JP7449379B2 - ピラジン誘導体とチオプリン誘導体を組み合わせてなるrnaウイルス感染症治療剤 - Google Patents
ピラジン誘導体とチオプリン誘導体を組み合わせてなるrnaウイルス感染症治療剤 Download PDFInfo
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Classifications
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
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- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表されるピラジン誘導体又はその塩と、6-メチルメルカプトプリンリボシド等のチオプリン誘導体を組み合わせて使用すると、RNAウイルスに対する抗ウイルス活性が増強されること、この増強作用の少なくとも一部は、細胞内におけるピラジン誘導体リボース三リン酸体の量の増加によることを見出し、本発明を完成した。
[1]
一般式[1]
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表されるピラジン誘導体又はその塩と、
一般式[2]
(式中、R4及びR5は、同一又は異なって水素原子又はヒドロキシル保護基を、R6は、水素原子、保護されてもよい一リン酸基、保護されてもよい二リン酸基又は保護されてもよい三リン酸基を、R7は、水素原子又は保護されてもよいアミノ基を、R8は、水素原子、C1-6アルキル基又は一般式[3]
(式中、R9は、水素原子、C1-6アルキル基又はカルボキシ基を;R10は、水素原子、C1-6アルキル基、ベンジル基又はp-ニトロベンジル基を示す。)で表される基を、Xは、酸素原子、硫黄原子、炭素原子又は保護されてもよいイミノ基を示す。)で表されるチオプリン誘導体を組み合わせてなる、RNAウイルス感染症治療剤。
[2]
R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である[1]に記載の治療剤。
[3]
R1が水素原子、R2がフッ素原子、及びR3が水素原子である[1]又は[2]に記載の治療剤。
[4]
R4、R5、R6及びR7が水素原子、R8がメチル基、及びXが酸素原子である[1]~[3]いずれか一に記載の治療剤。
[A]
一般式[1]
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表されるピラジン誘導体又はその塩と、
一般式[2]
(式中、R4及びR5は、同一又は異なって水素原子又はヒドロキシル保護基を、R6は、水素原子、保護されてもよい一リン酸基、保護されてもよい二リン酸基又は保護されてもよい三リン酸基を、R7は、水素原子又は保護されてもよいアミノ基を、R8は、水素原子、C1-6アルキル基又は一般式[3]
(式中、R9は、水素原子、C1-6アルキル基又はカルボキシ基を;R10は、水素原子、C1-6アルキル基、ベンジル基又はp-ニトロベンジル基を示す。)で表される基を、Xは、酸素原子、硫黄原子、炭素原子又は保護されてもよいイミノ基を示す。)で表されるチオプリン誘導体を対象に投与することを含む、RNAウイルス感染症の治療法。
[B]
RNAウイルス感染症治療薬を製造するための、一般式[1]
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表されるピラジン誘導体又はその塩と、
一般式[2]
(式中、R4及びR5は、同一又は異なって水素原子又はヒドロキシル保護基を、R6は、水素原子、保護されてもよい一リン酸基、保護されてもよい二リン酸基又は保護されてもよい三リン酸基を、R7は、水素原子又は保護されてもよいアミノ基を、R8は、水素原子、C1-6アルキル基又は一般式[3]
(式中、R9は、水素原子、C1-6アルキル基又はカルボキシ基を;R10は、水素原子、C1-6アルキル基、ベンジル基又はp-ニトロベンジル基を示す。)で表される基を、Xは、酸素原子、硫黄原子、炭素原子又は保護されてもよいイミノ基を示す。)で表されるチオプリン誘導体の使用。
[C]
RNAウイルス感染症の治療において使用するための、一般式[1]
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表されるピラジン誘導体又はその塩と、
一般式[2]
(式中、R4及びR5は、同一又は異なって水素原子又はヒドロキシル保護基を、R6は、水素原子、保護されてもよい一リン酸基、保護されてもよい二リン酸基又は保護されてもよい三リン酸基を、R7は、水素原子又は保護されてもよいアミノ基を、R8は、水素原子、C1-6アルキル基又は一般式[3]
(式中、R9は、水素原子、C1-6アルキル基又はカルボキシ基を;R10は、水素原子、C1-6アルキル基、ベンジル基又はp-ニトロベンジル基を示す。)で表される基を、Xは、酸素原子、硫黄原子、炭素原子又は保護されてもよいイミノ基を示す。)で表されるチオプリン誘導体の組み合わせ。
ハロゲン原子とは、フッ素原子、塩素原子、臭素原子及びヨウ素原子を意味する。C1-6アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec-ブチル、イソブチル、tert-ブチル、ペンチル、イソペンチル、2-メチルブチル、2-ペンチル、3-ペンチル及びヘキシル基などの直鎖状又は分枝鎖状のC1-6アルキル基を意味する。
アルC1-6アルキル基とは、ベンジル、ジフェニルメチル、トリチル、フェネチルおよびナフチルメチル基などのアルC1-6アルキル基を意味する。
C1-6アルコキシC1-6アルキル基とは、メトキシメチルおよび1-エトキシエチル基などのC1-6アルキルオキシC1-6アルキル基を意味する。
アシル基とは、ホルミル基、C2-6アルカノイル基、アロイル基または複素環式カルボニル基を意味する。
C1-6アルコキシカルボニル基とは、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、tert-ブトキシカルボニルおよび1,1-ジメチルプロポキシカルボニル基などの直鎖状または分枝鎖状のC1-6アルキルオキシカルボニル基を意味する。
アルC1-6アルコキシカルボニル基とは、ベンジルオキシカルボニルおよびフェネチルオキシカルボニル基などのアルC1-6アルキルオキシカルボニル基を意味する。
C1-6アルキルスルホニル基とは、メチルスルホニル、エチルスルホニルおよびプロピルスルホニル基などのC1-6アルキルスルホニル基を意味する。
アリールスルホニル基とは、ベンゼンスルホニル、p-トルエンスルホニルまたはナフタレンスルホニル基を意味する。
シリル基とは、トリメチルシリル、トリエチルシリルまたはトリブチルシリル基を意味する。
(式中、R1及びR2は、同一又は異なって水素原子又はハロゲン原子を;R3は、水素原子又はアミノ保護基を示す。)で表される化合物である。
ピラジン誘導体とチオプリン誘導体の併用効果について、ウイルスの細胞感染モデルで試験を行った。
培養液10%ウシ胎児血清添加イーグルMEM/カナマイシン60μg/mL(イーグルMEM/カナマイシン)培地中、5%二酸化炭素条件下、37℃で継代培養されているアフリカミドリザル腎Vero細胞をエチレンジアミン四酢酸トリプシン法によって剥離し、同培地で100μLに2×104個の細胞を含むように調製した懸濁液を96ウェルプレートに播種した。5%二酸化炭素条件下、37℃で一夜培養し、単層となったVero細胞を得た。
試験培地として、イーグルMEM/カナマイシン培地に1μg/mLとなるようL-1-トシルアミド-2-フェニルエチルクロロメチルケトン(TPCK)処理トリプシンを加えた培地を用いた。(1)で得られたVero細胞の培養上清を取り除き、各ウェルに、以下(A)~(C)を加えた。薬剤添加後、5%二酸化炭素条件下、35℃で2日間培養した。
(B)試験培地の4倍濃度のTPCK処理トリプシンを含むイーグルMEM/カナマイシン培地で4.0×103PFU/mLに調整したインフルエンザウイルス(PR/8/34(H1N1))液を50μL
(C)設定濃度の4倍濃度のT-705及び6-メチルメルカプトプリンリボシドの、各設定濃度の組み合わせを含む1%DMSO含有イーグルMEM/カナマイシン培地を50μL
T-705設定濃度(μM):
0,0.1,0.3,1,3,10,30,100,300,1000
6-メチルメルカプトプリンリボシド設定濃度(μM):
0,0.1,0.3,1,3,10
インフルエンザウイルスの増殖に伴って認められるCPEを、以下の方法で判定した。
前記の通り、ピラジン誘導体又はその塩は、細胞内でリボシルリン酸化を受ける。例えばT-705は、リボシルリン酸化により生じるT-705-4-ribofuranosyl-5-triphosphate(T-705RTP)がウイルスのRdRpタンパク質を阻害することによって抗ウイルス作用を示すことが知られている。試験例1で見られた6-メチルメルカプトプリンリボシドによるT-705の活性増強効果は、T-705RTP量の変化によるものかどうかを確認するため、Vero細胞における6―メチルメルカプトプリンリボシド処理下でのT-705RTP量を測定した。
(1-1)細胞内T-705RTPの抽出
6ウェルプレートの各ウェルに2×105cells播種したVero細胞をvehicle(0.0125%DMSO)又は様々な濃度の6-メチルメルカプトプリンリボシド、100μM T-705、又は両薬剤に5%二酸化炭素条件下、37℃で24時間培養した(例数3)。
残りすべての細胞懸濁液を1,000rpm、4℃、5分(MX-207、TOMY)遠心し、上清を除いた。次に細胞ペレットに1mL PBSを加えて再懸濁し、再度1,000rpm、4℃、5分で遠心後、上清を除いた。その後、300μLの70%メタノールを加えてよく懸濁した。サンプルはその後蛍光検出器付き高速液体クロマトグラフ(HPLC-FL)を用いて測定した。
細胞数の測定及びHPLC-FL分析を行い、各サンプル中のT-705RTP量を測定した。よく撹拌した細胞サンプル(上記(1-1)で調製)50μLに内標準として6-ブロモ-3-ヒドロキシ-2-ピラジンカルボキサミド溶液20μL及び蒸留水180μLを氷冷下で添加し遠心分離(約1600rpm,室温,5分,MICRO SINKER)後の上清をHPLCで分析した。HPLC分析にはC18カラムを使用し,弱酸性移動相にイオンペア試薬(テトラブチルアンモニウムブロミド)を添加することにより,T-705RTPをカラムに保持させた。蛍光検出の励起波長は370nm,蛍光波長は445nmとした。各細胞サンプルのHPLC面積比(T-705RTP/内標準)から,検量線の逆回帰によりT-705RTP濃度を求めた。T-705RTP量の変化を表2に示す。6-メチルメルカプトプリンリボシドにより、T-705処理後の細胞内T-705RTP量が増加したことが分かった。
Claims (3)
- 一般式[1]
一般式[2]
- R1が水素原子、R2がフッ素原子又は水素原子、及びR3が水素原子である請求項1記載の治療剤。
- R1が水素原子、R2がフッ素原子、及びR3が水素原子である請求項1又は2に記載の治療剤。
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WO2008099874A1 (ja) | 2007-02-16 | 2008-08-21 | Toyama Chemical Co., Ltd. | ピラジン誘導体を含有する医薬組成物およびピラジン誘導体を組み合わせて使用する方法 |
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WO2008099874A1 (ja) | 2007-02-16 | 2008-08-21 | Toyama Chemical Co., Ltd. | ピラジン誘導体を含有する医薬組成物およびピラジン誘導体を組み合わせて使用する方法 |
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DESPINS, S. et al.,Deciphering the molecular basis for nucleotide selection by the West Nile virus RNA helicase,Nucleic Acids Research,Vol. 38, No. 16,2010年,pp.5493-5506 |
FURUTA, Y. et al.,T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections,Antiviral Research,Vol.82,2009年,pp.95-102 |
GOVORKOVA, E.A. et al.,Neuraminidase Inhibitor-Rimantadine Combinations Exert Additive and Synergistic Anti-Influenza Virus,ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2004年,Vol. 48, No. 12,pp. 4855-4863 |
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