JP6633163B2 - インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス - Google Patents
インドールアミン2,3−ジオキシゲナーゼ阻害剤の合成のためのプロセス Download PDFInfo
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- JP6633163B2 JP6633163B2 JP2018187218A JP2018187218A JP6633163B2 JP 6633163 B2 JP6633163 B2 JP 6633163B2 JP 2018187218 A JP2018187218 A JP 2018187218A JP 2018187218 A JP2018187218 A JP 2018187218A JP 6633163 B2 JP6633163 B2 JP 6633163B2
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- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
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- 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
- 229960001278 teniposide Drugs 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000008733 trauma Effects 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
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 150000004654 triazenes Chemical class 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
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
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- 206010046766 uterine cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000005048 vimentin Anatomy 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
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
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- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、4−({2−[(アミノスルホニル)アミノ]エチル}アミノ)−N−(3−ブロモ−4−フルオロフェニル)−N’−ヒドロキシ−1,2,5−オキサジアゾール−3−カルボキシミドアミド(癌及び他の障害の治療において有用なインドールアミン2,3−ジオキシゲナーゼの阻害剤)を作製するプロセス及び中間体に関する。
IDOは、子宮内での胎児拒絶を防止する免疫抑制性プロセスにおいて役割を果たすと考えられている。40年以上前に、組織移植免疫学によって予測されるものにもかかわらず、妊娠の間に、遺伝的に異なる哺乳類胚が生存することが観察された(非特許文献6)。母親と胎児の解剖学的な分離及び胎児の抗原性未熟では、胎児の同種異系移植片の生存について完全に説明することができない。最近の注目は、母親の免疫学的寛容に集中している。IDOがヒト合胞体栄養細胞層細胞によって発現され、全身的なトリプトファン濃度が正常妊娠の間に落ちるので、母親−胎児の境界でのIDO発現が胎児の同種異系移植片の免疫学的拒絶を防止するのに必要であるという仮説が立てられた。この仮説を検証するために、妊娠マウス(同系胎児または同種異系胎児を保有する)を1MTへ曝露し、すべての同種異系胚で急速なT細胞誘導性拒絶が観察された。したがって、トリプトファンの異化によって、哺乳類胎児はT細胞の活性を抑制して拒絶に対して防御し、マウス妊娠の間のトリプトファン異化作用のブロックは、母親のT細胞が胎児の同種異系移植片拒絶を誘発することを可能にすると思われる(非特許文献7)。
腫瘍に向けた免疫不応答に寄与する1つのメカニズムは、寛容原性の宿主APCによる腫瘍抗原の提示であり得る。CD123(IL3RA)及びCCR6を共発現し、T細胞増殖を阻害する、ヒトIDOを発現する抗原提示細胞(APC)のサブセットも記述されている。成熟及び未成熟の両方のCD123陽性樹状細胞はT細胞活性を抑制し、このIDO抑制活性は1MTによってブロックされた(非特許文献10)。マウス腫瘍灌流リンパ節(TDLN)が、免疫抑制性レベルのIDOを構成的に発現する形質細胞様樹状細胞(pDC)のサブセットを含有することも実証された。インビトロでリンパ節細胞の0.5%のみを構成するにもかかわらず、これらのpDCは、pDCそれ自体によって提示された抗原へのT細胞応答を強力に抑制し、非抑制性APCによって提示された第三者抗原へのT細胞応答も優性様式で抑制した。pDCの集団内で、大部分の機能的なIDO媒介性の抑制因子活性は、B系譜マーカーのCD19を共発現するpDCの新規のサブセットと共に分離された。したがって、TDLN中のpDCによるIDO媒介性の抑制は宿主の抗腫瘍性のT細胞応答を強力に抑制する局所的な微小環境を生成するという仮説が立てられた(非特許文献11)。
Pg2はアミノ保護基であり、
Xはハロである。
式中、
各々のR1は独立してアミノ保護基であり、
R3はC1−6アルキルまたはベンジルである。
式F14の化合物
式中、
R2はC1−4アルキルであり、
R3はC1−6アルキルまたはベンジルである。
式中、
各々のR1は独立してアミノ保護基であり、
R2はC1−4アルキルであり、
R3はC1−6アルキルまたはベンジルである。
式中、
R3はC1−6アルキルまたはベンジルであり
各々のR1は独立してアミノ保護基である。
式中、R3はC1−6アルキルまたはベンジルであり、各々のR1は独立してアミノ保護基である。
i)式F19の化合物
ii)式F20の該化合物を、式Iの化合物
を含むプロセスも提供する。いくつかの実施形態において、当該変換は、当該組み合わせ後に塩酸水溶液を添加することを更に含む。
式中、R4は、C1−6アルキル、C1−6ハロアルキルまたはベンジルである。
式中、R4は、C1−6アルキル、C1−6ハロアルキルまたはベンジルである。
式Iの化合物は、酵素インドールアミン−2,3−ジオキシゲナーゼ(IDO)の活性を阻害することができる。例えば、式Iの化合物は、細胞中の、または阻害量の式Iの化合物の投与による酵素の修飾を必要とする個体中のIDOの活性の阻害に使用することができる。
1つ以上の追加の医薬用薬剤または治療方法、例えば抗ウイルス薬剤、化学療法剤もしくは他の抗癌剤、免疫促進剤、免疫抑制薬、照射、抗腫瘍ワクチン及び抗ウイルスワクチン、サイトカイン療法(例えばIL2、GM−CSFなど)、及び/またはチロシンキナーゼ阻害剤等を、IDOに関連する疾患、障害または病態の治療のために式Iの化合物と組み合わせて使用することができる。薬剤は単一投薬量形状で式Iの化合物と組み合わせることができるか、または薬剤は分離した投薬量形状として同時にもしくは連続して投与することができる。
医薬品として用いられた場合に、式Iの化合物は医薬組成物の形状で投与することができ、それは式Iの化合物及び薬学的に許容される担体の組み合わせである。これらの組成物は医薬技術分野において周知の様式で調製することができ、局所的または全身的な治療が所望されるかどうか及び治療される領域に依存して、多様な経路によって投与することができる。投与は、局所(眼及び粘膜(鼻腔内、膣及び直腸の送達が含まれる)が含まれる)、肺(例えば粉末またはエアロゾルの吸入または通気(ネビュライザーが含まれる)によって;気管内、鼻腔内、表皮及び経皮)、眼、経口、または非経口であり得る。眼送達のための方法には、局所投与(点眼薬)、バルーン付きカテーテルによる結膜下、眼周囲もしく硝子体内の注射もしくは導入、または結膜嚢中に外科的に設置された眼用インサートが含まれ得る。非経口投与には、静脈内、動脈内、皮下、腹腔内、もしくは筋肉内の注射もしくは点滴;または頭蓋内、例えば髄腔内もしくは脳室内の投与が含まれる。非経口投与は単一ボーラス用量の形状であり得るか、または例えば継続的な灌流ポンプによるものであり得る。局所投与のための医薬組成物及び製剤には、経皮パッチ、軟膏、ローション、クリーム、ゲル、点滴薬、坐薬、スプレー、液体及び粉末が含まれ得る。従来の医薬用担体、水性、粉末または油性の基剤、増粘剤及び同種のものは、必要であるかまたは所望され得る。
500mLのフラスコへ、tert−ブチル[2−({4−[4−(3−ブロモ−4−フルオロフェニル)−5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル]−1,2,5−オキサジアゾール−3−イル}アミノ)エチル]カルバメート(20g、41.2mmol)及びイソプロパノール(255mL)を投入した。スラリーを室温で撹拌した。塩化水素ガス(7.55g、207mmol、5.0当量)を表面下のガラス管により16分間にわたってスラリーへ添加した。次いで酢酸エチル(111mL)をバッチへ添加し、反応を43℃へ加熱し、7.5時間撹拌した。バッチを19℃へ冷却し、酢酸エチル(44mL)を添加した。スラリーを濾過し、もたらされた残渣を酢酸エチル(2×55mL)により洗浄した。単離した固体を減圧下で45℃で15時間乾燥して、オフホワイトから白色の固体として所望される産物(16.61g、95.5%の収率)を得た。1H NMR (300 MHz, DMSO−d6) δ 8.11 (bs, 3H), 7.78 (m, 1H), 7.73 (m, 1H), 7.59 (t, 1H, J = 8.7 Hz), 6.74 (t, 1H, J = 6.1 Hz), 3.50 (m, 2H), 3.02 (m, 2H); C12H11BrClFN6O3, (分子量421.61;遊離塩基のC12H10BrFN6O3、分子量385.15), LCMS (EI) m/e 385/387 (M+ + H).
トリアセトキシ水素化ホウ素ナトリウム(2.33g、11.0mmol、11.0当量)をトリフルオロ酢酸(12.0mL、155.8mmol、155.8当量)と混合した。もたらされた溶液を室温で30分間混合した。ジクロロメタン(10.0mL)及びアセトニトリル(6.0mL)中の3−(4−アミノ−1,2,5−オキサジアゾール−3−イル)−4−(3−ブロモ−4−フルオロフェニル)−1,2,4−オキサジアゾール−5(4H)−オン(5、0.342g、1.0mmol)及びtert−ブチル(2−オキソエチル)カルバメート(Sigma−Aldrich)(1.04g、6.51mmol、6.5当量)の溶液を、N2下で撹拌した。この溶液を−5℃へ冷却し、トリアセトキシ水素化ホウ素ナトリウム及びトリフルオロ酢酸の溶液を5分間にわたって滴加した。反応を室温で4時間撹拌した。HPLC及びLC−MS(M+−Boc+H:385/387、臭化物パターン)は、所望される産物と出発材料の比が4対1であることを示した。混合物を濃縮し、ジクロロメタン(10mL)により希釈した。溶液を0℃へ冷却し、4Nの水酸化ナトリウムを0〜5℃の温度を維持しながらゆっくり添加して、pHを8〜9へ調整した。水層をジクロロメタン(3×10mL)により抽出した。合わせたジクロロメタン溶液を重炭酸ナトリウム及びブラインにより洗浄し、硫酸ナトリウムの上で乾燥し、濃縮した。次いで粗製残渣をジクロロメタン(6.0mL)中で溶解し、もたらされた溶液を0℃へ冷却した。ジオキサン(3.0mL)中の4Nの塩酸を0〜5℃で滴加した。混合物を室温で20分間撹拌した。濾過によって沈殿物を収集し、ジエチルエーテルにより洗浄し、真空中で乾燥して、オフホワイト固体として所望される産物(289mg、54%)を得た。1H NMR (300 MHz, DMSO−d6) δ 8.11 (bs, 3H), 7.78 (m, 1H), 7.73 (m, 1H), 7.59 (t, 1H, J = 8.7 Hz), 6.74 (t, 1H, J = 6.1 Hz), 3.50 (m, 2H), 3.02 (m, 2H); C12H11BrClFN6O3, (分子量421.61;遊離塩基でC12H10BrFN6O3 、分子量385.15), LCMS (EI) m/e 385/387 (M+ + H).
5Lの丸底フラスコに、tert−ブタノール(253g、3.41mol、1.2当量)及びジクロロメタン(2.6L)を投入した。溶液を0.9℃へ冷却した。この溶液へ、クロロスルホニルイソシアネート(463g、3.27mol、1.15当量)を、10℃未満のバッチ温度を維持しながら43分間にわたって添加した。もたらされたtert−ブチル(クロロスルホニル)カルバメート溶液を3〜5℃で1時間保持した。
ステップ2b。ベンジル({[2−({[4−(3−ブロモ−4−フルオロフェニル)−5−オキソ−4,5−ジヒドロ−1,2,4−オキサジアゾール−3−イル]−1,2,5−オキサジアゾール−3−イル}アミノ)エチル]アミノ}スルホニル)カルバメート(18b)
N末端のHisタグを備えたヒトインドールアミン2,3−ジオキシゲナーゼ(IDO)を大腸菌中で発現させ、均一になるまで精製した。IDOは、トリプトファンのインドール核のピロール環の酸化的開裂を触媒して、N’−ホルミルキヌレニンをもたらす。アッセイは、50mMのリン酸カリウム緩衝液(pH6.5)中の20mMのアスコルビン酸塩、5μMのメチレンブルー及び0.2mg/mLのカタラーゼの存在下において、95nMのIDO及び2mMのD−Trpを使用して、文献中で記述されるように室温で遂行した。最初の反応速度、続いてN’−ホルミルキヌレニンの形成に起因する321nmでの吸収増加を連続的に記録した(Sono,M.,et al.,1980,J.Biol.Chem.255,1339−1345を参照)。式Iの化合物を実施例Aのアッセイにおいて試験し、200nM未満のIC50を有することが見出された。
HeLa細胞(#CCL−2)をAmerican Type Tissue Culture Collection(ATCC、Manassas、VA)から入手し、1.5g/Lの重炭酸ナトリウム、0.1mMの非必須アミノ酸、1mMのピルビン酸ナトリウム及び10%のウシ胎仔血清(すべてInvitrogenから)を含有するように調整した、2mMのL−グルタミン及びEarleのBSSを含有する最小必須培地(Eagle)中で通常法で維持した。細胞を、5%のCO2を供給した加湿インキュベーター中で37℃で維持した。アッセイを以下の通り遂行した。HeLa細胞を1ウェルあたり5×103の密度で96ウェル培養プレート中で播種し、一晩増殖させた。翌日に、IFN−γ(50ng/mLの最終濃度)及び化合物の連続希釈物(200μLの培養培地の全体積で)を、細胞の中へ添加した。48時間のインキュベーション後に、1ウェルあたり140μLの上清を新しい96ウェルプレートへ移した。10μLの6.1Nのトリクロロ酢酸(#T0699、Sigma)を各々のウェルの中へ混合し、50℃で30分間インキュベーションして、インドールアミン2,3−ジオキシゲナーゼによって産生されたN−ホルミルキヌレニンをキヌレニンへ加水分解した。次いで反応混合物を2500rpmで10分間遠心分離して沈殿物を除去した。1ウェルあたり100μLの上清を別の96ウェルプレートへ移し、100μlの酢酸中の2%(w/v)のp−ジメチルアミノベンズアルデヒド(#15647−7、Sigma−Aldrich)と混合した。キヌレニンに由来する黄色を、SPECTRAmax 250マイクロプレートリーダー(Molecular Devices)を使用して480nmで測定した。L−キヌレニン(#K8625、Sigma)を標準として使用した。標準(240、120、60、30、15、7.5、3.75、1.87μM)を、100μLの培養培地中で調製し、等体積の2%(w/v)のp−ジメチルアミノベンズアルデヒドと混合した。個別の濃度で阻害パーセントを決定し、二重で平均値を得た。データを非直線回帰の使用によって分析して、IC50値(Prism Graphpad)を生成した。Takikawa O,et al.,1988,J.Biol.Chem.,263(4):2041−8を参照されたい。
単球を白血球泳動(leukophoresis)によってヒト末梢単核球から集めた。次いで単球を、10%のウシ胎仔血清及び2mMのL−グルタミン(すべてInvitrogenから)を補足したRPMI 1640培地を使用して、96ウェルプレート中に1×106細胞/ウェルの密度で播種した。37℃で一晩の培養後に、接着細胞をプレート上で保持した。次いで接着単球を、100ng/mlのGM−CSF(#300−03、PeproTech)及び250ng/mlのIL−4(#200−04、PeproTech)により5〜7日間刺激し、続いて5μg/mLのSalmonella typhimuriumからのLPS(#437650、Sigma)及び50ng/mLのIFN−γ(#285−IF、R&D Systems)により追加の2日間活性化して、樹状細胞の成熟を誘導した。
インビボの抗腫瘍有効性は、改変した腫瘍同種異系移植/異種移植プロトコルを使用して試験することができる。例えば、IDO阻害が、免疫能のあるマウスにおいて細胞傷害性化学療法と相乗できることが文献中で記述されている(Muller,A.J.,et al.2005,Nat.Med.11:312−319)。この相乗性がT細胞に依存するということは、免疫能のあるシンジェニックマウスにおいて増殖させたマウス腫瘍の異種移植モデル(例えばB16及び関連バリアント、CT−26、LLC)における調査中のIDO阻害剤の相乗効果を、抗CD4中和抗体により処理されたシンジェニックマウスにおいて観察されたもの、または免疫力が低下したマウス(例えばnu/nu)において増殖された同じ腫瘍に比較することによって示された。
1.細胞単離及びウイルス感染
単球及びPBLを、白血球泳動(leukopheresis)パックの向流遠心分離式溶出によって、HIV−1、2及びB型肝炎の血清陰性のドナーから得ることができる。単球は、10%の非動化したプールヒト血清、1%のグルタミン、50μg/mLのゲンタマイシン、10μg/mLのシプロフロキサシン(Sigma)及び1000U/mLの高度に精製された組換えヒトマクロファージコロニー刺激因子を補足したDulbecco改変Eagle培地(DMEM、Sigma−Aldrich)中で、テフロンフラスコを使用して浮遊培養で培養する。培養7日後に、単球由来マクロファージ(MDM)を0.01の感染多重度でHIV−1ADAに感染させる。
4週齢の雄NOD/C.B−17 SCIDマウスを購入することができる(Jackson Laboratory)。動物を病原体不含有条件下の滅菌マイクロアイソレーターケージ中で維持する。すべての動物に、PBL移植の3日前にラット抗CD122(0.25mg/マウス)、ならびにPBL注射(20×106細胞/マウス)の1日前及び3日後にウサギアシアロ−GM1抗体(0.2mg/マウス)(Wako)の2回を腹腔内注射する。HIV−1ADAに感染させたMDM(10μL中で3×105細胞)をPBL再構成の8日後に頭蓋内(i.c.)注射し、hu−PBL−NOD/SCID HIVEマウスを生成する。HIV−1に感染させたMDMのi.c.注射の直後に、hu−PBL−NOD/SCID HIVEマウスに、対照(ベヒクル)または化合物ペレット(14日または28日の遅延放出、Innovative Research)を皮下(s.c)移植する。初期実験は、IDO化合物により処理されたhu PBL−NOD/SCID HIVE動物におけるウイルス特異的なCTLの誘導を確認するように設計される。これは、四量体染色、及び脳組織からのMDM排除の神経病理学的解析によって確認される。次いで、実験は、ヒトリンパ球再構成、体液性免疫反応及び神経病理学的変性を分析するように設計される。これらの実験において、7日目に動物から採血し、ヒトMDMのi.c.注射後14及び21日目に屠殺する。EDTA含有チューブ中に収集した血液をフローサイトメトリーのために使用し、血漿を、ELISAを使用するHIV−1 p24の検出のために使用する(Beckman Coulter(商標))。HIV−1特異的抗体は、製造業者説明書(Cambridge Biotech HIV−1ウエスタンブロットキット、Calypte Biomedical)に従ってウエスタンブロット試験によって検出される。類似の量のウイルス特異的な抗体が、対照動物及び化合物処理動物で検出される。合計3つの独立した実験を、3つの異なるヒト白血球ドナーを使用して遂行することができる。
2色FACS分析を、ヒトMDMのi.c.注射後1〜3週目に末梢血ならびに2及び3週目に脾細胞で遂行することができる。細胞を、ヒトCD4、CD8、CD56、CD3、IFN−γ(eBioscience)に対する蛍光色素コンジュゲートモノクローナル抗体(mAb)により4℃で30分間インキュベーションする。細胞性免疫応答を評価するために、IFN−γ細胞内染色を抗ヒトCD8及びFITCコンジュゲート抗マウスCD45と組み合わせて遂行して、マウス細胞を除外する。抗原に特異的なCTLを決定するために、HIV1gag(p17(アミノ酸77〜85)SLYNTVATL、SL−9)及びHIV−1pol[(アミノ酸476〜485)ILKEPVHGV、IL−9]についてのアロフィコシアニンコンジュゲート四量体染色を、赤血球凝集素/インターロイキン2(PHA/IL−2)刺激脾細胞で遂行する。NIH/National Institute of Allergy and Infections Disease、National Tetramer Core Facilitiesの推奨に従って、細胞を染色する。CellQuestソフトウェア(Becton Dickinson Immunocytometry System)を使用してFACS Calibur(商標)によりデータを分析した。
脳組織をMDMのi.c.注射後14及び21日目に収集し、4%のリン酸緩衝パラホルムアルデヒド中で固定し、パラフィン中に包埋するか、または後の使用のために−80℃で凍結する。包埋したブロックからの冠状断片を、注射部位を特定するために切断する。各々のマウスについて、30〜100枚(5μm厚)の連続切片をヒトMDM注射部位から切断し、3〜7枚のスライド(10切片分離れて)を分析する。脳切片をキシレンにより脱パラフィンし、アルコール勾配中で水和する。免疫組織化学的染色は、抗原性回復のための0.01mol/Lのクエン酸緩衝液中の95℃への30分間の加熱による抗原性回復を使用する、基本的な間接プロトコルに従う。マウス脳中でヒト細胞を特定するために、すべてのヒト白血球を特定するビメンチンに対するmAb(1:50、クローン3B4、Dako Corporation)を使用する。ヒトMDM及びCD8+リンパ細胞を、CD68(1:50希釈、クローンKP1)及びCD8(1:50希釈、クローン144B)抗体によりそれぞれ検出する。ウイルス感染細胞を、HIV−1 p24に対するmAb(1:10、クローンKal−1、すべてDakoから)により標識する。反応性のマウス小グリア細胞をIba−1抗体(1:500、Wako)により検出する。ヒトIDO(huIDO)の発現を、Department of Cell Pharmacology、Central Research Institute、Graduate School of Medicine, Hokkaido University、Sapporo、日本国から得たAbにより可視化する。一次抗体を適切なビオチン化二次抗体により検出し、アビジン−ビオチン複合体(Vectastain Elite ABCキット、Vector Laboratories)及びホースラディシュペルオキシダーゼ(HRP)をカップルしたデキストランポリマー(EnVision、Dako Corporation)により可視化する。免疫染色された切片をMayerのヘマトキシリンにより対比染色する。一次抗体を欠失した切片または無関係のIgGアイソタイプを取り込んだ切片を対照として供した。独立した2人の観察者が、盲検化様式で、各々のマウスからの各々の切片中のCD8+リンパ細胞、CD68+MDM及びHIV−1 p24+細胞の数を計数する。光学顕微鏡検査はNikon Eclipse 800顕微鏡(Nikon Instruments Inc)により遂行される。Iba1についての半定量分析(免疫染色によって占められる面積のパーセンテージ)を、コンピューター支援画像分析(Image−Pro(登録商標)Plus、Media Cybernetics)によって、従来記述されるように実行する。
データは、比較のためのStudentのt検定及びANOVAによりPrism(Graph Pad)を使用して分析することができる。0.05未満のP値を有意とみなした。
Poluektova LY,Munn DH,Persidsky Y,and Gendelman HE(2002).Generation of cytotoxic T cells against virus−infected human brain macrophages in a murine model of HIV−1 encephalitis.J.Immunol.168(8):3941−9.
[発明1]
式F5の化合物
[発明2]
Pg 1 が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項1に記載のプロセス。
[発明3]
Pg 1 がtert−ブトキシカルボニルである、請求項1に記載のプロセス。
[発明4]
前記反応が還元剤の存在下において遂行される、請求項1〜3のいずれか一項に記載のプロセス。
[発明5]
前記還元剤が水素化ホウ素還元剤である、請求項4に記載のプロセス。
[発明6]
前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項5に記載のプロセス。
[発明7]
前記式F7の化合物を脱保護して、式F8の化合物
[発明8]
前記脱保護が式F7の化合物を塩酸と反応させることを含む、請求項7に記載のプロセス。
[発明9]
前記式F8の化合物を、有機塩基の存在下においてPg 2 −NH−SO 2 −Xと反応させて、式F9の化合物
式中、
Pg 2 はアミノ保護基であり、
Xはハロである、
請求項7または8のいずれか一項に記載のプロセス。
[発明10]
Pg 2 が、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニルまたは9−フルオレニルメチルオキシカルボニルである、請求項9に記載のプロセス。
[発明11]
Pg 2 がtert−ブトキシカルボニルである、請求項9に記載のプロセス。
[発明12]
Xがクロロである、請求項9〜11のいずれか一項に記載のプロセス。
[発明13]
前記式F9の化合物を脱保護して、式F10の化合物
[発明14]
前記脱保護が式F9の化合物を塩酸と反応させることを含む、請求項13に記載のプロセス。
[発明15]
前記脱保護が、式F9の化合物を酢酸エチルを含む溶媒構成要素中で塩酸と反応させることを含む、請求項13に記載のプロセス。
[発明16]
前記式F10の化合物を塩基と反応させて、式Iの化合物
[発明17]
前記塩基が水酸化ナトリウムである、請求項16に記載のプロセス。
[発明18]
式F15の化合物
式中、
各々のR 1 は独立してアミノ保護基であり、
R 3 はC 1−6 アルキルまたはベンジルである、プロセス。
[発明19]
各々のR 1 が、C 2−4 アルケニル−C 1−3 アルキルまたはフェニル−C 1−3 アルキルであり、前記フェニル−C 1−3 アルキルが、1、2または3の独立して選択されるC 1−4 アルコキシ基によって随意に置換される、請求項18に記載のプロセス。
[発明20]
各々のR 1 がアリルである、請求項18に記載のプロセス。
[発明21]
各々のR 1 が4−メトキシベンジルである、請求項18に記載のプロセス。
[発明22]
R 3 がC 1−6 アルキルである、請求項18に記載のプロセス。
[発明23]
R 3 がtert−ブチルである、請求項18に記載のプロセス。
[発明24]
前記反応が還元剤の存在下において遂行される、請求項18〜23のいずれか一項に記載のプロセス。
[発明25]
前記還元剤が水素化ホウ素還元剤である、請求項24に記載のプロセス。
[発明26]
前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項25に記載のプロセス。
[発明27]
前記反応がトリフルオロ酢酸の存在下において遂行される、請求項24〜26のいずれか一項に記載のプロセス。
[発明28]
前記式F16の化合物を脱保護して、式F10の化合物
[発明29]
前記脱保護が式F16の化合物をトリフルオロ酢酸と反応させることを含む、請求項28に記載のプロセス。
[発明30]
前記脱保護が式F16の化合物を塩酸と反応させることを含む、請求項28に記載のプロセス。
[発明31]
式F15の前記化合物が、式F14の化合物
[発明32]
前記還元剤が水素化ジイソブチルアルミニウムである、請求項31に記載のプロセス。
[発明33]
前記式F14の化合物が、式F13の化合物
[発明34]
前記1つ以上のアミノ保護剤が、臭化アリル及び4−メトキシベンジルクロライドから選択される、請求項33に記載のプロセス。
[発明35]
前記保護が塩基の存在下において遂行される、請求項33または34のいずれか一項に記載のプロセス。
[発明36]
式F15の化合物
R 3 はC 1−6 アルキルまたはベンジルであり、
各々のR 1 は独立してアミノ保護基である)。
[発明37]
tert−ブチルアリル{[アリル(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
[発明38]
tert−ブチル(4−メトキシベンジル){[(4−メトキシベンジル)(2−オキソエチル)アミノ]スルホニル}カルバメートである、請求項36に記載の化合物。
[発明39]
式F17の化合物
[発明40]
R 4 がtert−ブチルである、請求項39に記載のプロセス。
[発明41]
R 4 がベンジルである、請求項39に記載のプロセス。
[発明42]
R 4 がエチルである、請求項39に記載のプロセス。
[発明43]
R 4 が2,2,2−トリクロロエチルである、請求項39に記載のプロセス。
[発明44]
前記反応が還元剤の存在下において実行される、請求項40〜43のいずれか一項に記載のプロセス。
[発明45]
前記還元剤がトリエチルシランである、請求項44に記載のプロセス。
[発明46]
前記反応が有機酸の存在下において実行される、請求項44または45のいずれか一項に記載のプロセス。
[発明47]
前記有機酸がトリフルオロ酢酸である、請求項46に記載のプロセス。
[発明48]
前記式F18の化合物を脱保護して、式F10の化合物
[発明49]
前記脱保護が、式F18の化合物を酢酸の存在下において亜鉛と反応させることを含む、請求項48に記載のプロセス。
[発明50]
式F10の前記化合物を塩基と反応させて、式Iの化合物
[発明51]
前記塩基が水酸化ナトリウムである、請求項50に記載のプロセス。
[発明52]
R 4 が9H−フルオレン−9−イルメチルである、請求項39に記載のプロセス。
[発明53]
前記反応が還元剤の存在下において実行される、請求項52に記載のプロセス。
[発明54]
前記還元剤がトリエチルシランである、請求項53に記載のプロセス。
[発明55]
前記反応が有機酸の存在下において実行される、請求項53または54のいずれか一項に記載のプロセス。
[発明56]
前記有機酸がメタンスルホン酸である、請求項55に記載のプロセス。
[発明57]
前記式F18の化合物を、式Iの化合物
[発明58]
前記塩基がN,N−ビス(2−アミノエチル)エタン−1,2−ジアミンである、請求項57に記載のプロセス。
[発明59]
前記変換が塩酸水溶液を前記第1の混合物へ添加することを更に含む、請求項57〜58のいずれか一項に記載のプロセス。
[発明60]
式F17の化合物
[発明61]
tert−ブチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明62]
ベンジルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明63]
エチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明64]
2,2,2−トリクロロエチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明65]
(9H−フルオレン−9−イル)メチルN−(2,2−ジメトキシエチル)スルファモイルカルバメートである、請求項60に記載の化合物。
[発明66]
i)式F19の化合物
ii)前記式F20の化合物を、式Iの化合物
を含む、プロセス。
本発明の様々な改変形態が、本明細書において記述されたものに加えて、前述の記述から当業者には明らかであろう。かかる改変形態も添付の請求項の範囲内であることが意図される。すべての特許、特許出願及び出版物を含む、本出願中で引用される各々の参考文献は、それらの全体が参照によって本明細書に援用される。
Claims (18)
- 式F15の化合物
式中、
各々のR1は独立してアミノ保護基であり、
R3はC1−6アルキルまたはベンジルである、プロセス。 - 各々のR1が、C2−4アルケニル−C1−3アルキルまたはフェニル−C1−3アルキルであり、前記フェニル−C1−3アルキルが、1、2または3の独立して選択されるC1−4アルコキシ基によって随意に置換される、請求項1に記載のプロセス。
- 各々のR1がアリルである、請求項1に記載のプロセス。
- 各々のR1が4−メトキシベンジルである、請求項1に記載のプロセス。
- R3がC1−6アルキルである、請求項1に記載のプロセス。
- R3がtert−ブチルである、請求項1に記載のプロセス。
- 前記反応が還元剤の存在下において遂行される、請求項1〜6のいずれか一項に記載のプロセス。
- 前記還元剤が水素化ホウ素還元剤である、請求項7に記載のプロセス。
- 前記水素化ホウ素還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項8に記載のプロセス。
- 前記反応がトリフルオロ酢酸の存在下において遂行される、請求項7〜9のいずれか一項に記載のプロセス。
- 前記式F16の化合物を脱保護して、式F10の化合物
- 前記脱保護が式F16の化合物をトリフルオロ酢酸と反応させることを含む、請求項11に記載のプロセス。
- 前記脱保護が式F16の化合物を塩酸と反応させることを含む、請求項11に記載のプロセス。
- 式F15の前記化合物が、式F14の化合物
- 前記還元剤が水素化ジイソブチルアルミニウムである、請求項14に記載のプロセス。
- 前記式F14の化合物が、式F13の化合物
- 前記1つ以上のアミノ保護剤が、臭化アリル及び4−メトキシベンジルクロライドから選択される、請求項16に記載のプロセス。
- 前記保護が塩基の存在下において遂行される、請求項16または17のいずれか一項に記載のプロセス。
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