ES2923652T3 - Inhibidores de la actividad LDHA - Google Patents
Inhibidores de la actividad LDHA Download PDFInfo
- Publication number
- ES2923652T3 ES2923652T3 ES18727384T ES18727384T ES2923652T3 ES 2923652 T3 ES2923652 T3 ES 2923652T3 ES 18727384 T ES18727384 T ES 18727384T ES 18727384 T ES18727384 T ES 18727384T ES 2923652 T3 ES2923652 T3 ES 2923652T3
- Authority
- ES
- Spain
- Prior art keywords
- thiophen
- alkyl
- thio
- group
- dione
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
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- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 title claims abstract description 75
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 title claims description 62
- 230000000694 effects Effects 0.000 title description 23
- 239000003112 inhibitor Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 230000004913 activation Effects 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 146
- 229910052736 halogen Inorganic materials 0.000 claims description 60
- 125000001424 substituent group Chemical group 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 41
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- -1 2-chloro-4-fluorophenyl Chemical group 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 25
- 230000005764 inhibitory process Effects 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 230000002265 prevention Effects 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 102100024580 L-lactate dehydrogenase B chain Human genes 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 101001051207 Homo sapiens L-lactate dehydrogenase B chain Proteins 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- VIYOREKDGJPDAL-UHFFFAOYSA-N 3-(2-chloro-4-fluorophenyl)sulfanyl-6-(4-morpholin-4-ylphenyl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=CC(=C1)F)SC1C(NC(CC1=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1)=O VIYOREKDGJPDAL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- IKKDBRYHNHPJEL-UHFFFAOYSA-N 3-(2,5-dichlorophenyl)sulfanyl-6-(4-morpholin-4-ylphenyl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=C(C=C1)Cl)SC1C(NC(CC1=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1)=O IKKDBRYHNHPJEL-UHFFFAOYSA-N 0.000 claims description 6
- IKUIRSQFPDRAQK-UHFFFAOYSA-N 3-(2-chloro-4-fluorophenyl)sulfanyl-6-[6-(cyclopentylmethoxy)pyridin-2-yl]-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=CC(=C1)F)SC1C(NC(CC1=O)(C1=CSC=C1)C1=NC(=CC=C1)OCC1CCCC1)=O IKUIRSQFPDRAQK-UHFFFAOYSA-N 0.000 claims description 6
- KQRCMGGAMVEQEA-UHFFFAOYSA-N 6-[6-(cyclopentylmethoxy)pyridin-2-yl]-3-(2,5-dichlorophenyl)sulfanyl-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound C1(CCCC1)COC1=CC=CC(=N1)C1(CC(C(C(N1)=O)SC1=C(C=CC(=C1)Cl)Cl)=O)C1=CSC=C1 KQRCMGGAMVEQEA-UHFFFAOYSA-N 0.000 claims description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 6
- 210000004556 brain Anatomy 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- BJIQEKSMSATHGA-UHFFFAOYSA-N 6-(6-bromopyridin-2-yl)-3-(2-chloro-4-fluorophenyl)sulfanyl-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound BrC1=CC=CC(=N1)C1(CC(C(C(N1)=O)SC1=C(C=C(C=C1)F)Cl)=O)C1=CSC=C1 BJIQEKSMSATHGA-UHFFFAOYSA-N 0.000 claims description 5
- DKPAMPWXUTVUBC-UHFFFAOYSA-N 6-[6-(cyclopentylmethoxy)pyridin-2-yl]-3-(2,3-dichlorophenyl)sulfanyl-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound C1(CCCC1)COC1=CC=CC(=N1)C1(CC(C(C(N1)=O)SC1=C(C(=CC=C1)Cl)Cl)=O)C1=CSC=C1 DKPAMPWXUTVUBC-UHFFFAOYSA-N 0.000 claims description 5
- UTWOFCHGWRXCQP-UHFFFAOYSA-N 6-[6-(cyclopentylmethoxy)pyridin-2-yl]-3-(2,4-dichlorophenyl)sulfanyl-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound C1(CCCC1)COC1=CC=CC(=N1)C1(CC(C(C(N1)=O)SC1=C(C=C(C=C1)Cl)Cl)=O)C1=CSC=C1 UTWOFCHGWRXCQP-UHFFFAOYSA-N 0.000 claims description 5
- 201000009030 Carcinoma Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 210000004185 liver Anatomy 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- MPHRDYMCSSTOSV-UHFFFAOYSA-N 3-(2,4-dichlorophenyl)sulfanyl-6-(4-morpholin-4-ylphenyl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=CC(=C1)Cl)SC1C(NC(CC1=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1)=O MPHRDYMCSSTOSV-UHFFFAOYSA-N 0.000 claims description 4
- QOZXXUQDVNHSND-UHFFFAOYSA-N 6-(6-bromopyridin-2-yl)-3-(2,3-dichlorophenyl)sulfanyl-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound BrC1=CC=CC(=N1)C1(CC(C(C(N1)=O)SC1=C(C(=CC=C1)Cl)Cl)=O)C1=CSC=C1 QOZXXUQDVNHSND-UHFFFAOYSA-N 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- FOZCSFRVTJWUIX-UHFFFAOYSA-N 3-(2,3-dichlorophenyl)sulfanyl-6-(4-morpholin-4-ylphenyl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=CC=C1Cl)SC1C(NC(CC1=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1)=O FOZCSFRVTJWUIX-UHFFFAOYSA-N 0.000 claims description 3
- JEIFJFIYSOYMNT-UHFFFAOYSA-N 3-(2-chlorophenyl)sulfanyl-6-(2-morpholin-4-ylpyrimidin-5-yl)-6-thiophen-3-yloxane-2,4-dione Chemical compound ClC1=C(C=CC=C1)SC1C(OC(CC1=O)(C1=CSC=C1)C=1C=NC(=NC=1)N1CCOCC1)=O JEIFJFIYSOYMNT-UHFFFAOYSA-N 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000012010 growth Effects 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 210000001685 thyroid gland Anatomy 0.000 claims description 3
- WZERHEYLHRAQCF-UHFFFAOYSA-N 3-(2-chloro-4-fluorophenyl)sulfanyl-6-(6-ethoxypyridin-2-yl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound ClC1=C(C=CC(=C1)F)SC1C(NC(CC1=O)(C1=CSC=C1)C1=NC(=CC=C1)OCC)=O WZERHEYLHRAQCF-UHFFFAOYSA-N 0.000 claims description 2
- ZTEFMHCAYWPPRS-UHFFFAOYSA-N 3-(2-chlorophenyl)sulfanyl-6-pyridin-2-yl-6-thiophen-3-yloxane-2,4-dione Chemical compound ClC1=C(C=CC=C1)SC1C(OC(CC1=O)(C1=CSC=C1)C1=NC=CC=C1)=O ZTEFMHCAYWPPRS-UHFFFAOYSA-N 0.000 claims description 2
- YWRDZRSMNUHCMP-UHFFFAOYSA-N 3-(2-chlorophenyl)sulfanyl-6-pyrimidin-5-yl-6-thiophen-3-yloxane-2,4-dione Chemical compound ClC1=C(C=CC=C1)SC1C(OC(CC1=O)(C1=CSC=C1)C=1C=NC=NC=1)=O YWRDZRSMNUHCMP-UHFFFAOYSA-N 0.000 claims description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 206010027654 Allergic conditions Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 208000008383 Wilms tumor Diseases 0.000 claims description 2
- GDHLLRNOMBGBNG-UHFFFAOYSA-N [5-(2,5-dichlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-6-oxo-2-thiophen-3-yl-1,3-dihydropyridin-4-yl] 2,2-dimethylpropanoate Chemical compound C(C(C)(C)C)(=O)OC=1CC(NC(C=1SC1=C(C=CC(=C1)Cl)Cl)=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1 GDHLLRNOMBGBNG-UHFFFAOYSA-N 0.000 claims description 2
- ITGVGDJCWPGVLQ-UHFFFAOYSA-N [5-(2,5-dichlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-6-oxo-2-thiophen-3-yl-1,3-dihydropyridin-4-yl] acetate Chemical compound C(C)(=O)OC=1CC(NC(C=1SC1=C(C=CC(=C1)Cl)Cl)=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1 ITGVGDJCWPGVLQ-UHFFFAOYSA-N 0.000 claims description 2
- JPXCEYXDCUOEII-UHFFFAOYSA-N [5-(2,5-dichlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-6-oxo-2-thiophen-3-yl-1,3-dihydropyridin-4-yl] pyridine-4-carboxylate Chemical compound C(C1=CC=NC=C1)(=O)OC=1CC(NC(C=1SC1=C(C=CC(=C1)Cl)Cl)=O)(C1=CSC=C1)C1=CC=C(C=C1)N1CCOCC1 JPXCEYXDCUOEII-UHFFFAOYSA-N 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- 210000003679 cervix uteri Anatomy 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
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- 208000032839 leukemia Diseases 0.000 claims description 2
- 208000030159 metabolic disease Diseases 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 230000002188 osteogenic effect Effects 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 210000000664 rectum Anatomy 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- SLYWPACVUWKZSI-UHFFFAOYSA-N 6-(5-bromopyridin-2-yl)-3-(2-chlorophenyl)sulfanyl-6-thiophen-3-yloxane-2,4-dione Chemical compound BrC=1C=CC(=NC=1)C1(CC(C(C(O1)=O)SC1=C(C=CC=C1)Cl)=O)C1=CSC=C1 SLYWPACVUWKZSI-UHFFFAOYSA-N 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 30
- 108010088350 Lactate Dehydrogenase 5 Proteins 0.000 abstract description 16
- 230000006806 disease prevention Effects 0.000 abstract description 2
- 229940002612 prodrug Drugs 0.000 abstract 1
- 239000000651 prodrug Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 150
- 210000004027 cell Anatomy 0.000 description 74
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 47
- 238000002360 preparation method Methods 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 40
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 38
- 238000000034 method Methods 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 36
- 239000000243 solution Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000007832 Na2SO4 Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- 238000003818 flash chromatography Methods 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 25
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 24
- 238000003556 assay Methods 0.000 description 23
- 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 description 21
- 239000008346 aqueous phase Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
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- 239000012043 crude product Substances 0.000 description 19
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 13
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 12
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 12
- 230000003833 cell viability Effects 0.000 description 11
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- 239000002904 solvent Substances 0.000 description 10
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- 108090000790 Enzymes Proteins 0.000 description 9
- IZVCVGFBUPOAFX-UHFFFAOYSA-N 6-(4-morpholin-4-ylphenyl)-6-thiophen-3-ylpiperidine-2,4-dione Chemical compound O1CCN(CC1)C1=CC=C(C=C1)C1(CC(CC(N1)=O)=O)C1=CSC=C1 IZVCVGFBUPOAFX-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000013058 crude material Substances 0.000 description 8
- 230000034659 glycolysis Effects 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- RDNZDMDLRIQQAX-UHFFFAOYSA-N piperidine-2,4-dione Chemical compound O=C1CCNC(=O)C1 RDNZDMDLRIQQAX-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- 239000007858 starting material Substances 0.000 description 8
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
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- JBZVDFRSLQHLHJ-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)sulfanyl-3-oxobutanoate Chemical compound ClC1=C(C=CC=C1)SC(C(=O)OC)C(C)=O JBZVDFRSLQHLHJ-UHFFFAOYSA-N 0.000 description 1
- POUXLKDHERPEPY-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)sulfanyl-5-hydroxy-3-oxo-5-pyrimidin-5-yl-5-thiophen-3-ylpentanoate Chemical compound ClC1=C(C=CC=C1)SC(C(=O)OC)C(CC(C1=CSC=C1)(C=1C=NC=NC=1)O)=O POUXLKDHERPEPY-UHFFFAOYSA-N 0.000 description 1
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- 230000002611 ovarian Effects 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- NMGOURSDBHCEBL-UHFFFAOYSA-N pyrimidin-5-yl(thiophen-3-yl)methanol Chemical compound C=1N=CN=CC=1C(O)C=1C=CSC=1 NMGOURSDBHCEBL-UHFFFAOYSA-N 0.000 description 1
- FREJAOSUHFGDBW-UHFFFAOYSA-N pyrimidine-5-carbaldehyde Chemical compound O=CC1=CN=CN=C1 FREJAOSUHFGDBW-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 239000003104 tissue culture media Substances 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- 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
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1707856.9A GB201707856D0 (en) | 2017-05-16 | 2017-05-16 | Compounds |
| PCT/GB2018/051333 WO2018211277A1 (en) | 2017-05-16 | 2018-05-16 | Ldha activity inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2923652T3 true ES2923652T3 (es) | 2022-09-29 |
Family
ID=59201440
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES18727384T Active ES2923652T3 (es) | 2017-05-16 | 2018-05-16 | Inhibidores de la actividad LDHA |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US11142520B2 (https=) |
| EP (1) | EP3625225B1 (https=) |
| JP (1) | JP2020520388A (https=) |
| CN (1) | CN110709393A (https=) |
| ES (1) | ES2923652T3 (https=) |
| GB (1) | GB201707856D0 (https=) |
| WO (1) | WO2018211277A1 (https=) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114450399A (zh) * | 2019-05-02 | 2022-05-06 | 卢万天主教大学 | 用于治疗癌症的乳酸脱氢酶抑制剂多肽 |
| WO2023215293A1 (en) | 2022-05-02 | 2023-11-09 | Athanor Biosciences, Inc. | Cancer eradicating – bio-nanoparticles (ce-bnp) |
| WO2025011479A1 (en) * | 2023-07-13 | 2025-01-16 | Meta Pharmaceuticals (Hk) Limited | Pyrazole based inhibitors of LDH and their use in immune and inflammatory diseases |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5789440A (en) * | 1993-11-19 | 1998-08-04 | Warner-Lambert Company | 5,6-dihydropyrone derivatives as protease inhibitors and antiviral agents |
| SK283240B6 (sk) | 1993-11-19 | 2003-04-01 | Parke, Davis & Company | 5,6-Dihydropyrónové deriváty ako inhibítory proteázy a protivírusové činidlá a farmaceutická kompozícia obsahujúca tieto deriváty |
| RU2016137674A (ru) * | 2014-03-17 | 2018-04-18 | Ф. Хоффманн-Ля Рош Аг | Производные пиперидиндиона |
| WO2015142903A2 (en) * | 2014-03-17 | 2015-09-24 | Genentech, Inc. | Method of controlling lactate production with piperdine-dione derivatives |
| WO2017055396A1 (en) | 2015-09-30 | 2017-04-06 | Selvita S.A. | Pyrazolidine derivatives and related compounds |
| GB201707852D0 (en) * | 2017-05-16 | 2017-06-28 | Arctic Pharma As | Compounds |
| GB201707846D0 (en) * | 2017-05-16 | 2017-06-28 | Spermatech As | Use |
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2017
- 2017-05-16 GB GBGB1707856.9A patent/GB201707856D0/en not_active Ceased
-
2018
- 2018-05-16 EP EP18727384.2A patent/EP3625225B1/en active Active
- 2018-05-16 WO PCT/GB2018/051333 patent/WO2018211277A1/en not_active Ceased
- 2018-05-16 ES ES18727384T patent/ES2923652T3/es active Active
- 2018-05-16 US US16/613,837 patent/US11142520B2/en active Active
- 2018-05-16 CN CN201880034909.5A patent/CN110709393A/zh active Pending
- 2018-05-16 JP JP2020514351A patent/JP2020520388A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB201707856D0 (en) | 2017-06-28 |
| WO2018211277A1 (en) | 2018-11-22 |
| JP2020520388A (ja) | 2020-07-09 |
| EP3625225B1 (en) | 2022-06-29 |
| EP3625225A1 (en) | 2020-03-25 |
| US20200165233A1 (en) | 2020-05-28 |
| US11142520B2 (en) | 2021-10-12 |
| CN110709393A (zh) | 2020-01-17 |
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