JP2023514236A - ピラジン化合物およびその調製方法と使用 - Google Patents
ピラジン化合物およびその調製方法と使用 Download PDFInfo
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
Description
I
式中、XおよびYは、それぞれ独立して、O、S、SeまたはNR6から選択され、R1、R2、R3、R4、R5、R6はそれぞれ独立して、H、重水素、ハロゲン、ヒドロキシル基、アミノ基、カルボキシル基、アミド基、エステル基、置換または無置換のアルキル基、重水素化アルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、置換または無置換のシクロアルキル基、置換または無置換の複素環基、置換または無置換のアルコキシ基、置換または無置換のアルキルカルボキシル基、置換または無置換のアルキルエステル基、-置換または無置換のアルキル基-OH、置換または無置換のアルコキシ基、アルキルアミノ基、-置換または無置換のアルキル基-NH2、置換または無置換のアリール基、置換または無置換のヘテロアリール基、置換または無置換のカーボネート基、カルバメート、-置換または無置換のアルキル-アシルアミノ基、-置換または無置換のアミノアルキルカルボキシレート、または上記の基の重水素化誘導体であり、n=0~6、m=0~5である。
ステップ(2):化合物イミダゾール(6.2g,90.5mmol)およびtert-ブチルジメチルシリルクロリド(13.6g,90.5mmol)をN,N-ジメチルホルムアミド(200ml)に溶解し、化合物2-0(5.0g,36.2mmol)を数回に分けて加え、室温で一晩撹拌した。反応が終了した後、水で希釈し、n-ヘキサンで抽出し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、得られた粗生成物の一部(3.7g)をメタノール(40ml)に溶解し、ヨウ素単体(0.4g)を加えて2時間撹拌し、反応が終了した後にチオ硫酸ナトリウムを加えてクエンチし、濃縮し、エーテルで希釈し、水で洗浄し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムクロマトグラフィーによって生成物2-1(2.0g,83%)を得た。1H NMR(400MHz,DMSO-d6)δ6.92(d,J=8.5Hz,2H),6.69-6.49(m,2H),4.41(t,J=5.2Hz,0H),3.40(td,J=7.1,5.3Hz,2H),2.49(t,J=7.1Hz,2H),0.78(s,9H),0.07(s,6H)。MS(ESI)m/z:253.2[M+H]+。
ステップ(3):窒素ガスの保護下で、化合物2-1(252mg,1mmol)およびトリホスゲン(112mg,0.34mmol)を無水ジクロロメタン(15ml)に溶解し、N,N-ジイソプロピルエチルアミン(0.1ml)を加え、室温で0.5時間撹拌した後、化合物1-1(304mg,2mmol)および4-ジメチルアミノピリジン(366mg,3mmol)を順次加え、室温で反応を一晩続けた。反応が終了した後、濃縮し、シリカゲルカラムクロマトグラフィーによって生成物2-2(241mg,56%)を得た。1H NMR(400MHz,CDCl3)δ6.88(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),5.05(s,2H),4.14(t,J=7.2Hz,2H),2.73(t,J=7.2Hz,2H),2.35(s,1H),2.31(s,1H),2.31(s,1H),0.79(s,9H),0.00(s,6H)。MS(ESI)m/z:431.2[M+H]+。
ステップ(4):化合物2-2(86mg,0.2mmol)をテトラヒドロフラン(10ml)に溶解し、フッ化水素酸溶液(1.0ml,2.0mmol)を加え、1時間還流反応させた。反応が終了した後、順に飽和炭酸水素ナトリウム溶液、水、飽和食塩水で洗浄し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムクロマトグラフィーによって生成物OLB-1(54mg,86%)を得た。1H NMR(400MHz,CDCl3)δ7.02(d,J=8.5Hz,2H),6.74(d,J=8.5Hz,2H),5.24(s,2H),4.30(t,J=7.2Hz,2H),2.88(t,J=7.2Hz,2H),2.53(s,1H),2.51(s,1H),2.50(s,1H)。MS(ESI)m/z:317.2[M+H]+。
ステップ(2):化合物1-2(17.5g,82mmol)、フタルイミドカリウム(21.0g,110mmol)およびヨウ化ナトリウム(0.5g,3.3mmol)をN,N-ジメチルホルミアミド(100ml)に溶解し、95℃で2時間撹拌した。反応が終了した後、濾過し、濾液を氷水に注ぎ、白色沈殿物を得、吸引濾過し、濾過ケーキをエタノールで再結晶させて生成物1-3(18.7g,81%)を得た。1H NMR(400MHz,DMSO-d6)δ8.01-7.79(m,4H),4.90(s,2H),2.53(s,3H),2.38(s,3H),2.21(s,3H)。MS(ESI)m/z:282.1[M+H]+。
ステップ(3):化合物1-3(2.8g,10mmol)をエタノール(30ml)に溶解し、ヒドラジン水和物(50%,1.0ml)を加え、2時間還流させた。反応が終了した後、濾過し、塩酸でpHを1~2に調整し、濾過し、濃縮し、水酸化ナトリウム溶液(20%)を加えて撹拌し、ジクロロメタンで抽出し、濃縮して生成物1-4(0.83g,55%)を得た。1H NMR(400MHz,DMSO-d6)δ8.07(dd,J=5.9,3.3Hz,1H),7.84(dd,J=5.9,3.3Hz,1H),3.81(s,2H),2.42(s,3H),2.42(s,3H),2.41(s,3H)。MS(ESI)m/z:152.1[M+H]+。
ステップ(4):窒素ガスの保護下で、化合物2-1(252mg,1mmol)およびトリホスゲン(112mg,0.34mmol)を無水ジクロロメタン(15ml)に溶解し、N,N-ジイソプロピルエチルアミン(0.1ml)を加え、室温で0.5時間撹拌した後、化合物1-4(302mg,2mmol)および4-ジメチルアミノピリジン(366mg,3mmol)を順次加え、室温で反応を一晩続けた。反応が終了した後、濃縮し、シリカゲルカラムクロマトグラフィーによって生成物2-3(265mg,62%)を得た。1H NMR(400MHz,CDCl3)δ6.90(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),4.24(d,J=3.5Hz,2H),4.11(t,J=7.1Hz,2H),2.71(t,J=7.1Hz,2H),2.30(s,9H),0.79(s,9H),0.00(s,6H)。MS(ESI)m/z:430.2[M+H]+。
ステップ(5):化合物2-3(85mg,0.2mmol)をテトラヒドロフラン(10ml)に溶解し、フッ化水素酸溶液(1.0ml,2.0mmol)を加え、1時間還流反応させた。反応が終了した後、順に飽和炭酸水素ナトリウム溶液、水、飽和食塩水で洗浄し、有機相を無水硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルカラムクロマトグラフィーによって生成物OLB-2(51mg,81%)を得た。1H NMR(400MHz,CDCl3)δ7.06(d,J=8.3Hz,2H),6.76(d,J=8.3Hz,2H),4.42(d,J=3.8Hz,2H),4.28(t,J=7.0Hz,2H),2.88(t,J=7.1Hz,2H),2.42(s,3H),2.42(s,3H),2.41(s,3H)。MS(ESI)m/z:316.2[M+H]+。
Claims (21)
- ピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩であって、前記ピラジン化合物は式Iに示すとおりであり、
I
式中、XおよびYは、それぞれ独立して、O、S、SeまたはNR6から選択され、R1、R2、R3、R4、R5、R6は、それぞれ独立して、H、重水素、ハロゲン、ヒドロキシル基、アミノ基、カルボキシル基、アミド基、エステル基、アルキル基、アルケニル基、アルキニル基、シクロアルキル基、複素環基、アルコキシ基、アルキルカルボキシル基、アルキルエステル基、-アルキル基-OH、アルコキシ基、アルキルアミノ基、-アルキル基-NH2、-アリール基、ヘテロアリール基、カーボネート基、カルバメート、-アルキル-アミド基、-アミノカルボン酸エステル、または上記の基の重水素化誘導体であり、n=0~6、m=0~5である、ことを特徴とするピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩。 - ピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩であって、前記ピラジン化合物は式Iに示すとおりであり、
I
式中、XおよびYは、それぞれ独立して、O、S、SeまたはNR6から選択され、R1、R2、R3、R4、R5、R6は、それぞれ独立して、H、重水素、ハロゲン、ヒドロキシル基、アミノ基、カルボキシル基、アミド基、エステル基、置換または無置換のアルキル基、重水素化アルキル基、置換または無置換のアルケニル基、置換または無置換のアルキニル基、置換または無置換のシクロアルキル基、置換または無置換の複素環基、置換または無置換のアルコキシ基、置換または無置換のアルキルカルボキシル基、置換または無置換のアルキルエステル基、-置換または無置換のアルキル基-OH、置換または無置換のアルコキシ基、アルキルアミノ基、-置換または無置換のアルキル基-NH2、置換または無置換のアリール基、置換または無置換の複素環アリール基、置換または無置換のカーボネート基、カルバメート、-置換または無置換のアルキル-アシルアミノ基、-置換または無置換のアミノアルキルカルボキシレート、または上記の基の重水素化誘導体であり、n=0~6、m=0~5である、ことを特徴とするピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩。 - nは、0、1、2、3、4、5または6であり、mは、0、1、2、3、4または5である、ことを特徴とする請求項1に記載のピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩。
- R1、R2、R3はメチル基または重水素化メチル基である、ことを特徴とする請求項1に記載のピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩。
- R4はHまたは重水素である、ことを特徴とする請求項1に記載のピラジン化合物、立体異性体、互変異性体およびその薬学的に許容される塩。
- 薬学的に許容される塩は、化合物と塩酸、硫酸、リン酸、臭化水素酸、硝酸、サリチル酸、シュウ酸、安息香酸、マレイン酸、フマル酸、クエン酸、コハク酸、酒石酸、C1-6脂肪カルボン酸、C1-6アルキルスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸またはカンファースルホン酸の塩である、ことを特徴とする請求項1または2に記載のピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩。
- 医薬組成物であって、治療有効量の1種以上の請求項1~8のいずれか一項に記載のピラジン化合物、立体異性体、互変異性体、およびその薬学的に許容される塩を含む、ことを特徴とする医薬組成物。
- 医薬組成物であって、治療有効量の1種以上の請求項11または12に記載の化合物を含む、ことを特徴とする医薬組成物。
- 1種以上の薬学的に許容される担体または賦形剤をさらに含む、ことを特徴とする請求項13または14に記載の医薬組成物。
- 他の治療剤をさらに含む、ことを特徴とする請求項13または14に記載の医薬組成物。
- 前記医薬組成物の医薬形態には、錠剤、顆粒剤、注射剤、ゲル剤、丸剤、カプセル剤、坐剤、インプラント、ナノ製剤および粉末注射剤が含まれる、ことを特徴とする請求項13または14に記載の医薬組成物。
- 請求項1~8のいずれか一項に記載のピラジン化合物、立体異性体、互変異性体およびその薬学的に許容される塩、ならびに請求項11または12に記載の神経変性疾患、炎症、酸化損傷、ミトコンドリア異常関連疾患、糖尿病および関連する糖尿病合併症を治療する医薬の調製における化合物の使用。
- 前記神経変性疾患はアルツハイマー病、パーキンソン病、ハンチントン病、前頭側頭型認知症、血管性認知症、HIV関連認知症、多発性硬化症、進行性側索硬化症、フリードライヒ運動失調症、神経因性疼痛および/または緑内障を含む、ことを特徴とする請求項18に記載の使用。
- 従来の医薬担体を含む投与単位製剤で、経口、注射、皮下、気道、経皮、非経口、直腸、局所外用、静脈内、筋肉内または他の方式によって投与される、ことを特徴とする請求項1~8のいずれか一項に記載のピラジン化合物、立体異性体、互変異性体およびその薬学的に許容される塩、ならびに請求項11または12に記載の化合物の使用方法。
- 前記医薬担体には、糖、デンプン、セルロース、麦芽、ゼラチン、タルクおよび植物油が含まれる、ことを特徴とする請求項20に記載の使用方法。
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