JP6754125B1 - Brap2作用増強剤 - Google Patents
Brap2作用増強剤 Download PDFInfo
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- JP6754125B1 JP6754125B1 JP2019188943A JP2019188943A JP6754125B1 JP 6754125 B1 JP6754125 B1 JP 6754125B1 JP 2019188943 A JP2019188943 A JP 2019188943A JP 2019188943 A JP2019188943 A JP 2019188943A JP 6754125 B1 JP6754125 B1 JP 6754125B1
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Abstract
Description
本実施形態に係るBRAP2作用増強剤は、下記式(1)又は(2)で表される化合物又はその塩を有効成分として含有する。
本実施形態に係る予防又は治療薬は、上述した本実施形態に係るBRAP2作用増強剤を有効成分として含有する。このため、本実施形態に係る予防又は治療薬は、BRAP2作用増強が有効な疾患又は症状に対して有効である。なお、「予防」には、疾患の発症を防ぐことのほか、発症の時期を遅らせることも含まれる。また、「治療」には、疾患の症状を消失又は軽減させることのほか、症状の進行の度合いを抑制することも含まれる。
本実施形態に係る免疫抑制剤は、上述した本実施形態に係るBRAP2作用増強剤を有効成分として含有する。
<合成例1:RID−B>
RID−Bは特開2006−117648号公報の実施例3に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 108-109℃;
IR (KBr): 2929, 2789, 1606, 1511, 1460, 1280, 1242, 1174, 1040, 836, 821 cm-1;
1H NMR (CDCl3): δ 7.19-7.09 (m, 7H, Ar), 6.89 (d, J = 8.4 Hz, 2H, Ar), 6.75 (d, J = 8.7 Hz, 2H, Ar), 6.55 (d, J = 8.7 Hz, 2H, Ar), 4.13 and 3.97 (t, J = 6.0 Hz, 4H, OCH2), 2.92 and 2.81 (t, J = 6.0 Hz, 4H, NCH2), 2.66-2.55 (m, 8 H, pyrroridinyl 2-H), 2.48 (q, J = 7.4 Hz, 2H, 3-H), 1.84-1.75 (m, 8H, pyrroridinyl 3-H), 0.93 (t, J = 7.4 Hz, 3H, 4-H);
13C NMR (CDCl3) δ 157.5, 156.7, 142.6, 140.9, 137.8, 136.3, 135.8, 131.8, 130.5, 129.7, 127.8, 125.8, 114.0, 113.3, 66.9, 66.7, 54.7, 54.7, 55.1, 55.1, 29.7, 29.0, 23.5, 23.4, 13.6;
HR MS (ESI): calcd for C34H43N2O2 (M+H+), 511.3319; found, 511.3319.
RID−S10は国際公開第2013/165005号の合成例1に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 161.3-161.9℃;
IR (KBr): 3400, 2966, 1606, 1505, 1227 cm-1;
1H NMR (300 MHz, CDCl3): δ 7.04-6.93 (m, 4H, Ar), 6.80-6.66 (m, 4H, Ar), 2.13 (q, J = 7.5 Hz, 4H, 3-H), 1.00 (t, J = 7.5 Hz, 6H, 4-H);
13C NMR (75 MHz, CDCl3): δ 156.4, 156.3, 141.8, 138.2, 136.6, 131.2, 115.6 (Ar, 1, 2), 25.3 (3), 13.7 (4);
HR MS (ESI): calcd for C18H20O2Na (M+Na+) 291.1356, found 291.1343.
RID−SB10は国際公開第2013/165005号の合成例1に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 81.7-82.3℃;
IR (KBr): 2962, 2800, 1604, 1512, 1458, 1280, 1242, 1172, 1041, 818 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.06-7.01 (m, 4H, Ar), 6.82-6.80 (m, 4H, Ar), 4.12 (t, J = 6.0 Hz, 4H, OCH2), 2.88 (t, J = 6.0 Hz, 4H, NCH2), 2.68-2.56 (m, 8H, pyrrolidinyl 2-H), 2.14 (q, J = 7.6 Hz, 4H, 3-H), 1.86-1.74 (m, 8H, pyrrolidinyl 3-H), 0.99 (t, J = 7.6 Hz, 6H, 4-H);
13C NMR (125 MHz, CDCl3): δ 157.1, 141.6, 136.4, 136.1 (Ar), 130.2 (1), 114.0 (2), 66.9 (OCH2), 55.1 (NCH2), 54.7 (pyrrolidinyl 2-C), 24.4 (3), 23.5 (pyrrolidinyl 3-C), 13.4 (4);
HR MS (ESI): calcd for C30H43N2O2 (M+H+) 463.3319, found 463.3303.
RID−SB17は国際公開第2013/165005号の合成例4に記載された方法に従って合成した。得られた化合物の物性データは以下のとおりである。
IR (neat): 2954, 2785, 1604, 1504, 1242 cm-1;
1H NMR (300 MHz, CDCl3): δ 7.00 (d, J = 8.7 Hz, 4H, Ar), 6.80 (d, J = 8.7 Hz, 4H, Ar), 4.07 (t, J = 6.0 Hz, 4H, OCH2), 2.88 (t, J = 6.0 Hz, 4H, NCH2), 2.66-2.56 (m, 8H, pyrrolidinyl 2-H), 2.09 (t, J = 7.8 Hz, 4H, 3-H), 1.85-1.76 (m, 8H, pyrrolidinyl 3-H), 1.40 (tt, J = 7.2, 7.2 Hz, 4H, 4-H), 1.30-1.11 (m, 8H, 5-H and 6-H), 0.84 (t, J = 6.9 Hz, 6H, 7-H);
13C NMR (125 MHz, CDCl3): δ 156.9, 139.1, 136.9, 136.6 (Ar), 130.4 (1), 113.9 (2), 66.8 (OCH2), 55.1 (NCH2), 54.7 (pyrrolidinyl 2-C), 31.8 (3), 31.6 (4), 28.2 (5), 23.5 (pyrrolidinyl 3-C), 22.4 (6), 14.0 (7);
HR MS (ESI): calcd for C36H55N2O2 (M+H+) 547.4258, found 547.4276.
RID−Gは特開2008−94836号公報の実施例4に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 94-95℃;
IR (neat): 3035, 2954, 1606, 1510, 837, 820 cm-1;
1H NMR (CDCl3): δ 7.17-7.07 (m, 7H, Ar-H), 6.88-6.86 (m, 2H, Ar-H), 6.76-6.73 (m, 2H, Ar-H), 6.54-6.51 (m, 2H, Ar-H), 4.03 (t, J = 6.5 Hz, 2H, OCH2), 3.87 (t, J = 6.5 Hz, 2H, OCH2), 2.48-2.45 (m, 4H, NCH2 and 3-H), 2.38 (t, J = 7.3 Hz, 2H, NCH2), 2.26 (s, 6H, CH3*2), 2.21 (s, 6H, CH3*2), 1.97 (tt, J = 7.3, 6.5 Hz, 2H, -CH2-), 1.86 (tt, J = 7.3, 6.5 Hz, 2H, -CH2-), 0.92 (t, J = 7.5 Hz, 3H, 4-H);
13C NMR (CDCl3): δ 157.7, 156.8 (Ar), 142.7 (1-C), 140.8 (2-C), 137.9, 136.2, 135.7, 131.9, 130.5, 129.7, 127.8, 125.8, 113.9, 113.2 (Ar), 66.1, 65.9 (OCH2), 56.5, 56.4 (NCH2), 45.51, 45.46 (CH3), 29.0 (3-C), 27.6, 27.5 (-CH2-), 13.6 (4-C);
HR MS (ESI): calcd for C32H43N2O2 (M+H+) 487.3319, found 487.3325.
RID−SG17は国際公開第2013/165005号の合成例4に記載された方法に従い、合成例1の1−(2−クロロエチル)ピロリジン塩酸塩を(3−クロロプロピル)ジメチルアミン塩酸塩とすることで合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
IR (neat): 3039, 2954, 2861, 1604, 1504, 1466, 1265, 1241, 1172, 1057, 833, 740 cm-1;
1H NMR (300 MHz, CDCl3): δ 6.99 (d, J = 8.7 Hz, 4H, Ar), 6.78 (d, J = 8.7 Hz, 4H, Ar), 3.98 (t, J = 6.3 Hz, 4H, OCH2), 2.45 (t, J = 6.9 Hz, 4H, NCH2), 2.26 (s, 12H, N(CH3)2), 2.10 (t, J = 7.5 Hz, 4H, 3-H), 1.94 (tt, J = 6.9, 6.3 Hz, 4H, NCH2CH2CH2O), 1.40 (tt, J = 7.5, 6.9 Hz, 4H, 4-H), 1.24-1.16 (m, 8H, 5-H, 6-H), 0.84 (t, J = 6.9 Hz, 6H, 7-H);
13C NMR (125 MHz, CDCl3): δ 157.1, 139.0, 136.9, 136.4 (Ar), 130.4 (1), 113.8 (2), 66.1 (OCH2), 56.5 (NCH2), 45.5 (N(CH3)2), 31.8 (3), 31.6 (4), 28.2 (5), 27.6 (NCH2CH2CH2O), 22.4 (6), 14.0 (7);
HR MS (ESI): calcd for C34H55N2O2 (M+H+) 523.4258, found 523.4242.
RID−Hは既報(Hasegawa et al.,European Journal of Medicinal Chemistry,2014,71,290)に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
Mp: 64-65 ℃;
IR (neat): 3034, 2957, 1605, 1507, 1173, 817 cm-1;
1H NMR (CDCl3): δ 7.17-7.07 (7H, m, Ar), 6.88-6.86 (2H, m, Ar), 6.76-6.73 (2H, m, Ar), 6.54-6.51 (2H, m, Ar), 4.04 (2H, t, J = 6.50 Hz, OCH2), 3.88 (2H, t, J = 6.50 Hz, OCH2), 2.63 (2H, t, J = 7.25 Hz, NCH2), 2.56-2.45 (12H, m, NCH2, 3-H and pyrrolidinyl 2-H), 2.02 (2H, tt, J = 7.25, 6.50 Hz, -CH2-), 1.92 (2H, tt, J = 7.25, 6.50 Hz, -CH2-), 1.81-1.75 (8H, m, pyrrolidinyl 3-H), 0.92 (3H, t, J = 7.50 Hz, 4-H);
13C NMR (CDCl3): δ 157.7, 156.8 (Ar), 142.7 (1-C), 140.8 (2-C), 137.9, 136.2, 135.7, 131.9, 130.5, 129.7, 127.8, 125.8, 113.9, 113.2 (Ar), 66.30, 66.07 (OCH2), 54.25, 54.20 (pyrrolidinyl 2-C), 53.22, 53.17 (NCH2), 29.0 (3-C), 28.95, 28.86 (-CH2-), 23.43, 23.40 (pyrrolidinyl 3-C), 13.6 (4-C);
HR MS (ESI): calcd for C36H47N2O2 (M+H+) 539.3638, found 539.3614.
RID−SH17は国際公開第2013/165005号の合成例4に記載された方法に従い、合成例1の1−(2−クロロエチル)ピロリジン塩酸塩を1−(3−クロロプロピル)ピロリジン塩酸塩とすることで合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 32.5-33.1℃;
IR (KBr): 2954, 2854, 1612, 1512, 1466, 1280, 1242, 1172, 1057, 818 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.00-6.98 (m, 4H, Ar), 6.80-6.77 (m, 4H, Ar), 3.99 (t, J = 6.5 Hz, 4H, OCH2), 2.63 (t, J = 7.5 Hz, 4H, NCH2), 2.56-2.53 (br m, 8H, pyrrolidinyl 2-H), 2.09 (t, J = 7.5 Hz, 4H, 3-H), 2.00 (tt, J = 7.5, 6.5 Hz, 4H, NCH2CH2CH2O), 1.81-1.78 (br m, 8H, pyrrolidinyl 3-H), 1.39 (quint, J = 7.5 Hz, 4H, 4-H), 1.25-1.15 (m, 8H, 5-H and 6-H), 0.84 (t, J = 7.5 Hz, 6H, 7-H);
13C NMR (125 MHz, CDCl3): δ 157.0, 139.0, 136.9, 136.4 (Ar), 130.4 (1), 113.8 (2), 66.2 (OCH2), 54.2 (NCH2), 53.2 (pyrrolidinyl 2-C), 31.8 (3), 31.6 (4), 28.8 (NCH2CH2CH2O), 28.2 (5), 23.4 (pyrrolidinyl 3-C), 22.5 (6), 14.0 (7);
HR MS (ESI): calcd for C38H59N2O2 (M+H+) 575.4571, found 575.4562.
4,4’−(4”−chloro−2”−phenylbut−1”−ene−1”,1”−diyl)diphenol(20.5mg,0.0584mmol)をDMF(0.58mL)に溶解させ、55%水素化ナトリウム(流動パラフィン分散剤,20.4mg,0.467mmol)を加えて50℃で15分撹拌した。室温にし、1−(2−クロロエチル)ピロリジン塩酸塩(32.8mg,0.193mmol)を少しずつ加えた。反応混合物を50℃で3時間撹拌した後、飽和塩化アンモニウム水溶液を0℃で加えて反応を停止し、塩化メチレンで抽出した。有機層を集合して無水硫酸ナトリウムで乾燥した後、これを濃縮した。残渣を薄層クロマトグラフィー(アンモニア性クロロホルム/メタノール=9/1)で精製した後、再度、薄層クロマトグラフィー(クロロホルム/メタノール=9/1)で精製すると淡黄色油状の化合物が得られた(5.2mg,18%)。得られた化合物の化学構造及び物性データは以下のとおりである。
IR (ATR): 3034, 2961, 2928, 2781, 1604, 1507, 1245 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.26-7.12 (m, 7H, Ar and 3'''-H), 6.91 (d, J = 7.5 Hz, 2H, Ar), 6.77-6.72 (m, 3H, Ar), 6.55 (d, J = 7.5 Hz, 2H, Ar), 5.10 (d, J = 10.5 Hz, 1H, 4-H), 4.88 (d, J = 17.0 Hz, 1H, 4-H), 4.15 (t, J = 5.5 Hz, 2H, OCH2), 3.97 (t, J = 5.5 Hz, 2H, OCH2), 2.92 (t, J = 6.0 Hz, 2H, NCH2), 2.81 (t, J = 6.0 Hz, 2H, NCH2), 2.67-2.65 (m, 4H, pyrrolidinyl 2-H), 2.59-2.57 (m, 4H, pyrrolidinyl 2-H), 1.83-1.81 (m, 4H, pyrrolidinyl 3-H), 1.80-1.77 (m, 4H, pyrrolidinyl 3-H);
13C NMR (125 MHz, CDCl3): δ 158.0, 157.1, 141.6, 140.5, 138.9, 137.7, 135.4, 135.0, 132.2, 132.2, 131.5, 127.8, 126.2, 116.8 (4), 113.8, 113.3, 66.9, 66.7, 55.1, 55.0, 54.7 and 54.7 (pyrrolidinyl 2-C), 23.5 and 23.4 (pyrrolidinyl 3-C);
HR MS (ESI): calcd for C34H41N2O2 (M+H+) 509.3163, found 509.3161.
(中間体の合成1)
まず、以下の方法で中間体である4,4’−(2’’−(4’’’−(benzyloxy)phenyl)but−1’’−ene−1’’,1’’−diyl)diphenolを合成した。
IR (ATR): 3302, 1606, 1507, 1238, 828 cm-1;
1H NMR (CD3OD): δ 7.37-7.24 (m, 5H, -OCH2Ph), 7.01-6.98 (m, 4H, Ar), 6.94 (d, J = 9.0 Hz, 4H), 6.68-6.61 (m, 2H, Ar), 6.42 (dd, J = 6.5, 2.0 Hz, 2H, Ar), 4.94 (s, 2H, -OCH2Ph), 4.87 (s, 2H, -OH) 2.44 (q, J = 7.5 Hz, 2H, 3''-H), 0.89 (t, J = 7.5 Hz, 3H, 4''-H);
13C NMR (CD3OD): δ 158.4, 157.0, 156.1, 141.0, 139.5, 138.7, 136.8, 136.6, 136.4, 133.1, 131.9, 131.6, 130.7, 129.4, 128.8, 128.6, 116.0, 115.8, 115.3, 115.1, 70.9 (-OCH2Ph), 29.8 (C3''), 14.1 (C4'');
HR MS (ESI): calcd for C29H25O3 (M+H+) 421.1798, found 421.1792.
次に、以下の方法で中間体であるRID−B−OBn2を合成した。
IR (ATR): 2928, 2873, 2788, 1606, 1508, 1241 cm-1;
1H NMR (CDCl3): δ 7.43-7.32 (m, 5H, -OCH2Ph), 7.14-7.12 (m, 2H, Ar), 7.04-7.02 (m, 2H, Ar), 6.90-6.88 (m, 2H, Ar), 6.80-6.76 (m, 4H, Ar), 6.56-6.57 (m, 2H, Ar), 5.00 (s, 2H, -OCH2Ph), 4.13 (t, J = 5.5 Hz, 2H, 1''-H), 3.99 (t, J = 5.5 Hz, 2H, 1''-H), 2.92 (t, J = 6.0 Hz, 2H, 2''-H), 2.82 (t, J = 6.0 Hz, 2H, 2''-H), 2.66-2.63 (m, 4H, 2-H or 2'-H), 2.61-2.58 (m, 4H, 2-H or 2'-H), 2.45 (q, J = 7.5 Hz, 2H, 3'''-H), 1.83-1.81 (m, 4H, 3-H or 3'-H), 1.80-1.77 (m, 4H, 3-H or 3'-H), 0.93 (t, J = 7.5 Hz, 3H, 4'''-H);
13C NMR (CDCl3): δ 157.4 and 156.9 and 156.6 (C4'''' or C4'''''), 140.3, 137.4, 137.1, 136.5, 136.0, 135.0, 131.9, 130.7, 130.5, 128.5, 127.8, 127.5, 114.2 and 114.0 and 113.4 (C3'''' or C3'''''), 69.8 (-OCH2Ph), 66.9 and 66.7 (C1''), 55.1 and 55.1 and 54.7 (C2 or C2' or C2''), 28.9 (C3'''), 23.4 and 23.4 (C3 or C3'), 13.7 (C4''');
HR MS: calcd for C41H49N2O3 (M+H+) 617.3738, found 617.3707.
アルゴン雰囲気下、室温で酢酸エチル(2.5mL)中のRID−B−OBn2(46.7mg,0.0757mmol)の溶液に、パラジウム炭素(10%,32.2mg,0.0303mmol)を加えた。反応混合物を暗所で水素雰囲気(1.0気圧)下、室温で2時間撹拌し、次いで明所でアルゴン雰囲気に移した。混合物をセライトの短いパッドを通して酢酸エチルで濾過し、溶媒を留去した後、粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;アンモニア性クロロホルム/メタノール=15/1)で精製してRID−B−OH2(30.1mg,75%)を無色の油状物質として得た。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 151.2-151.9℃;
IR (ATR): 3365, 2964, 2930, 2873, 2808, 1607, 1509, 1243, 1173, 832, 756 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.12-7.10 (m, 2H, Ar), 6.85 (dd, J = 7.0, 2.5 Hz, 2H, Ar), 6.74 (dd, J = 7.0, 2.5 Hz, 2H, Ar), 6.55 (d, J = 8.5 Hz, 2H, Ar), 6.48 (d, J = 3.0 Hz, 2H, Ar), 6.46 (d, J = 3.0 Hz, 2H, Ar), 4.12 (t, J = 6.0 Hz, 2H, OCH2), 3.96 (t, J = 6.0 Hz, 2H, OCH2), 2.93 (t, J = 5.5 Hz, 2H, NCH2), 2.85 (t, J = 5.5 Hz, 2H, NCH2), 2.69-2.63 (m, 8H, pyrrolidinyl 2-H), 2.42 (q, J = 7.0 Hz, 2H, 3-H), 1.85-1.78 (m, 8H, pyrrolidinyl 3-H), 0.91 (t, J = 7.0 Hz, 3H, 4-H);
13C NMR (125 MHz, CDCl3): δ 157.2, 156.3, 155.1, 140.7, 136.8, 136.8, 136.3, 133.5, 131.9, 130.8, 130.6, 115.2, 114.0, 113.2, 66.6 and 66.0 (OCH2), 55.0, 55.0, 54.6 and 54.4 (pyrrolidinyl 2-C), 28.9 (3), 23.4 and 23.2 (pyrrolidinyl 3-C), 13.7 (4);
HR MS (ESI): calcd for C34H43N2O3 (M+H+) 527.3268, found 527.3253.
RID−NBは国際公開第2009/035020号の実施例1(6)(i)に記載された方法に従って合成した。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 79.3-80.0℃;
IR (KBr): 3023, 2962, 2792, 1604, 1489, 1280, 1241, 1049, 825, 694 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.10 (t, J = 7.5 Hz, 2H, Ar), 7.04-7.03 (m, 1H, Ar), 7.01-6.99 (m, 2H, Ar), 6.95-6.93 (m, 2H, Ar), 6.79-6.75 (m, 3H, Ar), 6.70 (d, J = 8.5 Hz, 1H, Ar), 6.60 (dd, J = 8.5, 2.5 Hz, 1H, Ar), 4.16 (t, J = 5.5 Hz, 2H, OCH2), 4.12 (t, J = 5.5 Hz, 2H, OCH2), 2.96 (t, J = 5.5 Hz, 4H, NCH2), 2.92 (t, J = 8.5 Hz, 2H, 1-H), 2.78-2.71 (m, 10H, 2-H and pyrrolidinyl 2-H), 1.86-1.84 (br m, 8H, pyrrolidinyl 3-H);
13C NMR (125 MHz, CDCl3): δ 157.4, 157.2, 143.2, 137.7, 134.6 (4), 132.2 (3), 132.1, 130.6, 128.2, 127.5, 127.4, 125.6, 114.0, 113.8, 111.4, 66.5 (OCH2), 66.4 (OCH2), 55.0 (NCH2), 54.9 (NCH2), 54.7 (pyrrolidinyl 2-C), 54.6 (pyrrolidinyl 2-C), 30.7 (2), 28.9 (1), 23.4 (pyrrolidinyl 3-C);
HR MS (ESI): calcd for C34H41N2O2 (M+H+) 509.3163, found 509.3183.
RID−S10(110mg,0.410mmol)をDMF(4.1mL)に溶解させ、55%水素化ナトリウム(流動パラフィン分散剤,39.4mg,0.902mmol)を加えて50℃で15分撹拌した。これに1−(2−クロロエチル)ピロリジン塩酸塩(76.7mg,0.451mmol)を加えて50℃で7時間撹拌した。冷却後、反応混合物に飽和塩化アンモニウム水溶液を加えて反応を停止し、塩化メチレンで抽出した。有機層を集合して飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、これを濃縮した。残渣を薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=90/10/2)で精製すると目的の白色固体が得られた(72.8mg,49%)。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 131.8-132.5℃;
IR (KBr): 3433, 3031, 2962, 2870, 1604, 1504, 1272, 1234, 1172, 1049, 825 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.00-6.96 (m, 4H, Ar), 6.73-6.69 (m, 4H, Ar), 4.06 (t, J = 6.0 Hz, 2H, OCH2), 2.91 (t, J = 6.0 Hz, 2H, NCH2), 2.68-2.63 (m, 4H, pyrrolidinyl 2-H), 2.14 (q, J = 7.5 Hz, 2H, 3-H or 3’-H), 2.13 (q, J = 7.5 Hz, 2H, 3’-H or 3-H), 1.85-1.80 (m, 4H, pyrrolidinyl 3-H), 0.99 (t, J = 7.5 Hz, 6H, 4-H and 4’-H);
13C NMR (125 MHz, CDCl3): δ 156.7, 154.8, 141.1, 136.5, 136.2, 135.4, 130.5, 130.3, 115.1, 113.6 (Ar, 1, 2), 65.8 (OCH2), 55.2 (NCH2), 54.4 (pyrrolidinyl 2-C), 24.4 (3), 23.3 (pyrrolidinyl 3-C), 13.4 (4);
HR MS (ESI): calcd for C24H32NO2 (M+H+) 366.2428, found 366.2436.
55%水素化ナトリウム(流動パラフィン分散剤,10.4mg,0.238mmol)をDMF(0.3mL)に懸濁し、RID−S10−(OH/Me)(22.4mg,79.3μmol)を加えて50℃で15分撹拌した。これに1−(2−クロロエチル)ピロリジン塩酸塩(20.2mg,0.119mmol)を加えて50℃で12時間撹拌した。冷却後、反応混合物に飽和塩化アンモニウム水溶液を加えて反応を停止し、塩化メチレンで抽出した。有機層を集合して無水硫酸ナトリウムで乾燥した後、これを濃縮した。残渣を薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=90/3/2)で精製すると黄色油状の化合物が得られた(29.7mg,99%)。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 39.9-40.6℃;
IR (KBr): 3032, 2962, 2869, 1604, 1512, 1458, 1273, 1242, 1041, 818 cm-1;
1H NMR (400 MHz, CDCl3): δ 7.06-7.01 (m, 4H, Ar), 6.84-6.79 (m, 4H, Ar), 4.08 (t, J = 6.2 Hz, 2H, OCH2), 3.78 (s, 3H, OMe), 2.88 (t, J = 6.0 Hz, 2H, NCH2), 2.64-2.60 (m, 4H, pyrrolidinyl 2-H), 2.14 (q, J = 7.6 Hz 4H, 3-H and 3’-H), 1.82-1.78 (m, 4H, pyrrolidinyl 3-H), 1.00 (t, J = 7.4 Hz, 6H, 4-H and 4’-H);
13C NMR (100 MHz, CDCl3): δ 157.7, 157.1, 141.6, 136.3, 136.1, 130.3, 130.2, 113.9, 113.3, 66.9, 55.1 (NCH2), 54.7 (pyrrolidinyl 2-C), 24.4 (3), 23.5 (pyrrolidinyl 3-C), 13.4 (4);
HR MS (ESI): calcd for C25H34NO2 (M+H+) 380.2584, found 380.2598.
RID−S10−(B/OH)(34.0mg,93.0μmol)をDMF(0.93mL)に溶解させ、55%水素化ナトリウム(流動パラフィン分散剤,12.2mg,0.279mmol)を加えて50℃で15分撹拌した。これに2−クロロエチルメチルエーテル(14.4μL,0.158mmol)を加えて50℃で3時間撹拌した後、55%水素化ナトリウム(流動パラフィン分散剤,4.1mg,93.0μmol)、DMF(0.3mL)、及び2−クロロエチルメチルエーテル(8.5μL,93.3μmol)を加えて50℃で更に14時間撹拌した。冷却後、反応混合物に飽和塩化アンモニウム水溶液を加えて反応を停止し、塩化メチレンで抽出した。有機層を集合して飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、これを濃縮した。残渣を薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=90/10/2)で精製し、更に薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=9/6/2)で精製すると目的の白色固体が得られた(33.1mg,84%)。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 30.4-31.1℃;
IR (KBr): 3032, 2962, 2877, 1604, 1512, 1457, 1280, 1242, 1041, 825 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.04-7.00 (m, 4H, Ar), 6.84-6.80 (m, 4H, Ar), 4.08 (tt, J = 6.0, 5.3 Hz, 4H, OCH2), 3.73 (t, J = 4.8 Hz, 2H, MeOCH2), 3.44 (s, 3H, OMe), 2.88 (t, J = 6.3 Hz, 2H, NCH2), 2.62-2.60 (m, 4H, pyrrolidinyl 2-H), 2.14 (q, J = 7.3 Hz, 2H, 3-H or 3’-H), 2.13 (q, J = 7.3 Hz, 2H, 3’-H or 3-H), 1.81-1.78 (m, 4H, pyrrolidinyl 3-H), 1.00 (t, J = 7.5 Hz, 3H, 4-H or 4’-H), 0.99 (t, J = 7.5 Hz, 3H, 4’-H or 4-H);
13C NMR (125 MHz, CDCl3): δ 157.0, 156.9, 141.6, 136.5, 136.3, 136.0, 130.2, 113.9, 113.9 (Ar, 1, 2), 71.0 (MeOCH2), 67.1, 66.8 (OCH2), 59.2 (OMe), 55.1 (NCH2), 54.7 (pyrrolidinyl 2-C), 24.3 (3), 23.4 (pyrrolidinyl 3-C), 13.4 (4);
HR MS (ESI): calcd for C27H38NO3 (M+H+) 424.2846, found 424.2841.
まず、RID−S31を既報(Sato et al.,ACS Chem. Neurosci.,2012,3,105)に従って合成した。次に、RID−S31(21.7mg,86.0μmol)をDMF(0.67mL)に溶解し、55%水素化ナトリウム(流動パラフィン分散剤,12.8mg,0.293mmol)を加えて50℃で15分撹拌した。これに1−(2−クロロエチル)ピロリジン塩酸塩(24.8mg,0.146mmol)を加えて50℃で12時間撹拌した。冷却後、反応混合物に飽和塩化アンモニウム水溶液を加えて反応を停止し、塩化メチレンで抽出した。有機層を集合して無水硫酸ナトリウムで乾燥した後、これを濃縮した。残渣を薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=90/3/2)で精製すると黄色油状の化合物が得られた(30.5mg,quant.)。得られた化合物の化学構造及び物性データは以下のとおりである。
IR (neat): 3032, 2970, 2785, 1604, 1504, 1466, 1265, 1242, 1173, 1041, 825, 740 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.27-7.24 (m, 1H, Ar), 7.18-7.12 (m, 3H, Ar), 7.06-7.03 (m, 2H, Ar), 6.83-6.81 (m, 2H, Ar), 4.08 (t, J = 6.0 Hz, 2H, OCH2), 2.88 (t, J = 6.0 Hz, 2H, NCH2), 2.64-2.57 (m, 4H, pyrrolidinyl 2-H), 2.15 (q, J = 7.5 Hz, 2H, 3-H or 3’-H), 2.12 (q, J = 7.5 Hz, 2H, 3’-H or 3-H), 1.84-1.76 (m, 4H, pyrrolidinyl 3-H), 1.01 (t, J = 7.0 Hz, 3H, 4-H or 4’-H), 1.00 (t, J = 7.0 Hz, 3H, 4’-H or 4-H);
13C NMR (125 MHz, CDCl3): δ 157.0, 143.8, 141.9, 136.6, 136.0, 129.2, 127.9 (Ar), 125.9 (1), 113.9 (2), 66.7 (OCH2), 55.1 (NCH2), 54.7 (pyrrolidinyl 2-C), 24.3 (3), 23.4 (pyrrolidinyl 3-C), 13.4 (4);
HR MS (ESI): calcd for C24H32NO (M+H+) 350.2478 found 350.2491.
N−Biotinyl−caproylaminocaproic Acid(12.6mg,26.7μmol)をDMF(0.33mL)に溶解させ、2−メチル−6−ニトロ安息香酸無水物(11.0mg,32.1μmol)、ジメチルアミノピリジン(0.65mg,5.35μmol)、トリエチルアミン(22.4μL,0.160mmol)、及びDMF(0.66mL)を加えて10分間撹拌した。更に2−(3−Hydroxyphenyl)−1,1−bis{4−[2−(pyrrolidin−1−yl)ethoxy]phenyl}−1−butene(16.9mg,32.1μmol)とDMF(0.33mL)を加えて室温で1時間撹拌した。減圧下でこれを濃縮し、残渣を薄層クロマトグラフィー(クロロホルム/メタノール/アンモニア=90/10/2)で精製すると目的の化合物が得られた(9.8mg,39%)。得られた化合物の化学構造及び物性データは以下のとおりである。
mp: 150.8℃ (decompose);
IR (KBr): 3379, 3294, 3085, 2931, 2861, 1759, 1697, 1643, 1512, 1242, 1172, 1041, 833 cm-1;
1H NMR (500 MHz, methanol-d4): δ 7.17-7.11 (m, 3H, Ar), 6.96-6.92 (m, 3H, Ar), 6.83-6.81 (m, 2H, Ar), 6.76 (d, J = 8.5 Hz, 2H, Ar), 6.59 (d, J = 8.5 Hz, 2H, Ar), 4.47 (td, J = 8.0, 4.0 Hz, 1H, 8’’’-H), 4.28 (td, J = 8.0, 4.0 Hz, 1H, 7’’’-H), 4.15 (t, J = 5.5 Hz, 2H, OCH2), 4.00 (t, J = 5.5 Hz, 2H, OCH2), 3.20-3.13 (m, 5H, 6’-H, 6’’-H and 6’’’-H), 2.95 (t, J = 5.5 Hz, 2H, NCH2), 2.92-2.88 (m, 1H, 9’’’-H), 2.86 (t, J = 5.5 Hz, 2H, NCH2), 2.71-2.65 (m, 9H, pyrrolidinyl 2-H and 9’’’-H), 2.53 (t, J = 7.5 Hz, 2H, 2’-H), 2.47 (q, J = 7.5 Hz, 2H, 3-H), 2.19-2.15 (m, 4H, 2’’-H and 2’’’-H), 1.86-1.79 (m, 8H, pyrrolidinyl 3-H), 1.67-1.48 (m, 8H, 3’-H, 3’’-H, 3’’’-H and 5’’’-H), 1.43-1.40 (m, 4H, 5’-H and 5’’-H), 1.36-1.28 (m, 6H, 4’-H, 4’’-H and 4’’’-H), 0.93 (t, J = 7.5 Hz, 3H, 4-H);
13C NMR (125 MHz, methanol-d4): 176.0 (carboxyl), 176.0, 175.9 (6’-amide and 6’’-amide), 173.6 (carbamate), 159.1, 158.3, 152.1, 145.6, 140.2, 137.4 (Ar), 137.0 (1), 133.0, 131.6, 129.8, 128.5, 124.0, 115.2, 114.6 (2), 67.6, 67.3 (OCH2), 63.4 (7’’’), 61.6 (8’’’), 57.0 (6’’’), 56.1, 56.0 (NCH2), 55.6, 55.5 (pyrrolidinyl 2-C), 40.2, 40.2 (6’ and 6’’), 37.0, 36.8 (2’’ and 2’’’), 34.9 (2’), 30.1 (3), 29.8, 29.5 (5’ and 5’’), 27.6, 27.4, 27.4 (4’, 4’’ and 4’’’), 26.9, 26.7, 25.7, 25.6 (3’, 3’’, 3’’’ and 5’’’), 24.2, 24.2 (pyrrolidinyl 3-C), 13.9 (4);HR MS (ESI): calcd for C56H79N6O7S (M+H+) 979.5725, found 979.5688.
以下の試験では、ヒト白血病T細胞株であるJurkat細胞(DSファーマバイオメディカル社)を用いた。Jurkat細胞は、3.5μg/Lの2−mercaptoethanol(Wako社)、75mg/Lのカナマイシン硫酸塩(Wako社)、2g/LのNaHCO3(Wako社)、10%ウシ胎児血清(Biofill社)を含むRPMI1640培地(Sigma−Aldrich社)を使用し、37℃に設定した5% CO2インキュベーター(ESPEC社)内で培養した。
試験例1では、RID−B及び下記式で表される公知化合物のTamoxifen(本明細書において、「TAM」ともいう)をJurkat細胞に添加した場合の、細胞傷害を確認した。RID−Bを添加した場合のMTTアッセイの結果を図1Aに、TAMを添加した場合のMTTアッセイの結果を図1Dに示す。また、RID−Bを添加した場合のsubG1期解析の結果を図1Bに、TAMを添加した場合のsubG1期解析の結果を図1Eに示す。また、RID−Bを添加した場合の活性型caspase−3の検出の結果を図1Cに、TAMを添加した場合の活性型caspase−3の検出の結果を図1Fに示す。
2.5×105cells/mLに調整したJurkat細胞を96 well plateに80μLずつ分注後、RID−B及びTAMを各濃度で添加し、11時間作用させた。MTT試薬(Wako社)を各wellに10μLずつ添加し、37℃のCO2インキュベーター内で1時間作用させた。終了後、96穴プレートを1200rpmで5分間遠心し、上清を取り除いた。各wellにDMSO(Wako社)を100μLずつ添加し、生成したホルマザン沈殿を溶解した。マイクロプレートリーダー(Awareness Technology社)を用いて570nmの吸光度を測定することでミトコンドリアのNADH量を測定し、細胞生存率を数値化した。
2.0×105cells/mLに調整したJurkat細胞に、RID−Bが終濃度0.4μMと、TAMが終濃度20μMとなるように添加し、12時間作用させた。細胞を回収後、PBSで遠心洗浄し、500μLの0.1% Triton−100(Wako社)を含んだPBSで懸濁した。12.5μLの1mg/mL ヨウ化プロピジウム(PI)(Wako社)と5mg/mL RNase A(Wako社)を加えて懸濁し、20分間室温暗所で静置した。その後、ナイロンメッシュに通してFACS(Becton Dickinson社)でPIの蛍光強度を検出することでDNAの定量を行い、薬剤により断片化したDNA(subG1期)を測定した。
2.0×105cells/mLに調整したJurkat細胞に、RID−Bが終濃度0.4μM、TAMが終濃度20μMとなるように添加し、12時間作用させた。終了後、lysis bufferで可溶化を行った。BCA protein assayを用いて2.0mg/mLに調整した20μLのcell lysateと20μLのsample application bufferを混合したサンプルを100℃で3分間インキュベートした。タンパク質の分離には4%分離ゲルを重合させた12%又は15%SDSポリアクリルミドゲルを用いた。泳動終了後、転写を行い、PVDF膜を3%スキムミルク原液に浸し、室温で60分間ブロッキング操作を行った。その後、スキムミルク希釈液に移し代え、室温で30分間ブロッキング操作を2回行った。PVDF膜をビニール袋に移し、1000倍希釈の抗caspase−3抗体(Santa Cruz社)及び抗β−actin抗体(Cell Signaling Technology社)を含む抗体液を入れ、4℃で一晩抗体反応させた。反応後、一次抗体液を回収し、PVDF膜をTween−20−PBSで5分間、3回洗浄した。2000倍希釈のHRP標識抗体を入れ、室温で60分間反応させた。反応後、二次抗体液を捨て、0.1% Tween−20−PBSで15分間、3回洗浄した。ECL Western Blotting SubstrateをPVDF膜に注ぎ、1分間化学発光させた。その後、PVDF膜をImageQuant LAS 4000で撮影した。
試験例2では、RID−BをJurkat細胞に添加した場合のRas/Raf/MEK/ERK経路及びPI3K/Akt/mTOR経路への影響を確認した。
試験例2の結果より、RID−BがRas/Raf/MEK/ERK経路及びPI3K/Akt/mTORの両経路を阻害することが確認されたため、試験例3では、両経路を阻害することが知られているBRAP2に対するRID−Bによる影響をウェスタンブロッティングで確認した。
試験例4では、RID−BとBRAP2の結合の有無を確認した。
streptavidin−sepharose−beads(本明細書において、、単に「ビーズ」ともいう)をPBSで3回遠心洗浄した。lysis buffer(50mM HEPES(pH7.5)、150mM NaCl、10% glycerol、1% Triton X−100、1.5mM MgCl2、1mM EGTA、0.1% protease inhibitor cocktail(Sigma社))で可溶化したJurkat細胞溶解液の濃度を測定し、1つのサンプルが3.0mg/mLで500μLになるよう調整した。各サンプルにビーズを100μLずつ加え、1時間、4℃でローテーションし、ビーズに結合するタンパク質をあらかじめ除去した(プレクリア)。13000rpmで5分間遠心し、上清をプレクリア済みの細胞溶解液として回収した。プレクリアした細胞溶解液には先にRID−Bを終濃度が250μMになるように加えて4時間、4℃でローテーションさせ、その後、上記で合成したBio−RID−Bを終濃度が250μMになるように加えて4時間、4℃でローテーションした。
試験例5では、RID−BとBRAP2が直接結合しているか否かを確認した。
2cm角のPVDF膜をメタノールで10秒程度親水化後、Transfer buffer(13mM Tris−HCl、0.1mM glycine、30% MeOH、pH8.3)に1〜2分浸透させた。Avidin、BSA、human recombinant BRAP2(hBRAP2)を1μgずつそれぞれPVDF膜に滴下し、室温で20分間乾燥した。PVDF膜をTBST(TBS+0.5% Tween20)で洗浄後、5% skim milk/TBSTにて室温で1時間ブロッキングした。PVDF膜を洗浄後、12.5μM Bio−RID−B/TBSTと室温で2時間、反応させた。PVDF膜を洗浄後、2μg/mL hBRAP/TBSTと室温で2時間、次いで4℃で一晩反応させた。PVDF膜を洗浄後、Can Get Signal Solution 1(東洋紡社)で1:1000の割合で希釈した抗BRAP2抗体と室温で4時間反応させた。PVDF膜を洗浄後、1:2000の割合で希釈したanti−rabbit IgG,HRP−linked antibody (Cell Signaling Technology社)と室温で2時間反応させた。PVDF膜を洗浄後、Immobilon Forte Western HRP基質(Merck社)を用いて1分間反応させた。反応後、LuminoGraph I(アトー社)を用いて撮影した。結果を図4Bに示す。
結合試験1と同様に準備したPVDF膜に、hBRAP2を1μg、BSAを1μg、anti−rabbit IgG,HRP−linked antibodyを1μL、biotinylated alkaline phosphatase(Pierce社)を1μg滴下し、室温で20分間乾燥した。PVDF膜を洗浄後、結合試験1と同様にブロッキングした。PVDF膜を洗浄後、12.5μM Bio−RID−B/TBSTと室温で2時間、次いで4℃で一晩反応させた。PVDF膜を洗浄後、streptavidin−HRP/TBST(1:1000)と室温で2時間反応させた。PVDF膜を洗浄後、結合試験1と同様の方法を用いて撮影した。結果を図4Cに示す。
試験例6では、Jurkat細胞においてBRAP2をノックアウト(KO)した場合における、RID−Bによる細胞障害を確認した。
pSpCas9(BB)−2A−Puro(PX459)V2.0(plasmid#62988)(Addgene社)100ng/μLのBbsI部位を、BbsI(300U,濃度:5000units/mL)(New England Biolabs社)を用いて37℃で60分間インキュベートすることで切断した。CRISPR direct(URL:https://crispr.dbcls.jp/)で設計したBRAP2のgRNA(Top:CACCGGAAAGGCGCTGCGTTCGAAA(配列番号1),Bottom:AAACTTTCGAACGCAGCGCCTTTCC(配列番号2))をBbsI部位にDNA ligation kit(タカラバイオ社)を用いて制限酵素処理産物(20ng/μL)とBRAP2のgRNA(20ng/μL)を1:1の割合で混合し、16℃で3時間インキュベートし、ライゲーションすることでBRAP2ノックアウトプラスミドを構築した。Jurkat細胞へのトランスフェクションは、エレクトロポレーション法(Neon transfection system,Thermo Fisher Scientific社)を用いて行った。Jurkat細胞へトランスフェクションする4時間前にRPMI1640培地(FBS不含、抗生物質含有)でインキュベートした。Jurkat細胞を2.0×105cells/mLに調整し、PBS(Ca2+,Mg2+不含)で洗浄し、PBSを除去後、30μLのresuspension buffer Rで懸濁した。そこに10μLのプラスミドDNA(1μg/μL)を加えた。Neon pipette専用チップを装着後、細胞とプラスミドDNAの混合液を10μL吸引し、3mLのelectrolytic buffer Eが入ったNeon Tubeに設置した。pulse voltage 1350(V),pulse width 10(ms),pulse number 3の条件でトランスフェクションを行い、RPMI1640培地(FBS含有、抗生物質不含)で培養した。翌日にRPMI1640培地(FBS含有、75mg/L カナマイシン硫酸塩)で培養し、トランスフェクションを行ってから3日後から0.5μg/mLのpuromycin(Sigma Aldrich社)による薬剤セレクションを約1カ月間行った。シングルセルクローニングを行うために、薬剤セレクションを行ったJurkat細胞を1.0×105cellsに調整し、最終的な細胞数が1ウェルに1細胞になるよう段階希釈をして96穴プレートに100μLずつ播種した。2日毎に位相差顕微鏡でシングルセルのウェルを確認し、増殖したシングルセル由来のクローンを24穴プレート、12穴プレート、6穴プレートの順にスケールアップしながら培養していき、Jurkat(Mock)、Jurkat(ΔBRAP2)細胞の安定株を作製した。作製した細胞におけるBRAP2発現量を、抗BRAP2抗体を用いたウェスタンブロッティングで確認した。
試験例7では、BRAP2欠損におけるRas/Raf/MEK/ERK経路及びPI3K/Akt/mTOR経路への影響をウェスタンブロッティングで確認した。ウェスタンブロッティングは、抗p−ERK抗体、抗ERK抗体、抗p−Akt抗体、抗Akt抗体を用い、試験例1と同様の方法を用いて行った。結果を図6に示す。
CRISPR/Cas9によるBRAP2の欠損では、オフターゲット欠損により他のタンパク質も欠損することで、RID−Bの傷害抑制が生じている可能性が否定できない。そこで、試験例8では、BRAP2欠損株にMAT−FLAG−BRAP2を導入してBRAP2を再発現させた場合に、RID−Bによる細胞傷害が回復するか確認した。
MAT−FLAG−BRAP2プラスミドは国立感染症研究所の深澤征義先生より供与された。BRAP2欠損株は、トランスフェクションする4時間前にRPMI1640培地(FBS不含、抗生物質含有)でインキュベートした。BRAP2欠損株を2.0×105cells/mLに調整し、PBS(Ca2+、Mg2+不含)で洗浄し、PBSを除去後、resuspension buffer Rで懸濁した。そこにMAT−FLAG−BRAP2プラスミドDNAを添加した。pulse voltage 1350(V)、pulse width 10(ms)、pulse number 3の条件でトランスフェクションを行い、RPMI1640培地(FBS含有、抗生物質不含)で培養した。翌日にRPMI1640培地(FBS含有、75mg/L カナマイシン硫酸塩)で培養して、BRAP2再発現株を作製した。
試験例9では、他のRID−B類縁体における、BRAP2への作用増強能を有する構造を明らかにするために、上記で合成した化合物、TAM、下記式で表される4−OH−TAM、5−Fluorouracilを、Mock導入株及びBRAP2欠損株に添加した場合の細胞傷害を確認した。なお、subG1期解析において、RID−SB10、RID−SB17、RID−G、RID−SG17、RID−H、及びRID−SH17は終濃度0.5μMとなるように添加した。RID−UB及びRID−NBは終濃度1.5μMとなるように添加した。RID−B−OH2は終濃度1μMとなるように添加した。RID−S10−(B/OH)、RID−S10−(B/MEE)は終濃度20μMとなるように添加した。RID−S10−(B/Me)は終濃度25μMとなるように添加した。RID−SB31は終濃度40μMとなるように添加した。RID−S10は終濃度125μMとなるように添加した。それぞれの化合物を添加後、12時間作用させた。
Claims (6)
- 下記式(1)又は(2)で表される化合物又はその塩を有効成分として含有する、BRAP2作用増強が有効な疾患又は症状の予防又は治療薬であって、前記BRAP2作用増強が有効な疾患又は症状が、デングウイルス、サイトメガロウイルス、インフルエンザウイルス、HIV、又はC型肝炎ウイルスによるウイルス感染症である、予防又は治療薬。
- 下記式(3)で表される化合物。
- 下記式(4)で表される化合物。
- 請求項2又は3に記載の化合物又はその塩を有効成分として含有する、BRAP2作用増強剤。
- 請求項4に記載のBRAP2作用増強剤を有効成分として含有する、BRAP2作用増強が有効な疾患又は症状の予防又は治療薬であって、前記BRAP2作用増強が有効な疾患又は症状が、がん、炎症性疾患、自己免疫疾患、デングウイルス、サイトメガロウイルス、インフルエンザウイルス、HIV、又はC型肝炎ウイルスによるウイルス感染症である、予防又は治療薬。
- 請求項4に記載のBRAP2作用増強剤を有効成分として含有する、免疫抑制剤。
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