group Chemical group 0.000 claims 3
- 230000035772 mutation Effects 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- BOOMBLZEOHXPPX-BQYQJAHWSA-N (E)-3-[1-[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]-3-methylindol-4-yl]prop-2-enoic acid Chemical compound FC(C)(C)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N1C=C(C2=C(C=CC=C12)/C=C/C(=O)O)C BOOMBLZEOHXPPX-BQYQJAHWSA-N 0.000 claims 2
- 125000001931 aliphatic group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- QNNPJOOJDDDDNY-SFQUDFHCSA-N (2E)-2-[1-[3-(2,4-dichloro-5-fluorophenyl)-5-(1-prop-2-enoylpiperidin-4-yl)-1,2-oxazole-4-carbonyl]-3,4-dihydrobenzo[cd]indol-5-ylidene]acetic acid Chemical compound C(C=C)(=O)N1CCC(CC1)C1=C(C(=NO1)C1=C(C=C(C(=C1)F)Cl)Cl)C(=O)N1C=C2C=3C(=CC=CC1=3)\C(\CC2)=C\C(=O)O QNNPJOOJDDDDNY-SFQUDFHCSA-N 0.000 claims 1
- BFZBFTMWAHDZDP-SFQUDFHCSA-N (2E)-2-[1-[3-(2,4-dichloro-6-fluorophenyl)-5-(1-prop-2-enoylpiperidin-4-yl)-1,2-oxazole-4-carbonyl]-3,4-dihydrobenzo[cd]indol-5-ylidene]acetic acid Chemical compound C(C=C)(=O)N1CCC(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1F)Cl)Cl)C(=O)N1C=C2C=3C(=CC=CC1=3)\C(\CC2)=C\C(=O)O BFZBFTMWAHDZDP-SFQUDFHCSA-N 0.000 claims 1
- TXEIQQMABKQWLJ-NBVRZTHBSA-N (2E)-2-[1-[3-(2,4-dichlorophenyl)-5-(1-prop-2-enoylpiperidin-4-yl)-1,2-oxazole-4-carbonyl]-3,4-dihydrobenzo[cd]indol-5-ylidene]acetic acid Chemical compound C(C=C)(=O)N1CCC(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1)Cl)Cl)C(=O)N1C=C2C=3C(=CC=CC1=3)\C(\CC2)=C\C(=O)O TXEIQQMABKQWLJ-NBVRZTHBSA-N 0.000 claims 1
- CMZJOEOPYWOXKF-SFQUDFHCSA-N (2E)-2-[1-[5-(1-prop-2-enoylpiperidin-4-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]-3,4-dihydrobenzo[cd]indol-5-ylidene]acetic acid Chemical compound C(C=C)(=O)N1CCC(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N1C=C2C=3C(=CC=CC1=3)\C(\CC2)=C\C(=O)O CMZJOEOPYWOXKF-SFQUDFHCSA-N 0.000 claims 1
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims 1
- BVUMRBVNGXVXSA-BQYQJAHWSA-N (E)-3-[1-[3-(2,4-dichloro-6-fluorophenyl)-5-(2-fluoropropan-2-yl)-1,2-oxazole-4-carbonyl]-3-methylindol-4-yl]prop-2-enoic acid Chemical compound ClC1=C(C(=CC(=C1)Cl)F)C1=NOC(=C1C(=O)N1C=C(C2=C(C=CC=C12)/C=C/C(=O)O)C)C(C)(C)F BVUMRBVNGXVXSA-BQYQJAHWSA-N 0.000 claims 1
- MMJOWRUYBHASCG-JXMROGBWSA-N (E)-3-[1-[3-(2,4-dichlorophenyl)-5-(2-fluoropropan-2-yl)-1,2-oxazole-4-carbonyl]-3-methylindol-4-yl]prop-2-enoic acid Chemical compound ClC1=C(C=CC(=C1)Cl)C1=NOC(=C1C(=O)N1C=C(C2=C(C=CC=C12)/C=C/C(=O)O)C)C(C)(C)F MMJOWRUYBHASCG-JXMROGBWSA-N 0.000 claims 1
- UPPAAWQBZQBNIE-USRGLUTNSA-N (E)-3-[1-[5-(2-fluoropropan-2-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]-3-methylindol-4-yl]prop-2-enoic acid 2-methylpropan-2-amine Chemical compound CC(C)(C)N.Cc1cn(C(=O)c2c(noc2C(C)(C)F)-c2c(Cl)cc(Cl)cc2Cl)c2cccc(\C=C\C(O)=O)c12 UPPAAWQBZQBNIE-USRGLUTNSA-N 0.000 claims 1
- GUUIMFGRPPTLFX-AATRIKPKSA-N (E)-3-[1-[5-(3-methyloxetan-3-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]indol-4-yl]prop-2-enoic acid Chemical compound CC1(COC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N1C=CC2=C(C=CC=C12)/C=C/C(=O)O GUUIMFGRPPTLFX-AATRIKPKSA-N 0.000 claims 1
- LCOBXWZHLGWJIZ-BQYQJAHWSA-N (E)-3-[1-[5-tert-butyl-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]indol-4-yl]prop-2-enoic acid Chemical compound C(C)(C)(C)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N1C=CC2=C(C=CC=C12)/C=C/C(=O)O LCOBXWZHLGWJIZ-BQYQJAHWSA-N 0.000 claims 1
- OQCSPKPCFMSGAE-BQYQJAHWSA-N (E)-3-[3-methyl-1-[5-(1-prop-2-enoylpiperidin-4-yl)-3-(2,4,6-trichlorophenyl)-1,2-oxazole-4-carbonyl]indol-4-yl]prop-2-enoic acid Chemical compound C(C=C)(=O)N1CCC(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)Cl)Cl)C(=O)N1C=C(C2=C(C=CC=C12)/C=C/C(=O)O)C OQCSPKPCFMSGAE-BQYQJAHWSA-N 0.000 claims 1
- HWXBTNAVRSUOJR-GSVOUGTGSA-N (R)-2-hydroxyglutaric acid Chemical compound OC(=O)[C@H](O)CCC(O)=O HWXBTNAVRSUOJR-GSVOUGTGSA-N 0.000 claims 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 1
- 206010004593 Bile duct cancer Diseases 0.000 claims 1
- 208000003174 Brain Neoplasms Diseases 0.000 claims 1
- 208000005243 Chondrosarcoma Diseases 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 206010025323 Lymphomas Diseases 0.000 claims 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 1
- 206010057846 Primitive neuroectodermal tumour Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 210000001744 T-lymphocyte Anatomy 0.000 claims 1
- 208000024770 Thyroid neoplasm Diseases 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- HWXBTNAVRSUOJR-UHFFFAOYSA-N alpha-hydroxyglutaric acid Natural products OC(=O)C(O)CCC(O)=O HWXBTNAVRSUOJR-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 210000003719 b-lymphocyte Anatomy 0.000 claims 1
- 208000026900 bile duct neoplasm Diseases 0.000 claims 1
- 208000006990 cholangiocarcinoma Diseases 0.000 claims 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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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- Animal Behavior & Ethology (AREA)
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- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Claims (18)
1. Spoj predstavljen općom formulom (I) ili njegova farmaceutski prihvatljiva sol:
[image]
gdje
Z-Y predstavlja N-O ili O-N;
R1 predstavlja fenil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe A, ili piridil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe A;
R2 predstavlja -NR21R22, C1 do C6 alkil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe B, C3 do C6 cikloalkil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe C, ili 4- do 6-očlanu heterocikličnu grupu koja ima 1 ili 2 heteroatoma nezavisno odabrana iz grupe koja se sastoji od atoma dušika i atoma kisika u prstenu, gdje 4- do 6-očlana heterociklična grupa opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe C, i
premošćena struktura je opcionalno vezana unutar heterocikličnog prstena, ili je jedan C3 do C6 cikloalkil prsten opcionalno vezan na heterociklični prsten preko spiro veze;
R21 i R22 svako nezavisno predstavlja atom vodika, C1 do C6 alkil grupu, ili -C(=O)R23;
R23 predstavlja C2 do C6 alkenil grupu ili C2 do C6 alkinil grupu;
R3 predstavlja bilo koju od narednih formula (II) do (IV):
[image]
gdje
R31 predstavlja atom vodika, atom halogena, C1 do C6 alkil grupu opcionalno supstituiranu sa 1 do 3 atoma halogena, C3 do C6 cikloalkil grupu, ili C1 do C6 alkilkarbonil grupu,
R32 predstavlja atom vodika ili C1 do C6 alkil grupu, ili
R31 i R32 opcionalno zajedno formiraju cikloheksanski prsten,
R33 predstavlja atom vodika ili C1 do C6 alkil grupu, ili
R32 i R33 opcionalno zajedno formiraju ciklopropanski prsten,
R34 predstavlja atom vodika ili C1 do C6 alkil grupu,
R35 predstavlja C1 do C6 alkil grupu,
R36 predstavlja atom vodika ili C1 do C6 alkil grupu,
R37 predstavlja atom vodika ili C1 do C6 alkil grupu, ili
R36 i R37 opcionalno zajedno formiraju benzenov prsten,
R38 predstavlja atom vodika ili atom halogena,
X predstavlja atom dušika ili CH,
W predstavlja atom dušika ili CH, i
isprekidana linija predstavlja jednostruku vezu ili dvostruku vezu;
grupa A se sastoji od atoma halogena, C1 do C6 alkil grupe i C1 do C6 alkoksi grupe;
grupa B se sastoji od atoma halogena, hidroksi grupe, C1 do C6 alkoksi grupe, C1 do C6 alkilamino grupe, i di-C1 do C6 alkilamino grupe,
grupa C se sastoji od C2 do C6 alkenil grupe, atoma halogena, hidroksi grupe, cijano grupe, C1 do C6 alkil grupe koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz naredne grupe D, C1 do C6 alkoksi grupe, -NR211R212, -C(=O)R213, i -SO2R213;
R211 i R212 svako nezavisno predstavlja atom vodika ili C1 do C6 alkil grupu;
R213 predstavlja C2 do C6 alkenil grupu ili C2 do C6 alkinil grupu; i
grupa D se sastoji od amino grupe, C1 do C6 alkoksi grupe, di-C1 do C6 alkilamino grupe, okso grupe, i C3 do C6 cikloalkil grupe.
2. Spoj prema patentnom zahtjevu 1 ili njegova farmaceutski prihvatljiva sol, gdje u formuli (I), R1 predstavlja fenil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz grupe A.
3. Spoj prema patentnom zahtjevu 1 ili 2 ili njegova farmaceutski prihvatljiva sol, gdje u formuli (I), R2 predstavlja C1 do C6 alkil grupu koja opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz grupe B, ili 4- do 6-očlanu alifatičnu heterocikličnu grupu koja ima 1 ili 2 heteroatoma nezavisno odabrana iz grupe koja se sastoji od atoma dušika i atoma kisika u prstenu, gdje
4- do 6-očlana alifatična heterociklična grupa opcionalno ima 1 do 3 supstituenta nezavisno odabrana iz grupe C.
4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3 ili
njegova farmaceutski prihvatljiva sol, gdje u formuli (I),
R2 predstavlja bilo koju od narednih formula:
[image]
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 4 ili njegova farmaceutski prihvatljiva sol, gdje u formuli(I),
R3 predstavlja narednu formulu (IV') ili (V):
[image]
gdje
R3a predstavlja atom vodika ili C1 do C6 alkil grupu opcionalno supstituiranu sa 1 do 3 atoma halogena,
R3b predstavlja atom vodika ili C1 do C6 alkil grupu,
R3c predstavlja atom vodika ili C1 do C6 alkil grupu,
R3d predstavlja atom vodika ili C1 do C6 alkil grupu,
R3e predstavlja atom vodika ili atom halogena, i
isprekidana linija predstavlja jednostruku vezu ili dvostruku vezu.
6. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5 ili njegova farmaceutski prihvatljiva sol, gdje u formuli (I),
R3 predstavlja bilo koju od narednih formula:
[image]
7. Spoj prema patentnom zahtjevu 1 predstavljeno općom formulom VI ili njegova farmaceutski prihvatljiva sol:
[image]
gdje
R4, R5, i R6 svako nezavisno predstavlja atom vodika ili atom halogena,
R7 predstavlja bilo koju od narednih formula:
[image]
i
R8 i R9 svako nezavisno predstavlja atom vodika ili C1 do C6 alkil grupu.
8. Spoj prema patentnom zahtjevu 1 predstavljeno općom formulom VII ili njegova farmaceutski prihvatljiva sol:
[image]
gdje
R10, R11, i R12 svako nezavisno predstavlja atom vodika ili atom halogena,
R13 predstavlja bilo koju od narednih formula:
[image]
i
R14 predstavlja atom vodika ili C1 do C6 alkil grupu.
9. Spoj prema patentnom zahtjevu 1 odabrano iz naredne grupe ili njegova farmaceutski prihvatljiva sol:
(2E)-3-(1-{[5-(3-metiloksetan-3-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-1H-indol-4-il)prop-2-enska kiselina
(2E)-3-(1-{[5-(2-fluoropropan-2-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enska kiselina
(2E)-3-(1-{[5-(terc-butil)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-1H-indol-4-il)prop-2-enska kiselina
(2E)-3-(1-{[3-(2,4-dikloro-6-fluorofenil)-5-(2-fluoropropan-2-il)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enska kiselina
(2E)-3-(1-{[3-(2,4-diklorofenil)-5-(2-fluoropropan-2-il)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enska kiselina
(2E)-[1-{[5-(1-akriloilpiperidin-4-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-3,4-dihidrobenzo[cd]indol-5(1H)-iliden]etanska kiselina
(2E)-3-(1-{[5-(1-akriloilpiperidin-4-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enska kiselina
(2E)-[1-{[5-(1-akriloilpiperidin-4-il)-3-(2,4-dikloro-6-fluorofenil)-1,2-oksazol-4-il]karbonil}-3,4-dihidrobenzo[cd]indol-5(1H)-iliden]etanska kiselina
(2E)-[1-{[5-(1-akriloilpiperidin-4-il)-3-(2,4-dikloro-5-fluorofenil)-1,2-oksazol-4-il]karbonil}-3,4-dihidrobenzo[cd]indol-5(1H)-iliden]etanska kiselina
(2E)-[1-{[5-(1-akriloilpiperidin-4-il)-3-(2,4-diklorofenil)-1,2-oksazol-4-il]karbonil}-3,4-dihidrobenzo[cd]indol-5(1H)-iliden]etanska kiselina.
10. Spoj prema patentnom zahtjevu 1 koje je (2E)-3-(1-{[5-(2-fluoropropan-2-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enska kiselina ili njegova farmaceutski prihvatljiva sol.
11. Spoj prema patentnom zahtjevu 1 koje je (2E)-3-(1-{[5-(2-fluoropropan-2-il)-3-(2,4,6-triklorofenil)-1,2-oksazol-4-il]karbonil}-3-metil-1H-indol-4-il)prop-2-enske kiseline terc-butilamin sol.
12. Spoj prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegova farmaceutski prihvatljiva sol za primjenu kao inhibitor mutirane izocitratne dehidrogenaze 1.
13. Spoj prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegova farmaceutski prihvatljiva sol za primjenu kao inhibitor proizvodnje D-2-hidroksiglutarata.
14. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegovu farmaceutski prihvatljivu sol kao aktivni sastojak.
15. Spoj prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegova farmaceutski prihvatljiva sol za primjenu kao antitumorski agens protiv tumora koji ima mutaciju gena izocitratne dehidrogenaze 1.
16. Spoj prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegova farmaceutski prihvatljiva sol za primjenu u metodi za liječenje tumora koji ima mutaciju gena izocitratne dehidrogenaze 1.
17. Primjena spoja prema bilo kojem od patentnih zahtjeva 1 do 11 ili njegove farmaceutski prihvatljive soli za proizvodnju farmaceutske kompozicije za liječenje tumora koji ima mutaciju gena izocitratne dehidrogenaze 1.
18. Spoj ili njegova farmaceutski prihvatljiva sol za primjenu prema patentnom zahtjevu 15 ili patentnom zahtjevu 16, ili primjena prema patentnom zahtjevu 17, gdje tumor je tumor na mozgu (uključujući gliom), akutna mijeloidna leukemija, mijelodisplastični sindrom, mijeloproliferativni tumor, periferni limfom T stanica, hondrosarkom, osteosarkom, rak žučnog kanala, primitivni neuroektodermalni tumor, limfoblastični limfom B stanica, maligni melanom, rak prostate, kolorektalni rak i tiroidni rak.
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EP15845549.3A EP3202766B1 (en) | 2014-10-01 | 2015-10-01 | Isoxazole derivative as mutated isocitrate dehydrogenase 1 inhibitor |
PCT/JP2015/077916 WO2016052697A1 (ja) | 2014-10-01 | 2015-10-01 | 変異型イソクエン酸デヒドロゲナーゼ1阻害剤としてのイソキサゾール誘導体 |
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WO2017213910A1 (en) | 2016-06-06 | 2017-12-14 | Eli Lilly And Company | Mutant idh1 inhibitors |
WO2018010142A1 (en) | 2016-07-14 | 2018-01-18 | Shanghai Meton Pharmaceutical Co., Ltd | Iso-citrate dehydrogenase (idh) inhibitor |
CA3070878A1 (en) * | 2017-08-01 | 2019-02-07 | Deutsches Krebsforschungszentrum | Combination of midh1 inhibitors and dna hypomethylating agents (hma) |
WO2019146129A1 (ja) * | 2018-01-29 | 2019-08-01 | 富士フイルム株式会社 | イソクエン酸デヒドロゲナーゼ変異を有する腫瘍に対する医薬組成物および抗腫瘍剤ならびにその利用 |
WO2021176098A1 (en) | 2020-03-05 | 2021-09-10 | Université de Lausanne | Modulators of aralar for treating neurological disorders |
JP2022021331A (ja) | 2020-07-21 | 2022-02-02 | 第一三共株式会社 | テモゾロミドと変異型idh1酵素阻害剤の組み合わせ医薬 |
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