JP5963894B2 - ホスホネート化合物 - Google Patents
ホスホネート化合物 Download PDFInfo
- Publication number
- JP5963894B2 JP5963894B2 JP2015006124A JP2015006124A JP5963894B2 JP 5963894 B2 JP5963894 B2 JP 5963894B2 JP 2015006124 A JP2015006124 A JP 2015006124A JP 2015006124 A JP2015006124 A JP 2015006124A JP 5963894 B2 JP5963894 B2 JP 5963894B2
- Authority
- JP
- Japan
- Prior art keywords
- phosphonate
- compound
- bone
- compounds
- antiviral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 64
- 239000003443 antiviral agent Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 5
- 241000700629 Orthopoxvirus Species 0.000 claims description 4
- 230000000699 topical effect Effects 0.000 claims description 4
- 239000000443 aerosol Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 241000700721 Hepatitis B virus Species 0.000 claims description 2
- 239000007909 solid dosage form Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 34
- 239000000203 mixture Substances 0.000 abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 16
- 208000001132 Osteoporosis Diseases 0.000 abstract description 13
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- 208000036142 Viral infection Diseases 0.000 abstract description 9
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 8
- 208000035475 disorder Diseases 0.000 abstract description 6
- 230000004097 bone metabolism Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- -1 bisphosphonate compound Chemical class 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical class [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 41
- 229940122361 Bisphosphonate Drugs 0.000 description 37
- 150000004663 bisphosphonates Chemical class 0.000 description 34
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- YXQUGSXUDFTPLL-LURJTMIESA-N 4-amino-1-[[(5s)-2-hydroxy-2-oxo-1,4,2$l^{5}-dioxaphosphinan-5-yl]methyl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C[C@@H]1OCP(O)(=O)OC1 YXQUGSXUDFTPLL-LURJTMIESA-N 0.000 description 19
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- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 9
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- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 7
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
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- 125000003118 aryl group Chemical group 0.000 description 5
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Description
本発明は、新規ホスホネート化合物、それらを含有する組成物、それらの製造法、ならびに例えば骨粗鬆症およびその他の骨代謝障害、癌、ウイルス感染症などのような、様々な医学的障害の治療のためのそれらの用途に関する。
ホスホネート化合物は、様々な治療的恩典を提供することが以前より知られている。治療上の恩典を有するホスホネート化合物の特定の種類は、ビスホスホネート、すなわちピロリン酸結合の中心酸素原子が炭素により置換されているピロホスホネート類似体である。様々な置換基を、この中心炭素原子に結合し、異なる程度の薬効を有するビスホスホネート化合物誘導体を生成することができる。これらの誘導体は、下記の一般構造を有する:
本発明は、ホスホネート化合物の類似体を提供する。本発明に従い使用するために考案されたホスホネート化合物は、骨吸収を低下させるか、または骨芽細胞もしくは骨細胞のアポトーシスを阻害するようなものに加え、癌、様々なウイルス感染症などの治療に有用であるようなヌクレオチドホスホネート類似体の生体活性、選択性、または生物学的利用能を改良するものを含む。本発明の化合物は、置換または非置換のアルキルグリセロール、アルキルプロパンジオール、アルキルエタンジオール、または関連した部分に共有結合した(直接的またはリンカー分子を介して間接的)ホスホネートを含んでいる。本発明の別の局面において、本明細書に記載されたホスホネート化合物の類似体を含有する薬学的製剤が提供される。
本発明のホスホネート化合物は下記の構造を有する:
式中、
R1およびR1'は、独立して、-H、任意に置換された-O(C1-C24)アルキル、-O(C1-C24)アルケニル、-O(C1-C24)アシル、-S(C1-C24)アルキル、-S(C1-C24)アルケニル、または-S(C1-C24)アシルであり、ただし少なくとも1個のR1およびR1'はHではなく、かつ該アルケニルまたはアシル部分は任意に1〜6個の二重結合を有し;
R2およびR2'は、独立して、-H、任意に置換された-O(C1-C7)アルキル、-O(C1-C7)アルケニル、-S(C1-C7)アルキル、-S(C1-C7)アルケニル、-O(C1-C7)アシル、-S(C1-C7)アシル、-N(C1-C7)アシル、-NH(C1-C7)アルキル、-N((C1-C7)アルキル))2、オキソ、ハロゲン、-NH2、-OH、または-SHであり;
R3は、任意のリンカーL上の官能基またはCα上の利用可能な酸素原子に連結された、薬学的に活性を有するホスホネート、ビスホスホネートまたは薬学的に活性を有する化合物のホスホネート誘導体であり;
Xは、存在する場合には、
であり;
Lは、原子価結合または式-J-(CR2)t-G-の二官能連結分子であり(式中、tは1〜24の整数であり、JおよびGは、独立して、-0-、-S-、-C(O)O-、または-NH-であり、かつRは、-H、置換もしくは非置換のアルキル、またはアルケニルである);
mは0〜6の整数であり;および
nは0または1である。
エチドロネート:1-ヒドロキシエチリデンビスホスホン酸(EDHP);
クロドロネート:ジクロロメチレンビスホスホン酸(Cl2MDP);
チルドロネート:クロロ-4-フェニルチオメチレンビスホスホン酸;
パミドロネート:3-アミノ-1-ヒドロキシプロピリデンビスホスホン酸(ADP);
アレンドロネート:4-アミノ-1-ヒドロキシブチリデンビスホスホン酸;
オルパドロネート:3-ジメチルアミノ-1-ヒドロキシプロピリデンビスホスホン酸(ジメチル-APD);
イバンドロネート:3-メチルペンチルアミノ-1-ヒドロキシプロピリデンビスホスホン酸(BM21.0955);
EB-1053:3-(1-ピロリジニル)-1-ヒドロキシプロピリデンビスホスホン酸;
リセドロネート:2-(3-ピリジニル)-1-ヒドロキシ-エチリデンビスホスホン酸;
アミノ-オルパドロネート:3-(N,N-ジイメチルアミノ-1-アミノプロピリデン)ビスホスホネート(IG9402)など。
1-O-ヘキサデシルプロパンジオール-3-アレンドロネートの合成
A. ヘキサデシルオキシプロピルメチルホスファイト(b)
ヘキサデシルオキシプロピルメチルホスファイトを、Kers, A.、Kers, I.、Stawinski, J.、Sobkowski, M.、Kraszewski, A.、Synthesis、1995年4月、427-430頁に記述された方法を用いて調製した。0℃に保った亜リン酸ジフェニル(14g、60mmol)のピリジン(50mL)溶液に、ヘキサデシルオキシプロパン-1-オール(6.0g、20mmol)のピリジン(25mL)溶液をゆっくり加えた。混合物を1時間撹拌した後、無水メタノール(10mL)を加えた。さらに1時間撹拌した後、残渣をシリカゲルに吸着して、勾配溶出法(ヘキサンから20%酢酸エチル/80%ヘキサン)を使用してクロマトグラフィーを行い、溶媒を蒸発させて、純粋な化合物2を蝋状の低融点の固体(4.5g、収率60%)として得た。
ジメチル4-フタルイミドブタノイルホスホネート(1b、3.0g、7.9mmol、米国特許第5,039,819号の記述により調製した)およびヘキサデシルオキシプロピルメチルホスファイト(2、2.9g、9mmol)のピリジン(50mL)溶液にトリエチルアミン(0.2g、2mmol)を加えた。混合物を室温で5時間撹拌した後、減圧下で溶媒を取り除いた。残渣をシリカゲルに吸着し、クロマトグラフィー(酢酸エチル)を行い、化合物3b(3.5g、63%)を粘性のあるオイルとして得た。
上記で得た化合物3b(3.0g、4.3mmol)を乾燥したアセトニトリル(50mL)に溶解して0℃に冷却した。ブロモトリメチルシラン(3.9g、25.5mmol)のアセトニトリル(25mL)溶液をゆっくり加え、さらに2時間撹拌した。混合物を割った氷の中にゆっくり注いだ。生じた沈殿物を減圧濾過により回収し、減圧乾燥して、1.2gの4b(42%収率)を得た。
化合物4b(300mg、0.45mmol)を1,4-ジオキサン(20mL)およびメタノール(5mL)の混合物に溶解した。無水ヒドラジンを加えて、室温で4時間撹拌した。分離した沈殿物を減圧濾過により回収し、1,4-ジオキサンで洗浄した。固体をエタノールに懸濁して、メタノールアンモニア(3mL)を加えた。10分間撹拌した後、生じた固体を濾過により回収し、エタノールで洗浄し、減圧乾燥して、220mg HDP-アレンドロネート(5b)をトリアンモニウム塩として得た。FT-IRによる解析は、フタルイミド保護基が除去したことを示した。
エレクトロスプレーMS m/e 532(MH+)、530(MH-)
1-O-ヘキサデシルプロパンジオール-3-パミドロネート(5a)の合成
1-O-ヘキサデシルプロパンジオール-3-パミドロネートは、3-フタルイミドプロパン酸を用いてジメチル3-フタルイミドプロパノイルホスホネート(1a)を調製する点を除いて、(スキーム1について)類似の方法によって調製される。化合物1aを化合物2で濃縮して、トリメチルビスホスホネート3aを得る。上記の段階Cおよび段階Dで脱保護して、示したようにHDP-パミドロネートを得る。
1-O-オクタデシル-2-O-メチルsn-グリセロ-3-アレンドロネートの合成
ヘキサデシルオキシプロピル以外の親油性基を持つプロドラックは、実施例1の段階Aでヘキサデシルオキシプロパン-1-オールを様々な長鎖アルコールに置き換えて調製される。例えば、1-O-オクタデシル-2-O-メチル-sn-グリセロールと亜リン酸ジフェニルをピリジン中で反応させた後、メタノール処理によって1-O-オクタデシル-2-O-メチル-sn-グリセリルメチルホスファイトを得る。このジアルキルホスファイトとホスホネート1bを濃縮した後、段階Cおよび段階Dで脱保護して、1-O-オクタデシル-2-O-メチル-sn-グリセロ-3-アレンドロネートを得る。スキーム2は、他のビスホスホネート複合体で側鎖に1級アミノ基を持たないものの合成を表している。この場合には、フタルイミド基での保護とヒドラジン分解は不要である。
HDP-アミノ-オルパドロネートの合成
スキーム3は、1-アミノビスホスホネート複合体の合成を示している。実施例1の化合物2、1-(ジメチルアミノ)プロピオニトリル、およびOrlovskii、V. V.; Vovsi、B. A.、J. Gen Chem. USSR(Engl. Transl.)1976、46:294-296に記述された手順を用いてビスホスホネートトリメチルエステル3を調製する。実施例1の段階Cに記述されるように、ブロモトリメチルシランで脱メチル化し、HDP-アミノ-オルパドロネートを得る。
1-O-ヘキサデシルプロパンジオール-3-スクシニル-アレンドロネートの合成
スキーム4は、親化合物の脂質基が1級アミノ基に結合しているビスホスホネート複合体の合成を示す。テトラメチル-(4-フタルイミド-1-ヒドロブチリデン)ビスホスホネート(2.0g、4.4mmol)を0.2Mメタノールヒドラジン(100mL)に溶解して、室温で3日間撹拌した。混合物を半分量に濃縮したら、固体が分離し始めた。その固体を濾過して除き、濾液を濃縮乾燥した。プロトンNMRは、この化合物がテトラメチル-(4-アミノ-1-ヒドロキシブチリデン)ビスホスホネートであることを示した。これを50℃で一晩、5酸化リンで乾燥させた。化合物1.2gをピリジン(25mL)およびN,N-ジメチルホルムアミド(25mL)の混合物に懸濁して、3-スクシニル-1-ヘキサデシルプロパン(1.76g、4.4mmol )を加えた。ジシクロヘキシルカルボジイミド(2.52g、12.21mmol)を加え、混合物を室温で2日間撹拌した。混合物を濾過して、濾液をシリカゲルに吸着し、ジクロロメタン(0%〜20%)によりメタノールの増加する勾配でフラッシュクロマトグラフィーをして、スクシニル化化合物を得た。これを、アセトニトリルに入れたトリメチルシリルブロマイドで脱保護することにより、メタノールから結晶化することにより精製した表題の化合物を得た。
アデフォビルヘキサデシルオキシプロピルエステル、および1-O-オクタデシル-sn-グリセリルエステルの合成
アデフォビル(1.36g、5mmol)および3-ヘキサデシルオキシ-1-プロパノール(1.8g、6mmol) を乾燥したピリジン中に混合して、DCC(2.06g、10mmol)を加えた。混合物を加熱還流して18時間攪拌した後、冷却して濾過した。濾液は、減圧下で濃縮して、残渣をシリカゲルのショートカラムに注いだ。9:1ジクロロメタン/メタノールでカラムの溶出を行い、ヘキサデシルオキシプロピル-アデフォビル(HDP-ADV)を白い粉末として得た。
AZT-ホスホネートヘキサデシルオキシプロピルエステルの合成
AZT (3'-アジド-3'-5'-ジデオキシチミジン-5'-ホスホン酸) のホスホネート類似体は、公表された手順(Hakimelahi, G. H.; Moosavi-Movahedi, A. A.; Sadeghi, M. M.; Tsay, S-C.; Hwu, J. R. Journal of Medicinal Chemistry、1995 38、4648-4659)を用いて合成した。
環式シドフォビルにおける、ヘキサデシルオキシプロピル、オクタデシルオキシプロピル、オクタデシルオキシエチル、およびヘキサデシルエステルの合成
シドフォビル(1.0g、3.17mmol)を撹拌したN,N-DMF(25mL)懸濁液に、 N,N-ジシクロヘキシル-4-モルフォリンカルボキシアミジン(DCMC、1.0g、3.5mmol)を加えた。混合物を一晩攪拌してシドフォビルを溶解した。この澄んだ溶液を他の漏斗に満たして、1,3-ジクロヘキシルカルボジイミド(1.64g、7.9mmol)を撹拌した熱いピリミジン溶液(25mL、60℃)に、ゆっくり(30分で)加えた。この反応混合液を100℃で16時間攪拌して室温に冷却して、減圧下で溶媒を取り除いた。残渣をシリカゲルに吸着して、勾配溶出法(CH2Cl2+MeOH)を用いてフラッシュカラムクロマトグラフィーにより精製した。そのUV活性産物を、最終的に5:5:1 CH2Cl2/MeOH/H2Oで溶出して、溶媒を蒸発させ、860mgの白い固体を得た。1Hおよび31P NMRスペクトルをとると、これが環式シドフォビルのDCMC塩(収率=44%)であることが示された。
シドフォビルにおける、ヘキサデシルオキシプロピル、オクタデシルオキシプロピル、オクタデシルオキシエチル、およびヘキサデシルエステルの合成
上記のヘキサデシルオキシプロピル-環式CDVを0.5M NaOHに溶解して室温で1.5時間撹拌した。50%酢酸水を滴下してpHを約9に調整した。沈殿したHDP-CDVを濾過により単離した後、水で洗浄し乾燥して、(3:1 p-ジオキサン/水)で再結晶化してHDP-CDVを得た。
環式-ガンシクロビルホスホネートヘキサデシルオキシプロピルエステルの合成
ガンシクロビルの環式ホスホネート類似体を公表された手順(Reist, E.J.; Sturm, P.A.; Pong, R.Y.; Tanga, M. J.およびSidwell, R.W.、「抗ウイルス剤の評価のためのアシクロヌクレオシドホスホネートの合成(Synthesis of acyclonucleoside phosphonates for evaluation as antiviral agents)」、17〜34頁、J, C. Martin(編)、抗ウイルス剤としてのヌクレオチド類似体(Nucleotide Analogues as Antiviral Agents)、American Chemical Society、Washington、D.C.)を用いて調製した。cGCVホスホネートをDMF中でDCMC塩に変換後、1-ブロモ-3-ヘキサデシルオキシプロパンで処理して、混合物を80℃で6時間加熱した。アルキル化産物をフラッシュクロマトグラフィーにより単離して、HDP-環式-GCVホスホネートを得た。
ガンシクロビルホスホネートヘキサデシルオキシプロピルエステルの合成
上記で得たHDP-環式-GCVホスホネートを0.5M NaOHに溶解して、室温で撹拌して非環式ジエステルに変換した。溶液を50%酢酸水で中和して、3:1 p-ジオキサン/水で再結晶化した産物を沈殿させた。
1-O-ヘキサデシルオキシプロパンアレンドロネートはMLO-Y4骨細胞のデキサメタソン誘導性のアポトーシスを阻害する
MLO-Y4骨細胞を指示された濃度の1-O-ヘキサデシルオキシプロパンアレンドロネート(HDP-アレンドロネート)により、1時間、前処理して、次にデキサメタソン(終濃度10-4M)存在下および非存在下で、6時間細胞をインキュベートした。死細胞率をトリパンブルーの取り込み(Plotkinら、J Clin Invest 104:1363-1374、1999)により決定した。その結果を図1に示す。線分は3回の独立した測定の平均±SDを表す。データを、一元配置分散分析(スチューデント-クルーズ-ニューマン(Student-Keuls-Newman)試験)により解析した。*p<0.05。HDP-アレンドロネートはデキサメタソン誘導性のアポトーシスを10-8から10-5Mで阻害する。
1-O-ヘキサデシルオキシプロパンアレンドロネートは頭蓋冠細胞のデキサメタソン誘導性のアポトーシスを阻害する
頭蓋冠細胞を新生児C57 BL/6Jマウスから取り、組織培養へ移した。細胞を指示された濃度のHDP-アレンドロネートにより前処理を行い、次に10-4Mデキサメタソン存在下および非存在下で、6時間細胞をインキュベートした。死細胞率をトリパンブルーの取り込み(Plotkinら、J Clin Invest 104:1363-1374、1999)により決定した。その結果を図2に示す。線分は、3回の独立した測定の平均±SDを表す。データを一元配置分散分析(スチューデント-クルーズ-ニューマン試験)で解析した。*p<0.05。HDP-アレンドロネートは10-8Mまたはそれより高濃度で、デキサメタソン誘導性の死細胞率の増加を阻害した(p=<0.05)。0.05μMのDEVD(アポトーシスのペプチド阻害剤)に細胞を曝して死細胞率の増加が示されなかったため、DEVDはデキサメタソン誘導性のアポトーシスを阻害することが示された。
1-O-ヘキサデシルオキシプロパンアレンドロネートによる卵巣摘出ラットの骨吸収の阻害
両卵巣の摘出手術をしたSprague-Dawley雌ラット(250gm〜280gm)群に4-アミノ-1-ヒドロキシブチリデン-1,1-ビスホスホン酸ジナトリウム塩又は1-O-ヘキサデシルプロパンジオール-3-アレンドロネートを4〜12週間、 0 mg/kg/日から8 mg/kg/日の用量で皮下注射する。12週目に、対照群に含まれるラットを屠殺し、それぞれ動物において大腿骨の灰分を回収する。または、投薬の方法は経口であってもよい。個体それぞれの大腿骨の灰分質量が測定され、各群の値が骨量の指標と比較されて、処理プロトコール中の骨の減少の相対的な阻害が測定される。1-O-ヘキサデシルプロパンアレンドロネートで処理された動物は対照の卵巣摘出動物に比べて骨量の減少が阻害されていることを表す。
1-O-オクタデシルオキシプロピル-アレンドロネートによるヒト骨粗鬆症における骨吸収の阻害
閉経後の女性の2つの群を、それぞれ偽薬または1-O-オクタデシルオキシプロピル-アレンドロネートで、0.1 mg/kg/日から100 mg/kg/日の経口用量で2〜3年にわたり処理する。処理群のそれぞれは、処理期間にわたり連続して、骨塩密度、脊椎骨折発生率、x線写真撮影試験による脊椎変形の進行、および身長の減少について観察される。様々な処理群において測定値を比較し、処理群間のアレンドロネート治療の形態における有効性を判定する。1-O-オクタデシルオキシプロピルアレンドロネートで処理された群は、偽薬群に比べて、骨折が減少し、骨密度の減少率が少ないと思われる。
1-O-オクタデシルオキシプロピル-アミノ-オルパドロネートによるステロイド誘導性のヒト骨粗鬆症における骨形成の刺激
ステロイド誘導性の骨粗鬆症に罹患した患者群を、1-O-オクタデシルオキシプロピル-アミノ-オルパドロネートまたは偽薬で、0.1mg/kg/日〜100mg/kg/日の経口用量で、1ヶ月から1年間の期間処理する。処理群のそれぞれは、この処理期間にわたって連続して、骨塩密度、脊椎骨折発生率、x線写真撮影試験による脊椎変形の進行、および身長の減少について観察される。様々な処理群において測定値を比較し、処理群間の1-O-オクタデシルオキシプロピル-アミノ-オルパドロネート治療の有効性を判定する。偽薬処理と比較したところ、1-O-オクタデシルオキシプロピル-アミノ-オルパドロネートで処理された患者では、骨密度が増大し、かつ骨折が減少している。
ヒトサイトメガロウイルス(HCMV)に対するホスホネートヌクレオチド類似体の抗ウイルス活性および選択性
HCMV抗ウイルスアッセイ法:HCMV DNAに関する抗ウイルスアッセイ法は、Dankner, W.M.、Scholl, D.、Stanat, S.C.、Martin, M.、Souke, R.L.およびSpector, S.A.、J. Virol. Methods、21:293-298(1990)に記載されているように行った。簡単に述べると、24-ウェル培養皿中の亜集密なMRC-5細胞を、2%FBSおよび抗生物質を含有するイーグル(Eagle)最小必須培地(E-MEM)中の様々な濃度の薬物により、24時間、前処理した。この培地を除去し、HCMV株を、薬物非含有ウェルにおいて5日内に、3-4+細胞変性効果(CPE)を生じるような希釈で添加した。このウイルスを、37℃で1時間吸着させ、吸引し、かつ薬物希釈物を交換した。5日間インキュベーションした後、HCMV DNAを、Diagnostic Hybrids社(Athens、OH)のCMV抗ウイルス感受性試験キット(CMV Antivirus Susceptibility Test Kit)を用いる核酸ハイブリダイゼーションにより、3つ組で定量した。培地を除去し、かつ製造業者の指示に従い細胞を溶解した。Hybriwix(商標)フィルターに溶解液を吸着した後、60℃で一晩ハイブリダイズした。Hybriwix(商標)は、73℃で30分間洗浄し、かつガンマカウンターで計測した。結果を、EC50(50%阻害濃度)として示す。
EC50−50%有効濃度;CC50 - 50%細胞傷害性濃度;選択性指標−CC50/EC50。EC50の結果は、ADVが2個組で1回反復し行われる以外は、3〜6回の測定の平均である。
ポックスウイルス複製に対するHDP-cCDVのインビトロ作用
シドフォビル(CDV)、環式シドフォビル(cCDV)、および1-O-ヘキサデシルプロパンジオール-3-cCDV(HDP-cCDV)の活性を、ワクシニアウイルスまたは牛痘ウイルスに感染したヒト包皮繊維芽細胞における抗ウイルス活性について、細胞変性効果(CPE)の用量依存型の低下を測定することにより試験した。予備的ワクシニアおよび牛痘のEC50値を、ヒト包皮繊維芽細胞(HFF)のCPE減少アッセイ法において決定した。こうして得られたデータを表3に示す。
1-O-ヘキサデシルプロパンジオール-3-アデフォビル(HDP-ADV)のHIV-1複製に対するインビボ作用
本発明の化合物によるHIV-1複製の阻害における予備的実験は、下記のように行った。薬物アッセイ法は、Larderら、Antimicrobial Agents & Chemotherapy、34:436-441(1990)に既述のように行った。HIV-1LAI感染したHT4-6C細胞を、指示された薬物に曝露し、かつ37℃で3日間インキュベーションした。これらの細胞を、クリスタルバイオレットで固定し、プラークを可視化した。抗ウイルス活性は、薬物で処理した試料において測定した対照プラーク(薬物なし)に対する割合(%)として評価した。EC50は、プラーク数を50%減少するようなμM濃度である。HIV-1感染したHT4-6C細胞において、アデフォビルの活性を、AZT(シドブジン)および1-O-ヘキサデシルプロパンジオール-3-アデフォビル(HDPADV)と比較した。結果を表5に示す。
EC50−50%有効濃度;CC50 - Vero細胞における50%細胞傷害性濃度;選択性指標−CC50/EC50。EC50値は、4回の実験の平均である。
ヘルペスウイルス複製に対するシドフォビル類似体の作用
HSV-1抗ウイルスアッセイ法:24-ウェル培養皿中の亜集密なMRC-5細胞を、培地を除去し、HSV-1ウイルスを薬物添加していないウェルにおいて20〜24時間で3-4+ CPEの結果をもたらすように希釈して添加することにより接種した。これは、37℃で1時間吸収させ、吸引し、かつ2%FBSおよび抗生物質を含有するE-MEM中の様々な濃度の薬物と交換した。およそ24時間インキュベーションした後、HSV DNAを、Diagnostic Hybrids社(Athens、OH)のHSV抗ウイルス感受性試験キット(HSV Antivirus Susceptibility Test Kit)を用いて、核酸ハイブリダイゼーションにより3つ組で定量した。培地を除去し、細胞を製造業者の指示に従い溶解した。Hybriwix(商標)フィルターに溶解物を吸着した後、一晩60℃でハイブリダイズした。Hybriwixを、73℃で30分間洗浄し、ガンマカウンターで計測した。細胞傷害性は、実施例17に記したように評価した。こうして得られたEC50およびCC50を表7に示す。
表2と同じ略号:EC50−50%有効濃度;CC50 - 50%細胞傷害性濃度;選択性指標−CC50/EC50。EC50値は、2つ組で1回測定したHDP-CDVを除いて、2回の実験の平均である。
Claims (8)
- 固体の剤形として製剤化される、請求項1〜4のいずれか一項記載の抗ウイルス剤。
- カプセル剤、錠剤、エアゾール、液剤、または懸濁剤として製剤化されるか、または局所製剤もしくは溶液である、請求項1〜4のいずれか一項記載の抗ウイルス剤。
- オルトポックスウイルスに対して有効である、請求項1〜4のいずれか一項記載の抗ウイルス剤。
- B型肝炎ウイルスに対して有効である、請求項3〜4のいずれか一項記載の抗ウイルス剤。
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WO2001039724A2 (en) | 1999-12-03 | 2001-06-07 | The Regents Of The University Of California, San Diego | Phosphonate compounds |
US7163932B2 (en) * | 2001-06-20 | 2007-01-16 | Merck Frosst Canada & Co. | Aryldifluoromethylphosphonic acids for treatment of diabetes |
FR2837490B1 (fr) * | 2002-03-21 | 2009-04-17 | Univ Paris 13 | Nouveaux derives de bisphosphonates, leurs preparations et utilisations |
ATE455121T1 (de) * | 2001-07-16 | 2010-01-15 | Univ Paris 13 | Herstellungsverfahren von derivate von bisphosphonaten |
ATE541575T1 (de) * | 2002-03-06 | 2012-02-15 | Effrx Pharmaceuticals Sa | Brausetabletten, enthaltend alendronat |
US7488496B2 (en) | 2002-03-06 | 2009-02-10 | Christer Rosen | Effervescent compositions comprising bisphosphonates and methods related thereto |
CN1656109A (zh) * | 2002-04-26 | 2005-08-17 | 吉里德科学公司 | 非核苷逆转录酶抑制剂 |
AU2003901813A0 (en) * | 2003-04-15 | 2003-05-01 | Vital Health Sciences Pty Ltd | Pharmaceutical derivatives |
US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
WO2004096286A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
WO2004096285A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Anti-infective phosphonate conjugates |
WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
KR20060022647A (ko) | 2003-04-25 | 2006-03-10 | 길리애드 사이언시즈, 인코포레이티드 | 키나아제 억제 포스포네이트 유사체 |
US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
WO2004096287A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
EP1678321A1 (en) | 2003-10-24 | 2006-07-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
JP4692283B2 (ja) * | 2003-12-12 | 2011-06-01 | アステラス製薬株式会社 | 悪性黒色腫治療剤 |
WO2005063751A1 (en) | 2003-12-22 | 2005-07-14 | Gilead Sciences, Inc. | 4’-substituted carbovir-and abacavir-derivatives as well as related compounds with hiv and hcv antiviral activity |
WO2005090370A1 (en) * | 2004-02-05 | 2005-09-29 | The Regents Of The University Of California | Pharmacologically active agents containing esterified phosphonates and methods for use thereof |
WO2006076015A2 (en) * | 2004-04-30 | 2006-07-20 | The Regents Of The University Of California | 1-[2-(phosphonomethoxy)ethyl]-cytosine and analogs thereof |
ES2363160T3 (es) | 2004-07-27 | 2011-07-22 | Gilead Sciences, Inc. | Conjugados de fosfonato nucelosidico como agentes anti-vih. |
WO2006055525A2 (en) * | 2004-11-15 | 2006-05-26 | Ceptyr, Inc. | Protein tyrosine phosphatase inhibitors and methods of use thereof |
EP1831235B1 (en) | 2004-12-16 | 2013-02-20 | The Regents of The University of California | Lung-targeted drugs |
US8071574B2 (en) * | 2005-02-22 | 2011-12-06 | John Dennis Bobyn | Implant improving local bone formation |
US20060219637A1 (en) * | 2005-03-29 | 2006-10-05 | Killeen Kevin P | Devices, systems and methods for liquid chromatography |
WO2006130217A2 (en) * | 2005-04-01 | 2006-12-07 | The Regents Of The University Of California | Substituted phosphate esters of nucleoside phosphonates |
JP2008538354A (ja) * | 2005-04-08 | 2008-10-23 | キメリクス,インコーポレイテッド | ウイルス感染症およびその他の内科疾患を治療するための化合物、組成物および方法 |
JP2008535862A (ja) * | 2005-04-08 | 2008-09-04 | キメリクス,インコーポレイテッド | ポックスウイルス感染の治療のための化合物、組成物および方法 |
AU2006239677A1 (en) * | 2005-04-25 | 2006-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Use of compounds to enhance processivity of telomerase |
US7914810B2 (en) * | 2005-05-06 | 2011-03-29 | Synthes Usa, Llc | Methods for the in situ treatment of bone cancer |
US8114843B2 (en) | 2005-11-18 | 2012-02-14 | The Regents Of The University Of California | Photoreactive regulator of protein function and methods of use thereof |
US7749983B2 (en) | 2006-05-03 | 2010-07-06 | Chimerix, Inc. | Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates |
US20120010170A1 (en) * | 2007-04-27 | 2012-01-12 | Painter George R | "Methods of Reducing Nephrotoxicity in Subjects Administered Nucleoside Phosphonates" |
JP2011508740A (ja) * | 2007-12-27 | 2011-03-17 | エピファニー バイオサイエンシズ, インク. | 抗ウイルス化合物 |
EP3085377A1 (en) | 2008-01-25 | 2016-10-26 | Chimerix, Inc. | Methods of treating viral infections |
AU2009268681B2 (en) | 2008-07-08 | 2014-10-02 | Gilead Sciences, Inc. | Salts of HIV inhibitor compounds |
US8628812B2 (en) | 2008-12-30 | 2014-01-14 | Pepsico, Inc. | Preservative system for acidic beverages based on sequestrants |
EP2270021A1 (en) * | 2009-06-18 | 2011-01-05 | Centre National de la Recherche Scientifique | Phosphonates synthons for the synthesis of phosphonates derivatives showing better bioavailability |
WO2011005510A2 (en) * | 2009-06-22 | 2011-01-13 | Cerapedics, Inc. | Peptide conjugates and uses thereof |
US8614200B2 (en) | 2009-07-21 | 2013-12-24 | Chimerix, Inc. | Compounds, compositions and methods for treating ocular conditions |
BR112012002551A2 (pt) | 2009-08-03 | 2017-06-13 | Chimerix Inc | composição e métodos de tratamento de infecções virais e tumores induzidos por vírus |
EP2483283B1 (en) * | 2009-10-02 | 2015-01-07 | Straitmark Holding AG | Method for the manufacture of aminohydroxy diphosphonic acids |
PT2534150T (pt) | 2010-02-12 | 2017-05-02 | Chimerix Inc | Métodos para tratar uma infecção viral |
EP2558466A4 (en) | 2010-04-14 | 2013-11-13 | Univ California | PHOSPHONATES HAVING REDUCED TOXICITY FOR THE TREATMENT OF VIRAL INFECTIONS |
US9278135B2 (en) | 2010-04-26 | 2016-03-08 | Chimerix Inc. | Methods of treating retroviral infections and related dosage regimes |
AU2015201895B2 (en) * | 2010-08-31 | 2016-11-17 | Emergent Biodefence Operations Lansing Llc | Phosphonate ester derivatives and methods of synthesis thereof |
RU2015141024A (ru) * | 2010-08-31 | 2018-12-26 | Чимерикс, Инк. | Производные эфиров фосфоновых кислот и способы их синтеза |
US8884027B2 (en) | 2010-10-22 | 2014-11-11 | University Of Rochester | Melampomagnolide B derivatives as antileukemic and cytotoxic agents |
WO2013033450A2 (en) * | 2011-08-31 | 2013-03-07 | Mallinckrodt Llc | Remote assembly of targeted nanoparticles using h-phosphonate-ene/-yne hydrophosphonylation reactions |
CA2857490C (en) | 2011-12-22 | 2020-03-31 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
WO2014035945A1 (en) * | 2012-08-28 | 2014-03-06 | Glaxosmithkline Llc | Pharmaceutical compositions |
EP3401320B1 (en) * | 2013-03-15 | 2020-05-13 | The Regents of the University of California | Acyclic nucleoside phosphonate diesters for use in treating human papilloma virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia |
UA116825C2 (uk) | 2013-11-15 | 2018-05-10 | Чимерикс Інк. | Морфологічні форми гексадецилоксипропілових складних ефірів фосфонової кислоти і способи їх синтезу |
AU2015217221A1 (en) | 2014-02-13 | 2016-08-11 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and their uses |
CN106456658A (zh) | 2014-03-14 | 2017-02-22 | 全技术公司 | 硒有机化合物的组合物和其使用方法 |
EP3164136A4 (en) | 2014-07-02 | 2018-04-04 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
RS63250B1 (sr) | 2014-09-15 | 2022-06-30 | Univ California | Nukleotidni analozi |
US10160778B2 (en) | 2014-10-27 | 2018-12-25 | Concert Pharmaceuticals, Inc. | Pyrimidine phosphonic acid esters |
CA2978085C (en) | 2015-03-06 | 2023-01-17 | Atea Pharmaceuticals, Inc. | .beta.-d-2'-deoxy-2'-.alpha.-fluoro-2'-.beta.-c-substituted-2-modified-n6-substituted purine nucleotides for hcv treatment |
AU2016255725B2 (en) | 2015-04-27 | 2021-09-23 | The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center | EGR1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions |
US10377782B2 (en) | 2015-09-15 | 2019-08-13 | The Regents Of The University Of California | Nucleotide analogs |
WO2017048252A1 (en) | 2015-09-15 | 2017-03-23 | Alltech, Inc. | Compositions of selenoorganic compounds and methods of use thereof |
RU2628456C1 (ru) * | 2016-06-29 | 2017-08-17 | Федеральное Государственное Бюджетное Учреждение Науки Институт Молекулярной Биологии Им. В.А. Энгельгардта Российской Академии Наук (Имб Ран) | Новые пиримидиновые ингибиторы репликации аденовируса человека |
US10711029B2 (en) | 2016-07-14 | 2020-07-14 | Atea Pharmaceuticals, Inc. | Beta-d-2′-deoxy-2′-alpha-fluoro-2′-beta-c-substituted-4′fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection |
PT3512863T (pt) | 2016-09-07 | 2022-03-09 | Atea Pharmaceuticals Inc | Nucleótidos de purina 2'-substituídos-n6-substituídos para tratamento de vírus de rna |
WO2019027920A1 (en) | 2017-08-01 | 2019-02-07 | Gilead Sciences, Inc. | CRYSTALLINE FORMS OF ETHYL ((S) - (((((2R, 5R) -5- (6-AMINO-9H-PURIN-9-YL) -4-FLUORO-2,5-DIHYDROFURAN-2-YL) OXY ) METHYL) (PHENOXY) PHOSPHORYL) -L-ALANINATE (GS-9131) FOR THE TREATMENT OF VIRAL INFECTIONS |
RU2670204C1 (ru) * | 2017-12-01 | 2018-10-19 | федеральное государственное бюджетное учреждение "Национальный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи" Министерства здравоохранения Российской Федерации | Производные 2-тиоурацила, обладающие противоаденовирусной активностью |
JP7076158B2 (ja) * | 2017-12-21 | 2022-05-27 | 深▲チェン▼市塔吉瑞生物医薬有限公司 | 新規抗ウイルス性ヌクレオシド系逆転写酵素阻害剤 |
AU2019207625A1 (en) | 2018-01-09 | 2020-07-30 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
CN114502172A (zh) | 2019-08-22 | 2022-05-13 | 爱默蕾大学 | 核苷前药及其相关用途 |
WO2021173713A1 (en) | 2020-02-27 | 2021-09-02 | Atea Pharmaceuticals, Inc. | Highly active compounds against covid-19 |
US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
CR20230100A (es) | 2020-08-24 | 2023-04-28 | Gilead Sciences Inc | Compuestos fosfolípidos y usos de los mismos |
TW202344257A (zh) | 2020-10-16 | 2023-11-16 | 美商基利科學股份有限公司 | 磷脂化合物及其用途 |
Family Cites Families (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1944530A (en) | 1929-04-08 | 1934-01-23 | Ig Farbenindustrie Ag | Phosphoric acid esters |
DE2009341C3 (de) | 1970-02-27 | 1979-06-21 | Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V., 3400 Goettingen | 3-Octadecyloxy-propanol-(l)-phosphorsäure-monocholinester und Verfahren zu dessen Herstellung |
US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
FR2586685B1 (fr) * | 1985-09-03 | 1987-12-11 | Protex Manuf Prod Chimiq | Procede de preparation de nouveaux agents dispersants cationiques |
FI83421C (fi) * | 1989-06-21 | 1991-07-10 | Huhtamaeki Oy | Foerfarande foer framstaellning av farmakologiskt anvaendbara metylenbisfosfonsyraderivat. |
US5411947A (en) * | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
US5463092A (en) * | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
EP0481214B1 (en) | 1990-09-14 | 1998-06-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
EP0477454A1 (en) * | 1990-09-28 | 1992-04-01 | Merrell Dow Pharmaceuticals Inc. | Novel phosphonate derivatives of certain nucleosides |
US5672697A (en) * | 1991-02-08 | 1997-09-30 | Gilead Sciences, Inc. | Nucleoside 5'-methylene phosphonates |
JPH05339280A (ja) * | 1991-04-26 | 1993-12-21 | Japan Tobacco Inc | (n−二環置換)アミノメチレンビスフォスフォン酸誘導体 |
JP3341303B2 (ja) * | 1991-07-11 | 2002-11-05 | 東レ株式会社 | メチレンジホスホン酸誘導体、その製造方法およびその医薬用途 |
US5879700A (en) * | 1991-10-15 | 1999-03-09 | Hostetler; Karl Y. | Nucleoside analogue phosphates for topical use |
US5618804A (en) | 1992-07-10 | 1997-04-08 | Toray Industries, Inc. | Methanediphosphonic acid derivative, process for production thereof and use for pharmaceuticals |
JP3580377B2 (ja) * | 1993-06-29 | 2004-10-20 | 三菱化学株式会社 | ホスホナートヌクレオチドエステル誘導体 |
CA2126601A1 (en) | 1993-06-29 | 1994-12-30 | Mitsubishi Chemical Corporation | Phosphonate-nucleotide ester derivatives |
US5627185A (en) * | 1994-11-23 | 1997-05-06 | Gosselin; Gilles | Acyclovir derivatives as antiviral agents |
CH690163A5 (fr) * | 1995-07-28 | 2000-05-31 | Symphar Sa | Dérivés gem-diphosphonates substitués utiles en tant qu'agents anti-cancers. |
US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
US6048913A (en) * | 1996-12-19 | 2000-04-11 | Kao Corporation | Coating composition for teeth |
US6686462B2 (en) * | 1997-02-28 | 2004-02-03 | The Regents Of The University Of California | Antiviral compounds and methods of administration |
NZ550116A (en) | 1997-08-18 | 2008-03-28 | Neurochem Int Ltd | Phosphono-carboxylate compounds for treating amyloidosis |
FR2781228B1 (fr) | 1998-07-16 | 2000-09-29 | Pf Medicament | Phosphonates insatures derives d'indole |
WO2001039724A2 (en) | 1999-12-03 | 2001-06-07 | The Regents Of The University Of California, San Diego | Phosphonate compounds |
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