JP6522807B2 - ベンゾオキサゼピンオキサゾリジノン化合物及び使用方法 - Google Patents
ベンゾオキサゼピンオキサゾリジノン化合物及び使用方法 Download PDFInfo
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- JP6522807B2 JP6522807B2 JP2017567339A JP2017567339A JP6522807B2 JP 6522807 B2 JP6522807 B2 JP 6522807B2 JP 2017567339 A JP2017567339 A JP 2017567339A JP 2017567339 A JP2017567339 A JP 2017567339A JP 6522807 B2 JP6522807 B2 JP 6522807B2
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- 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
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
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- 231100001274 therapeutic index Toxicity 0.000 description 1
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- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
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- 229950009158 tipifarnib Drugs 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 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
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 229940062627 tribasic potassium phosphate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000010304 tumor cell viability Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229930190906 verrucarin Natural products 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-IELIFDKJSA-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-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.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 CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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- 201000005102 vulva cancer Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000002689 xenotransplantation Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
37 CFR 1.53(b)に基づいて出願された本非仮特許出願は、参照により全体が本明細書に援用される2015年7月2日出願の米国仮出願第62/188018号及び2015年8月14日出願の同第62/205127号の米国特許法119条(e)に基づく利益を主張する。
本発明は概して、がんなどの過剰増殖性障害に対する活性を有するベンゾオキサゼピンオキサゾリジノン化合物に関する。本発明はまた、哺乳動物細胞のin vitro、in situ及びin vivoでの診断若しくは治療のための、又は関連する病的状態のための化合物の使用方法に関する。
I
を有する化合物、並びにその立体異性体、幾何異性体、互変異性体、及び薬学的に許容される塩に関する。様々な置換基が本明細書において定義される。
a) 式Iのベンゾオキサゼピンオキサゾリジノン化合物;及び
b) 乳がんの治療的処置における使用のための指示書
を含むキットである。
置換基の数を示す場合、「1以上の」という用語は、1つの置換基から可能な限りの数の置換までの範囲、すなわち置換基による水素1個の置換からすべての水素の置換までをいう。「置換基」という用語は、親分子上の水素原子を置き換える原子又は原子群を意味する。「置換されている(substituted)」という用語は、特定の基が1以上の置換基を有することを言う。任意の基が複数の置換基を有することができ、かつ、種々の可能な置換基が提供される場合、置換基は独立に選択され、同じである必要はない。「無置換の(unsubstituted)」という用語は、特定の基が置換基を有しないことを意味する。「任意選択的に置換され(optionally substituted)」という用語は、特定の基が無置換であるか、又は可能な置換基の群から独立に選択される1以上の置換基で置換されていることを意味する。置換基の数を示す場合、「1以上の」という用語は、1つの置換基から可能な限りの数の置換まで、すなわち置換基による水素1個の置換からすべての水素の置換までを意味する。
本発明は、がんの治療において有用な、式Iのベンゾオキサゼピンオキサゾリジノン化合物であって、以下の構造
I
から選択される化合物、並びにその立体異性体、幾何異性体、互変異性体及び薬学的に許容される塩[上式中:
R1は、-CH3、-CH2CH3、-CH(CH3)2、-CHF2、-CH2F、及び-CF3から選択され;
Xは、
から選択され、波線は結合部位を示し;
R2は、H、C1-C6アルキル、シクロプロピル、及びシクロブチルから選択され、F、-OCH3又は-OHで置換されていてもよい。
Ia
Ib
式Iの化合物の酵素活性(又は他の生物学的活性)の阻害剤としての相対的効力は、各化合物が所定の程度まで活性を阻害する濃度を測定し、その結果を比較することにより確定させることが可能である。典型的には、好ましい決定は、生化学アッセイにおいて活性の50%を阻害する濃度、すなわち50%阻害濃度又は「IC50」である。IC50値の決定は、当技術分野で一般的な手法を用いて達成可能である。一般に、IC50は、試験濃度範囲の阻害剤の存在下で、所与の酵素の活性を測定することにより決定することができる。その後、使用した阻害剤濃度に対して、酵素活性の実験的に得られた値をプロットする。(任意の阻害剤の非存在下での活性と比較して)50%酵素活性を示す阻害剤の濃度をIC50値とする。同様に、他の阻害濃度も、活性の適切な決定により定義することが可能である。例えば、いくつかの状況では、90%阻害濃度すなわちIC90などを確立することが望ましい場合がある。
表1
タセリシブ、GDC−0032、及びRoche RG7604として知られているこの化合物(CAS登録番号1282512−48−4、Genentech Inc.)は、2−(4−(2−(1−イソプロピル−3−メチル−1H−1,2,4−トリアゾル−5−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−1H−ピラゾール−1−イル)−2−メチルプロパンアミドというIUPAC名及び以下の構造:
タセリシブ
を有し、その立体異性体、幾何異性体、互変異性体、及び薬学的に許容される塩を含む。
ピクチリシブ、GDC−0941、Roche RG−7321、及びピクトレリシブとして知られているこの化合物(CAS登録番号957054−30−7、Genentech Inc.,)は、PI3Kアイソフォームの強力な多標的クラスI(パン)阻害剤である。GDC−0941は現在、進行固形腫瘍の治療の第2相臨床試験中である。GDC−0941は、4−(2−(1H−インダゾール−4−イル)−6−((4−(メチルスルホニル)ピペラジン−1−イル)メチル)チエノ[3,2−d]ピリミジン−4−イル)モルホリンと呼ばれ(米国特許第7781433号;米国特許第7750002号;Folkes et al (2008) Jour. of Med. Chem. 51(18):5522-5532)、以下の構造:
ピクチリシブ
を有し、その立体異性体、幾何異性体、互変異性体、及び薬学的に許容される塩を含む。
本発明の化合物の、PI3Kβ、PI3Kδ及びPI3Kγに対する選択性を有するPI3Kαの阻害剤として作用する能力は、実施例901の方法を用いて決定された。表2A及び2Bはまた、米国特許第8242104号の実施例901の方法を用いて決定されたFP Kiデータを含む。
表2B 比較化合物によるPI3Kアイソフォームの生化学的阻害
式Iの化合物によるPI3Kα選択性の合理的根拠は、特定の結合相互作用に存在し得る。
実施例903の方法に記載のように、PI3Kα野生型(親)、ヘリカルドメイン変異体E545K、及びキナーゼドメイン変異体H1047RといったSW48同質遺伝子細胞株におけるPI3K経路の阻害を測定することにより、本発明の化合物が変異型PI3Kαを含む細胞に対して優先的に作用する能力を決定した。
表3B 比較化合物によるSW48同質遺伝子におけるP−PRAS40の阻害
実施例904の方法を用いて、HCC1954及びKPL4細胞(PI3Kα変異型H1047R)、並びにMCF7細胞(PI3Kα変異型E545K)における抗増殖性EC50を測定することにより、PI3K変異腫瘍細胞の生存率を低下させる本発明の化合物の能力を決定した。表4は、本発明の式Iの化合物102、103及び105が、比較化合物タセリシブ(米国特許第8242104号の化合物196)、ピクチリシブ及び化合物436(米国特許第8242104号)と同レベルの効力で、HCC1954、KPL4及びMCF7細胞における増殖を阻害することを示す。
表4 変異型PI3K−アルファ腫瘍細胞における抗増殖活性
In vivo腫瘍異種移植モデルにおける腫瘍増殖を阻害する本発明の化合物の能力を、実施例905に記載の方法を用い、KPL4乳がん細胞株(PI3Kα突然変異体H1047R)を使用して決定した。図2A及び2Bは、式Iの化合物102及び103がそれぞれ、毎日のPO(経口)投与を用いて用量依存的にin vivoでKPL4腫瘍の増殖を強く阻害することができることを示している。化合物102及び103の投与はすべて、処置に関連する体重減少が観察されず、良好な耐容性を示した。
本発明の化合物は、治療すべき状態に適切な任意の経路で投与され得る。適切な経路には、経口、非経口(皮下、筋肉内、静脈内、動脈内、皮内、髄腔内、及び硬膜外)、経皮、経直腸、経鼻、局所(口腔内及び舌下を含む)、膣内、腹腔内、肺内、及び鼻腔内が含まれる。局所免疫抑制治療の場合、該化合物は、移植前に移植片を灌流又は他の方法で阻害剤と接触させることを含む病巣内投与で投与することができる。好ましい経路は、例えばレシピエントの状態によって変化し得ることが理解されよう。経口投与される場合、該化合物は、薬学的に許容される担体又は賦形剤と共に丸薬、カプセル剤、錠剤等として製剤化され得る。非経口投与される場合、該化合物は、以下に詳述するように、薬学的に許容される非経口ビヒクルと共に、単位投薬注射可能形態で製剤化され得る。
本発明の式Iの化合物は、がんなどの、PI3Kに関連する異常な細胞の増殖、機能又は行動に起因する疾患又は障害に罹患しているヒト又は動物の患者を治療するために有用であり、したがって、上に記載の本発明の化合物の投与を含む方法によって治療され得る。がんに罹患しているヒト又は動物の患者はまた、上で定義した本発明の化合物のそれらへの投与を含む方法によって治療され得る。それにより、患者の状態を改善又は回復させることができる。
本発明の化合物は、ヒトを含む哺乳動物の治療的処置のために使用するために、通常、薬学的組成物として標準的な薬務に従って製剤化される。本発明のこの態様によれば、薬学的に許容される希釈剤又は担体と共に本発明の化合物を含有する薬学的組成物が提供される。
式Iの化合物は、単独で用いても、又は炎症若しくは過剰増殖性障害(例えばがん)などの、本明細書に記載の疾患若しくは障害の治療のための追加の治療剤と組み合わせて用いてもよい。特定の実施態様において、式Iの化合物は、抗炎症性若しくは抗過剰増殖特性を有するか又は炎症、免疫応答障害若しくは過剰増殖性障害(例えばがん)を治療するために有用な第2の治療用化合物と共に、組み合わせ医薬製剤又は併用療法の投与レジメンに組み込まれる。追加の治療剤は、Bcl−2阻害剤、JAK阻害剤、抗炎症剤、免疫調節剤、化学療法剤、アポトーシス促進剤、神経栄養因子、心血管疾患治療剤、肝疾患治療剤、抗ウイルス剤、血液障害治療剤、糖尿病治療剤、及び免疫不全障害治療剤であり得る。第2の治療剤は、NSAID抗炎症剤であってもよい。第2の治療剤は、化学療法剤であってもよい。組み合わせ医薬製剤又は投与レジメンの第2の化合物は、互いに悪影響を与えないように式Iの化合物を補完する活性を好ましくは有する。このような化合物は、意図した目的に有効な量で組み合わされて適切に存在する。一実施態様では、本発明の組成物は、式Iの化合物あるいはその立体異性体、互変異性体、溶媒和物、代謝産物又は薬学的に許容される塩又はプロドラッグを含み、NSAIDなどの治療剤と組み合わされる。
本明細書に記載の式Iのin vivo代謝産物も、本発明の範囲内に含まれる。このような産物は例えば、投与された化合物の酸化、還元、加水分解、アミド化、脱アミド化、エステル化、脱エステル化、酵素的切断等から生じ得る。したがって、本発明は、本発明の化合物をその代謝産物を生じるのに十分な時間にわたって哺乳動物と接触させることを含む方法によって生じる化合物を含めた、式Iの化合物の代謝産物を含む。
本発明の別の実施態様において、上記の疾患及び障害の治療に有用な材料を含有する製品又は「キット」が提供される。一実施態様では、キットは、式Iの化合物あるいはその立体異性体、互変異性体、溶媒和物、代謝産物又は薬学的に許容される塩又はプロドラッグを収容する容器を備える。キットは、容器に貼られているか又は付属するラベル又は添付文書をさらに備えていてもよい。「添付文書」という用語は、治療製品の商品パッケージに通例含まれる、効能、用法、用量、投与、禁忌、及び/又は当該治療製品の使用に関する警告についての情報を含む説明書をいうのに使用される。適切な容器には、例えばボトル、バイアル、シリンジ、ブリスターパッグ等が含まれる。容器は、ガラス又はプラスチックなどの様々な材料から形成されていてよい。容器は、病態を治療するのに有効な式Iの化合物又はその製剤を収容することができ、無菌アクセスポートを有していてもよい(例えば、容器は、皮下注射針で穿刺可能な、ストッパーを有する静脈内溶液のバッグ又はバイアルであってもよい)。組成物中の少なくとも1の活性剤が、式Iの化合物である。ラベル又は添付文書は、組成物ががんなどの選択した状態を治療するために使用されることを表示する。さらに、ラベル又は添付文書は、治療される患者が過剰増殖性障害、神経変性、心臓肥大、疼痛、片頭痛又は神経外傷性疾患若しくは事象等の障害を有する患者であることを表示してもよい。一実施態様において、ラベル又は添付文書は、異常な細胞増殖に起因する障害を治療するのに式Iの化合物を含む組成物を使用することができることを表示する。ラベル又は添付文書はまた、組成物が他の障害を治療するのに使用することができることを表示してもよい。代替的に、又は追加的に、製造品は、薬学的に許容される緩衝剤、例えば注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンガー溶液及びデキストロース溶液を収容する第2の容器をさらに備えていてもよい。製造品は、他の緩衝剤、希釈剤、フィルター、針及びシリンジ等、商業的観点及び使用者の観点から望ましいその他の材料をさらに備えていてもよい。
式Iの化合物は、特に本明細書に含まれる説明に照らして、化学の技術分野で周知の過程及びComprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, 例えば第3巻; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990)(それぞれ出典明示により援用される)に記載されている他のヘテロ環のための過程と類似の過程を含む合成経路によって、合成することができる。出発物質は一般に、Aldrich Chemicals(ウィスコンシン州ミルウォーキー)などの商業的供給源から入手可能であるか、又は当業者に周知の方法を使用して容易に調製される (例えば、Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), 又はBeilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin(補遺版含む)(Beilsteinオンラインデータベースを介しても入手可能)に概要が記載された方法により調製される)。
スキーム1
a)MgCl2、トリエチルアミン、パラホルムアルデヒド、アセトニトリル、熱;b)オキサルデヒド、水酸化アンモニウム、熱;c)炭酸セシウム、1,2−ジブロモエタン、DMF、熱;d)N−ヨードスクシンイミド、DMF、熱;e)i.EtMgBr、THF、−20℃、ii.塩化アンモニウム水溶液
f)4−置換オキサゾリジン−2−オン、Cu(OAc)2、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン、炭酸カリウム、ジオキサン、熱;g)L−プロリン、CuI、K3PO4、DMSO、熱;h)塩化アンモニウム、トリエチルアミン、HATU(1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート)
i)4,4,5,5−テトラメチル−2−(テトラメチル−1,3,2−ジオキサボラン−2−イル)−1,3,2−ジオキサボラン、KOAc、Pd(dppf)Cl2、ジオキサン、熱;j)H2O2、水、0°C;k)(2R)−2−ヒドロキシプロパン酸メチル、トリフェニルホスフィン、DEAD、ジオキサン;l)N−ヨードスクシンイミド、DMF、熱;m)EtMgBr、THF、−40°C;n)4−置換オキサゾリジン−2−オン、CuI、トランス−N,N−ジメチル−1,2−シクロヘキサンジアミン、炭酸カリウム、ジオキサン、熱;o)アンモニア、メタノール
DMSO ジメチルスルホキシド
ESI エレクトロスプレーイオン化
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー質量分析
min 分
N 正常
NMR 核磁気共鳴
RT 保持時間
窒素の不活性雰囲気でパージし、維持した20Lの四口丸底フラスコに、3−ブロモフェノール(1300g、7.51mol)、ジクロロマグネシウム(1078g、11.3mol)、トリエチルアミン(3034g、30.0mol)及びアセトニトリル(7.8L)を入れた。この混合物を40℃で30分間撹拌した。この混合物にパラホルムアルデヒド(676g、22.6mol)を80℃で加えた。得られた溶液を76℃で6時間撹拌した。この反応を5回繰り返した。合わせた反応混合物を12Lの塩化水素水溶液(4N)の添加によりクエンチした。溶液のpH値を濃塩化水素水溶液(12N)で5に調整した。得られた溶液を1x20Lの酢酸エチルで抽出した。有機抽出物を減圧中でエバポレートした。残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶離:石油エーテル中15%酢酸エチル)で精製し、粗生成物を得た。これを2.4Lのtert−ブチルメチルエーテル:ヘキサン(1:4)で洗浄した。得られた固体を濾過により回収し、7.0kg(78%)の表題化合物を黄色固体として得た。
20Lの四口丸底フラスコに、4−ブロモ−2−ヒドロキシベンズアルデヒド(700g、3.50mol)のメタノール(7.0L)及びオキサルデヒド(oxaldehyde)(40%)(2540g、17.5mol)の溶液を入れ、続いて、温度を40℃未満に維持しつつ、アンモニア水(25−28%、3500g)を撹拌しながら4時間にわたり滴下した。得られた溶液を30−35℃で15時間撹拌した。この反応を9回繰り返した。温度を45℃未満に保ちながら、合わせた9回分の反応混合物を減圧中でエバポレートした。残留物を100Lの酢酸エチルで30分間撹拌しながら希釈した。固形物を濾過して取り除き、得られた溶液を水で希釈した。水性相を35Lの酢酸エチルで抽出した。有機抽出物を減圧下でエバポレートし、残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:石油エーテル中5−75%酢酸エチル)で精製し、2.4kg(29%)の表題化合物を黄色固体として得た。
20Lの四口丸底フラスコに5−ブロモ−2−(1H−イミダゾール−2−イル)フェノール(1.4kg、5.86mol)をN,N−ジメチルホルムアミド(14L)及び炭酸セシウム(7.2kg、22.1mol)に溶解した溶液を入れた。この混合物を20分間撹拌した。この反応混合物に1,2−ジブロモエタン(4.1kg、21.8mol)を加えた。得られた溶液を85−90℃で4−12時間撹拌し、15℃まで冷まし、濾過した。その濾過ケーキを3.0Lの酢酸エチルで洗浄した。濾液を14Lの酢酸エチルで希釈した。合わせた有機抽出物をブライン(4×14L)で洗浄し、無水硫酸ナトリウム上で乾燥させ、濾過し、減圧中でエバポレートし、1.1kg(71%)の表題化合物を淡黄色固体として得た。LCMS (ESI): [M+H]+ =265; 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.4, 1H), 7.35-7.24 (m, 3H), 7.06 (s, 1H), 4.47-4.42 (m, 4H).
20Lの四口丸底フラスコに、9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(2.5kg、9.43mol)とN,N−ジメチルホルムアミド(12.5L)を入れ、続いてN−ヨードスクシンイミド(6.0kg、26.7mol)を撹拌しながら数回に分けて添加した。得られた溶液を60℃で12時間撹拌し、水/氷浴で15℃に冷却し、12.5Lの水/氷で希釈し、濾過した。濾過した固形物を石油エーテルから再結晶化させ、4.0kg(82%)の表題化合物を黄色固体として得た。
窒素の不活性雰囲気でパージし、維持した20Lの四口丸底フラスコに、9−ブロモ−2,3−ジヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(800g、1.55mol)とテドロヒドロフラン(2.4L)を入れ、続いてエチルマグネシウムブロミド(エーテルに溶解した1N溶液、1.7L)を撹拌しながら−20℃で3.5時間かけて滴下した。その反応混合物を氷/塩浴を用いて−15℃に保ちながら3時間撹拌した。得られた混合物を3.0Lの飽和塩化アンモニウム水溶液の添加によりクエンチし、酢酸エチル(2×8.0L)で抽出した。合わせた有機抽出物をブライン(2x10L)で洗浄し、無水硫酸ナトリウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物を酢酸エチル:石油エーテル(1:5)8.0Lで粉砕し、濾過し、石油エーテルで洗浄して表題化合物501g(83%)を褐色固体として得た。LCMS (ESI): [M+H]+ = 391; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.7, 1H), 7.55 (s, 1H), 7.30-7.25 (m, 2H), 4.45-4.41 (m, 4H).
9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(500mg、1.28mmol)、(R)−4−イソプロピルオキサゾリジン−2−オン(231mg、1.79mmol)、ヨウ化第1銅(48.7mg、0.256mmol)、トランス−N,N’−ジメチル−1,2−シクロヘキサンジアミン(91μL、0.575mmol)及び炭酸カリウム(246mg、1.79mmol)の混合物をジオキサン(1.25mL)に懸濁させ、反応混合物を超音波処理下、アルゴンで脱気した。得られた混合物を100℃で24時間加熱した。反応を停止させ、室温に冷ました。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、0.965g(〜42%)の表題化合物(9−Br:9−I生成物の〜1:2混合物)を得た。LCMS (ESI): [M+H]+ = 391/393/439.
(R)−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−イソプロピルオキサゾリジン−2−オンと(R)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−イソプロピルオキサゾリジン−2−オン(440mg、1.0mmol)、ヨウ化第1銅(19.0mg、0.1mmol)、(L)−乳酸(318μL、3.0mmol)及び炭酸セシウム(1.95g、6.0mmol)の混合物をジメチルスルホキシド(2.0mL)/水(2.0mL)に懸濁させた。得られた混合物を120℃で24時間加熱した。反応を停止させ、室温に冷ました。1N塩酸(6.0mL)の添加により反応を中和した。反応物を酢酸エチルとブラインとに分配した。合わせた有機抽出物を硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、334mg(51%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 330.
(R)−3−(9−ヒドロキシ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−イソプロピルオキサゾリジン−2−オン(334mg、1.01mmol)をTHF(5.0mL)中に溶媒和させた。(2R)−2−ヒドロキシプロパン酸メチル(145μL、1.52mmol)及びトリフェニルホスフィン(399mg、1.52mmol)を加え、反応物を室温で攪拌した。アゾジカルボン酸ジイソプロピル(299μl、1.52mmol)を加え、反応混合物を室温で1.5時間撹拌した。反応物を減圧中でエバポレートし、粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、421mg(定量的)の表題化合物を得た。LCMS (ESI): [M+H]+ = 416.
(S)−2−((2−((R)−4−イソプロピル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(421mg、1.00mmol)及び水酸化リチウム一水和物(128mg、3.00mmol)をTHF/水(4.0mL/2.0mL)中に溶媒和させ、反応物を室温で撹拌した。反応混合物を室温で1時間撹拌し、その後1N塩酸(3.0mL)で中和し、減圧中でトルエンと共沸させた。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:酢酸エチル中、2Nのアンモニアのメタノール溶液0−40%)で精製し、260mg(64%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 402.
(S)−2−((2−((R)−4−イソプロピル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸(260mg、0.647mmol)、塩化アンモニウム(69.3mg、1.29mmol)及び1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(369mg、0.97)をN,N−ジメチルホルムアミド(5.0mL)中に溶媒和させた。N,N−ジイソプロピルエチルアミン(332μL、1.94mmol)を加え、反応混合物を室温で1時間撹拌した。得られた混合物を減圧中でエバポレートし、残留物をシリカゲル上でのフラッシュカラムクロマトグラフィー(溶媒勾配:酢酸エチル中0−10%メタノール)で精製した。生成物を逆相C18カートリッジ(溶媒勾配:水中0−95%アセトニトリル、0.1%水酸化アンモニウム緩衝液)でさらに精製し、凍結乾燥させて128mg(43%)の101を得た。LCMS (ESI): RT(min) = 3.38, [M+H]+ = 401, method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.23 (s, 2H), 6.68 (dd, J = 8.8, 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 4.60 (q, J = 6.6 Hz, 1H), 4.49 - 4.45 (m, 1H), 4.41 - 4.33 (m, 5H), 4.30 - 4.27 (dd, J = 8.9, 3.9 Hz, 1H), 2.49 - 2.47 (m, 1H), 1.40 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.74 (d, J = 7.0 Hz, 3H).
0℃のD−アラニノールのトルエン溶液(8.65g、0.12mmol)とKOH水溶液(124mL、12.5%水溶液、0.28mmol)との混合物に、内部温度が<5℃に保たれるような速度でホスゲン(72.7mL、トルエン中20%、0.14mmol)を加えた。その反応混合物を0℃でさらに40分間撹拌し、その後蒸発乾固させた。粗残留物を工業用変性アルコール(industrial methylate spirit)で抽出し、スラリーを濾過し、濾液を減圧中でエバポレートした。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中40−100%酢酸エチル)で精製し、10.4g(90%)の表題化合物を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 6.00 (br s, 1H), 4.50 (t, J = 6.5 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.95 (dd, J = 7.8, 6.2 Hz, 1H), 1.30 (d, J = 6.1 Hz, 3H).
9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(30.0g、76.7mmol)、(R)−4−メチルオキサゾリジン−2−オン(7.70g、76.7mmol)、ヨウ化第1銅(1.61g、8.40mmol)、トランス−N,N’−ジメチル−1,2−シクロヘキサンジアミン(2.7mL、16.9mmol)と炭酸カリウム(14.9g、107mmol)の混合物を1,4−ジオキサン(200mL)に懸濁させ、反応混合物を超音波処理下、アルゴンで脱気した。得られた混合物を100℃で16時間加熱した。その反応混合物をアンモニア水溶液(〜16%)で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、13.4g(〜42%)の表題化合物(9−Br:9−I生成物の〜2:1混合物)を得た。1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 7.6 Hz, 0.33H), 8.11 (d, J = 6.9 Hz, 0.66H), 7.42 - 7.38 (m, 1H), 7.28 - 7.24 (m, 1.33H), 7.23 - 7.18 (m, 0.66H), 4.77 - 4.68 (m, 1H), 4.58 (t, J = 8.3 Hz, 1H), 4.49 - 4.39 (m, 2H), 4.37 - 4.30 (m, 2H), 4.08 (dd, J = 8.4, 4.5 Hz, 1H), 1.57 - 1.50 (m, 3H).
(R)−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−メチルオキサゾリジン−2−オンと(R)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−メチルオキサゾリジン−2−オンとの混合物80mgをキラルSFCで分離し、35.0mgの表題化合物を得た。LCMS (ESI): [M+H]+ = 412.0; 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.35 (s, 1H), 4.64 - 4.54 (m, 2H), 4.47 - 4.41 (m, 4H), 4.09 - 4.06 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H).
ジメチルスルホキシド(4.0mL)に(R)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−メチルオキサゾリジン−2−オン(414mg、1.01mmol)、L−プロリン(579mg、5.03mmol)、ヨウ化第1銅(81mg、0.42mmol)及び三塩基性リン酸カリウム(128mg、6.03mmol)を入れた混合物を80℃で18時間加熱した。粗反応混合物をISOLUTE(登録商標)SCX−2カートリッジ(溶媒勾配:ジクロロメタン中、2Nのアンモニアのメタノール溶液0−30%)で精製し、その後シリカゲル上でのフラッシュクロマトグラフィーで精製し、262mg(65%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 399.
(2−((R)−4−メチル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−L−プロリン(262mg、0.66mmol)、塩化アンモニウム(70mg、1.31mmol)及びN,N−ジイソプロピルエチルアミン(0.34mL、1.97mmol)のN,N−ジメチルホルムアミド(3.0mL)溶液に、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(374mg、0.98mmol)を加え、反応混合物を室温で6時間撹拌した。得られた混合物を減圧中でエバポレートし、シリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:酢酸エチル中0−10%メタノール)で精製し、その後逆相HPLCでさらに精製し、凍結乾燥させて110mg(42%)の102を白色固体として得た。LCMS (ESI): RT (min) = 2.60 [M+H]+ = 398.0, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.8 Hz, 1H), 7.37 (br s, 1H), 7.12 (s, 1H), 7.02 (br s, 1H), 6.28 (dd, J = 8.9, 2.4 Hz, 1H), 5.99 (d, J = 2.4 Hz, 1H), 4.58 - 4.47 (m, 2H), 4.38 - 4.25 (m, 4H), 4.05 - 3.96 (m, 1H), 3.92 - 3.87 (m, 1H), 3.56 - 3.47 (m, 1H), 3.24 - 3.16 (m, 1H), 2.21 - 2.10 (m, 1H), 2.00 - 1.86 (m, 3H), 1.37 (d, J = 5.9 Hz, 3H).
工程1: (R)−2−((tert−ブチルジメチルシリル)オキシ−1−フェニルエタン−1−アミン
(R)−2−アミノ−2−フェニルエタノール(50g、0.36mol)のジクロロメタン(500mL)溶液に、4−(ジメチルアミノ)ピリジン(9.0g、73.6mmol)とトリエチルアミン(102mL、0.73mmol)を加えた。反応混合物を氷浴で冷却し、tert−ブチルジメチルシリルクロリド(54.8g、0.36mol)のジクロロメタン(300mL)溶液を、内部温度を<10℃に保ちながらゆっくりと添加した。反応混合物を常温に温め、一晩撹拌した。得られた混合物を水、ブラインで2回で洗浄し、硫酸ナトリウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗油状物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中5−50%酢酸エチル)で精製し、65.0g(71%)の表題化合物を無色の油状物として得た。1H NMR (400 MHz, CDCl3) δ 7.38 - 7.23 (m, 5H), 4.07 (dd, J = 8.4, 3.9 Hz, 1H), 3.72 (dd, J = 9.7, 3.9 Hz, 1H), 3.51 (dd, J = 9.5, 8.5 Hz, 1H), 1.72 (br s, 2H), 0.90 (s, 9H), 0.02 (s, 6H).
トルエン(2.0L)に(R)−2−((tert−ブチルジメチルシリル)オキシ)−1−フェニルエタン−1−アミン(63.5g、253mmol)、3,3,3−トリフルオロ−2−オキソプロピオン酸エチルエステル(48.5g、285mmol)及びp−トルエンスルホン酸ピリジニウム(6.76g、36.9mmol)が入った混合物をディーン・スターク還流装置の条件下で16時間加熱した。反応混合物を、常温に冷却し、減圧中でエバポレートした。得られた残留物にジエチルエーテル(3.75L)を添加し、未溶解固体を濾過により除去した。結果として得られたエーテル溶液は、精製せずに次の工程でそのまま使用した。
(R)−2−((2−((tert−ブチルジメチルシリル)オキシ)−1−フェニルエチルl)イミノ)−3,3,3−トリフルオロプロパン酸エチルのジエチルエーテル溶液(0℃)(上記工程2からの粗生成物、253mmolとみなす)に、水素化アルミニウムリチウム(755mL、1.0Nテトラヒドロフラン溶液、755mmol)を、温度を<8℃に保ちながらゆっくり加えた。反応混合物を周常温に温め、16時間撹拌し、温度を<10℃に保ちながら水(31mL)、次いでNaOH(31mL、15%水溶液)、続いて水(93mL)を滴下してクエンチした。得られた沈殿物をCelite(登録商標)での濾過により除去し、濾液をシリカゲルパッドに通した。濾液を減圧中でエバポレートし、得られた粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中10−80%酢酸エチル)で精製し、28g(45%)の表題化合物(最初に溶出する異性体)を白色固体として得た。1H NMR (400 MHz, CDCl3) δ 7.39 - 7.30 (m, 5H), 4.15 (dd, J = 9.0, 4.1 Hz, 1H), 3.75 (dd, J = 10.7, 4.0 Hz, 1H), 3.68 - 3.54 (m, 3H), 3.14 - 3.06 (m, 1H), 2.43 (br s, 1H), 2.22 (br s, 1H), 2.04 (br s, 1H).
(S)−3,3,3−トリフルオロ−2−(((R)−2−ヒドロキシ−1−フェニルエチル)アミノ)プロパン−1−オール(28.0g、112mmol)のエタノール溶液(300mL)に、HCl(118mL、メタノール中1.25N)及びHCl(28.4mL、ジオキサン中4N)、続いて水酸化パラジウム炭素(3.86g、20重量%)を加え、反応混合物を水素雰囲気下で6.5時間撹拌した。反応混合物を濾過し、濾液を減圧中でエバポレートした。残留物をジエチルエーテルで粉砕して、17.1g(92%)の表題化合物を白色固体として得た。[α]D -9° (c = 2.0, ethanol); 1H NMR (400 MHz, MeOD-d4) δ 4.19 - 4.11 (m, 1H), 3.96 (dd, J = 12.3, 4.3 Hz, 1H), 3.89 (dd, J = 12.1, 5.9 Hz, 1H).
トルエン(85mL)に(S)−2−アミノ−3,3,3−トリフルオロプロパン−1−オール塩酸塩(12.6g、76.1mmol)及びKOH(12.5%水溶液、175mL、0.39mol)が入った強撹拌混合物(13℃)に、温度を10℃に保ちながらホスゲン(78mL、トルエン中20%溶液、0.157mmol)を滴下した。反応混合物をさらに15分間、10℃で撹拌し、減圧中でエバポレートした。残留固体を高温の工業用変性アルコールで抽出し、Celite(登録商標)パッドで濾過し、濾液を減圧下でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中30−100%酢酸エチル)で精製し、8.87g(75%)の表題化合物を白色固体として得た。[α]D +18° (c = 1.0, methanol); 1H NMR (400 MHz, CDCl3) δ 6.01 (br s, 1H), 4.58 (t, J = 9.4 Hz, 1H), 4.51 (dd, J = 9.7, 3.9 Hz, 1H), 4.35 - 4.27 (m, 1H).
9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(24.6g、62.9mmol)、(S)−4−トリフルオロメチルオキサゾリジン−2−オン(8.87g、57.2mmol)、ヨウ化第1銅(2.2g、11.4mmol)、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン(3.6mL、22.9mmol)及び炭酸カリウム(15.8g、114mmol)をジオキサン(200mL)に懸濁させ、超音波処理下、アルゴンで脱気した。その反応混合物を100℃で16時間加熱した。得られた混合物をアンモニア水溶液(〜16%)で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、8.11g(〜31%)の表題化合物(9−Iと9−Br生成物の7:3混合物)を得た。1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 8.6 Hz, 0.3H), 8.04 (d, J = 8.6 Hz, 0.7H), 7.49 - 7.44 (m, 0.7H), 7.42 - 7.41 (m, 1.7H), 7.34 - 7.31 (m, 0.3H), 7.27 - 7.26 (m, 0.3H), 5.55 - 5.47 (m, 1H), 4.76 - 4.71 (m, 1H), 4.66 - 4.63 (m, 1H), 4.50 - 4.41 (m, 4H).
ジメチルスルホキシド(7.0mL)に(S)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−(トリフルオロメチル)オキサゾリジン−2−オンと(S)−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−(トリフルオロメチル)オキサゾリジン−2−オン(960mg、9−I:9−Brが7:3の混合物、〜2.19mmol)、L−プロリン(630mg、5.48mmol)、ヨウ化第1銅(84mg、0.44mmol)、及び三塩基性リン酸カリウム(1.86g、8.88mmol)を入れた混合物を100℃で18時間加熱した。冷めた反応混合物を撹拌ジクロロメタン(140mL)に加え、得られた懸濁液をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:ジクロロメタン中2NのNH3/MeOH 0−35%)で精製し、262mg(65%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 453.
DMF(5.0mL)中に(2−((S)−2−オキソ−4−(トリフルオロメチル)オキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−L−プロリン(582mg、1.29mmol)、塩化アンモニウム(138mg、2.57mmol)及びN,N−ジイソプロピルエチルアミン(1.0mL、5.80mmol)を入れた氷冷混合物に、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(1.22g、3.21mmol)を10分かけて少しずつ加えた。反応混合物を室温で15分間撹拌し、その後酢酸エチルと希重炭酸水素ナトリウム水溶液とに分配した。水相を酢酸エチルで抽出し、合わせた有機抽出物を水、次いでブラインで連続的に洗浄し、硫酸ナトリウム上で乾燥させ、減圧下でエパポレートさせた。粗生成物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:ジクロロメタン中0−10%メタノール)で精製し、シリカゲル上でさらに精製し(溶媒勾配:酢酸エチル中0−80%酢酸メチル)し、最後にアセトニトリルから再結晶化し、245mg(42%)の103を黄褐色の固体として得た。LCMS (ESI): RT (min) = 3.34 [M+H]+ = 452.2, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.9 Hz, 1H), 7.40 (br s, 1H), 7.21 (s, 1H), 7.05 (br s, 1H,), 6.32 (dd, J = 8.9, 2.4 Hz, 1H), 6.03 (d, J = 2.4 Hz, 1H), 5.50 - 5.42 (m, 1H), 4.73 (t, J = 9.3 Hz, 1H), 4.62 (dd, J = 10.1, 2.4 Hz, 1H), 4.40 - 4.34 (m, 4H), 3.96 - 3.93 (m, 1H), 3.58 - 3.53 (m, 1H), 3.27 - 3.20 (m, 1H), 2.29 - 2.15 (m, 1H), 2.03 - 1.91 (m, 3H).
工程1: (R)−4−エチル−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−オキサゾリジン−2−オン及び(R)−4−エチル−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)オキサゾリジン−2−オン
9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(1.5g、3.84mmol)、(R)−4−エチルオキサゾリジン−2−オン(618mg、5.37mmol)、ヨウ化第1銅(146mg、0.767mmol)、トランス−N,N’−ジメチル−1,2−シクロヘキサンジアミン(272μL、1.73mmol)と炭酸カリウム(742mg、5.37mmol)の混合物をジオキサン(4.5mL)に懸濁させ、反応混合物を超音波処理下、アルゴンで脱気した。得られた混合物を100℃で24時間加熱した。反応を停止させ、室温に冷ました。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)でそのまま精製し、680mg(42%)の表題化合物(9−Br:9−I生成物の〜1:2混合物)を得た。LCMS (ESI): [M+H]+ = 378/380/426.
(R)−4−エチル−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)オキサゾリジン−2−オンと(R)−4−エチル−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)オキサゾリジン−2−オン(680mg、1.6mmol)、ヨウ化第1銅(30.5mg、0.16mmol)、(L)−乳酸(421μL、4.80mmol)及び炭酸セシウム(3.12g、6.01mmol)の混合物をジメチルスルホキシド(3.0mL)/水(3.0mL)に懸濁させ、反応混合物を超音波処理下、アルゴンで脱気した。得られた混合物を120℃で24時間加熱した。反応混合物を停止させ、室温に冷まし、1N塩酸(6.0mL)の添加により中和し、その後酢酸エチルとブラインとに分配した。合わせた有機抽出物を硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、196mg(39%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 316.
(R)−4−エチル−3−(9−ヒドロキシ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)オキサゾリジン−2−オン(196mg、0.623mmol)をTHF(5.0mL)中に溶媒和させた。(2R)−2−ヒドロキシプロパン酸メチル(89μL、0.934mmol)及びトリフェニルホスフィン(245mg、0.934mmol)を加え、反応物を室温で攪拌した。その後アゾジカルボン酸ジイソプロピル(183μl、0.934mmol)を加え、反応混合物を室温で1.5時間撹拌した。反応物を減圧中でエバポレートし、得られた残留物をシリカゲル上でのフラッシュカラムクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、214mg(86%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 402.
(S)−2−((2−((R)−4−エチル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(214mg、0.534mmol)をメタノール(20mL、140mmol)中7Nアンモニアの中に溶媒和させた。その反応混合物を室温で3時間撹拌した。得られた混合物を減圧中でエバポレートし、逆相C18クロマトグラフィー(溶媒勾配:水中0−95%アセトニトリル、0.1%水酸化アンモニウム緩衝液)で精製し、凍結乾燥させて163mg(79%)の104を得た。LCMS (ESI): RT(min) = 3.12, [M+H]+ = 387, method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.9 Hz, 1H), 7.50 (s, 1H), 7.21 (s, 2H), 6.68 (dd, J = 8.8, 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 4.61 (q, J = 6.6 Hz, 1H), 4.52 - 4.46 (m, 2H), 4.40 - 4.32 (m, 4H), 4.20 - 4.15 (m, 1H), 1.85 - 1.76 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H), 0.80 (t, J = 7.5 Hz, 3H).
工程1: 9−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン
窒素の不活性雰囲気でパージし、維持した3Lの4つ口丸底フラスコに、ジオキサン(1.5L)、9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(150g、566mmol)、4,4,5,5−テトラメチル−2−(テトラメチル−1,3,2−ジオキサボラン−2−イル)−1,3,2−ジオキサボラン(217g、855mmol)、酢酸カリウム(165g、1.68mol、2.97当量)、及びPd(dppf)Cl2(42g、57.4mmol)を入れた。得られた溶液を90℃で一晩撹拌した。得られた固体を濾過し、濾液を減圧中でエバポレートした。得られた粗生成物をシリカゲル上でのフラッシュクロマトグラフィー(溶出剤:石油エーテル中25%酢酸エチル)で精製し、154g(87%)の表題化合物を明黄色の油状物として得た。
5Lの4つ口丸底フラスコに、ジクロロメタン(1.0L)と9−(4,4,5,5−テトラメチル−1,3,2−ジオキサボラン−2−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(100g、320mmol)を入れ、続いて30%過酸化水素水溶液(700mL、8.82mol)を0℃で撹拌しながら滴下した。反応混合物を室温で一晩攪拌した。得られた混合物を、過酸化水素が残らなくなるまでNa2SO3水溶液で洗浄した。得られた溶液を酢酸エチルで抽出し(4×5L)、有機抽出物を合わせ、無水硫酸ナトリウム上で乾燥させ、濾過し、減圧中でエバポレートし、表題化合物216g(粗製、溶媒を含有)を得、これをさらに精製することなく次の工程に進んだ。
窒素の不活性雰囲気でパージし、維持した5Lの4つ口丸底フラスコに、ジオキサン(3.0L)、5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−オール(136g、673mmol)、メチル(2R)−2−ヒドロキシプロパン酸メチル(91g、874mmol)、トリフェニルホスフィン(265g、1.01mol)を入れた。これに続いて、アゾジカルボン酸ジエチル(176g、1.01mol)を10℃で1時間かけて添加した。得られた溶液を室温で一晩撹拌した。反応混合物を減圧中でエバポレートし、得られた粗生成物をシリカゲル上でのフラッシュクロマトグラフィー(溶出剤:石油エーテル中50%酢酸エチル)で精製し、170g(88%)の表題化合物を明黄色の油固体として得た。
窒素の不活性雰囲気でパージし、維持した5Lの4つ口丸底フラスコに、N,N−ジメチルホルムアミド(3.0L)、(S)−2−((5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(335g、1.16mol)、及びN−ヨードスクシンイミド(262g、1.16mol)を入れた。反応混合物を50℃で3時間撹拌した。その後、得られた溶液を5Lの水/氷の添加によりクエンチした。固体を濾過で回収し、5Lの酢酸エチルで抽出し、減圧下でエバポレートした。粗生成物をシリカゲル上でのフラッシュクロマトグラフィー(溶出剤:石油エーテル中15%酢酸エチル)で精製し、200g(32%)の表題化合物を黄色の固体として得た。
窒素の不活性雰囲気でパージし、維持した10Lの4つ口丸底フラスコに、テトラヒドロフラン(5L)及び(S)−2−((2,3−ジヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(296g、548mol)を入れた。これに続いて、−50℃でエチルマグネシウムブロミド(384mL、テトラヒドロフラン中2N)を添加した。反応混合物を−40℃で4時間撹拌した。その後、得られた溶液を1Lの飽和塩化アンモニウム水溶液の添加によりクエンチし、酢酸エチルで抽出した(2×3L)。合わせた有機抽出物を無水硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗生成物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:石油エーテル中25−40%酢酸エチル)で精製し、131g(58%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 415; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.5 Hz, 1H), 7.00 (s, 1H), 6.67 - 6.63 (m, 1H), 6.49 (d, J = 1.2 Hz, 1H), 4.81-4.42 (m, 1H), 4.41 - 4.39 (m, 2H), 4.39 - 4.30 (m, 2H), 3.76 (s, 3H), 1.63 (d, J = 3.45 Hz, 3H).
ジオキサン(20mL)に(S)−2−((2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(1.33g、3.20mmol)、(S)−4−トリフルオロメチルオキサゾリジン−2−オン(500mg、3.20mmol)、ヨウ化第1銅(240mg、1.30mmol)、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン(200mg、1.30mmol)、及び炭酸カリウム(880mg、640mmol)を入れた混合物を超音波処理下、アルゴンで脱気し、反応混合物を100℃で6時間加熱した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、890mg(63%)の表題化合物を白色固体として得た。LCMS (ESI): [M+H]+ = 442.
メチル (S)−2−((2−((S)−2−オキソ−4−(トリフルオロメチル)オキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパノエート (S)−メチル 2−((2−((S)−4−(トリフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパノエート(890mg、2.01mmol)の溶液の入ったアンモニア溶液(10mL、メタノール中7N、70mmol)を室温で18時間撹拌した。反応混合物を減圧下でエバポレートし、得られた固体をジクロロメタンから再結晶し、減圧中で乾燥させ、562mg(65%)の105を白色固体として得た。LCMS (ESI): RT (min) = 3.41, [M+H]+ = 427, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 9.1 Hz, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 6.73 (dd, J = 9.0, 2.5 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 5.53 - 5.44 (m, 1H), 4.74 (t, J = 9.6 Hz, 1H), 4.69 - 4.61 (m, 2H), 4.48 - 4.38 (m, 4H), 1.43 (d, J = 6.6 Hz, 3H).
工程1: (R)−2,2−ジメチル−[1,3]ジオキソラン−4−カルバルデヒド
過ヨウ素酸ナトリウム(57.0g、270mmol)を熱水(115mL)に溶解し、シリカ(200g、60A 220−440メッシュ、粒径35−75μm)を添加した。流動性粉末が得られるまで、この混合物を激しく撹拌した。これを1,2:5,6−ビス−O−(1−メチルエチリデン)−D−マンニトール(50g、190mmol)のジクロロメタン(1.0L)溶液に加え、反応物を室温で1時間攪拌した。得られた混合物をNa2SO4のパッドで濾過し、固形物をジクロロメタンで十分に洗浄した。合わせた有機抽出物を減圧中でエバポレートし、37.2g(75%)の表題化合物を無色油状物として得た。1H NMR (400 MHz, CDCl3) δ 9.73 (d, J = 1.9 Hz, 1H), 4.38 (ddd, J = 7.4, 4.7, 1.9 Hz, 1H), 4.18 (dd, J = 8.8, 7.4 Hz, 1H), 4.10 (dd, J = 8.8, 4.7 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 3H).
水浴中で冷却した(R)−2,2−ジメチル−[1,3]ジオキソラン−4−カルバルデヒド(7.08g,54mmol)のジクロロメタン(50mL)溶液に、ジエチルアミノ硫黄トリフルオリド(8.4mL、62.6mmol)を滴下し、その反応混合物を室温で3時間撹拌した。得られた混合物を、急速に撹拌している氷冷飽和重炭酸ナトリウム水溶液に滴下した。その混合物をジクロロメタンでさらに抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートして6.58g(79%)の粗表題化合物を橙色の油状物として得た。1H NMR (400 MHz, CDCl3) δ 5.69 (td, J = 55.8, 4.9 Hz, 1H), 4.27 - 4.17 (m, 1H), 4.16 - 4.03 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).
HCl含有ジオキサン(4N、10.8mL、43.2mmol)を、(R)−4−ジフルオロメチル−2,2−ジメチル[1,3]ジオキソラン(6.58g、43.2mmol)のメタノール(40mL)溶液に添加し、その反応混合物を室温で30分間撹拌した。得られた混合物を減圧中でエバポレートし、アセトニトリルと共沸させた。残留物をN,N−ジメチルホルムアミド(10mL)に溶解し、tert−ブチルジメチルシリルクロリド(6.53g、43.2mmol)、トリエチルアミン(9.0mL、64.9mmol)及び4−(ジメチルアミノ)ピリジン(触媒)を加えた。その反応混合物を室温で1時間撹拌した。得られた混合物を水で洗浄し、その後ジクロロメタン(30mL×3)で抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。得られた粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−30%酢酸エチル)で精製し、3.43g(35%)の表題化合物を黄色の油状物として得た。1H NMR (400 MHz, CDCl3) δ 5.66 (td, J = 56.4, 4.6 Hz, 1H), 3.76 - 3.60 (m, 2H), 2.46 (d, J = 6.4 Hz, 1H), 0.81 (s, 9H), 0.00 (s, 6H).
トリフルオロメタンスルホン酸無水物(2.9mL、17.4mmol)を(R)−3−(tert−ブチルジメチルシラニルオキシ)−1,1−ジフルオロプロパン−2−オール(3.43g、15.1mmol)とピリジン(2.0mL、24.2mmol)のジクロロメタン(50mL)溶液に−20℃で滴下し、その反応混合物を−20℃で20分間、その後0℃で1時間撹拌した。得られた混合物を0.5NのHCl水溶液で希釈し、ジクロロメタンで抽出した。合わせた有機層を硫酸マグネシウム上で乾燥させ、減圧中でエバポレートした。粗残留物をN,N−ジメチルホルムアミド(10mL)に溶解し、アジ化ナトリウム(2.96g、45.5mmol)を加え、反応混合物を室温で2時間撹拌した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートして4.50gの粗表題化合物を得た。1H NMR (400 MHz, CDCl3) δ 5.74 (td, J = 55.4, 4.4 Hz, 1H), 3.81 - 3.71 (m, 2H), 3.58 - 3.47 (m, 1H), 0.81 (s, 9H), 0.00 (s, 6H).
水酸化パラジウム炭素(200mg、20%)を、((R)−2−アジド−3,3−ジフルオロプロポキシ)−tert−ブチルジメチルシラン(4.50g、粗製、〜15.1mmolと仮定)を酢酸エチル(20mL)とメタノール(2.0mL)に溶解した溶液に加え、反応物を水素バルーン下で16時間撹拌した。反応物を濾過し、新鮮な水酸化パラジウム炭素(400mg、20%)を加え、反応混合物を水素バルーン下で16時間撹拌した。得られた混合物を濾過し、濾液を減圧中でエバポレートし、3.08g(90%)の粗表題生成物を無色油状物として得た。1H NMR (400 MHz, CDCl3) δ 5.66 (td, J = 57.0, 4.7 Hz, 1H), 3.71 - 3.57 (m, 2H), 3.00 - 2.89 (m, 1H), 1.42 (br s, 2H), 0.82 (s, 9H), 0.00 (s, 6H).
HCl含有ジオキサン(4N、5.0mL、20mmol)を、(R)−1−(tert−ブチルジメチルシラニルオキシメチル)−2,2−ジフルオロエチルアミン(Org. Lett., Vol. 9, No. 1, 2007, 41-44) (2.30g、10.3mmol)のメタノール(5.0mL)溶液に加え、反応混合物を室温で2時間攪拌した。その混合物を減圧中でエバポレートし、得られた油状物をジエチルエーテルで粉砕して固体を得、これを減圧中で乾燥させた。固体をトルエン(20mL)とKOH(2.50g、水20mLに44.6mmol)の混合物に0℃で溶解した。ホスゲン(16.3mL、トルエン中20%)を滴下し、冷却浴を除去し、反応混合物を1時間撹拌した。混合物を減圧中でエバポレートし、得られた残留物を高温工業用メタノールで抽出し、固体を濾過により回収した。濾液を減圧中でエバポレートし、得られた粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、830mg(68%)の表題化合物をオフホワイトの固体として得た。[α]D = +10.1 (c = 2.37, CHCl3).1H NMR (400 MHz, CDCl3) δ 5.96 (br s, 1H), 5.78 (td, J = 55.3, 4.8 Hz, 1H), 4.54 (t, J = 9.2 Hz, 1H), 4.42 (dd, J = 9.6, 4.4 Hz, 1H), 4.17 - 4.06 (m, 1H).
ジオキサン(10mL)に9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(741mg、1.90mmol)、(S)−4−ジフルオロメチルオキサゾリジン−2−オン(260mg、1.90mmol)、ヨウ化第1銅(72mg、0.38mmol)、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン(120μL、0.76mmol)、及び炭酸カリウム(524mg、3.79mmol)が入った混合物を超音波処理下、アルゴンで脱気した。その反応混合物を100℃で16時間加熱した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、438mg(50%)の表題化合物を得た。LCMS (ESI): [M+H]+ = 448; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.7 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.29 (s, 1H), 6.64 (t, J = 56.8 Hz, 1H), 4.86 (ddd, J = 24.0, 9.2, 4.0 Hz, 1H), 4.73 (dd, J = 9.3, 4.0 Hz, 1H), 4.53 (t, J = 9.3 Hz, 1H), 4.46 - 4.41 (m, 2H), 4.38 - 4.32 (m, 2H).
ジメチルスルホキシド(2.0mL)に(S)−4−(ジフルオロメチル)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)オキサゾリジン−2−オン(218mg、0.49mmol)、L−プロリン(112mg、vmmol)、ヨウ化第1銅(19mg、0.10mmol)及び三塩基性リン酸カリウム(207mg、0.98mmol)を入れた混合物を超音波処理下、アルゴンで脱気した。その反応混合物を100℃で16時間加熱した。得られた混合物をジクロロメタン(30mL)で希釈し、その後シリカゲルフラッシュカートリッジ(10g)に直接装填し、溶離し(溶媒勾配:ジクロロメタン中、2NのNH3/メタノール5−30%)、粗製の表題化合物を得た。LCMS (ESI): [M+H]+ = 435.
1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェートHATU(259mg、0.68mmol)を、(S)−1−(2(2−((S)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−L−プロリン(粗製、〜0.49mmol)、塩化アンモニウム(52mg、0.97mmol)及びトリエチルアミン(136μL、0.97mmol)のN,N−ジメチルホルムアミド(2.0mL)溶液に少しずつ加え、反応混合物を室温で15分間撹拌した。得られた混合物を飽和重炭酸ナトリウム水溶液で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:ジクロロメタン中、2NのNH3/メタノール0−10%)で精製し、82mg(39%)の106をオフホワイトの固体として得た。LCMS (ESI): RT (min) = 3.31, [M+H]+ = 434, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.9 Hz, 1H), 7.36 (br s, 1H), 7.16 (s, 1H), 7.01 (br s, 1H), 6.68 (t, J = 55.9 Hz, 1H), 6.28 (dd, J = 8.9, 2.4 Hz, 1H), 6.00 (d, J = 2.4 Hz, 1H), 4.97 - 4.86 (m, 1H), 4.60 - 4.49 (m, 2H), 4.39 - 4.28 (m, 4H), 3.94 - 3.88 (m, 1H), 3.56 - 3.48 (m, 1H), 3.25 - 3.16 (m, 1H), 2.22 - 2.11 (m, 1H), 2.01 - 1.86 (m, 3H).
工程1: (S)−2−((2−((S)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル
ジオキサン(8.0mL)に(S)−2−((2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(414mg、1.00mmol)、(S)−4−ジフルオロメチルオキサゾリジン−2−オン(143mg、1.05mmol)、ヨウ化第1銅(38mg、0.20mmol)、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン(60mg、0.40mmol)、及び炭酸カリウム(280mg、2.00mmol)を入れた混合物を超音波処理下、アルゴンで脱気し、反応混合物を100℃で6時間加熱した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−60%酢酸エチル)で精製し、386mg(91%)の表題化合物を白色固体として得た。LCMS (ESI): [M+H]+ = 424.
(S)−2−((2−((S)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(386mg、0.91mmol)の溶液の入ったアンモニア溶液(10mL、メタノール中7N、70mmol)を室温で18時間撹拌した。反応混合物を減圧中でエバポレートし、得られた白色固体をジクロロメタンで粉砕し、減圧中で乾燥させ、325mg(87%)の107を白色固体として得た。LCMS (ESI): RT (min) = 3.32, [M+H]+ = 409, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 7.57 (br s, 1H), 7.30 - 7.25 (m, 2H), 6.88 - 6.58 (m, 2H), 5.04 - 4.92 (m, 1H), 4.68 - 4.53 (m, 3H), 4.45 - 4.37 (m, 4H), 1.44 (d, J = 6.3 Hz, 3H).
工程1: (R)−1−((tert−ブチルジメチルシリル)オキシ)−3−フルオロプロパン−2−オール
tert−ブチルジメチルシリルクロリド(1.60g、10.63mmolを、(R)−3−フルオロプロパン−1,2−ジオール(1.00g、10.6mmol)、トリエチルアミン(1.93mL、13.8mmol)と触媒4−(ジメチルアミノ)ピリジンのジクロロメタン溶液に0℃で加え、反応混合物を室温まで温め、室温で16時間撹拌した。反応混合物を水で希釈し、ジクロロメタンで抽出した。合わせた有機画分をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。得られた粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−40%酢酸エチル)で精製し、1.80g(81%)の表題化合物を無色の油状物として得た。1H NMR (400 MHz, CDCl3) δ 4.45 - 4.36 (m, 1H), 4.34 - 4.25 (m, 1H), 3.87 - 3.73 (m, 1H), 3.66 - 3.56 (m, 2H), 2.30 (d, J = 6.0 Hz, 1H), 0.82 (s, 9H), 0.00 (s, 6H).
トリフルオロメタンスルホン酸無水物(1.67mL、9.93mmol)を(R)−1−(tert−ブチルジメチルシリル)オキシ)−3−フルオロプロパン−2−オール(1.80g、8.60mmol)とピリジン(1.2mL、13.8mmol)のジクロロメタン溶液に−20℃で滴下し、その反応混合物を−20℃で20分間、その後0℃で30時間撹拌した。反応混合物を0.5NのHCl水溶液で希釈し、ジクロロメタンで抽出した。合わせた有機抽出物を硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。残留物をN,N−ジメチルホルムアミド(5.0mL)に溶解し、アジ化ナトリウム(1.68g、25.9mmol)を加えた。その反応混合物を室温で2時間撹拌した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートして粗表題化合物を得、これを精製せず次工程で用いた。1H NMR (400 MHz, CDCl3) δ 4.58 - 4.26 (m, 2H), 3.75 - 3.63 (m, 2H), 3.62 - 3.46 (m, 1H), 0.80 (s, 9H), 0.00 (s, 6H).
水酸化パラジウム(400mg、炭素上20%)を、((S)−2−アジド−3−フルオロプロポキシ)−tert−ブチルジメチルシラン(粗製、8.60mmolと仮定)を酢酸エチル(15mL)とメタノール(5.0mL)に溶解した溶液に加え、反応混合物を水素バルーン下で16時間撹拌した。得られた混合物を濾過し、新鮮な水酸化パラジウム(400mg、炭素上20%)を加え、反応物を水素バルーン下で16時間撹拌した。得られた混合物を濾過し、濾液を減圧中でエバポレートし、表題化合物を生成物:出発物質の〜2:1混合物として得、これを精製せずに次工程で用いた。
HCl含有ジオキサン(4N、2.0mL、8.00mmol)を(S)−1−((tert−ブチルジメチルシリル)オキシ)−3−フルオロプロパン−2−アミン(粗製、8.60mmolと仮定)のメタノール(3.0mL)溶液に添加し、得られた混合物を室温で2時間撹拌した。反応混合物を減圧中でエバポレートした。得られた残留物をトルエン(20mL)とKOH(2.89g、51.6mmol、水12.5%)の混合物に0℃で溶解した。この混合物にホスゲン(13.6mL、トルエン中20%)を滴下し、冷却浴を取り除き、得られた混合物を1時間撹拌した。この反応混合物を減圧中でエバポレートし、得られた残留物を熱い工業用変性アルコールで抽出した。濾液を減圧中でエバポレートし、得られた残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中50−100%酢酸エチル)で精製し、450mg(44%、3工程)の表題化合物をオフホワイトの固体として得た。1H NMR (400 MHz, CDCl3) δ 5.69 (br s, 1H), 4.59 - 4.42 (m, 2H), 4.42 - 4.32 (m, 1H), 4.25 - 4.08 (m, 2H).
9−ブロモ−2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン(722mg、1.85mmol)、(S)−4−フルオロメチルオキサゾリジン−2−オン(220mg、1.85mmol)、3,4,7,8−テトラメチル−1,10−フェナントロリン(131mg、0.55mmol)、Cu(OAc)2.H2O(74mg、0.37mmol)、炭酸カリウム(510mg、3.70mmol)及びジオキサン(6.0ml)の混合物を管に密封し、その混合物を超音波処理下、アルゴンで脱気した。その反応混合物を100℃で72時間加熱した。得られた反応混合物を15%アンモニア水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。得られた粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−100%酢酸エチル)で精製し、390mg(53%)の表題化合物(9−Brと9−I生成物の約2:1混合物)を得た。LCMS (ESI): [M+H]+ = 382/384/430; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 9.3 Hz, 0.7H), 8.05 (d, J = 8.8 Hz, 0.3H), 7.43 - 7.37 (m, 0.6H), 7.29 (s, 1.2H), 7.23 - 7.18 (m, 1.2H), 5.03 - 4.66 (m, 3H), 4.60 (t, J = 8.5 Hz, 1H), 4.54 (dd, J = 8.6, 4.3 Hz, 1H), 4.47 - 4.43 (m, 2H), 4.37 - 4.33 (m, 2H).
ジメチルスルホキシド(2.0mL)に(S)−3−(9−ブロモ−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−(フルオロメチル)オキサゾリジン−2−オンと(S)−3−(9−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−2−イル)−4−(フルオロメチル)オキサゾリジン−2−オン(270mg、2:1混合、〜0.71mmol)、L−プロリン(163mg、1.41mmol)、ヨウ化第1銅(27mg、0.14mmol)、及び三塩基性リン酸カリウム(300mg、1.41mmol)を入れた混合物を超音波処理下、アルゴンで脱気した。その反応混合物を100°Cで2時間加熱した。得られた混合物を室温に冷却し、ジメチルスルホキシド(1.0mL)で希釈した。塩化アンモニウム(227mg、4.20mmol)、トリエチルアミン(0.98mL、7.10mmol)、1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシド ヘキサフルオロホスフェート(1.61g、4.20mmol)を加え、その反応混合物を室温で30分間撹拌した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:DCM中0−10%メタノール)で精製し、150mg(51%)の108を得た。LCMS (ESI): [M+H]+ = 416; 1H NMR (400 MHz, d6-DMSO) δ 8.02 d, J = 8.7 Hz, 1H), 7.36 (br s, 1H), 7.16 (s, 1H), 7.01 (br s, 1H), 6.28 (dd, J = 7.7, 2.5 Hz, 1H), 6.00 (d, J = 2.5 Hz, 1H), 4.97 (ddd, J = 48.5, 10.0, 2.8 Hz, 1H), 4.78 - 4.53 (m, 3H), 4.40 - 4.27 (m, 5H), 3.94 - 3.88 (m, 1H), 3.56 - 3.48 (m, 1H), 3.25 - 3.16 (m, 1H), 2.22 - 2.11 (m, 1H), 1.99 - 1.87 (m, 3H).
工程1: (S)−2−((2−((S)−4−(フルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル
ジオキサン(8.0mL)に(S)−2−((2−ヨード−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(414mg、1.00mmol)、(S)−4−フルオロメチルオキサゾリジン−2−オン(123mg、1.05mmol)、ヨウ化第1銅(38mg、0.20mmol)、トランス−N,N’−ジメチルシクロヘキサン−1,2−ジアミン(60mg、0.40mmol)、及び炭酸カリウム(280mg、2.00mmol)を入れた混合物を超音波処理下、アルゴンで脱気し、反応混合物を100℃で18時間加熱した。得られた混合物を水で希釈し、酢酸エチルで抽出した。合わせた有機抽出物をブラインで洗浄し、硫酸マグネシウム上で乾燥させ、濾過し、減圧中でエバポレートした。粗残留物をシリカゲル上でのフラッシュクロマトグラフィー(溶媒勾配:シクロヘキサン中0−80%酢酸エチル)で精製し、305mg(75%)の表題化合物を白色固体として得た。LCMS (ESI): [M+H]+ = 406.
(S)−2−((2−((S)−4−(フルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパン酸メチル(300mg、0.74mmol)の溶液の入ったアンモニア溶液(10mL、メタノール中7N、70.0mmol)を室温で18時間撹拌した。得られた白色固体を濾過し、減圧中でエバポレートし、190mg(66%)の109を白色固体として得た。LCMS (ESI): RT (min) = 2.91, [M+H]+ = 391, Method = A; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 8.9 Hz, 1H), 7.54 (br s, 1H), 7.27 (s, 1H), 7.25 (br s, 1H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.00 (ddd, J = 48.4, 9.8, 2.6 Hz, 1H), 4.83 - 4.57 (m, 4H), 4.45 - 4.37 (m, 5H), 1.43 (d, J = 6.6 Hz, 3H).
PI3K結合アッセイは、小分子PI3K阻害剤の生化学的効力を決定するためのものである。PI3K脂質キナーゼ反応は、PIP2:3PS脂質基質(Promega#V1792)及びATPの存在下で実施される。キナーゼ反応の終了後、脂質基質のリン酸化によるATPからADPへの代謝を、Promega ADP−GloTM(Promega#V1792)アッセイを用いて検出する。表5のように、各PI3Kアイソフォームについて以下の条件を用いて反応が行われる。
表5
Chen等及びNacht等(Chen, P., Y. L. Deng, S. Bergqvist, M. D. Falk, W. Liu, S. Timofeevski及びA. Brooun 「Engineering of an isolated p110alpha subunit of PI3Kalpha permits crystallization and provides a platform for structure-based drug design」, (2014) Protein Sci 23(10): 1332-1340; Nacht, M., L. Qiao, M. P. Sheets, T. St Martin, M. Labenski, H. Mazdiyasni, R. Karp, Z. Zhu, P. Chaturvedi, D. Bhavsar, D. Niu, W. Westlin, R. C. Petter, A. P. Medikonda及びJ. Singh 「Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kalpha」, J. Med. Chem. 56(3): 712-721)に従い、N末端切断型p110α(アルファ)を生成した。
PI3Kα野生型(親)、ヘリカルドメイン変異型E545K、及びキナーゼドメイン変異型H1047RといったSW48同質遺伝子細胞株におけるPI3K経路の阻害を測定することにより、本発明の化合物が変異型PI3Kα(アルファ)を含む細胞に対して優先的に作用する能力を決定した。下記のアッセイは、小分子PI3Kα阻害剤の細胞効力及び変異体選択性(mutant selectivity)を決定するためのものである。このアッセイは、PI3Kα WT、PI3Kα変異型E545K/+(Horizon Discovery 103−001)又はPI3Kα変異型H1047R/+(HorizonDiscovery103−005)を発現する同質遺伝子細胞株を利用する。各細胞株におけるPI3KαによるpPRAS40阻害の効力は、化合物処理の24時間後に測定される。PI3Kα阻害剤の変異体選択性は、WT対E545K細胞株及びWT対H1047R細胞株におけるEC50効力比によって決定される。
細胞を384ウェルプレートに16時間播種した(1ウェルあたり1,500個)。2日目に、9段階1:3化合物希釈物を96ウェルプレート中でDMSOで作製した。その後、Rapidplateロボット(Zymark Corp.)を使用して、化合物を増殖培地にさらに希釈した。その後、384ウェル細胞プレート内の4連ウェルに希釈した化合物を加え、37℃、5%CO2でインキュベートした。4日後、Cell Titer−Glo(Promega)を製造者の指示に従って用いて発光により生存細胞の相対数を測定し、Wallac Multilabel Reader(Perkin−Elmer)で読み取った。EC50値は、Prism 6.0ソフトウェア(GraphPad)を用いて算出した。
マウス:メスの重症複合免疫不全マウス(SCID(登録商標)、C.B−17/Charles River Hollister)は、10から11週齢であり、試験の第0日に15.8〜25.09グラムのBW範囲を有する。これらの動物には、自由摂取水(逆浸透、1ppmCl)、並びに18.0%の粗タンパク質、5.0%の粗脂肪及び5.0%の粗繊維からなるNIH 31 Modified and Irradiated Lab Diet(登録商標)が与えられる。マウスは、21〜22℃(70〜72°F)及び湿度40〜60%の12時間光周期で、静止型マイクロアイソレーター内の放射線照射したALPHA−Dri(登録商標)bed−o’cobs(登録商標)Laboratory Animal Beddingに収容される。ジェネンテックは、拘束、管理、外科手術、飼料及び体液調節、並びに獣医医療に関する実験動物の管理と使用に関するガイドライン(Guide for Care and Use of Laboratory Animals)の推奨事項に明確に従っている。ジェネンテックにおける実験動物の管理と使用プログラムは、国際実験動物管理公認協会(AAALAC)により認定されており、このことは、実験動物の管理と使用の一般に受け入れられている基準のコンプライアンスを確かなものにしている。
腫瘍体積(mm3)=(w2l)/2(式中、w=腫瘍の幅(mm)、l=腫瘍の長さ(mm))
腫瘍重量は、1mgが腫瘍体積の1mm3と等しいと仮定して、推定することができる。
Claims (21)
- 式I:
I
から選択される化合物、並びにその立体異性体、互変異性体及び薬学的に許容される塩[上式中:
R1は、-CH3、-CH2CH3、-CH(CH3)2、-CHF2、-CH2F、及び-CF3から選択され;
Xは、
{上式中、波線は結合部位を示す}から選択され、
R2は、H、C1-C6アルキル、シクロプロピル、及びシクロブチルから選択され、F、-OCH3又は-OHで置換されていてもよい]。 - 式Ia:
Ia
の、請求項1に記載の化合物。 - 式Ib:
Ib
の、請求項1に記載の化合物。 - R1が-CHF2及び-CH2Fから選択される、請求項2又は3に記載の化合物。
- R2が-CH3である、請求項1〜4のいずれか一項に記載の化合物。
- 以下から選択される、請求項1〜5のいずれか一項に記載の化合物:
(S)−2−((2−((R)−4−イソプロピル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパンアミド;
(S)−1−(2−((R)−4−メチル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)ピロリジン−2−カルボキサミド;
(S)−1−(2−((S)−2−オキソ−4−(トリフルオロメチル)オキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)ピロリジン−2−カルボキサミド;
(S)−2−((2−((R)−4−エチル−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパンアミド;
(S)−2−((2−((S)−2−オキソ−4−(トリフルオロメチル)オキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパンアミド;
(S)−1−(2−((S)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)ピロリジン−2−カルボキサミド;
(S)−2−((2−((S)−4−(ジフルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパンアミド;
(S)−1−(2−((S)−4−(フルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)ピロリジン−2−カルボキサミド;及び
(S)−2−((2−((S)−4−(フルオロメチル)−2−オキソオキサゾリジン−3−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)オキシ)プロパンアミド。 - 請求項1〜6のいずれか一項に記載の化合物及び薬学的に許容される担体、滑剤、希釈剤又は賦形剤を含む薬学的組成物。
- 薬学的に許容される担体、滑剤、希釈剤又は賦形剤が二酸化ケイ素、粉末セルロース、微結晶性セルロース、ステアリン酸金属塩、アルミノケイ酸ナトリウム、安息香酸ナトリウム、炭酸カルシウム、ケイ酸カルシウム、コーンスターチ、炭酸マグネシウム、アスベストフリータルク、ステアロウェットC、スターチ、スターチ1500、ラウリル硫酸マグネシウム、酸化マグネシウム、及びこれらの組み合わせから選択される、請求項7に記載の薬学的組成物。
- 薬学的に許容される担体、滑剤、希釈剤又は賦形剤と請求項1〜6のいずれか一項に記載の化合物を組み合わせることを含む、薬学的組成物を製造するための方法。
- 請求項1〜6のいずれか一項に記載の化合物の治療的有効量を含む、がんを治療するための医薬であって、がんが乳がん及び非小細胞肺がんから選択される、医薬。
- 5−FU、ドセタキセル、エリブリン、ゲムシタビン、コビメチニブ、イパタセルチブ、パクリタキセル、タモキシフェン、フルベストラント、GDC−0810、デキサメタゾン、パルボシクリブ、ベバシズマブ、ペルツズマブ、トラスツズマブ エムタンシン、トラスツズマブ、及びレトロゾールから選択される追加の治療剤がさらに投与される、請求項10に記載の医薬。
- がんが乳がんである、請求項10又は11に記載の医薬。
- 乳がんがエストロゲン受容体陽性(ER+)乳がんである、請求項12に記載の医薬。
- 乳がんサブタイプがベーサル(Basal)型又はルミナル(Luminal)型である、請求項12に記載の医薬。
- がんが、E542K、E545K、Q546R、H1047L、及びH1047Rから選択されるPIK3CA変異体を発現する、請求項12に記載の医薬。
- がんがPTEN変異体を発現する、請求項12に記載の医薬。
- がんがHER2陽性である、請求項12に記載の医薬。
- 患者がHER2陰性、ER(エストロゲン受容体)陰性、及びPR(プロゲステロン受容体)陰性である、請求項12に記載の医薬。
- a) 請求項7に記載の薬学的組成物;及び
b) 乳がんの治療的処置における使用のための指示書
を含む、乳がんの治療的処置のためのキット。 - がんが乳がん及び非小細胞肺がんから選択される、患者におけるがんを治療するための医薬の製造のための、請求項1〜6のいずれか一項に記載の化合物の使用。
- がんが乳がん及び非小細胞肺がんから選択される、患者におけるがんを治療するための使用のための、請求項1〜6のいずれか一項に記載の化合物。
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