JP2018517698A - テノホビルモノベンジルエステルホスファミドプロドラッグ、その調製方法及び使用 - Google Patents
テノホビルモノベンジルエステルホスファミドプロドラッグ、その調製方法及び使用 Download PDFInfo
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- JP2018517698A JP2018517698A JP2017561871A JP2017561871A JP2018517698A JP 2018517698 A JP2018517698 A JP 2018517698A JP 2017561871 A JP2017561871 A JP 2017561871A JP 2017561871 A JP2017561871 A JP 2017561871A JP 2018517698 A JP2018517698 A JP 2018517698A
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- Prior art keywords
- tenofovir
- compound
- monobenzyl ester
- compounds
- hydrocarbon group
- Prior art date
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- 229960004556 tenofovir Drugs 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
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- 229940002612 prodrug Drugs 0.000 title abstract description 15
- 239000000651 prodrug Substances 0.000 title abstract description 15
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
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- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 11
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 150000004677 hydrates Chemical class 0.000 claims abstract description 3
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- 239000000203 mixture Substances 0.000 claims description 26
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 13
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 229910052711 selenium Inorganic materials 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
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- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
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Abstract
Description
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C10直鎖炭化水素基、C3−C10分岐炭化水素基、C3−C10シクロ炭化水素基、C6−C10芳香族炭化水素基またはヘテロアリール基から選ばれ、ここで、前記置換は、1〜3つの独立にO、S、N、Seから選ばれるヘテロ原子による置換、あるいはR1とR2、R1とR3、R2とR3が、これらを連結する構造部分とともに形成する置換または無置換の3〜8員環。
Zは、OまたはSから選ばれ、
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C6直鎖炭化水素基、C3−C6分岐炭化水素基、C3−C6シクロ炭化水素基、C6−C10芳香族炭化水素基またはヘテロアリール基から選ばれる。
Zは、Oから選ばれ、
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C6直鎖炭化水素基、C3−C6分岐炭化水素基、C6−C10芳香族炭化水素基から選ばれる。
ステップA:塩基の存在下で、テノホビルがハロゲン化ベンジルまたはベンジルアルコールと反応してテノホビルモノベンジルエステル中間体を得る。
ステップB:テノホビルモノベンジルエステル中間体と、各種の末端NH基含有の化合物とを反応させて本発明のテノホビルモノベンジルエステルホスファミド類化合物を生成する。
HPLC逆相クロマトグラフィーカラム分離、あるいはHPLCキラルクロマトグラフィーカラム分離:実施例2の化合物2(200mg)を取って、HPLC調製分離(調製カラム:Diamonsil C18,5μm,150x21.1mm;移動相:20%アセトニトリル水溶液(V/V))を経て、アイソクラティック溶出した後に、化合物2a(83mg;保留時間14min)及び化合物2b(90mg;保留時間17min)が得られた。
実施例7の表2のいずれか1つのキラル化合物1.2kg、フマル酸285g、及び3Lアセトニトリルを取って反応器に入れ、混合物を加熱、還流して、固体を溶解させ、熱いうちにろ過し、5℃まで冷却した後、16時間保存して、生成物をろ過、分離し、アセトニトリルを用いて洗浄し、乾燥して白色の粉末を得た。
プロドラッグ化合物にとって、最も重要なことは、プロドラッグの体系における安定性及びターゲット器官部分における代謝活性であり、体系(胃腸管、血液など)における安定性が高ければ高いほど、ターゲット器官(リンパ、肝臓)において親薬物に代謝する活性が高く、化合物の毒性が低く、薬効が高くなる。試験例における本発明の化合物、参照化合物などのプロドラッグは、いずれも活性親薬物のテノホビル(TFV)に代謝した後、抗ウイルスの役割を果たす。
リアルタイム蛍光定量PCR(qPCR)法によって、HepG2.2.15細胞の上清におけるHBV DNAの含有量を検出して、化合物のHepG2.2.15細胞における抗B型肝炎ウイルス活性を測定し、Cell−titer Blueによって被験化合物のHepG2.2.15細胞活性に対する影響を検出した。
下記式を用いて阻害百分率を算出した。
9.1薬品:化合物3、参照化合物(CN201380030061.6、請求項36に示す化合物を化合物7及びその異性体と略称する)の希釈及び濃度は実施例1と同じであった。
9.1.化合物、参照化合物(CN01813161GS−7340、TDF)の希釈及び濃度は実施例1と同じであった。
下記安定性試験方法は、従来技術に従って行った、安定性実験の表に示すデータはテスト条件下で、被験化合物の培養の異なる時点後の残留百分率である。
安定性の初歩的な研究の実験データに示すように、化合物3a、3bはGS−7340、7bに比べ、ヒト肝臓S9における安定性が匹敵し、及び活性親薬物に代謝される速度が匹敵し、肝細胞において、同じ濃度の化合物が相当な活性を有することを示す。
11.1.実験細胞と化合物の調製
実験は、AVivaBiosciences社から得られる安定的にhERGカリウムイオンチャネルを発現することができるCHO細胞を採用し、細胞を37℃、5%CO2で、一定の湿度環境において培養した。
化合物を、室温下で、Multiclamp patch−clamp amplifier上で、全細胞パッチクランプ技術を採用してテストを行い、出力信号は、DIgiDAta 1440A/D−D/Aパネルを採用してデジタル化し、Pclamp10ソフトウェアで記録制御を行った。最小密封抵抗は500MOhmsとし、最小特異hERG電流は0.4nAとして、品質の制御を行った。
Clampfit(V10.2,Molecular Devices)を採用して、Excel 2003とGraphPad Prism 5.0に対してデータの分析を行った。電流の算出式は以下の通りである。
12.1.実験動物、薬物調製方法及び投薬方案
12匹のICRマウス(雄性、体重30±5g、Charles River Laboratories動物センターから購入)をランダムに各組3匹の4組に分け、投薬する前に、12h断食させ、断食期間に水を自由に飲ませた。分析天秤に精密に30mgの化合物3を秤量し、100μLの75%エタノールを入れて溶解させ、さらに、生理食塩水を6mLまで入れて、均一にボルラックス混合し、超音波して用意した。テノホビルプロドラッグの投薬剤量は50mg/kgで、投薬量は10mL/kgであった。
サンプルの採集方案:マウスに対して、胃内投与で投薬した後、15min、30min、1h及び3hに、眼窩から0.5mL採血し、犠牲死させ、肝臓組織を取って洗浄し、秤量し、肝臓は、1:1の比例に基づいて、生理食塩水を入れてホモジネートし、−40℃で冷蔵庫に保存して、待機させた。
Thermo TSQquantum液質複合計器及びクロマトグラフィーカラム:Thermo Hypersil GOLD(2.1×150mm)を採用し、内部標準Theophyllineで、HPLC−MSの検体を取り込んだ後、グラジエント溶出分析を行って、内部標準、化合物1と代謝生成物のテノホビル(TFV)の保留時間及びピークの面積を記録し、SRM定量検出方法によって分析を行った。
Claims (10)
- 一般式Xを有するテノホビルモノベンジルエステルホスファミド類化合物、その水和物、溶媒和物、薬学的に許容可能な塩またはその分割された単一異性体であって、
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C10直鎖炭化水素基、C3−C10分岐炭化水素基、C3−C10シクロ炭化水素基、C6−C10芳香族炭化水素基またはヘテロアリール基から選ばれ、ここで、前記置換は、1〜3つの独立にO、S、N、Seから選ばれるヘテロ原子による置換、
あるいはR1とR2、R1とR3、R2とR3が、これらを連結する構造部分とともに形成する置換または無置換の3〜8員環。 - Zは、OまたはSから選ばれ、
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C6直鎖炭化水素基、C3−C6分岐炭化水素基、C3−C6シクロ炭化水素基、C6−C10芳香族炭化水素基またはヘテロアリール基から選ばれる請求項1に記載のテノホビルモノベンジルエステルホスファミド類化合物。 - Zは、Oから選ばれ、
R1、R2、R3、R4、R5は、それぞれ独立にH、置換または無置換のC1−C6直鎖炭化水素基、C3−C6分岐炭化水素基、C6−C10芳香族炭化水素基から選ばれる請求項2に記載のテノホビルモノベンジルエステルホスファミド類化合物。 - 化合物は以下から選ばれる請求項3に記載のテノホビルモノベンジルエステルホスファミド類化合物。
- 化合物1、2、3、5の異性体は、それぞれ1aと1b、2aと2b、3aと3b、5aと5bであり、構造が下記の通りである請求項4に記載のテノホビルモノベンジルエステルリン酸アミド類化合物。
- 請求項1乃至5のいずれか一項に記載のテノホビルモノベンジルエステルホスファミド類化合物の調製方法であって、
塩基の存在下で、テノホビルがハロゲン化ベンジルまたはベンジルアルコールと反応してテノホビルモノベンジルエステル中間体を得るステップAと、
テノホビルモノベンジルエステル中間体と、各種の末端NH基含有の化合物、好ましくは、アミノ酸エステル類化合物、アミノ酸アミド類化合物とを反応させて、本発明のテノホビルモノベンジルエステルホスファミド類化合物を生成するステップBとを含むことを特徴とするテノホビルモノベンジルエステルホスファミド類化合物の調製方法。 - ステップAにおいて、テノホビルは、臭化ベンジルまたはベンジルアルコールと反応することが好ましく、塩基は各種の無機または有機塩基であってもよいが、有機塩基が好ましい請求項6のいずれか一項に記載のテノホビルモノベンジルエステルホスファミド類化合物の調製方法。
- 薬物組成物であって、
請求項1乃至4のいずれか一項に記載のテノホビルモノベンジルエステルホスファミド類化合物、またはその水和物、またはその溶媒和物、またはその薬学的に許容可能な塩またはその分割された単一異性体を含有し、ここで、前記薬物組成物は、薬学的に許容可能な担体をさらに含有することを特徴とする薬物組成物。 - 請求項1乃至5のいずれか一項に記載のテノホビルモノベンジルエステルホスファミド類化合物、またはその水和物、またはその溶媒和物、またはその薬学的に許容可能な塩またはその分割された単一異性体の、ウイルス感染性疾患を治療する薬物の調製における使用。
- 請求項9に記載のテノホビルモノベンジルエステルリン酸アミノ類化合物、またはその水和物、またはその溶媒和物、またはその薬学的に許容可能な塩またはその分割された単一異性体の、HIV感染またはB型肝炎あるいはB型肝炎ウイルスによる疾患を治療する薬物の調製における使用。
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RU2719594C2 (ru) | 2020-04-21 |
JP6679624B2 (ja) | 2020-04-15 |
HK1246799A1 (zh) | 2018-09-14 |
MY191515A (en) | 2022-06-28 |
RU2017145357A3 (ja) | 2019-09-04 |
KR20180016437A (ko) | 2018-02-14 |
SG11201709786WA (en) | 2017-12-28 |
IL255892A (en) | 2018-01-31 |
AU2016270101B2 (en) | 2020-01-23 |
CA2987473A1 (en) | 2016-12-08 |
EP3305795B1 (en) | 2020-05-06 |
US20180127445A1 (en) | 2018-05-10 |
TW201702246A (zh) | 2017-01-16 |
EP3305795A4 (en) | 2019-02-06 |
EP3305795A1 (en) | 2018-04-11 |
TWI692479B (zh) | 2020-05-01 |
WO2016192560A1 (zh) | 2016-12-08 |
CN106188139B (zh) | 2020-02-18 |
IL255892B (en) | 2020-11-30 |
CN107709340A (zh) | 2018-02-16 |
US10233202B2 (en) | 2019-03-19 |
CN106188139A (zh) | 2016-12-07 |
CN107709340B (zh) | 2020-03-17 |
AU2016270101A1 (en) | 2017-12-14 |
RU2017145357A (ru) | 2019-07-01 |
ES2806726T3 (es) | 2021-02-18 |
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