JP2022062191A - 自己免疫疾患の処置 - Google Patents
自己免疫疾患の処置 Download PDFInfo
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- JP2022062191A JP2022062191A JP2022016315A JP2022016315A JP2022062191A JP 2022062191 A JP2022062191 A JP 2022062191A JP 2022016315 A JP2022016315 A JP 2022016315A JP 2022016315 A JP2022016315 A JP 2022016315A JP 2022062191 A JP2022062191 A JP 2022062191A
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Abstract
Description
・ベータインターフェロン1a(Avonex)
・ベータインターフェロン1a(Rebif)
・ベータインターフェロン1b(Betaferon)
・グラチラマー酢酸塩(Copaxone)
・Natalizumabは、第一選択薬よりも再発率を低下させる;しかし、進行性多巣性白質脳症のような副作用の問題のために、これは、他の処置法に反応しないか又は重症疾患のために確保される第二選択薬である。
・Fingolimod(Gilenya)-急速に進行する重症再発寛解型MS(1年に2回以上の再発)の人々のために、そしてベータインターフェロン剤の1つでの処置にもかかわらずMSが活動性を維持している人々の第二選択処置薬として、2011年3月に認可された。
・フマル酸ジメチル(Tecfidera)は、2013年にFDAから認可を受けたもので、MSの再発寛解型の成人用の経口第一選択治療法である。
・Teriflunomide(Aubagio)は、2012年9月にFDAの承認を受けたもので、再発型MSの処置用の経口投与可能な免疫調節薬である。
・Mitoxantroneは、その使用が、重度の副作用、収縮機能不全、不妊症及び急性骨髄性白血病により制限されるが、他の医薬品に反応しない患者のための第三選択肢である。
成分を表1にリストされる順序で加えた。8-[14C]グアニン溶液を反応物に加える前に、[8-14C]グアニンが0.01M HCl水溶液として供給されるため、溶液を0.01M NaOH 等容量(vol/vol)で中和した。Saccharomyces cerevisiae由来の酵母tRNAのストック溶液を、ヌクレアーゼフリーの超純水中で2吸光度単位(260nm)の濃度にした。N末端ポリヒスチジンタグを含む組換え大腸菌(Escherichia coli(E. coli))tRNAグアニントランスグリコシラーゼ酵素(大腸菌TGT)は、以前に報告(Boland et al., 2009)されたとおりBL21 BL21(DE3)tgt::Kmr細胞において産生された。
各反応をトリプリケイトで準備して、37℃で1時間インキュベートした。反応の各成分を表2に示す順序で加え、最後にtRNA*を加えることにより反応を開始させた。「化合物」とは、調査中の分子を指す。
このアッセイ(図1参照)では、200μM キューイン塩基(キューイン-インサーターゼ酵素複合体の天然基質)による最大置換は、240pmol[14C]グアニンである。バックグラウンド値は≦10pmolである。したがって、≧50pmolの置換はTGTの基質として陽性と考えられる。
グアニン、キューイン、N-((2-アミノ-4-オキソ-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)-3-フェニルプロパン-1-アミニウム・クロリド(化合物Iとして示される)及び7-メチルグアニンを、酵母tRNA中のグアニンを置換する能力について評価した。先ず、酵母tRNAに、大腸菌TGT酵素により[8-14C]グアニン(tRNA*)を供給した。各反応において、2A260吸光度単位のtRNA*を、特定分子200μMと一緒に使用した。反応物をDEAEセルロースカラム 1ml上で処理した。反応フロースルー及び洗浄液を集めて、置換[14C]グアニンの存在について液体シンチレーション計数によって分析した。
カラムの調製及び平衡化:Dowex-1x8(メッシュサイズ200~400)を秤量して滅菌50mlチューブに入れ、1M HCl水溶液で3回洗浄することにより樹脂を供給した。次に中性pHに達するまで樹脂をMilli-Q H2O(各20ml)で5~6回洗浄した。カラム(Bio-rad 10mLプラスチックカラム)に湿ったDowex 1mLを準備した(湿性混合物をアプライし、沈降させ、充填容量が1mLに達するまで更にアプライした)。充填樹脂をmilli-Q H2O 10容量(v/v)で濯ぐことにより、中性pH及び着実な充填が達成されたことを確実にした。
20mM HEPES(pH8)
10mM MgCl2
0.1mM ピロリン酸ホスホリボシル(PRPP-アッセイ当日に新たに作る)
20μM[8-14C]-グアニン
400μM 被験化合物
Stromnes and Goverman, (2006)に記載されているとおり、慢性の単相性EAEを8~10週齢のメスのC57BL/6マウスに誘発させた。動物を氷冷リン酸緩衝生理食塩水(PBS)で経心灌流して、脾臓を取り出した。
2-アミノ-5-(((3-フェニルプロピル)アミノ)メチル)-3,7-ジヒドロ-4H-ピロロ[2,3-d]ピリミジン-4-オン
N-((2-アミノ-4-オキソ-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)-3-フェニルプロパン-1-アミニウム・クロリド
2-アミノ-5-((ブチルアミノ)メチル)-3,7-ジヒドロ-4H-ピロロ[2,3-d]ピリミジン-4-オン
N-((2-アミノ-4-オキソ-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)ブタン-1-アミニウム・クロリド
2-アミノ-5-((ヘキシルアミノ)メチル)-3,7-ジヒドロ-4H-ピロロ[2,3-d]ピリミジン-4-オン
N-((2-アミノ-4-オキソ-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)ヘキサン-1-アミニウム・クロリド
キューイン;2-アミノ-5-((((1S,4S,5R)-4,5-ジヒドロキシシクロペンタ-2-エン-1-イル)アミノ)メチル)-3,7-ジヒドロ-4H-ピロロ[2,3-d]ピリミジン-4-オン
キューインHCl 2-アミノ-5-[[[(1S,4S,5R)-4,5-ジヒドロキシ-2-シクロペンテン-1-イル]アミノ]メチル]-1,7-ジヒドロ-4H-ピロロ[2,3-d]ピリミジン-4-オン、一塩酸塩。
膀胱の問題には
・ボツリヌス毒素(Botox)
・デスモプレシン(Desmospray、Desmotabs)
・オキシブチニン(Ditropan、Lyrinel)
・トルテロジン(Detrusitol)
鬱病には
・アミトリプチリン(Triptafen)
・フルオキセチン(Prozac)
・イミプラミン(Tofranil)
・パロキセチン(Seroxat)
勃起不全には
・アルプロスタジル(Caverject、MUSE、Viridal Duo)
・クエン酸シルデナフィル(Viagra)
・タダラフィル(Cialis)
・バルデナフィル(Levitra)
疲労には
・アマンタジン(Lysovir、Symmetrel)
・モダフィニル(Provigil)
視神経炎には
・ステロイド
疼痛には
・アミトリプチリン(Triptafen)
・カルバマゼピン(Tegretol)
・ガバペンチン(Neurontin)
・イブプロフェン
・イミプラミン(Tofranil)
・ラモトリジン(Lamictal)
・フェニトイン(Epanutim)
・プレガバリン(Lyrica)
歩行の問題には
・ファムプリジン(Fampyra)
情動調節障害(Psuedobulbar)には
・Nuedexta
痙性及び痙攣には
・バクロフェン(Lioresal)
・ボツリヌス毒素(Botox)
・カルバマゼピン(Tegretol)
・クロナゼパム(Rivotril)
・ダントロレン(Dantrium)
・ジアゼパム(Valium)
・ガバペンチン(Neurontin)
・フェノール
・テトラヒドロカンナビノール及びカンナビジオール(Sativex)
・チザニジン(Zanaflex)
振戦には
・クロナゼパム(Rivotril)
・視床切除術
三叉神経痛には
・カルバマゼピン(Tegretol)
・ガバペンチン(Neurontin)
・オクスカルバゼピン(Trileptal)
・フェニトイン(Epanutim)
・プレガバリン(Lyrica)
本発明における使用に適した種々の分子の合成法を以下に記載する。
全ての出発物質及び試薬は市販されており、Fluorochemから購入された2-アミノ-3H-ピロロ[2,3-d]ピリミジン-4(7H)-オンを除いて、Aldrichから得られた。
撹拌棒を含む50cm3丸底フラスコに、2-アミノ-3H-ピロロ[2,3-d]ピリミジン-4(7H)-オン(2.00g、13.33mmol)を仕込んだ。フラスコにセプタムを取り付け、Ar雰囲気下に置いた。新たに蒸留したピリジン(20.00cm3)をシリンジで加え、生じた懸濁液を氷上で冷却した。この溶液をこの温度で平衡にさせ(約5分)、次いで塩化オクタノイル(6.80cm3、39.99mmol)を滴下した。生じた懸濁液を85℃で30分間加熱した。室温に冷却後、6.5%エタノール性アンモニア(60cm3)を加えて、生じた懸濁液を室温で一晩撹拌した。生成物の沈殿物を真空濾過により取り出して、エタノール、続いてジエチルエーテルで洗浄することにより、純粋な所望の生成物(2.56g、70%)を黄色の固体として得た、融点>300℃(分解)。Akimoto et al. 1986及びAkimoto et al. 1988に基づく手順。
δH (400 MHz, DMSO-d6): 0.86 (3H, t, J 5.1), 1.26 (8H, m), 1.58 (2H, 見かけ 5重項), 2.01 (1H, br s, NH), 2.43 (2H, t, J 5.1), 6.40 (1H, d, J 2.0), 7.01 (1H, d, J 2.0), 11.43 (1H, br s, NH), 11.67 (1H, br s, NH)
HRMS (m/z ESI-):実測値: 275.1517 ([M-H]- C14H19N4O2;要求値: 275.1508)
撹拌棒を含む50cm3反応容器に、2-オクタノイルアミノ-ピロロ[2,3-d]ピリミジン-4-オン(1.00g、3.60mmol)、ジベンジルアミン(2.00cm3、10.80mmol)、ホルマリン(349.00μL、12.60mmol)及び80%水性酢酸(36cm3)を仕込んだ。生じた懸濁液を60℃で20時間加熱し、室温に冷却し、0.5M HCl(36cm3)で希釈して室温で30分間撹拌した。この混合物を濃アンモニア水溶液(36cm3)で中和してクロロホルム(3×50cm3)で抽出した。有機抽出物を合わせ、乾燥させ(MgSO4)て蒸発乾固した。粗残渣をカラムクロマトグラフィー(9:1のジクロロメタン-MeOH~7:3のジクロロメタン-MeOH)により精製することによって、所望の化合物(1.45g、84%)を黄色の粉末として得た、融点>300℃(分解)。Akimoto et al. 1986及びAkimoto et al. 1988に基づく手順。
δH (400 MHz, DMSO-d6): 0.86 (3H, t, J 7.1), 1.25 (8H, m), 1.57 (2H, m) 2.42 (2H, t, J 7.1), 3.57 (4H, s), 3.76 (2H, s), 6.88 (1H, s), 7.23 (2H, t, J 7.3), 7.31 (4H, 見かけ t), 7.41 (4H, d, J 7.3), 11.34 (1H, s, NH), 11.57 (1H, s, NH), 11.68 (1H, s, NH)
HRMS (m/z ESI+):実測値: 486.2863 ([M+H]+ C29H36N5O2;要求値: 486.2869)
撹拌棒を含む大きなカルーセル管に、2-オクタノイルアミノ-5-((ジベンジル)アミノ)メチル)-ピロロ[2,3-d]ピリミジン-4-オン(100.0mg、0.21mmol)、3-フェニルプロピルアミン(146.00μL、1.03mmol)及び1:1のTHF-メタノール(2.00cm3)を仕込んだ。この懸濁液を脱気して反応容器を密封した。懸濁液を75℃で24時間加熱し、室温に冷却して、5M KOH(146.00μL)で処理して室温で65時間撹拌した。溶液を真空中で濃縮して、粗残渣をカラムクロマトグラフィー(9:0.9:0.1のジクロロメタン-MeOH-NH4OH)により精製した。微量不純物を除去するために、生じた固体をHPLCグレードのヘキサン、次にジエチルエーテルで洗浄した。これにより、所望の化合物(28mg、46%)を橙色の粉末として得た、融点>300℃(分解)。Akimoto et al. 1986及びAkimoto et al. 1988に基づく手順。
δH (600 MHz, DMSO-d6): 1.24 (1H, br s, NH), 1.66 (2H, 見かけ 5重項,), 1.91 (1H, s, NH), 2.44 (2H, t, J 6.9,), 2.57 (2H, t, J 6.9,), 3.59 (2H, s,), 6.15 (2H, br s,), 6.45 (1H, s,), 7.15 (1H, t, J 7.4,), 7.16 (3H, m), 7.25 (2H, 見かけ t,), 10.70 (1H, br s)
δC (600 MHz, DMSO-d6): 30.6, 32.9, 45.2, 47.5, 48.6, 79.2, 98.7 (q), 113.6 (q), 125.5, 128.2, 128.3, 142.3 (q), 152.2 (q), 160.5 (C=O)
νmax (フィルム)/cm-1: 697, 748, 749, 1080, 1420, 1596, 2927
HRMS (m/z ESI+): 実測値: 298.1662 ([M+H]+ C16H20N5O;要求値: 298.1668)
アルゴンの陽圧下の乾燥丸底フラスコ内で、無水THF(90mL)中のNaOMe(7.14g、0.13mol)の懸濁液を-5℃に冷却した。ギ酸メチル(9mL、0.15mol)をシリンジで1分間かけて滴下し、-5℃で20分間撹拌を続けた。次に、クロロアセトニトリル(8.33mL、0.13mol)を滴下漏斗により45分間かけて滴下した。混合物は白色から黄色に変わり、-5℃で更に2時間撹拌したところ、反応混合物は橙色になった。浴を取り外して、反応物が室温まで温まるに任せた。反応混合物のアリコートを濃HCl 1滴で処理して、TLCにより分析すると、100% EtOAcで溶出する、Rf=0.45の所望の生成物の存在を示した。混合物を0℃に冷却して、濃HCl(12mL)を滴下すると、その間に混合反応物がサクランボ赤色(cherry red)になった。生じた懸濁液をセライト(celite)パッドで濾過して、濾液が無色になるまでセライトをEtOAcで洗浄した。集めた濾液を水浴で40℃以下の温度で減圧濃縮することにより、クロロ(ホルミル)アセトニトリル1を黒色の油状物として定量的収率で与えたが、これを更に精製することなく使用した。Brooks 2012に基づく手順。
δH (400 MHz, CDCl3) 9.38 (s, 1H).
δC NMR (400 MHz, DMSO-d6) δ 168.2, 126.6, 67.8.
2,4-ジアミノ-6-ヒドロキシピリミジン(3.00g、24mmol)を、ミリポア水(90mL)中の酢酸ナトリウム(6.4g、76mmol)の溶液に加えて50℃で1時間撹拌した。50℃のうちに、mQ水(44mL)中の粗クロロ(ホルミル)アセトニトリル(3.00g、32mmol)の溶液を滴下漏斗で滴下すると、その間に反応はベージュ色になったが、50℃で18時間加熱を続け、その後、反応を100℃まで3時間加熱した。反応混合物が室温まで冷却するに任せて、濾過により固体を取り出した。固体をEtOHに懸濁して、固体が溶解するまで5M KOH水溶液を加えた。活性炭を溶液に加えて、混合物を30分間撹拌した後、濾過により固体を除去した。濾液のpHを濃HCl水溶液でpH=6に調整すると、その間に沈殿物が形成され、これを濾過によって集めた。最終の微量の水を固体から除去するために、これをトルエン/メタノールの1/1混合物に溶解し、次に減圧濃縮した。得られた固体をP2O5で乾燥させることにより、所望の化合物(1.68g、9.6mmol、収率40%)をベージュ色の固体として与えた。Brooks 2012に基づく手順。
δH (400 MHz, DMSO-d6) δ 11.98 (br s, 1H) 10.74 (br s, 1H), 7.59 (s, 1H), 6.43 (s, 2H).
δC(100 MHz, DMSO-d6) δ 158.0, 154.3, 152.1, 128.2, 116.4, 99.2, 86.0.
HRMS (m/z ESI-): C7H5N5O [M-H]- 実測値 174.0415 要求値: 174.0416.
アルゴン雰囲気下の乾燥丸底フラスコ内で、塩化トリチル(1.20g、4.28mmol)を、無水ピリジン(29mL)中の2-アミノ-4,7-ジヒドロ-4-オキソ-3H-ピロロ[2,3-d]ピリミジン-5-カルボニトリル(0.50g、2.85mmol)の溶液に加えた。この混合反応物を90℃で48時間加熱した。反応混合物を減圧下で濃縮し、次いでシリカゲルに吸収させ、2% MeOHで開始し10%まで上昇する勾配のジクロロメタン/MeOHで溶出するシリカゲルのフラッシュクロマトグラフィーにより精製した。所望の化合物を褐色の固体(0.63g、1.5mmol、収率53%)として得た。
Oelgen 2008に基づく手順。
δH (400 MHz, DMSO-d6) δ 11.80 (br s, 1H); 10.64 (br s, 1H), 7.56 (s, 1H), 7.41(s, 1H), 7.29-7.28 (m, 12H), 7.23-7.17 (m, 3H), 5.73 (s, 1H).
HRMS (m/z ESI+): C26H18N5O [M-H]+ 実測値 416.1514 要求値: 416.1511.
HMDS(6mmol、1.3mL)を、丸底フラスコ内の無水トルエン(8mL)中の4,7-ジヒドロ-4-オキソ-2-[(トリフェニルメチル)アミノ]-3H-ピロロ[2,3-d]ピリミジン-5-カルボニトリル(1.30g、3mmol)と硫酸アンモニウム(397mg、0.3mmol)との混合物に加えた。還流冷却器を取り付けて、フラスコを還流温度で一晩加熱した。混合物を室温に冷却して、減圧下で濃縮した。陽圧のアルゴン下で、粗反応混合物を無水ジクロロメタン(8mL)に可溶化して-78℃に冷却した。この温度で、DiBAL-H(4.5mL、ジクロロメタン中1M、4.5mmol)を滴下した。2時間後、TLC(EtOAc 100%)により分析すると、少量の出発物質が残っていることを示した。そのため、DiBAL-H溶液を更に2mL滴下した。1時間後、反応が完了し、H2O/AcOHの混合物(9/1、3.5mL)を-78℃で加えた。反応混合物がゆっくりと室温まで温まるに任せた。EtOAc/H2Oの混合物(1/1、300mL)を反応混合物に加えて、室温で2時間撹拌を続けた。層を分離し、有機層をブラインで洗浄して、水層をEtOAcで抽出した。合わせた有機画分をMgSO4で乾燥させ、濾過して減圧で濃縮した。粗反応生成物を、EtOAcで溶出するシリカゲルのパッドを通して濾過することにより、黄色の固体(1.01g、2.38mmol、76%)を与えた。Brooks 2010及びBrooks 2012に基づく手順。
δH (400 MHz, DMSO-d6) 11.82 (s, 1H), 10.63 (s, 1H), 9.99 (s, 1H), 7.54 (s, 1H), 7.31-7.27 (m, 13H), 7.23-7.19 (m, 3H).
HRMS (m/z ESI-): C26H18N4O2[M-H]- 実測値 419.1508 要求値: 419.1508.
一般手順A:メタノール(5cm3)中のN-((4-オキソ-2-(トリチルアミノ)-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)ホルムアミド(200.0mg、0.48mmol)及び硫酸ナトリウム(5.0mg)の懸濁液にアルゴン雰囲気下で3-フェニルプロピルアミン(74.00μL、0.52mmol)を加え、生じた懸濁液を室温で2時間撹拌した。次いで水素化ホウ素ナトリウム(55.00mg、1.43mmol)を加え、反応混合物を室温で更に1時間撹拌した。水(5cm3)を加えて、生じた懸濁液を10分間撹拌した後、ジクロロメタン(3×5cm3)で抽出した。合わせた有機層を乾燥させ(MgSO4)、真空中で濃縮することにより、粗生成物を生成し、これをフラッシュクロマトグラフィー(9:1のジクロロメタン-MeOH)により精製することによって、所望の化合物を白色の固体(210mg、41.8%)として生成した、融点>300℃(分解)。Brooks 2010及びBrooks 2012に基づく手順。
1H (400 MHz, DMSO-d6): 1.73 (2H, 5重項, J 7.8), 2.56 (4H, m), 3.74 (1H, s), 6.42 (1H, s, H-6), 7.19 (20H, m), 7.45 (1H, bs, NH), 10.78 (1H, bs, NH)
13C (400 MHz, DMSO-d6): 31.7, 32.8, 45.4, 47.8, 70.4 (q), 99.7 (q), 114.9, 117.6 (q), 125.9, 126.0, 126.9, 128.0, 128.6, 129.0, 142.6 (q), 145.4 (q), 150.0 (q), 150.4 (q), 159.7 (C=O)
HRMS (m/z - ESI+): 実測値: 540.2757 [M+H]+ C35H34N5O 要求値: 540.2765)
νmax/cm-1: 1542, 1611, 1670, 2868, 2951
一般手順B:撹拌棒を含む5cm3の反応容器に、5-((3-フェニルプロピルアミノ)メチル)-2-(トリチルアミノ)-3H-ピロロ[2,3-d]ピリミジン-4(7H)-オン(210.0mg、0.39mmol)及び1.25M メタノール性HCl(3cm3)を仕込んだ。生じた溶液を室温で16時間撹拌した。沈殿した生成物を真空濾過により取り出して、ジクロロメタンで洗浄することにより、所望の化合物を白色の粉末(84mg、68%)として生成した、融点>300℃(分解)。Brooks 2010及びBrooks 2012に基づく手順。
δH (600 MHz, DMSO-d6): 1.90 (2H, 見かけ 5重項), 2.63 (2H, t, J 7.8), 2.90 (2H, m), 4.13 (2H, t, J 5.2), 6.57 (2H, bs), 6.80 (1H, d, J 2.3), 7.16 (3H, m), 7.26 (2H, t, J 7.0), 9.11 (2H, bs), 11.05 (1H, m, NH), 11.31 (1H, ブロード 2重項, NH)
δC (125 MHz, DMSO-d6): 27.6, 32.1, 42.9, 45.6, 48.9, 98.6, 108.7 (q), 117.9 (q),126.4, 128.6, 128.7, 140.9 (q), 152.9 (q), 160.5 (C=O)
HRMS (m/z ESI+): 実測値: 298.1662 (M+ C16H20N5O 要求値: 298.1664)
νmax (フィルム)/cm-1: 1456, 1625, 2443, 2713, 2756, 2873, 2933, 3184
N-((4-オキソ-2-(トリチルアミノ)-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)ホルムアミド(200.00mg、0.48mmol)、n-ブチルアミン(95.00μL、0.95mmol)及びNaBH4(55mg、1.43mmol)を用いて一般手順Aのとおり調製することにより、所望の生成物を白色の粉末(200mg、88%)として生成した、融点>300℃(分解)。
δH(400 MHz, DMSO-d6): 0.84 (3H, t, J 7.3), 1.30 (2H, 見かけ 6重項), 1.51 (2H, 見かけ 5重項), 2.82 (2H, t, J 7.3), 4.01 (2H, s), 6.62 (1H, s), 7.24 (15H, m), 7.57 (1H, bs), 11.07 (1H, bs)
δC(400 MHz, DMSO-d6):13.9, 19.6, 28.0, 42.9, 46.0, , 70.6 (q), 99.4 (q), 108.9, 118.0 (q), 127.0, 128.1, 129.0, 145.2 (q), 150.5 (q), 150.6 (q), 160.3 (C=O)
νmax (フィルム)/cm-1: 1545, 1613, 1672, 2870, 2956
HRMS (m/z ESI+):実測値: 478.2600 ([M+H]+ C30H32N5O; 要求値: 478.2607)
5-((ブチルアミノ)メチル)-2-(トリチルアミノ)-3H-ピロロ[2,3-d]ピリミジン-4(7H)-オン(108mg、0.39mmol)及び1.25M メタノール性HCl(3cm3)を用いて一般手順Bのとおり調製することにより、所望の生成物を白色の粉末(72mg、67%)として生成した、融点>300℃(分解)。
δH (400 MHz, DMSO-d6): 0.86 (3H, t, J 7.4), 1.31 (2H, 見かけ 6重項), 1.57 (2H, 見かけ 5重項), 2.90 (2H, m), 4.12 (2H, t, J 5.3), 6.49 (2H, bs), 6.81 (1H, s), 9.01 (2H, bs), 10.98 (2H, bs), 11.29 (1H, bs)
δC (400 MHz, DMSO-d6): 18.7, 24.7, 32.7, 47.4, 50.6, 103.6 (q), 114.0, 123.2 (q), 153.3 (q), 157.6 (q), 164.7 (C=O)
HRMS (m/z ESI+): 実測値: 236.1518 (M+ C11H18N5O 要求値: 236.1511)
νmax (フィルム)/cm-1: 1456, 1625, 1668, 2443, 2713, 2756, 2873, 2933, 3184
N-((4-オキソ-2-(トリチルアミノ)-4,7-ジヒドロ-3H-ピロロ[2,3-d]ピリミジン-5-イル)メチル)ホルムアミド(200.0mg、0.48mmol)、n-ヘキシルアミン(125.00μL、0.95mmol)及び水素化ホウ素ナトリウム(55mg、1.43mmol)を用いて一般手順Aのとおり調製することにより、所望の生成物を白色の粉末(200mg、83.0%)として生成した、融点>300℃(分解)。
δH(400 MHz, DMSO-d6): 0.82 (3H, t, J 7.4), 1.20 (6H, m), 1.34 (2H, 見かけ 5重項), 2.40 (2H, t, J 7.4), 3.60 (2H, s), 6.30 (1H, s), 7.23 (15H, m), 7.37 (1H, bs), 10.62 (1H, bs)
δC(400 MHz, DMSO-d6):14.4, 22.5, 26.8, 31.6, 29.6, 45.2, 48.3, 70.4 (q), 99.7 (q), 115.2, 116.7 (q), 127.0, 128.1, 129.0, 145.4 (q), 150.1 (q), 150.5 (q), 159.7 (C=O)
νmax (フィルム)/cm-1: 1552, 1648, 1734, 2856, 2928
HRMS (m/z ESI-):実測値: 504.2769 ([M-H]- C32H34N5O; 要求値: 504.2763)
5-((ヘキシルアミノ)メチル)-2-(トリチルアミノ)-3H-ピロロ[2,3-d]ピリミジン-4(7H)-オン(190mg、0.39mmol)及び1.25M メタノール性HCl(3cm3)を用いて一般手順Bのとおり調製することにより、所望の生成物を白色の粉末(70mg、64.8%)として生成した、融点>300℃。
δH (400 MHz, DMSO-d6): 0.83 (3H, t, J 7.2), 1.25 (6H, m), 1.59 (2H, 見かけ 6重項, J 7.2), 2.87 (2H, m), 4.11 (2H, t, J 5.3), 6.71 (2H, bs), 6.84 (1H, d, J 3.6), 9.11 (2H, bs), 11.25 (1H, bs), 11.46 (1H, bs)
δC (400 MHz, DMSO-d6): 14.3, 22.3, 25.8, 25.9, 31.1, 42.6, 46.1, 98.9 (q), 109.3 (q), 118.5, 148.1 (q), 152.8 (q), 159.8 (C=O)
νmax (フィルム)/cm-1:1578, 1625, 1669, 2429, 2712, 2861, 2930, 2957, 3266
HRMS (m/z ESI+): 実測値: 264.1830 ([M+H]+ C13H22N5O 要求値: 264.1824)
本明細書に記載される全ての実施例は、HPRTのインヒビターでも基質でもない。
Claims (11)
- 自己免疫疾患の処置に使用するためのキューイン-インサーターゼ酵素複合体の基質として作用可能な分子。
- 自己免疫疾患の処置に使用するためのキューイン-インサーターゼ酵素複合体の基質として作用可能な分子であって、ヒポキサンチン-グアニンホスホリボシルトランスフェラーゼ(HPRT)の基質ではない、分子。
- 自己免疫疾患の処置に使用するためのキューイン-インサーターゼ酵素複合体の基質として作用可能な分子であって、インターフェロンガンマ産生を低下させる効果も有する、分子。
- 自己免疫疾患の処置に使用するためのキューイン-インサーターゼ酵素複合体の基質として作用可能な分子であって、HPRTの基質ではなく、かつインターフェロンガンマ産生を低下させる効果を有する、分子。
- キューイン-インサーターゼ酵素複合体の基質として作用可能な分子が、グアニン置換アッセイにおいて≧50pmolの置換を有している、先行する請求項のいずれか記載の使用。
- 分子が、HPRTアッセイにおいて対照の≧60%量でGMP生成物を生じる、先行する請求項のいずれか記載の使用。
- 分子が、100μMの濃度で野生型細胞におけるインターフェロンガンマ産生を低下させる、先行する請求項のいずれか記載の使用。
- 自己免疫疾患が、関節リウマチ、潰瘍性大腸炎、乾癬、糖尿病、及びクローン病を含む炎症性腸疾患から選択される請求項1~7記載の使用;並びに移植拒絶反応を抑制する薬剤としての請求項1~7記載の使用。
- 自己免疫疾患が、多発性硬化症である、請求項1~7記載の使用。
- 追加の治療剤と組み合わせた、請求項1~9記載の使用。
- 前記治療剤が、患者における多発性硬化症の損傷の影響を処置するための医薬品である、請求項10記載の使用。
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WO2016141243A1 (en) * | 2015-03-03 | 2016-09-09 | The Regents Of The University Of California | Enzymatic modification of nucleic acids |
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JPS58157790A (ja) | 1982-03-16 | 1983-09-19 | Takeda Chem Ind Ltd | 7−デアザプリン誘導体およびその製造法 |
JPS5936615A (ja) | 1982-08-24 | 1984-02-28 | Takeda Chem Ind Ltd | 発がん予防剤 |
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AU2015326936B2 (en) | 2021-01-21 |
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