JP2019528318A - 血液脳関門通過能を有する置換キナゾリン化合物 - Google Patents
血液脳関門通過能を有する置換キナゾリン化合物 Download PDFInfo
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- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 229950006451 sorbitan laurate Drugs 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- CIOAGBVUUVVLOB-OUBTZVSYSA-N strontium-89 Chemical compound [89Sr] CIOAGBVUUVVLOB-OUBTZVSYSA-N 0.000 description 1
- 229940006509 strontium-89 Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940032085 sucrose monolaurate Drugs 0.000 description 1
- 229940035023 sucrose monostearate Drugs 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229950004550 talazoparib Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
式中で、R1は独立してC1−10アルキル基、C3−12シクロアルキル基、C1−C2ペルフルオロアルキル基、複素環基、C1−C2ペルフルオロアルコキシ基、C2−C5エポキシ基又は重水素化アルキル基からなる群より選択される。
R2は独立してC1−10アルキル基、C3−12シクロアルキル基、C1−C2ペルフルオロアルキル基又は重水素化アルキル基からなる群より選択される。
R3は独立してハロゲン原子、C1−10アルキル基、C1−10アルコキシ基又はC2−10アルキニル基からなる群より選択される。
R4は独立して水素原子又はハロゲン原子からなる群より選択される。
R1は独立してメチル基又はオキセタンからなる群より選択され、
R2は独立してメチル基又は重水素化メチル基からなる群より選択され、
R3は独立して塩素原子又はエチニル基からなる群より選択され、
R4は独立して水素原子又はフッ素原子からなる群より選択される。
1)本発明のキナゾリン誘導体及びその薬学的に許容されるその塩は、予想外の血液脳関門通過能、及びプロテインキナーゼ阻害剤としての薬物特性を有し、特に、上皮成長因子受容体の特定の活性化変異(例えば、上皮成長因子受容体EGFRエクソン21 L858R活性化変異体及びエクソン19 Exon 19 del欠失活性化変異体)に媒介される病状への対応に適用され、異常なプロテインキナーゼ活性関連障害、例えば、がん、がんの脳転移、がんの髄膜転移、及び中枢神経系疾患等の治療又は予防に適用され得る。
2)本発明のキナゾリン誘導体及びその薬学的に許容される塩は、低排出率を有し、且つP−糖タンパク質の基質ではないため、P−糖タンパク質による薬剤耐性を低下させることができる。
3)本発明のキナゾリン誘導体及びその薬学的に許容される塩は、良好な薬物動態学的特性及び高生物活性を有し、服薬による患者に対する負担を減軽し、患者の服薬コンプライアンスを向上させることができる。
用語「改善」及び「治療」は、互換的に使用でき、両方とも疾患の発生又は発展(例えば、本明細書に記載の疾患又は障害)を低減、減軽、抑制、減少、阻止又は安定化することを意味し、有益又は期待できる結果を得るために使用される方法を指すが、治療上の有益性及び/又は予防上の有益性に限られない。
「疾患」とは、細胞、器官又は組織の正常機能を損害又は干渉する如何なる病状又は障害を指す。
「マーカー」とは、疾患又は障害に関連する如何なる変化を指す。例えば、疾患又は障害により表現レベル又は活性が変化する如何なるタンパク質又はポリヌクレオチドである。
ee値=(90−10)/100=80%。
一実施形態において、本発明は、式(I)の化合物又はその塩、そのプロドラッグ、そのプロドラッグの塩、その水和物、溶媒和物若しくは結晶多形体を提供する。
R1は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基、複素環基、C1−C2ペルフルオロアルコキシ基、エポキシ基又は重水素化アルキル基からなる群より選択され、
R2は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基又は重水素化アルキル基からなる群より選択され、
R3は独立してハロゲン、アルキル基、低級アルキル基、アルコキシ基又はアルキニル基からなる群より選択され、
R4は独立して水素原子又はハロゲンからなる群より選択される。
R1は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基、複素環基、C1−C2ペルフルオロアルコキシ基、エポキシ基又は重水素化アルキル基からなる群より選択され、
R2は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基又は重水素化アルキル基からなる群より選択され、
R3は独立してハロゲン、アルキル基、低級アルキル基、アルコキシ基又はアルキニル基からなる群より選択され、
R4は独立して水素原子又はハロゲンからなる群より選択される。
R1は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基、複素環基、C1−C2ペルフルオロアルコキシ基、エポキシ基又は重水素化アルキル基からなる群より選択され、
R2は独立してアルキル基、低級アルキル基、シクロアルキル基、C1−C2ペルフルオロアルキル基又は重水素化アルキル基からなる群より選択され、
R3は独立してハロゲン、アルキル基、低級アルキル基、アルコキシ基又はアルキニル基からなる群より選択され、
R4は独立して水素原子又はハロゲンからなる群より選択される。
(R/S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R/S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
(R/S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R/S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R/S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(R/S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
(R)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
(R)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(R)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
(S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
(S)−6−{[3,3−ジフルオロ−1−メチルピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン
(S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン
(S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン
(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン
(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン
中間体である5−フルオロ−4−メトキシ−2−ニトロベンゾニトリルA6及び1−ブロモ−5−フルオロ−4−(重水素化メトキシ)−2−ニトロベンゼンC1の合成
合成経路は、以下の通りである。
0℃でA1(2.0g、10.5mmol)とトリエチルアミン(1.3g、12.6mmol)のジクロロメタン(10ml)溶液にクロロギ酸エチル(1.4g、12.6mmol)のジクロロメタン(3ml)の溶液を1滴ずつ滴下した。0℃で反応混合物を1時間撹拌しながら室温に昇温させた。次いで、反応混合物を水で2回洗浄した。有機層を硫酸マグネシウムで乾燥させ、真空蒸発させることで、無色油状物として生成物A2(2.7g、収量100%)を得た。
10℃でA2(2.7g、10.3mmol)の濃硫酸(4.6mL)溶液に発煙硝酸(0.73ml、15.5mmol)を1滴ずつ滴下した。1時間後、反応混合物を氷/水に入れ、酢酸エチルで2回抽出した。合わせた有機層を水、重炭酸ナトリウム及び塩水で洗浄した後、硫酸ナトリウムで乾燥させ、真空蒸発させることで残留物を得た。残留物をシリカゲルカラム(n−ヘキサン/酢酸エチル=20/1)で精製して黄色油状物として生成物A3(3.0g、収量94.6%)を得た。
A3(3.0g、9.8mmol)のメタノール(17ml)溶液に重炭酸ナトリウム(1.6g、19.6mmol)を加えた。反応混合物を60℃で3時間撹拌した後、メタノールを真空蒸発させた。水(15ml)を残留物に加え、水層に5molの塩化水素溶液を加えてpH=5に調整した。酢酸エチルで水層を2回抽出した。合わせた有機層を硫酸マグネシウムで乾燥させ、真空蒸発させることで、黄色固体として生成物A4(2.3g、収量100%)を得た。
A4(2.31g、9.8mmol)のN,N−ジメチルホルムアミド(18.5ml)溶液に炭酸カリウム(2.7g、19.6mmol)及びヨウ化メチル(1.22ml,19.6mmol)を加えた。反応混合物を60℃で3時間撹拌した。得られた混合物を水と酢酸エチルとの間で分離した。有機層を硫酸ナトリウムで乾燥させ、真空蒸発させることで、黄色固体として生成物A5(2.35g、収量97%)を得た。
A4(1.5g、6.36mmol)のテトラヒドロフラン(19.5ml)及びトルエン(34.5ml)の溶液に、アゾジホルミルジピペリジン(4.81g、19.08mmol)、重水素化メタノール(688mg、19.08mmol)及びトリブチルホスフィン(3.86g、19.08mmol)を加えた。混合物を65℃3時間撹拌した後、反応混合物を室温に冷却した。酢酸エチル(20ml)を加え、混合物を濾過し、有機相を濃縮し、シリカゲルカラム(n−ヘキサン/酢酸エチル=20:1)で精製することで、淡黄色固体として生成物C1(1.50g、収量93.6%)を得た。
A5(5.17g、20.7mmol)とシアン化亜鉛(1.46g、12.4mmol)の混合物のN,N−ジメチルアセトアミド(104ml)溶液を撹拌した後、窒素で空気を置換し、その後、パラジウム触媒Pd2(dba)3(1.90g、2.07mmol)及び配位子である2−ジシクロヘキシルホスフィノ−2’−(N,N−ジメチルアミン)−ビフェニル(815mg、2.07mmol)を加え、反応混合物を110℃で5時間撹拌した。その後、室温に冷却し、酢酸エチルに希釈し、珪藻土で濾過した。有機溶液を塩水で洗浄した後、硫酸ナトリウムで乾燥させ、真空濃縮した後、シリカゲルカラム(酢酸エチル/n−ヘキサン:1:50〜1:10)で精製することで、淡黄色固体として生成物A6(3.47g、収量85.7%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:8.28(d, J = 10.7 Hz, 1H), 8.13(d, J = 7.5 Hz, 1H), 4.08(s, 1H). LC−MS:(ESI) m/z=197(M+H)+
合成経路は以下の通りである。
ベンゾトリアゾール(47g、394.5mmol)のメタノール(300ml)溶液に、B1(81.7g、394.5mmol)及び37%ホルムアルデヒド(37.9ml、512.9mmol)を加え、得られた混合物を室温で16時間撹拌した。真空下、混合物を除去し、残留物を水(500ml)に入れ、酢酸エチルで抽出(500ml×3)した後、硫酸ナトリウムで乾燥させ、濾過し濃縮することで、黄色油状物として生成物B2(132g、収量98.8%)を得た。
室温下、亜鉛粉(56g、862mmol)のテトラヒドロフラン(500ml)溶液にトリメチルクロロシラン(49g、452mmol)を加えた。得られた懸濁液を室温下で15分間撹拌した後、ジフルオロブロモ酢酸エチル(96g、474mmol)を1滴ずつ滴下し、混合物を15分間撹拌した。次いで、室温下でB2(146g、431mmol)のテトラヒドロフラン(500ml)溶液を加え、一夜撹拌した。得られた混合物を重炭酸ナトリウム(2.5升)の飽和水溶液に入れ、酢酸エチル(500ml)で抽出し、珪藻土で濾過して分離し、有機相を硫酸ナトリウムで乾燥させ、濾過し、濃縮することで残留物を得た。残留物をシリカゲルカラム(酢酸エチル/n−ヘキサン=1/50〜1/20)で精製することで、黄色油状物として生成物B3(90g、収量60.8%)を得た。
−70℃で、ジイソプロピルアミン(63.0g、629mmol)のテトラヒドロフラン(500ml)溶液に、n−ブチルリチウム(2.5Mヘキサン、231.5ml、576mmol)溶液を滴下し、得られた混合物を−10℃に昇温させて30分間反応させた。反応系を−70℃に冷却した後、B3(90g、262mmol)のテトラヒドロフラン溶液(500L)を1滴ずつ滴下した。30分間撹拌しながら室温に徐々に昇温させ、さらに1時間撹拌した。混合物を飽和塩化アンモニウム水溶液(500ml)に入れ、酢酸エチル(500L×3)で抽出し、有機相を硫酸ナトリウムで乾燥させ、濾過して濃縮することで、黄色油状物として生成物B4(90.7g)を得た。粗製物を精製せずにそのまま次のステップに用いた。
B4(90g、302mmol)を6mol塩酸(900ml)の水溶液に加え、混合物を3時間加熱環流した。室温に冷却した後、混合物を8mol水酸化ナトリウム(1升)にゆっくりと入れ、酢酸エチル(1L)で3回抽出し、有機相を4−5Lに濃縮した後、n−ヘキサン(600ml)を加え、混合物を1時間撹拌し、濾過することで、白色固体として生成物B5(34g、収量46.5%(2つのステップ))を得た。
B5(34g、139mmol)のメタノール(730ml)溶液に0−5℃で水素化ホウ素ナトリウム(7.9g、209mmol)を少しずつ加えた。混合物を0−5℃でさらに15分間撹拌した後、重炭酸ナトリウム水溶液(0.1mol、54ml)を加え、混合物を5分間撹拌し、混合物を硫酸ナトリウムで乾燥させ、濃縮し、シリカゲルカラム(酢酸エチル /n−ヘキサン= 1/2〜1/10)で精製することで、無色油状物として生成物B6( 30g、収量97.1%)を得た。
B6(30g、134 mmol)のエタノール(600ml)溶液に触媒である水酸化パラジウム/活性炭(10%、3.0g)を加え、混合物を水素バルーン下で4時間撹拌した。混合物を濾過して濃縮し、白色固体として生成物B7(15.8g、収量85.8%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:5.43(d, J = 5.1Hz, 1 H), 3.71(m, 1 H,), 2.98(m, 1 H), 2.84 − 2.57(m, 2 H), 2.23(s, 1 H), 1.85 − 1.64(m, 1 H), 1.60 − 1.34(m, 1 H)。LC−MS:(ESI) m/z=138.0(M+H)+
B7(250mg、1.8mmol)のジクロロメタンD(20ml)溶液にジ−tert−ブチルジカーボネート(392mg、1.8mmol)を加えた。窒素ガスの保護下で、反応混合物を12時間撹拌しながら反応1させた。水を該溶液に加えた。ジクロロメタン(20ml)で抽出し、有機相を硫酸ナトリウムで乾燥させ、濾過し、真空濃縮した後、n−ヘキサンで洗浄することで、白色固体として生成物B8(350mg、収量82.1%)を得た。1HNMR(400 MHz, DMSO−d6) δ 5.76(d, J = 5.4 Hz, 1H), 4.02 − 3.66(m, 2H), 3.68 − 3.44(m, 2H), 3.29(s, 1H), 1.75(ddd, J = 11.3, 7.6, 3.8 Hz, 1H), 1.70 − 1.50(m, 1H), 1.40(s, 8H)。
室温下で、B7(500mg、3.6mmol)の88%ギ酸溶液(941mg、18.0mmol)に37〜40%のホルムアルデヒド(584mg、7.2mmol)溶液を加えた。溶液を78℃で30分間撹拌した。該混合物を水酸化ナトリウム水溶液で洗浄してpHを9〜10に調整した。酢酸エチル(30ml×3)で混合物を抽出した後、有機相を硫酸ナトリウムで乾燥させ、濃縮することで、白色固体として生成物C2(340mg、収量62.5%)を得た。1H NMR(400 MHz, DMSO−d6) δ 5.48(d, J = 5.4 Hz, 1H), 3.79 − 3.48(m, 1H), 2.74(dd, J = 22.1, 12.2 Hz, 1H), 2.46 − 2.34(m, 1H), 2.20(s, 4H), 1.90 − 1.69(m, 1H), 1.69 − 1.47(m, 1H)。LC−MS:(ESI) m/z=152[M+H]+
合成経路は、以下の通りである。
水素化ナトリウム(529mg、13.2mmol)のN,N−ジメチルアセトアミド(10ml)溶液に、50℃、窒素ガスの保護下で、A6(1.29g、6.6mmol)及びB8(1.40g、5.9mmol)のN,N−ジメチルアセトアミド(13ml)溶液を滴下した。50℃で1時間撹拌した。混合物を塩化アンモニウムの飽和溶液に入れ、酢酸エチルで抽出した。有機相を塩水で洗浄し、硫酸ナトリウムで乾燥させ、真空濃縮し、シリカゲルカラム(酢酸エチル /n−ヘキサン=1:10〜1:2)で精製することで、黄色固体として生成物A7(2.39g、収量88.0%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:7.99(s, 1H), 7.94(s, 1H), 5.37 − 5.21(m, 1H), 4.01(s, 3H), 3.99−3.96(m, 1H), 3.70(m, 1H), 3.61(m, 1H), 3.30(m, 1H), 2.09(m, 1H), 1.80(m, 1H), 1.43(s, 9H). LC−MS:(ESI) m/z=414(M+H)+
A7(130mg、0.31mmol)の酢酸エチル(4ml)溶液にパラジウム炭素触媒(13mg)を加えた。水素バルーン下、20℃で混合物を2時間撹拌した。珪藻土でこの混合物を濾過し、濾液を真空濃縮することで、黄色油状物として生成物A8(105mg、収量88.0%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:7.11(s, 1H), 6.43(s, 1H), 5.82(s, 2H), 4.54 − 4.34(m, 1H), 3.92 − 3.78(m, 1H), 3.77(s, 3H), 3.66(m, 1H), 3.61 − 3.51(m, 1H), 3.30(m, 1H), 1.94 − 1.82(m, 1H), 1.76(m, 1H), 1.43(s, 9H). LC−MS:(ESI) m/z=384(M+H)+
A8(100mg、0.26mmol)とN,N−ジメチルホルムアミドジメチルアセタール(155mg、1.3mmol)のトルエン(2ml)溶液における混合物を、100℃、窒素ガスの保護下で20時間撹拌した。混合物を真空濃縮することで、残留物を得た。残留物をシリカゲルカラム(ジクロロメタン/メタノール=50:1)で精製することで、黄色油状物として生成物A9(90mg、78.9%)を得た。1HNMR:(400 MHz, DMSO) δ ppm:7.95(s, 1H), 7.32(s, 1H), 6.78(s, 1H), 4.73 − 4.61(m, 1H), 3.96 − 3.88(m, 1H), 3.86(s, 3H), 3.66 − 3.53(m, 2H), 3.30(m, 1H), 3.08(s, 3H), 2.98(s, 3H), 1.95(m, 1H), 1.77(m, 1H), 1.42(s, 9H). LC−MS:(ESI) m/z=439(M+H)+
<化合物7、23、25の合成>
(R/S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(7)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(23)と(S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(25)への分割
合成経路は、以下の通りである。
A9(90mg、0.21mmol)と3−クロロ−2−,4−ジフルオロアニリン(38mg、0.23mmol)の醋酸(2mL)溶液における混合物を120℃窒素ガスの保護下で3時間撹拌した。冷却した後、重炭酸ナトリウムの飽和溶液で処理してpH=8に調整し、ジクロロメタンで抽出した。有機相を硫酸ナトリウムで乾燥させ、真空濃縮することで、残留物を得た。残留物を塩酸/酢酸エチル(2ml、2N)中で15時間撹拌した。重炭酸ナトリウム飽和溶液でpH=8に処理し、ジクロロメタンで抽出した。有機相を硫酸ナトリウムで乾燥させ、真空濃縮することで残留物を得た。残留物を分取TLC(ジクロロメタン/メタノール=13:1)精製し、白色固体として生成物A10(20mg、収量21.5%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:9.60(s, 1H), 8.40(s, 1H), 7.99(s, 1H), 7.59(td, J = 8.7, 5.8 Hz, 1H), 7.41(td, J = 8.9, 1.5 Hz, 1H), 7.27(s, 1H), 4.91 − 4.80(m, 1H), 3.98(s, 3H), 3.18(m, 1H), 2.96 − 2.84(m, 2H), 2.72 − 2.63(m, 1H), 2.13 − 2.03(m, 1H), 1.99(m, 1H),1.92−1.78(m, 1H). LC−MS:(ESI) m/z=457(M+H)+
A10(20mg、0.044mmol)とオキセタン−3−オン(11mg、0.15mmol)のメタノール(1ml)溶液に、25℃、窒素ガスの保護下で塩化亜鉛のエチルエーテル溶液(0.15ml、0.15mmol)を加えた。混合物を25℃で15分間撹拌した後、シアノ水素化ホウ素ナトリウム(9.4mg、0.15mmol)を1回限りで加えた。該混合物を50℃で2時間撹拌しながら加熱した。冷却した後、水を加え、ジクロロメタンで抽出した。有機相を硫酸ナトリウムで乾燥させ、真空濃縮して残留物を得、残留物を分取TLC(ジクロロメタン / メタノール=20:1)で精製することで、白色固体としてラセミ混合物である生成物7(14mg、収量62.2%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:9.70(s, 1H), 8.40(s, 1H), 8.06(s, 1H), 7.59(td, J = 8.7, 6.0 Hz, 1H), 7.41(td, J = 8.9, 1.5 Hz, 1H), 7.28(s, 1H), 4.91 − 4.79(m, 1H), 4.58(td, J = 6.6, 3.2 Hz, 2H), 4.47(td, J = 6.2, 2.3 Hz, 2H), 3.98(s, 3H), 3.70 − 3.57(m, 1H), 2.98 − 2.84(m, 1H), 2.76 − 2.63(m, 1H), 2.61 − 2.54(m, 1H), 2.45 − 2.35(m, 1H), 2.20 − 2.07(m, 1H), 1.99(m, 1H). LC−MS:(ESI) m/z=513(M+H)+
HPLCキラル分離用カラムOJ−H(4.6*100*5um)を用いて、化合物7のラセミ混合物(240mg)をメタノール(0.2%メタノールアンモニア)により精製することで、鏡像異性的に純粋な化合物23(83mg、ee%>99%, LC−MS:(ESI) m/z=513(M+H)+)及び鏡像異性的に純粋な化合物25(72mg、 ee%>99%, LC−MS:(ESI) m/z=513(M+H)+)を得た。
<化合物2、12及び14の合成>
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン 2の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン(12)と(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン(14)への分割
合成経路は、以下の通りである。
A9(210mg、0.48mmol)及び2−フルオロ− 3−((トリメチルシリルアルキル)エチニル)アニリン(199mg、0.96mmol)の醋酸(4.2ml)における混合物を、80℃、窒素ガスの保護下で16時間撹拌した。冷却した後、重炭酸ナトリウム飽和溶液でpH=8に処理し、ジクロロメタンで抽出した。有機相を硫酸ナトリウムで乾燥させ、真空濃縮することで残留物を得、シリカゲルカラム(n−ヘキサン/酢酸エチル=10:1〜2:1)で精製することで、黄色油状物として生成物A11(145mg、収量50%)を得た。1HNMR:(400 MHz, DMSO−d6) δppm:9.54(s, 1H), 8.41(s, 1H), 8.04(s, 1H), 7.69 − 7.57(m, 1H), 7.34 − 7.23(m, 2H), 4.95 − 4.89(m, 1H), 3.98(s, 3H), 3.92 − 3.75(m, 2H), 3.63 − 3.56(m, 1H), 3.53 − 3.45(m, 1H), 2.11 − 2.02(m, 1H), 1.98 − 1.87(m, 1H), 1.44(s, 9H), 0.27(s, 9H)。LC−MS:(ESI) m/z=601(M+H)+
A11(145mg、0.24mmol)の酢酸エチル(5ml)溶液に4mol酢酸エチル/塩酸(2.5ml)を加え、室温下で1時間撹拌した。水(2×5ml)で該混合物を抽出し、水相用を飽和重炭酸ナトリウム水溶液でpH=8に処理し、ジクロロメタン(2×10ml)で抽出した。有機相を合わせ、硫酸ナトリウムで乾燥させ、真空濃縮することで、黄色油状物として生成物A12(110mg、収量91.0%)を得た。1HNMR:(400 MHz, DMSO−d6) δ ppm:9.50(s, 1H), 8.40(s, 1H), 7.99(s, 1H), 7.61(t, J = 7.6 Hz, 1H), 7.44(t, J = 7.2 Hz, 1H), 7.30 − 7.18(m, 2H), 4.91 − 4.83(m, 1H), 3.98(s, 3H), 3.26 − 3.12(m, 1H), 3.00 − 2.83(m, 2H), 2.74 − 2.63(m, 1H), 2.12 − 2.03(m, 1H), 1.91 − 1.80(m, 1H), 0.26(s, 9H)。 LC−MS:(ESI) m/z=501(M+H)+
A12(110mg、0.22mmol)及びオキセタン−3−オン(55mg、0.77mmol)のメタノール(5.5ml)溶液に、塩化亜鉛のエチルエーテル溶液(0.77ml、0.77mmol)を加え、25℃、窒素ガスの保護下で、混合物を25℃で15分間撹拌した後、シアノ水素化ホウ素ナトリウム(48.0mg、0.77mmol)を1回限りで加えた。該混合物を50℃で2時間反応させた。冷却した後、水(10ml)を溶液に加え、ジクロロメタン(10ml)で抽出した。有機相を硫酸ナトリウムで乾燥させ、真空濃縮することで、粗製のA13を得た。該粗製物を精製せずにそのまま次のステップに用いた。
A13のテトラヒドロフラン(3.7ml)溶液にフッ化テトラブチルアンモニウムのテトラヒドロフラン溶液(0.24ml)を1mol加えた。室温で1時間反応させた後、ジクロロメタン(10ml)及び水(10ml)を加え、次に有機相を分離して真空濃縮することで残留物を得、分取HPLCカラムで精製することで、淡黄色固体としてラセミ混合物である生成物2(60mg、収量56.6%、2段階反応)を得た。1HNMR:(400 MHz, DMSO−d6) δppm:9.54(s, 1H), 8.40(s, 1H), 8.02(s, 1H), 7.62(t, J = 7.1 Hz, 1H), 7.47(t, J = 7.0 Hz, 1H), 7.37 − 7.22(m, 2H), 4.87 − 4.80(m, 1H), 4.61 − 4.56(m, 2H), 4.56(s, 1H), 4.47(td, J = 6.2, 2.0 Hz, 2H), 3.98(s, 3H), 3.71 − 3.58(m, 1H), 2.95 − 2.87(m, 1H), 2.74 − 2.66(m, 1H), 2.60 − 2.55(m, 1H), 2.42 − 2.33(m, 1H), 2.18 − 2.09(m, 1H), 2.04 − 1.95(m, 1H)。LC−MS:(ESI) m/z=485(M+H)+。
HPLCキラル分離用カラムOJ−H(4.6*100*5um)を用いて、化合物2のラセミ混合物(174mg)をメタノール(0.2%メタノールアンモニア)により精製することで、鏡像異性的に純粋な化合物12(54mg、ee%>99%, LC−MS:(ESI) m/z=485(M+H)+)及び鏡像異性的に純粋な化合物14(50mg、ee%>99%, LC−MS:(ESI) m/z=485(M+H)+)を得た。
化合物1、11及び13の合成:(R/S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(1)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(11)と(S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−メトキシキナゾリン−4−アミン(13)への分割
<化合物9、27及び29の合成>
(R/S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(9)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(27)と(S)−N−(3−クロロ−2,4−ジフルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(29)への分割
<化合物8、24及び26の合成>
(R/S)−6−[3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(8)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(24)と(S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(26)への分割
<化合物6、20及び22の合成>
(R/S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン(6)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン(20)と(S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2−フルオロフェニル)−7−メトキシキナゾリン−4−アミン(22)への分割
<化合物3、15及び17の合成>
(R/S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(3)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(15)と(S)−N−(3−クロロ−2−フルオロフェニル)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−7−重水素化メトキシキナゾリン−4−アミン(17)への分割
<化合物4、16及び18の合成>
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(4)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(16)と(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2−フルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(18)への分割
<化合物5、19及び21の合成>
(R/S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(5)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(19)と(S)−6−[(3,3−ジフルオロ−1−メチルピペリジン−4−イル)オキシ]−N−(3−エチニル−2,4−ジフルオロフェニル)−7−メトキシキナゾリン−4−アミン(21)への分割
<化合物10、28及び30の合成>
(R/S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(10)の合成、及びHPLCキラル分離用カラムによる、鏡像異性的に純粋な(R)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(28)と(S)−6−{[3,3−ジフルオロ−1−(オキセタン−3−イル)ピペリジン−4−イル]オキシ}−N−(3−エチニル−2,4−ジフルオロフェニル)−7−重水素化メトキシキナゾリン−4−アミン(30)への分割
<生物学的データ>
CellTiter−Glo(CTG)assayにより、EGFR活性化変異(エクソン19欠失Exon 19 Del)タンパク質を有する腫瘍細胞の細胞生存率測定を行った。約5000個の細胞を各ブランクの96ウェルプレートに接種し、16時間後、割合で希釈した化合物を加え、薬物添加の72時間後、室温で30分間平衡化した。各ウェルに100μlのCellTiter−Glo薬剤を加え、オービタルシェーカーを用いて2分間かけて均一に混合することで細胞溶解を誘導した。プレートを室温で10分間インキュベートして発光シグナルを安定させた。TECAN Infinite M1000 Pro機器に発光シグナルを記録した。
化合物が血液脳関門(BBB)を通過できるか否かを確認するために、試験化合物をラットに投与した。投与した4時間後、ラットを安楽死させ、血液及び脳組織を収集し、化合物の濃度を分析して測定した。血液脳関門透過性は、化合物の脳組織中濃度と血漿中濃度との比として定義される。P−糖タンパク質は、血液脳関門排出タンパク質であるため、P−糖タンパク質の基質を頭蓋内から排出する。
Claims (10)
- 式(I)で表される構造を含むことを特徴とする化合物。
R2は独立してC1−10アルキル基、C3−12シクロアルキル基、C1−C2ペルフルオロアルキル基又は重水素化アルキル基からなる群より選択され、
R3は独立してハロゲン原子、C1−10アルキル基、C1−10アルコキシ基又はC2−10アルキニル基からなる群より選択され、
R4は独立して水素原子又はハロゲン原子からなる群より選択される。) - R1は独立してメチル基又はオキセタンからなる群より選択され、
R2は独立してメチル基又は重水素化メチル基からなる群より選択され、
R3は独立して塩素原子又はエチニル基からなる群より選択され、
R4は独立して水素原子又はフッ素原子からなる群より選択される、ことを特徴とする請求項1に記載の化合物。 - 請求項1又は2に記載の化合物、その塩、そのプロドラッグ、そのプロドラッグの塩、その溶媒和物、その水和物又はその結晶多形体、及び薬学的に許容される補助材料又は補助成分を含むことを特徴とする医薬組成物。
- 請求項1又は2に記載の化合物を活性成分とし、血液脳関門を通過することができることを特徴とする上皮成長因子受容体EGFR活性化変異阻害剤。
- 上皮成長因子受容体EGFRタンパク質が媒介する疾患を治療又は予防する薬物の製造における請求項1又は2に記載の化合物、請求項3に記載の医薬組成物、或いは請求項4に記載の阻害剤の使用。
- 前記タンパク質は、上皮成長因子受容体EGFR活性化変異キナーゼであることを特徴とする請求項5に記載の使用。
- 前記活性化変異は、上皮成長因子受容体EGFRのエクソン19欠失活性化変異又はエクソン21 L858R活性化変異を含むことを特徴とする請求項6に記載の使用。
- 前記疾患は、がん、増殖性疾患、中枢神経系疾患又はがんの中枢神経転移性疾患であることを特徴とする請求項5に記載の使用。
- 前記疾患は、非小細胞肺がんであることを特徴とする請求項8に記載の使用。
- 前記疾患は、脳転移を伴う非小細胞肺がんであることを特徴とする請求項9に記載の使用。
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PCT/CN2017/106616 WO2018086446A1 (zh) | 2016-11-08 | 2017-10-17 | 具有穿过血脑屏障能力的取代的喹唑啉化合物 |
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WO2019196621A1 (zh) * | 2018-04-09 | 2019-10-17 | 威尚(上海)生物医药有限公司 | 喹唑啉类化合物在治疗具有EGFRv3活化突变的癌症药物中的用途 |
WO2019196620A1 (zh) * | 2018-04-09 | 2019-10-17 | 威尚(上海)生物医药有限公司 | 喹唑啉类化合物与阿瓦斯汀在制备防止疾病的联合用药物中的用途 |
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CN110903283B (zh) * | 2018-09-17 | 2021-01-01 | 南京雷正医药科技有限公司 | 一种取代的喹唑啉类化合物、包含该化合物的药物组合物和该化合物的用途 |
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