JP2018509434A - 腎臓及び/又は肝臓疾患を治療するための組成物 - Google Patents
腎臓及び/又は肝臓疾患を治療するための組成物 Download PDFInfo
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- JP2018509434A JP2018509434A JP2017548937A JP2017548937A JP2018509434A JP 2018509434 A JP2018509434 A JP 2018509434A JP 2017548937 A JP2017548937 A JP 2017548937A JP 2017548937 A JP2017548937 A JP 2017548937A JP 2018509434 A JP2018509434 A JP 2018509434A
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- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- AVBGNFCMKJOFIN-UHFFFAOYSA-N triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
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Abstract
Description
Aは、
R1〜R9は、独立にC、N、O、又はSであり、
Qは、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ、及びC1〜6アルコキシから独立に選択され、
nは、0、1、2、3、又は4であり、
Xは、-OH、又は
Xが-OHのとき、Aは非置換型のフェニルではない]
の化合物、又はその薬理学的に許容される塩、立体異性体、ジアステレオマー、エナンチオマー、ラセミ体、水和物、及び/若しくは溶媒和物に関する。
Aは、
R1〜R9は、独立にC、N、O、又はSであり、
Qは、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ、及びC1〜6アルコキシから独立に選択され、
nは、0、1、2、3、又は4であり、
Xは、-OH又は
Xが-OHのとき、Aは非置換型のフェニルではない]
により表わされ、又はその薬理学的に許容される塩、立体異性体、ジアステレオマー、エナンチオマー、ラセミ体、水和物、及び/若しくは溶媒和物である。
P5、P8、P11、P22、P26、P40、及びP41の合成
P5、P8、P11、P22、P26、P40、及びP41を調製するのに用いられる合成経路を図1に示す。初めに、3-ヒドロキシ桂皮酸をエステル化してエステル(1)とし、これを次に水素付加してプロピオン酸エチル(2)とし、臭素で処理してアリール臭化物(3)を得た。アリール臭化物(3)及び3-ベンジルオキシフェニルボロン酸間の鈴木クロスカップリング反応により、ビフェニル(4)を得、その後アンモニアと共にアミノリシス反応を行い、アミド(5)を得た。化合物5をN-フェニルトリフルアミドと反応させると、アリールトリフレート(6)が得られ、それをその後チオアニソール/TFAで処理して、アリールトリフレート(7)を得た。
(E)-エチル-3-(3-ヒドロキシフェニル)アクリレート(1)の生成
エタノール(260mL)中の(E)-エチル-3-(3-ヒドロキシフェニル)アクリレート(1) (62.62g、326.0mmol)、及び10%パラジウム炭素(50% wtの水)を、その3バッチについて、水素が140psiのオートクレーブ内で1時間撹拌した。3バッチを一まとめにし、セライトを通じて濾過し、エタノールで徹底洗浄した。濾過液を濃縮して、エチル-3-(3-ヒドロキシフェニル)プロパノエート(2)を、淡黄褐色の油状物(63.23g、100%)として得た。1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.92 (br s, 1H), 6.85 - 6.80 (m, 3H), 4.24 (q, 2H, J 7.1 Hz), 3.00 (t, 2H, J 7.5 Hz), 2.72 (t, 2H, J 7.5 Hz), 1.34 (t, 3H, J 7.1 Hz).
乾燥DCM (500mL)中の3-(3-ヒドロキシフェニル)プロパノエート(2) (50.0g、0.258mol)及び炭酸カルシウム(33.5g、0.335mol)からなる混合物を激しく撹拌しながら、臭素(13.25mL、0.258mol)を、2時間にわたりゆっくりと添加した。水(60mL)に溶解したメタ重亜硫酸ナトリウム(12.5g、65.79mmol)を添加した。次に、反応混合物を、乾燥し、濾過し、濃縮して、エチル-3-(2-ブロモ-5-ヒドロキシフェニル)プロパノエート(3)を、淡黄褐色の油状物として得た(69.27g、98%)。1H NMR (400 MHz, CDCl3) δ 7.32 (d, 1H, J 8.6 Hz), 6.75 (d, 1H, J 3.0 Hz), 6.58 (dd, 1H, J 8.6, 3.0 Hz), 6.28 (s, 1H), 4.12 (q, 2H, J 7.2 Hz), 2.96 (t, 2H, J 7.5 Hz), 2.62 (t, 3H, J 7.5 Hz), 1.22 (q, 3H, J 7.2 Hz). 13C NMR (100 MHz, CDCl3) δ 174.2, 155.6, 140.6, 133.6, 117.5, 115.6, 114.3, 61.3, 34.3, 31.5, 14.2. EIMS: m/z 実測値: M+・ 272.0028, C11H13BrO3の計算値 272.0043. EIMS: m/z 272 (M+・, 5%), 193 (86), 165 (100).
ジメトキシエタン(650mL)に溶解したエチル-3-(2-ブロモ-5-ヒドロキシフェニル)プロパノエート(3) (35.0g、128.0mmol)の溶液を、窒素で10分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(0) (3.50g、3.03mmol)を添加し、反応混合物を更に15分間撹拌した。炭酸カリウムの2M水溶液(200mL、0.40mmol)、その後に3-ベンジルオキシフェニルボロン酸(35.0g、154.0mmol)を添加した。反応混合物を2時間加熱還流し、次に周囲温度まで冷却し、2M塩酸及び酢酸エチル間で分別した。各層を分離し、水層をもう一度、酢酸エチルで抽出した。一まとめにした有機性の抽出物を水及びブラインで洗浄し、濃縮して黄褐色の油状物として粗生成物を得た。未精製の物質を、セライト上に事前吸収させ、次にヘプタンに溶解したDCMのグラジエント(50〜100% DCM)、次にDCMに溶解した酢酸エチルのグラジエント(2〜6%の酢酸エチル)を用いて溶出させるクロマトグラフィー(DCVC)で処理して、濃縮後に物質を黄色の油状物として得た(47.6g、99%)。これをDCM及びヘプタンから再結晶化させて、エチル-3-(3'-(ベンジルオキシ)-4-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパノエート(4)を、3回の操作で淡黄色の固形物として得た(38.47g、80%)、mp 85.7〜87.2℃。1H NMR (400 MHz, CDCl3) δ 7.43 (m, 2H), 7.37 (m, 2H), 7.33 - 7.24 (m, 2H), 7.06 (d, 1H, J 8.2 Hz), 6.94 (m, 1H), 6.87 (m, 2H), 6.75 (d, 1H, 2.6 Hz), 6.70 (dd, 1H, 8.2, 2.6 Hz), 5.43 (br s, 1H), 5.07 (s, 2H), 4.06 (q, 2H, J 7.1 Hz), 2.86 (t, 2H, J 8.1 Hz), 2.39 (t, 2H, J 8.1 Hz), 1.18 (t, 3H, J 7.1 Hz). 13C NMR (100 MHz, CDCl3) δ 173.7, 158.7, 155.4, 142.9, 139.5, 137.2, 134.4, 131.5, 129.4, 128.8, 128.1, 127.7, 122.4, 116.1, 115.9, 113.6, 113.5, 70.2, 60.8, 35.5, 28.6, 14.3. EIMS: m/z 実測値: M+・ 376.1658, C24H24O4の計算値 376.1669. EIMS: m/z 376 (M+・, 24%), 91 (100).
エチル-3-(3'-(ベンジルオキシ)-4-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパノエート(4) (30.0g、79.80mmol)、メタノール(150mL)、及び30%アンモニア水溶液(450mL)を、周囲温度で1週間撹拌した。得られた固形物を濾過により収集した。未精製の物質をDCM及びヘプタンから再結晶化させて、3-(3'-(ベンジルオキシ)-4-ヒドロキシ-[1,1'-ビフェニル-2-イル)プロパンアミド(5)を、無色の四角い板状として得た(12.8g、46%)、mp 119.5〜120.5℃。1H NMR (400 MHz, DMSO-d6) δ 9.39 (br s, 1H), 7.46 (m, 2H), 7.39 (t, 2H, J 7.1 Hz), 7.31 (q, 2H, J 7.6 Hz), 7.23 (br s, 1H), 6.96 (m, 2H), 6.87 (m, 1H), 6.83 (d, 1H, J 7.6 Hz), 6.73 (br s, 1H), 6.71 (d, 1H, J 2.4 Hz), 6.64 (dd, 1H, J 8.2, 2.5 Hz), 5.12 (s, 2H), 2.67 (t, 2H, J 7.7 Hz), 2.21 (t, 2H, J 7.7 Hz). 13C NMR (100 MHz, DMSO-d6) δ 175.4, 158.7, 155.9, 143.0, 139.3, 137.2, 133.9, 131.6, 129.5, 128.8, 128.2, 127.7, 122.3, 116.3, 116.2, 113.8, 113.6, 70.2, 36.8, 29.2. EIMS: m/z 実測値: M+・ 347.1515, C22H21NO3の計算値 347.1516. EIMS: m/z 347 (M+・, 19%), 91 (100).
DCM (100mL)中の3-(3'-(ベンジルオキシ)-4-ヒドロキシ-[1,1'-ビフェニル-2-イル)プロパンアミド(5) (8.0g、21.0mmol)の混合物に、N-フェニルトリフルアミド(8.21g、23.0mmol)、その後にトリエチルアミン(3.2mL、23.0mmol)を添加した。反応混合物を周囲温度で20時間撹拌し、次に分液漏斗に移し、水(2×)及びブラインで洗浄し、次に濃縮して黄褐色の油状物を得た。未精製の油状物をセライト上に事前吸収させ、次にDCMに溶解した酢酸エチルのグラジエント(0〜25%の酢酸エチル)を用いて溶出させるクロマトグラフィー(DCVC)で処理した。同一分画を一まとめにし、DCM及びヘプタンから再結晶化させて、2-(3-アミノ-3-オキソプロピル)-3'-(ベンジルオキシ)-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(6)を無色の針状として得た(10.73g、65%)、mp 104.0〜106.0℃。1H NMR (400 MHz, CDCl3) δ 7.41 - 7.27 (m, 6H), 7.23 (d, 1H, J 8.2 Hz), 7.17 (d, 1H, J 2.6 Hz), 7.11 (dd, 1H, J 8.4, 2.6 Hz), 6.98 (m, 1H), 6.82 (m, 2H), 5.57 (br s, 1H), 5.16 (br s, 1H), 5.06 (s, 2H), 2.89 (t, 2H, J 7.9 Hz), 2.21 (t, 2H, J 7.9 Hz). 13C NMR (100 MHz, CDCl3) δ 173.9, 158.9, 148.9, 142.2, 141.2 (2つのシグナルは一致), 136.9, 132.0, 129.8, 128.8, 128.3, 127.7, 122.0, 121.8, 119.2, 118.9 (d, J320.6 Hz) 115.8, 114.4, 70.2, 36.3, 28.8. EIMS: m/z 実測値: M+・ 479.1004, C23H20F3NO5 32Sの計算値 479.1009. EIMS: m/z 479 (M+・, 7%), 91 (100).
トリフルオロ酢酸(10mL)中の2-(3-アミノ-3-オキソプロピル)-3'-(ベンジルオキシ)-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(6) (10.29g、22.0mmol)、及びチオアニソール(5.05mL、43.0mmol)を、ストッパー付きのフラスコ内で、周囲温度で2日間撹拌した。反応混合物を氷浴中で冷却し、次に氷水上に注入し、分液漏斗に移した。生成物を酢酸エチルで抽出した。有機相を水及びブラインで洗浄し、乾固するまで濃縮した。未精製の物質をセライト上に事前吸収させ、次にヘプタンに溶解したDCMのグラジエント(50、75、及び100%のDCM)、その後にDCMに溶解したメタノールのグラジエント(1〜5%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)で処理した。清浄な物質を含有する分画を一まとめにして濃縮し、次にメタノール及び1,2-ジクロロエタンから再結晶化させて、2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(7)を無色の針状として得た(6.19g、74%)、mp 126.2〜127.3℃。1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.42 (s, 1H), 7.38 - 7.20 (m, 4H), 6.86 - 6.66 (m, 4H), 2.80 (t, 2H, J 8.1 Hz,), 2.28 (t, 2H, J 8.1 Hz,). 13C NMR (100 MHz, DMSO-d6) δ 173.0, 157.3, 148.3, 142.2, 141.9, 140.7, 131.7, 129.5, 121.4, 119.6, 118.8, 116.7, 115.8, 114.6, 35.5, 28.0. EIMS: m/z 実測値: M+・ 389.0533, C16H14F3NO2 32Sの計算値 389.0539. EIMS: m/z 389 (M+・, 32%), 211 (60), 197 (100).
トルエン(10mL)及びエタノール(2mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イル-トリフルオロメタンスルホネート(7) (0.50g、1.29mmol)、ピリジン-3-ボロン酸(0.20g、1.60mmol)、及び炭酸ナトリウム水溶液(1M) (3.0mL、3.0mmol)からなる混合物を窒素で10分間脱気した。テトラキス(トリフェニルホスフィン)パラジウム(0) (0.10g、0.09mmol)を添加し、反応混合物を、すべてのトリフレート出発物質が消費されるまで、密閉容器内において、85℃で加熱した。反応混合物を周囲温度まで冷却し、次に2M塩酸及び酢酸エチル間で分別した。各層を分離した。有機層をTLCによりチェックし、所望の生成物がほとんど含まれないことが判明し、それを廃棄した。水層を塩基性にし、酢酸エチル(2×)で再抽出した。一まとめにした有機層を水及びブラインで洗浄し、乾固するまで濃縮してクリーム状の固形物を得た(260mg)。未精製の物質を、セライト上に事前吸収させ、次にDCMに溶解したメタノールのグラジエント(0〜10%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)で処理した。清浄な物質を含有する分画を一まとめにし、DCM及びメタノールから再結晶化させて、3-(3'-ヒドロキシ-4-(ピリジン-3-イル)-[1,1'-ビフェニル]-2-イル)プロパンアミド(P5)を、無色の固形物として得た(0.09g、21%)、mp 196〜198℃。1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.92 (m, 1H), 8.58 (m, 1H), 8.10 (m, 1H), 7.67 (m, 1H), 7.59 (dd, 1H, J 2.0, 7.9 Hz), 7.50 (m, 1H), 7.25 (m, 3H), 6.78 (m, 4H), 2.84 (m, 2H), 2.33 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 173.4, 157.1, 148.4, 147.6, 141.9, 141.3, 139.4, 136.0, 135.4, 134.0, 130.4, 129.3, 127.4, 124.3, 123.8, 119.6, 115.8, 114.1, 36.1, 28.1. EIMS: m/z 実測値: M+・ 318.1358, C20H18N2O2の計算値 318.1363. EIMS: m/z 318 (M+・, 92%), 273 (38), 259 (100). HPLC純度(40% ACN / H2O, 264 nm): 98.90%.
P5の方法に基づき、トルエン(10mL)及びエタノール(2mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(7) (0.32g、0.82mmol)、チオフェン-3-ボロン酸(0.132g、1.03mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.056g、0.05mmol)、及び炭酸ナトリウム水溶液(1M) (2.0mL、2.0mmol)から調製した。未精製の物質を、DCMに溶解したメタノールのグラジエント(0〜5%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)により精製した。清浄な物質を含有する分画を一まとめにし、DCM及びメタノールから再結晶化させて、3-(3'-ヒドロキシ-4-(チオフェン-3-イル)-[1,1'ビフェニル]-2-イル)プロパンアミド(P8)を、ベージュ色の固形物として得た(0.13g、50%)、mp 211〜212℃。1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.88 - 7.84 (m, 1H), 7.68 - 7.63 (m, 2H), 7.59 - 7.54 (m, 2H), 7.27 - 7.19 (m, 2H), 7.16 (d, 1H, J 7.9 Hz), 6.80 - 6.68 (m, 4H), 2.80 (t, 2H, J 7.9 Hz), 2.30 (t, 2H, J 7.9 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.4, 157.1, 142.2, 141.3, 140.2, 139.0, 134.2, 130.1, 129.3, 127.0, 126.6, 126.2, 123.7, 120.8, 119.7, 115.8, 113.9, 36.2, 28.2. EIMS: m/z 実測値: M+・ 323.0964, C19H17NO2 32Sの計算値 323.0975. EIMS: m/z 323 (M+・, 100%), 305 (36), 277 (53), 264 (64). HPLC純度(40% ACN / H2O, 274 nm): 99.78%.
P5の方法に基づき、トルエン(10mL)及びエタノール(2mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(7) (0.50g、1.29mmol)、フラン-3-ボロン酸(0.18g、1.60mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.10g、0.09mmol)、及び炭酸ナトリウム水溶液(1M) (2.5mL、2.50mmol)から調製した。未精製の物質を、DCMに溶解したメタノールのグラジエント(0〜10%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)により精製し、次にDCM及びメタノールから再結晶化させて、3-(4-(フラン-3-イル)-3'-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパンアミド(P11)を、ベージュ色の棒状物として得た(0.23g、58%)、mp 191〜192℃。1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H),8.20 - 8.16 (m, 1H), 7.78 - 7.73 (m, 1H), 7.58 - 7.54 (m, 1H), 7.49 - 7.44 (m, 1H), 7.26 - 7.18 (m, 2H), 7.14 (d, 1H, J 7.9 Hz), 6.99 - 6.94 (m, 1H), 6.80 - 6.67 (m, 4H), 2.79 (t, 2H, J 8.3 Hz), 2.29 (t, 2H, J 8.3 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.4, 157.1, 144.3, 142.2, 140.1, 139.2, 139.0, 130.9, 130.0, 129.2, 126.0, 125.6, 123.1, 119.6, 115.8, 113.9, 108.7, 36.1, 28.1. EIMS: m/z 実測値: M+・ 307.1204, C19H17NO3の計算値 307.1203. EIMS: m/z 307 (M+・, 100%), 248 (50). HPLC純度(40% ACN / H2O, 265 nm): 99.33%.
P5の方法に基づき、トルエン(10mL)及びエタノール(2mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イル-トリフルオロメタンスルホネート(7) (0.50g、1.29mmol)、tert-ブチル-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-1H-ピラゾール-1-カルボキシレート(0.47g、1.61mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.10g、0.09mmol)、及び炭酸ナトリウム水溶液(1M) (3.0mL、3.00mmol)から調製した。未精製の物質を、DCMに溶解したメタノールのグラジエント(0〜20%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)により精製した。DCMに溶解した酢酸エチルのグラジエント(50〜100%の酢酸エチル)、次に酢酸エチルに溶解したメタノールのグラジエント(1〜5%のメタノール)を用いて溶出させるラジアルクロマトグラフィーにより物質を更に精製して、3-(3'-ヒドロキシ-4-(1H-ピラゾール-4-イル)-[1,1'-ビフェニル]-2-イル)プロパンアミド(P22)を、ベージュ色の結晶として得た(0.10g、26%)、mp 161.5〜163.2℃。1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.44 (s, 1H), 8.13 (br s, 1H), 7.99 (br s, 1H), 7.58 - 7.54 (m, 1H), 7.49 - 7.42 (m, 1H), 7.28 - 7.19 (m, 2H), 7.10 (d, 1H, J 7.9 Hz), 6.79 - 6.67 (m, 4H), 2.78 (t, 2H, J 7.9 Hz), 2.29 (t, 2H, J 7.9 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.6, 157.1, 142.4, 139.0, 138.9, 136.3, 131.9, 130.1, 129.2, 125.5 (2つのシグナルは一致), 122.8, 121.0, 119.7, 115.9, 113.8, 36.2, 28.2. EIMS: m/z 実測値: M+・ 307.1314 C18H17N3O2の計算値 307.1315. EIMS: m/z 307 (M+・, 100%), 248 (57). HPLC純度(35% ACN / 0.1% TFA, 270 nm): 99.08%.
P5の方法に基づき、トルエン(20mL)及びエタノール(4mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イル-トリフルオロメタンスルホネート(7) (1.00g、2.58mmol)、ピリミジン-5-ボロン酸(0.40g、3.20mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.20g、0.18mmol)、及び炭酸ナトリウム水溶液(1M) (6.0mL、6.00mmol)から調製した。未精製の物質を、DCMに溶解したメタノールのグラジエント(0〜7.5%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC) (×2)により精製し、次にメタノールから再結晶化させて、3-(3'-ヒドロキシ-4-(ピリミジン-5-イル)-[1,1-ビフェニル]-2-イル)プロパンアミド(P26)を、薄いレモン色の固形物として得た(0.17g、20%)、mp 191.9〜193.5℃。1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.20 (s, 1H), 9.17 (s, 2H), 7.77-7.75 (m, 1H), 7.69 - 7.66 (m, 1H), 7.32 - 7.22 (m, 2H), 7.25 (br s, 1H), 6.81 - 6.71 (m, 4H), 2.87 - 2.80 (m, 2H), 2.37 -2.13 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 173.4, 157.24, 157.18, 154.7 (2つのシグナルは一致), 142.1, 141.7, 139.6, 133.1, 132.7, 130.5, 129.3, 127.4, 124.4, 119.6, 115.8, 114.2, 36.0, 28.1. EIMS: m/z 実測値: M+・ 319.1310, C19H17N3O2の計算値 319.1315. EIMS: m/z 319 (M+・, 70%), 274 (48), 260 (100). HPLC純度(40% ACN / H2O, 265 nm): 99.87%.
DCM (200mL)中の2,4-ジメチルチアゾール(23.37g、0.207mol)及び炭酸カルシウム(26.90g、270mmol)からなる混合物を激しく撹拌し、これにDCM (100mL)に溶解した臭素溶液(11.10mL、217mmol)をゆっくりと添加した。3時間後、TLC (DCM)により反応をチェックしたが、完全ではなかった。反応が完了するまで、DCM (2×20mL)に溶解した臭素(2×3.00mL、117.10mmol)を更に2容量必要とした。水(60mL)に溶解したメタ重亜硫酸ナトリウム(16.0g、84.17mmol)を、反応混合物にゆっくりと添加した。より多くの水を添加し、反応混合物を分液漏斗に移した。各層を分離し、水層をDCMを用いてもう一度抽出した。一まとめにした有機層を、1M炭酸ナトリウム溶液(2×)及び水で洗浄し、濃縮して5-ブロモ-2,4-ジメチルチアゾール(8)を、淡黄褐色の油状物として得た(38.40g、97%)。1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 2.24 (s, 3H).
THF (20mL)に溶解した5-ブロモ-2,4-ジメチルチアゾール(8) (5.00g、26.0mmol)及び1,2-ジブロモエタン(0.24g、1.3mmol)の溶液を、マグネシウム(削状) (0.65g、26.8mmol)を含有するフラスコに一滴ずつ1時間かけて添加した。反応混合物を75℃に4時間加熱し、周囲温度まで冷却し、次に第2の反応フラスコのカニューレを経由して滴下漏斗に移した。次に、グリニヤール試薬を、0℃で、THF (10mL)に溶解したイソプロピルピナコールボレートの溶液(5.30mL、26.00mmol)に一滴ずつ添加した。添加完了後、反応混合物を周囲温度まで加温し、20時間撹拌した。反応物を約10℃まで冷却し、次に反応混合物がpH7となるように、酢酸(1.03mL、25.50mmol)をゆっくりと添加した。溶媒をロータリーエバポレーションにより除去し、次に酢酸エチルを添加し、やはりロータリーエバポレーションにより除去した。未精製の油状物をセライト上に事前吸収させ、次にヘプタンに溶解した酢酸エチルのグラジエント(0〜30%の酢酸エチル)を用いて溶出させるクロマトグラフィー(DCVC)で処理した。所望の物質を含有する分画を一まとめにし、濃縮して2,4-ジメチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)チアゾール(9)を、凝固した淡黄色の油状物として得た(1.65g、26%)。1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3H), 2.53 (s, 3H), 1.26 (s, 12H). 13C NMR (50 MHz, DMSO-d6) δ 170.4, 163.2, 84.1, 24.9, 19.1, 17.6 (1つのシグナルは認められず). EIMS: m/z 実測値: M+・ 239.1143, C11H18NO2 11B32Sの計算値 239.1146. EIMS: m/z 239 (M+・, 66%), 224 (45), 182 (37), 139 (53), 71 (100).
P5の方法に基づき、トルエン(20mL)及びエタノール(4mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イルトリフルオロメタンスルホネート(7) (1.00g、2.58mmol)、2,4-ジメチル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)チアゾール(0.76g、3.20mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.24g、0.21mmol)、及び炭酸ナトリウム水溶液(1M) (6.0mL、6.00mmol)から調製した。未精製の物質を、ジクロロメタンに溶解したメタノールのグラジエント(0〜5%メタノール)を用いて溶出させるクロマトグラフィー(DCVC)により精製し、次にメタノールから再結晶化させて3-(4-(2,4-ジメチルチアゾール-5-イル)-3'-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパンアミド(P40)を、黄色の結晶として得た(0.23g、26%)、mp 196.6〜199.4℃。1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 7.38 (s, 1H), 7.32 - 7.19 (m, 4H), 6.81 - 6.69 (m, 4H), 2.80 (t, 2H, J 7.8 Hz), 2.63 (s, 3H), 2.42 (s, 3H), 2.27 (t, 2H, J 7.8 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.3, 162.5, 157.2, 146.7, 141.8, 140.8, 139.2, 130.7, 130.4, 130.1, 129.3, 129.1, 126.2, 119.6, 115.8, 114.1, 35.9, 27.9, 18.7, 16.0. EIMS: m/z 実測値: M+・ 352.1230, C20H20N2O2 32Sの計算値 352.1240. EIMS: m/z 352 (M+・, 100%), 334 (41), 293 (35). HPLC純度(35% ACN / 0.1% TFA, 256 nm): 98.64%.
P5の方法に基づき、トルエン(10mL)及びエタノール(2mL)中の2-(3-アミノ-3-オキソプロピル)-3'-ヒドロキシ-[1,1'-ビフェニル]-4-イル-トリフルオロメタンスルホネート(7) (0.50g、1.29mmol)、3,5-ジメチルイソオキサゾール-4-ボロン酸(0.23g、1.60mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0) (0.10g、0.09mmol)、及び炭酸ナトリウム水溶液(1M) (2.5mL、2.50mmol)から調製した。未精製の物質を、DCMに溶解したメタノールのグラジエント(0〜5%のメタノール)を用いて溶出させるクロマトグラフィー(DCVC)により精製し、次にDCM及びメタノールから再結晶化させて、3-(4-(3,5-ジメチルイソオキサゾール-4-イル)-3'-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパンアミド(P41)を薄いレモン色の固形物として得た(0.15g、33%)、mp 203〜204℃。1H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 7.32 - 7.30 (m, 1H), 7.28 - 7.20 (m, 4H), 6.81 - 6.70 (m, 4H), 2.52 - 2.49 (m, 2H), 2.44 (s, 3H), 2.32 - 2.25 (m, 2H), 2.27 (s, 3H). 13C NMR (50 MHz, DMSO-d6) δ 173.3, 165.1, 158.2, 157.1, 142.0, 140.5, 139.0, 130.0, 129.3, 129.2, 128.8, 126.2, 119.6, 115.8, 115.7, 114.0, 35.9, 27.9, 11.4, 10.6. EIMS: m/z 実測値: M+・ 336.1459, C19H17N3O2の計算値 336.1468. EIMS: m/z 実測値: M+・ 336.1459, C20H20N2O3の計算値 336.1468. EIMS: m/z 336 (M+・, 86%), 292 (100). HPLC純度(40% ACN / H2O, 275 nm): 97.36%.
P9の合成
P5、P8、P11、P22、P26、P40、及びP41の調製に用いられる合成経路を図3に示す。要するに、ビフェニルエステル(4)をN-フェニルトリフルアミドと共に反応させて、保護されたアリールトリフレート(10)を生成し、その後にチオアニソール/TFAで処理することにより、アリールトリフレートエステル(11)を調製した。アリールトリフレートエステル(11)及びピロール間で、パラジウム触媒型クロスカップリング反応を行うと、次に所望のターアリール(teraryl)化合物(12)が得られ、そのアミノリシス反応からP9が生成される。
化合物6を生成するのに用いられる方法に基づき、(100mL)中のエチル-3-(3'-(ベンジルオキシ)-4-ヒドロキシ-[1,1'-ビフェニル]-2-イル)プロパノエート(4) (8.0g、21.00mmol)、N-フェニルトリフルアミド(8.21g、23.00mmol)、及びトリエチルアミン(3.2mL、23.00mmol)から調製した。未精製の物質を、シリカゲルのプラグを通過させて精製し、溶出させることにより、エチル-3-(3'-(ベンジルオキシ)-4-(((トリフルオロメチル)スルホニル)オキシ)-[1,1'-ビフェニル]-2-イル)プロパノエート(10)が、次のステップで使用するのに十分な純度を有する黄色の油状物として得られた(定量的収率)。1H NMR (400 MHz, DMSO-d6) δ 7.46 - 7.23 (m, 7H), 7.20 - 7.11 (m, 2H), 7.02 - 6.97 (m, 1H), 6.88 - 6.83 (m, 2H), 5.08 (s, 2H), 4.06 (q, 2H, J 7.2Hz), 2.90 (t, 2H, J 7.9 Hz), 2.39 (t, 2H, J 7.9 Hz), 1.18 (t, 3H, J 7.2 Hz). 13C NMR (100 MHz, DMSO-d6) δ 172.6, 158.9, 148.9, 142.4, 141.2, 141.1, 137.0, 132.0, 129.8, 128.8, 128.3, 127.7, 123.7, 121.9, 121.8, 119.1, 115.8, 114.4, 70.3, 60.8, 34.9, 28.4, 14.3. EIMS: m/z 実測値: M+・ 508.1160, C25H23F3O6 32Sの計算値 508.1162. EIMS: m/z 508 (M+・, 10%), 91 (100).
化合物7を生成するのに用いられる方法に基づき、TFA (10mL)中のエチル-3-(3'-(ベンジルオキシ)-4-(((トリフルオロメチル)スルホニル)オキシ)-[1,1'-ビフェニル]-2-イル)プロパノエート(10) (10.67g、21.0mmol)、及びチオアニソール(5mL、42.62mmol)から調製した。未精製の物質をセライト上に事前吸収させ、次にヘプタンに溶解したDCMのグラジエント(50〜100%のDCM)を用いて溶出させるクロマトグラフィー(DCVC)で処理し、その後にDCM及びヘプタンから再結晶させて、エチル-3-(3'-ヒドロキシ-4-(((トリフルオロメチル)スルホニル)オキシ)-[1,1'-ビフェニル]-2-イル)プロパノエート(11)を無色のプリズム状として得た(4.84g、55%)、mp 90.8〜91.9℃。1H NMR (400 MHz, DMSO-d6) δ 7.30 - 7.23 (m, 2H), 7.19 - 7.11 (m, 2H), 6.87 - 6.78 (m, 2H), 6.76 - 6.73 (m, 1H), 5.73 (s, 1H), 4.07 (q, 2H, J 7.2 Hz), 2.95 (t, 2H, J 7.9 Hz), 2.44 (t, 2H, J 7.9 Hz), 1.19 (t, 3H, J 7.2 Hz). 13C NMR (100 MHz, DMSO-d6) δ 173.0, 155.9, 148.9, 142.2, 141.3, 140.9, 132.0, 130.0, 121.8, 121.6, 119.0 (q, J=321.2 Hz) 119.2, 116.2, 115.0, 61.1, 35.1, 28.5, 14.3. EIMS: m/z 実測値: M+・ 418.0690, C18H17F3O6 32Sの計算値 418.0692. EIMS: m/z 418 (M+・, 100%), 373 (38), 211 (61), 197 (82).
1,4-ジオキサン(4.5mL)を含有するオーブン乾燥したμWバイアル(2〜5mL)を10分間脱気し、その後、Pd2(dba)3 (0.07mmol、66mg)、2-ジシクロヘキシルホスフィノ-2'-(N,N-ジメチルアミノ)ビフェニル(DavePhos) (0.07mmol、28mg)、及びK3PO4 (1.1mmol、228mg)を添加し、20分間撹拌した状態で放置した。次に、エチル-3-(3'-ヒドロキシ-4-(((トリフルオロメチル)スルホニル)オキシ-[1,1'-ビフェニル]-2-イル)プロパノエート(11) (300mg、0.72mmol)及びピロール(4.30mmol、298μL)を添加し、バイアルを密閉し、反応混合物を100℃で16時間加熱した。溶媒を蒸発させ、シリカ製の小型のカラムを通じて残留物を濾過し、酢酸エチル:PEが3:7の比で溶出させた。溶媒を蒸発させた後、残留物を、5:95の酢酸エチル:PEから1:4の酢酸エチル:PEを用いて溶出させるDCVCにより精製し、エチル-3-(3'-ヒドロキシ-4-(1H-ピロール-1-イル)-[1,1'-ビフェニル]-2-イル)プロパノエート(12)を黄色の油状物として得た(159mg、72%)。1H NMR (400 MHz, MeOH-d4) δ 7.39 (m, 1H), 7.36 (dd, 1H, J 8.4, 2.4 Hz), 7.30 - 7.18 (m, 4H), 6.84 - 6.72 (m, 3H), 6.28 (m, 2H), 4.02 (q, 2H, J 7.1 Hz), 2.97 (m, 2H), 2.45 (m, 2H), 1.14 (t, 3H, J 7.1 Hz). 13C NMR (100 MHz, MeOH-d4) δ 174.7, 158.6, 143.7, 141.4, 140.9, 140.8, 132.4, 130.6, 121.8, 121.6, 120.1, 118.9, 117.3, 117.1, 111.5, 61.7, 36.2, 29.8, 14.6. EIMS: m/z 実測値: M+・ 335.1510, C21H21NO3の計算値 335.1516. EIMS: m/z 335 (M+・, 100%).
エチル-3-(3'-ヒドロキシ-4-(1H-ピロール-1-イル)-[1,1'-ビフェニル]-2-イル)プロパノエート(12) (145mg、0.43mmol)を、メタノール(4mL)に溶解し、それに30%のアンモニア水溶液(2.5mL)を添加し、反応混合物を室温で16時間撹拌した状態で放置した。次に、アンモニア(1mL)を更に添加し、それに続いて24時間後に更に追加(1mL)した。更に16時間撹拌を継続し、その後、酢酸エチル(20mL)及び水(20mL)を添加した。混合物を分別し、有機相を乾燥し、溶媒を蒸発させた。残留物を熱メタノール中に溶解し、脱色チャコールを添加し、反応物を加温したフィルターペーパーを通じて濾過して透明な溶液を得た。しばらくして固体が形成され、それを収集し、冷却メタノールで洗浄して、3-(3'-ヒドロキシ-4-(1H-ピロール-1-イル)-[1,1'-ビフェニル]-2-イル)プロパンアミド(P9)を白色結晶として得た(81mg、61%)、mp 221〜224℃。1H NMR (400 MHz, DMSO-d6) δ 9.52 (br s, 1H); 7.50 (m, 1H), 7.42 (dd, 1H, J 2.4, 8.4 Hz), 7.36 (m, 2H), 7.25 - 7.19 (m, 3H), 6.79 - 6.69 (m, 4H), 6.28 (m, 2H), 2.80 (m, 2H), 2.31 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 173.3, 157.1, 141.7, 140.1, 139.0, 138.5, 130.7, 129.3, 119.7 (2つのシグナルは一致), 118.9, 116.9, 115.9, 114.0, 110.4, 35.9, 28.2. EIMS: m/z 実測値: M+・ 306.1355, C19H18N2O2の計算値 306.1363. EIMS: m/z 306 (M+・, 28%), 288 (100). HPLC純度(35% ACN / 0.1 % TFA, 270 nm): 99.33%.
中間体(2E)-3-[3'-(ベンジルオキシ)-4-トリフルオロメタンスルホネート-ビフェニル-2-イル]プロプ-2-エナミドの合成
中間体(2E)-3-[3'-(ベンジルオキシ)-4-トリフルオロメタンスルホネート-ビフェニル-2-イル]プロプ-2-エナミドを調製するのに用いられる合成経路を図4に示す。
ピペリジン(1.47mL)を、ピリジン(150mL)中の4-ブロモ-3-ホルミル-フェノール(25.0g、0.124mol)及びマロン酸(15.53g、0.149mol)の混合物に添加し、4時間加熱還流した。塩酸(2M、500mL)を添加する少し前に反応混合物を冷却し、濃塩酸(33%、約50〜100mL)でpH1〜2に酸性化した。懸濁液を約10℃まで冷却し、塩酸(2M、60mL)を用いた真空濾過洗浄により固形物を収集し、18時間真空下で乾燥した。この未精製の物質には、1H NMRが示すように、水及びピリジン塩酸塩が含まれたので、それを酢酸エチル(1.3L)に取り込み、塩酸(2M、2×750mL)で洗浄し、硫酸マグネシウム上で乾燥し、濾過した。濾過液を濃縮乾固させて、標題化合物を灰色の粉末として得た(23.63g、0.0972mol、78%)。1H NMR (400 MHz, DMSO-d6) d ppm 12.62 (br. s., 1 H) 9.91 (s, 1 H) 7.76 (d, J=16.0 Hz, 1 H) 7.48 (d, J=8.6 Hz, 1 H) 7.19 (d, J=2.3 Hz, 1 H) 6.80 (dd, J=8.8, 2.5 Hz, 1 H) 6.41 (d, J=16.0 Hz, 1 H); HPLC (水/ACN + 0.1% TFA勾配) 220 nmに98.9%; LCMS [M+H]+ = 242.9 , [M-H]- = 242.0.1H NMR分析が示すように、約2〜5mol%の未知不純物。
塩化オキサリル(16mL、0.19mol)を、ジクロロメタン(200mL)及びジメチルホルムアミド(0.5mL)中の(2E)-3-(2-ブロモ-5-ヒドロキシフェニル)プロプ-2-エン酸(23.50g、0.0967mol)懸濁液に、0℃で10分にわたり添加した。反応混合物を室温までゆっくりと加温し、1時間撹拌した。塩化オキサリル(16mL、0.19mol)を更に添加し、5時間加熱還流し、次に室温で16時間撹拌した。反応混合物を濃縮乾固して、未精製の酸塩化物中間体を得た。
水(60mL)、トルエン(160mL)、及びエタノール(100mL)からなる混合物中の、(2E)-3-(2-ブロモ-5-ヒドロキシフェニル)プロプ-2-エナミド(10.00g、41.31mmol)、3-ベンジルオキシフェニルボロン酸(12.22g、53.58mmol)、及び炭酸カリウム(17.34g、0.125mol)からなる混合物を窒素で10分間バブリングした後、テトラキス(トリフェニルホスフィン)パラジウム(0) (1.21g、10.5mmol)を添加し、混合物を2.5時間加熱還流した。混合物を短時間冷却し、水(200mL)で希釈し、塩酸(2M、約400mL、pH0〜1)を添加して酸性化し、酢酸エチル(3×300mL)で抽出した。一まとめにした有機性の抽出物を硫酸マグネシウム上で乾燥し、濾過した。濾過液を濃縮乾固させ、残留物をフラッシュクロマトグラフィー(シリカ、酢酸エチル/ヘキサンによる10〜100%グラジエント)により精製して、標題化合物を褐色の固形泡状物として得た(14.37g、101%)。1H NMR (400 MHz, DMSO-d6) d 9.71 (s, 1 H) 7.39 - 7.48 (m, 4 H) 7.29 - 7.38 (m, 4 H) 7.17 (d, J=8.2 Hz, 1 H) 7.09 (s, 1 H) 7.06 (d, J=2.4 Hz, 1 H) 7.01 (dd, J=8.2, 2.4 Hz, 1 H) 6.83 - 6.90 (m, 2 H) 6.81 (d, J=7.4 Hz, 1 H) 6.49 (d, J=15.6 Hz, 1 H) 5.12 (s, 2 H); HPLC (水/ACN + 0.1% TFA勾配) 220 nmに88.2%; LCMS [M+H]+ = 346.2, [M-H]- = 344.1. 1H NMR分析が示すように、約11wt%の酢酸エチル及び14mol%の未知不純物。
N-フェニルビス(トリフルオロ-メタンスルホンアミド) (16.35g、45.77mmol)を、氷浴中で冷却されたアセトニトリル(200mL)に溶解した(2E)-3-[3'-(ベンジルオキシ)-4-ヒドロキシビフェニル-2-イル]プロプ-2-エナミド(14.27g、41.33mmol)及び炭酸カリウム(11.63g、84.15mmol)の溶液に1分にわたり少量ずつ添加した。反応混合物を室温まで加温し、1時間激しく撹拌した。シリカゲルを添加し、混合物を濃縮し、フラッシュクロマトグラフィー(シリカ、酢酸エチル/ヘキサンによる10〜100%のグラジエント)により精製して、標題化合物を薄茶色の固形泡状物として得た(15.95g、81%)。1H NMR (400 MHz, DMSO-d6) d 7.78 (d, J=2.4 Hz, 1 H) 7.52 - 7.61 (m, 3 H) 7.43 - 7.50 (m, 2 H) 7.37 - 7.43 (m, 3 H) 7.29 - 7.37 (m, 2 H) 7.21 (br. s., 1 H) 7.11 (dd, J=8.2, 2.4 Hz, 1 H) 6.96 - 7.03 (m, 1 H) 6.90 (d, J=7.4 Hz, 1 H) 6.69 (d, J=15.6 Hz, 1 H) 5.15 (s, 2 H); HPLC (水/ACN + 0.1% TFA勾配) 220 nmに95.0%; LCMS [M+H]+ = 478.1. 1H NMR分析が示すように、微量の不純物。
P3、P46、P47、P48、P49、及びP50の中間体の合成
P3、P46、P47、P48、P49、及びP50の中間体を調製するのに用いられる合成経路を図5に示す。
3'-[(1E)-3-アミノ-3-オキソプロプ-1-エン-1-イル]-3''-ベンジルオキシ-1,1':4',1''-テルフェニル-3-カルボン酸
P3、P46、P47、P48、P49、及びP50の合成
P3、P46、P47、P48、P49、及びP50を調製するのに用いられる合成経路を図6に示す。
P1、P6、及びP33の合成
P1、P6、及びP33を調製するのに用いられる合成経路を以下に記載する。
カップリング手順A
P38、P42、P43、P44、及びP45の合成
P38、P42、P43、P44、及びP45を調製するのに用いられる合成経路を以下に記載する。
P4の合成
P4を調製するのに用いられる合成経路を以下に記載する。
P104の合成
P104を調製するのに用いられる合成経路を図7に示す。
化合物のin vitroスクリーニング
xCELLigence SPシステム(Roche社)を、A10胚性血管平滑筋細胞(ATCC、CRL-1476)を試験化合物で処置した後に、細胞インピーダンス(細胞インデックス)の変化を測定するのに用いた。このin vitroでの細胞に基づく実験系では、負性インピーダンスプロファイルがラットの血圧低下と相関する-インピーダンスの低下は血管拡張と関連し、またインピーダンスの増加は血管収縮と関連する(Stallaert W, Dorn JF, van der Westhuizen E, Audet M & Bouvier M. Impedance responses reveal β-adrenergic signaling pluridensitometry and allow classification of ligands with distinct signalling profiles PLoS ONE 2012; 7(1):e29420, doi:10.1371/journal.pone.0029420)。
化合物のin vivoスクリーニング
14週齢のSHR (2.2%の塩分食(Glen Forrest Stockfeeders社)を与えた)を、ゼロ時間対照(14週齢のラット)、試験化合物処置用飲料溶液(500pmol/kg/分で脱イオン蒸留水に溶解)、又は対照用飲料溶液(脱イオン蒸留水に溶解した5%エタノール)に無作為に割り振った。ゼロ時間対照群(14週齢のラット)に割り振られたラットを麻酔し、その腎臓及び肝臓を摘出した一方、対照及び試験化合物による処置に割り振られたラットを週2回秤量し、またその飲料溶液摂取量をモニタリングして、飲料溶液中の試験化合物濃度の調整を可能にし、4週間の試験期間にわたり一定量を維持した。テールカフ・プレチスモグラフィー(PowerLab、ADInstruments社製、Castle Hill、NSW、Australia)により、血圧を週2回測定した。4週間後、ラットを麻酔し(18週齢のラット)、その腎臓及び肝臓を摘出した。
化合物のin vitro及びin vivoスクリーニングの比較
様々な試験化合物で処置した、A10血管平滑筋細胞内の細胞インピーダンス、及びSHRにおける肝線維症のレベルを比較することにより、本in vitroアッセイ法は、肝臓内の線維症を減少させる本試験化合物の能力を予測可能にすることが明らかとなった(図16、R2=0.618)。
Claims (23)
- 式
Aは、
R1〜R9は、独立にC、N、O、又はSであり、
Qは、C1〜6アルキル、ハロ、C0〜6アルキルカルボン酸、アミノ、ヒドロキシ、及びC1〜6アルコキシから独立に選択され、
nは、0、1、2、3、又は4であり、
Xは、-OH、又は
Xが-OHのとき、Aは非置換型のフェニルではない]
の化合物、又はその薬理学的に許容される塩、立体異性体、ジアステレオマー、エナンチオマー、ラセミ体、水和物、及び/若しくは溶媒和物。 - Qが、-CH3、-C(O)OH、-F、-NH2、-OH、及び-OCH3から独立に選択される、請求項1に記載の化合物。
- R5〜R9が、独立にC又はNである、請求項1又は2に記載の化合物。
- nが、0、1、又は2である、請求項1〜3のいずれか一項に記載の化合物。
- C0〜6アルキルカルボン酸が、カルボン酸である、請求項1〜4のいずれか一項に記載の化合物。
- Xが、-OHである、請求項1〜5のいずれか一項に記載の化合物。
- Xが、
-
-
- 請求項1〜9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賦形剤を含む医薬組成物。
- 対象の腎臓及び/又は肝臓疾患を予防的又は治療的に処置する方法であって、請求項1〜9のいずれか一項に記載の化合物又は請求項10に記載の医薬組成物を、前記対象に投与するステップを含む、方法。
- 前記処置が、腎線維症及び/又は肝線維症の進行を予防する、減少させる、又は遅らせる、請求項11に記載の方法。
- 前記処置が、確立した腎線維症及び/又は肝線維症を減少させる、請求項11に記載の方法。
- 前記処置が、腎尿細管細胞死を予防する、減少させる、又は遅らせる、請求項11に記載の方法。
- 前記処置が、肝脂肪の蓄積を予防する、減少させる、又は遅らせる、請求項11に記載の方法。
- 前記処置が、正常な組織構造を復元する、請求項11に記載の方法。
- 腎臓及び/又は肝臓疾患を予防的又は治療的に処置するための医薬品の製造のための、請求項1〜9のいずれか一項に記載の化合物の使用。
- 前記医薬品が、腎線維症及び/又は肝線維症の進行を予防する、減少させる、又は遅らせる、請求項17に記載の使用。
- 前記医薬品が、確立した腎線維症及び/又は肝線維症を減少させる、請求項17に記載の使用。
- 前記医薬品が、腎尿細管細胞死を予防する、減少させる、又は遅らせる、請求項17に記載の使用。
- 前記医薬品が、肝脂肪の蓄積を予防する、減少させる、又は遅らせる、請求項17に記載の使用。
- 前記薬剤が、正常な組織構造を復元する、請求項17に記載の使用。
- 式
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