EA016945B1 - ПИРИДОПИРИМИДИНОНОВЫЕ ИНГИБИТОРЫ PI3Kα - Google Patents
ПИРИДОПИРИМИДИНОНОВЫЕ ИНГИБИТОРЫ PI3Kα Download PDFInfo
- Publication number
- EA016945B1 EA016945B1 EA200800760A EA200800760A EA016945B1 EA 016945 B1 EA016945 B1 EA 016945B1 EA 200800760 A EA200800760 A EA 200800760A EA 200800760 A EA200800760 A EA 200800760A EA 016945 B1 EA016945 B1 EA 016945B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pyrimidin
- methyl
- ethyl
- pyrido
- ethylamino
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 19
- IAAQUOVTPAMQCR-UHFFFAOYSA-N 1h-pyrido[3,2-d]pyrimidin-2-one Chemical compound C1=CC=C2NC(=O)N=CC2=N1 IAAQUOVTPAMQCR-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 264
- 150000003839 salts Chemical class 0.000 claims abstract description 84
- 238000000034 method Methods 0.000 claims abstract description 75
- 239000012453 solvate Substances 0.000 claims abstract description 60
- -1 aryl C1-6 alkyl Chemical group 0.000 claims description 319
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 214
- 239000000203 mixture Substances 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 239000001257 hydrogen Substances 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 50
- 206010028980 Neoplasm Diseases 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 150000002367 halogens Chemical group 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 201000011510 cancer Diseases 0.000 claims description 32
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 30
- 125000003282 alkyl amino group Chemical group 0.000 claims description 25
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 22
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 18
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 16
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 150000003254 radicals Chemical class 0.000 claims description 14
- 201000009030 Carcinoma Diseases 0.000 claims description 12
- 125000004497 pyrazol-5-yl group Chemical group N1N=CC=C1* 0.000 claims description 12
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- 208000005017 glioblastoma Diseases 0.000 claims description 11
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 claims description 11
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 10
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 10
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 10
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 9
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 9
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 9
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 9
- 125000006413 ring segment Chemical group 0.000 claims description 9
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 8
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- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 8
- 230000003993 interaction Effects 0.000 claims description 8
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 8
- 125000001724 1,2,3-oxadiazol-4-yl group Chemical group [H]C1=C(*)N=NO1 0.000 claims description 7
- 125000004503 1,2,3-oxadiazol-5-yl group Chemical group O1N=NC=C1* 0.000 claims description 7
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 7
- 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims description 7
- 125000004509 1,3,4-oxadiazol-2-yl group Chemical group O1C(=NN=C1)* 0.000 claims description 7
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 7
- 210000003494 hepatocyte Anatomy 0.000 claims description 7
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 7
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 7
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 7
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 claims description 7
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000001506 1,2,3-triazol-5-yl group Chemical group [H]N1N=NC([H])=C1[*] 0.000 claims description 5
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 5
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- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 5
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
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- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- CUPOOAWTRIURFT-UHFFFAOYSA-N thiophene-2-carbonitrile Chemical compound N#CC1=CC=CS1 CUPOOAWTRIURFT-UHFFFAOYSA-N 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
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- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- RODCZGBQVPTRTI-UHFFFAOYSA-N but-1-en-2-yl(tributyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C(=C)CC RODCZGBQVPTRTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 3
- 201000000170 Thyroid lymphoma Diseases 0.000 claims 1
- 150000007942 carboxylates Chemical class 0.000 claims 1
- 230000008520 organization Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- 238000005160 1H NMR spectroscopy Methods 0.000 description 100
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
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- 239000000243 solution Substances 0.000 description 61
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
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Classifications
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- 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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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
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- Dispersion Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72457105P | 2005-10-07 | 2005-10-07 | |
| US74371906P | 2006-03-23 | 2006-03-23 | |
| PCT/US2006/039734 WO2007044813A1 (en) | 2005-10-07 | 2006-10-09 | PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kα |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200800760A1 EA200800760A1 (ru) | 2008-08-29 |
| EA016945B1 true EA016945B1 (ru) | 2012-08-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200800760A EA016945B1 (ru) | 2005-10-07 | 2006-10-09 | ПИРИДОПИРИМИДИНОНОВЫЕ ИНГИБИТОРЫ PI3Kα |
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| EP (2) | EP1940839B1 (enExample) |
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| BR (1) | BRPI0617159B8 (enExample) |
| CA (1) | CA2623770C (enExample) |
| DK (1) | DK1940839T3 (enExample) |
| EA (1) | EA016945B1 (enExample) |
| ES (1) | ES2432046T3 (enExample) |
| GE (1) | GEP20115304B (enExample) |
| HR (1) | HRP20130902T1 (enExample) |
| IL (1) | IL190292A (enExample) |
| NO (1) | NO343136B1 (enExample) |
| NZ (2) | NZ566903A (enExample) |
| PL (1) | PL1940839T3 (enExample) |
| RS (1) | RS52953B (enExample) |
| WO (1) | WO2007044813A1 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2426654C (en) | 2000-10-23 | 2010-12-21 | Smithkline Beecham Corporation | 2,4,8-trisubstituted-8h-pyrido[2,3-d}pyrimidin-7-one compounds |
| MY145343A (en) * | 2005-03-25 | 2012-01-31 | Glaxo Group Ltd | Novel compounds |
| CN101282948A (zh) * | 2005-10-07 | 2008-10-08 | 埃克塞里艾克西斯公司 | N-(3-氨基-喹喔啉-2-基)-磺酰胺衍生物及其作为磷脂酰肌醇3-激酶抑制剂的用途 |
| EP1931670B1 (en) * | 2005-10-07 | 2012-09-12 | Exelixis, Inc. | Pyridopyrimidinone inhibitors of pi3k |
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