JP2013503197A - 新規なヌクレオシドホスホネート及びそのアナログ - Google Patents
新規なヌクレオシドホスホネート及びそのアナログ Download PDFInfo
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- JP2013503197A JP2013503197A JP2012527052A JP2012527052A JP2013503197A JP 2013503197 A JP2013503197 A JP 2013503197A JP 2012527052 A JP2012527052 A JP 2012527052A JP 2012527052 A JP2012527052 A JP 2012527052A JP 2013503197 A JP2013503197 A JP 2013503197A
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- Prior art keywords
- compound
- substituted
- alkyl
- hydrogen
- cycloalkyl
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- C07F9/40—Esters thereof
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Abstract
Description
R1及びR2は、それぞれ独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、R4CO2−、R5O−、−R6S(O)k、ハロ、ヘテロアルキル、−N3、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、若しくは置換ヘテロアリールアルキルである。あるいは、式(I)の化合物では、R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル又は置換シクロヘテロアルキルであってもよく;
Xは、−CH2−であり;
nは、0又は1であり;
kは、0、1又は2であり;
R3は、水素、1価のカチオン又は親油基であり;
R4、R5及びR6は、それぞれ独立して、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル又は置換ヘテロアリールアルキルである。;
ただし、R1及びR2の少なくとも1つが水素ではないか、あるいは、R1及びR2が何れも水素である場合、
Bは以下の構造:
ここで、式中、
R101は、−OR104、−SR105、−NR106NH2又は−NR107NHSO2Meであり、R102は、水素、アルキル、ハロ又は−NR108R109であり、R103は、水素又はアルキルであり、R104、R105、R106、R107、R108、R109はそれぞれ独立して、水素又はアルキルであり、;
R1及びR2が、それらを構成する原子同士が相互に結合してなる、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル又は置換シクロヘテロアルキルである場合、R1とR2とを結合する炭素結合は二重結合であり得;
また、R1及びR2が、それぞれ独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、R4CO2−、R5O−、−R6S(O)k、ハロ、ヘテロアルキル、−N3、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル又は置換ヘテロアリールアルキルである場合、R1とR2とを結合する炭素結合は二重結合であり得る。
R300は、ヌクレオチドホスホネート又は抗ウイルス性ホスホネートであり、そのヌクレオチド若しくはヌクレオシド又は抗ウイルス性ホスホネートのプリン塩基若しくはピリミジン塩基が、以下に示す構造のピリミジン塩基R301:
式中、R220は、水素、ヒドロキシル、ハロ、アルキル、−OR224、−SR225、−NR226NH2、−NR227NHSO2Me、−NR228R229であり、R221は、水素、アルキル、ハロ又は−NR228R229であり、R222は、水素又はアルキルであり、R224、R225、R226NH2、R227、R228、R229は、水素又はアルキルであり;
Xは−(R202)C(R202’)−であり;
Lは、原子価結合、又は一般式:−J−(CR230)t−G−(ここで、式中、tは1〜24の整数であり、J及びGはそれぞれ独立して、−O−、−S−、−C(O)O−又はNH−であり、R230は、水素、アルキル又は置換アルキルである。)で表される二官能性分子であり;
mは0〜6の整数であり;
nは0又は1であり;
ただし、R201及びR201’は、何れもOC(O)R204、−SC(O)R206又はこれらの組合せではないものとし;同一の炭素原子に結合したR202及びR202’は、何れもOC(O)R208、−SC(O)R210、−NR211R212、又は−NC(O)R213ではないものとする。
特に記載がない限り、本明細書で使用する技術用語及び科学用語は、全て本発明が属する技術分野の当業者が一般に理解しているのと同様の意味を有する。ここで開示される全ての特許出願及び刊行物は、参照によりその全体を本明細書に援用される。なお、本明細書の用語に複数の定義が存在する場合、他に記載がない限り、このセクションの定義が優先する。
かかる化合物の部分構造を示す場合には、分子の残部に対する部分構造の結合点を角括弧で表記する。また、式(I)及び(II)中に示される、以下の記号:
1991) や、Harrison et al., Compendium of Synthetic Organic
Methods, Vols.1-8. (John Wiley and Sons, 1971-1996)等に記載されている。代表的なアミノ基の保護基としては、ホルミル、アセチル、トリフルオロアセチル、ベンジル、ベンジルオキシカルボニル(「CBZ」)、tert−ブトキシカルボニル(「Boc」)、トリメチルシリル(「TMS」)、2−トリメチルシリル−エタンスルホニル(「SES」)、トリチル基、置換トリチル基、アリルオキシカルボニル、9−フルオレニルメチルオキシカルボニル(「FMOC」)、ニトロ−ベラトリルオキシカルボニル(「NVOC」)等が挙げられるが、これらに限定されるものではない。代表的なヒドロキシ基の保護基としては、該ヒドロキシ基がアシル化あるいはアルキル化されたもの、例えばベンジルエーテルや、トリチルエーテル、アルキルエーテル、テトラヒドロピラニルエーテル、トリアルキルシリルエーテル、アリルエーテル等が挙げられるが、これらに限定されるものではない。
任意の基又はラジカルを構成する飽和炭素原子の置換に用い得る基(置換基)としては、特に限定されるものではないが、例えば、−Ra、ハロ、−O−、=O、−ORb、−SRb、−S−、=S、−NRcRc、=NRb、=N−ORb、トリハロメチル、−CF3、−CN、−OCN、−SCN、−NO、−NO2、=N2、−N3、−S(O)2Rb、−S(O)2NRb、−S(O)2O−、−S(O)2ORb、−OS(O)2Rb、−OS(O)2O−、−OS(O)2ORb、−P(O)(O−)2、−P(O)(ORb)(O−)、−P(O)(ORb)(ORb)、−C(O)Rb、−C(S)Rb、−C(NRb)Rb、−C(O)O−、−C(O)ORb、−C(S)ORb、−C(O)NRcRc、−C(NRb)NRcRc、−OC(O)Rb、−OC(S)Rb、−OC(O)O−、−OC(O)ORb、−OC(S)ORb、−NRbC(O)Rb、−NRbC(S)Rb、−NRbC(O)O−、−NRbC(O)ORb、−NRbC(S)ORb、−NRbC(O)NRcRc、−NRbC(NRb)Rb、NRbC(NRb)NRcRcが挙げられる。ここで、式中、Raは、アルキル、シクロアルキル、ヘテロアルキル、シクロヘテロアルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキルからなる群から選択され、;Rbは各々独立して水素又はRaであり、;Rcは各々独立してRb若しくは、2つのRcが窒素原子と結合し形成された、4員、5員、6員又は7員シクロヘテロアルキル(酸素(O)、窒素(N)、硫黄(S)からなる群から選択される1〜4個の任意のヘテロ原子を含み得る)である。より具体的には、例えば−NRcRcは、−NH2、−NH−アルキル、N−ピロリジニル、N−モルホリニルを包含する。
本明細書で用いる略語の一例を以下に示す。:
5−ホスホノ−ペント−2−エン−1−イル アデニン=PPen−A
5−ホスホノ−ペント−2−エン−1−イル シトシン=PPen−C
5−ホスホノ−ペント−2−エン−1−イル グアニン=PPen−G
5−ホスホノ−ペント−2−エン−1−イルチミン=PPen−T
5−ホスホノ−ペント−2−エン−1−イルウラシル=PPen−U
ヘキサデシルオキシプロピル=HDP
オクタデシルオキシエチル=ODE
オレイルオキシエチル=OLE
オレイルオキシプロピル=OLP
第1の態様では、下記式(I)又は下式(II)で表される置換ホスホネート又は該化合物の塩、溶媒和物若しくは水和物が提供される。:
ただし、R1及びR2の少なくとも1つが水素ではないか、あるいは、R1及びR2のいずれもが水素である場合、Bは以下の構造:
ここで、式中、R101は、−OR104、−SR105、−NR106NH2又は−NR107NHSO2Meであり、R102は、水素、アルキル、ハロ又は−NR108R109であり、R103は、水素又はアルキルであり、R104、R105、R106、R107、R108、R109はそれぞれ独立して、水素又はアルキルである。また、R1及びR2が、それらを構成する原子同士が相互に結合してなる、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル又は置換シクロヘテロアルキルである場合、R1とR2とを結合する炭素結合は二重結合であり得;また、R1及びR2がそれぞれ独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、R4CO2−、R5O−、−R6S(O)k、ハロ、ヘテロアルキル、−N3、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル又は置換ヘテロアリールアルキルである場合、R1とR2とを結合する炭素結合は二重結合であり得る。
また、R9は以下の構造:
ここで、R22及びR22aはそれぞれ独立して、水素、R23CO2−、R24O−、R25S−、R26COS、R27CON−、R28NH−、R28NR29−、オキソ、ハロゲン、NH2、−OH、−SHであり、R23、R24、R25、R26、R27、R28、R29、R30はそれぞれ独立して(C1〜C7)アルキルである。ただし、R22及びR22aは、両方がハロゲン、R23CO2−、R26COS、R27CON−、R28NH−、R28NR29−、NH2、−OH、−SH又はこれらの組合せではないものとし、R10及びR10aの何れかがオキソである場合には、他方は制限されないものとする。また、mは0〜6の整数、例えば0、1又は2であってもよいし、或いは0又は1であってもよい。さらに、mは0であり得る。また他の実施形態では、R10及びR10aは水素である。さらに他の実施形態では、R22及びR22aは水素である。さらに他の実施形態では、R10及びR10a、R22及びR22aは水素である。また他の実施形態では、R3は以下の構造:
さらに他の実施形態では、R3は以下の構造:
さらに他の実施形態では、R3は、アセチル、バリル、ジピボキシル、ビス(ピバロイルオキシメチル)又はジソプロキシルである。さらに他の実施形態では、R3は、ヘキサデシルオキシプロピル、オクタデシルオキシエチル又はオレイルオキシエチルである。また他の実施形態では、R8は、R12Oである。ここで、R12は、(CH2)t−CH3であり、tは0〜24である。またtは、8、10、12、13、14、15、16、17、18、19又は20であってもよく、13、14、15、16、17、18、19、20であってもよい。さらに、tは、15、16、17、18、19、20であってもよく、17、18、19、20であってもよい。また、tは、15、17、18であり得る。
ここで、式中、R110は、水素、アルキル、置換アルキル、−OH、ハロ、アリール又はヘテロアリールであり、R111は、水素又はアルキルであり、R101は、水素、ヒドロキシル、ハロ、アルキル、−OR104、−SR105、−NR106NH2、−NR107NHSO2Me又は−NR108R109であり、R102は、水素、アルキル、ハロ又は−NR108R109であり、R103、R104、R105、R106、R107、R108、R109はそれぞれ独立して、水素又はアルキルであり、R103は、水素又はアルキルである。
ここで、R110は、水素又はアルカニルであってもよく、水素又はメチルであってもよい。幾つかの実施形態では、R108及びR109はそれぞれ独立して、水素、アルカニル又はシクロアルカニルである。また他の実施形態では、R108は、水素、メチル又はシクロプロピルである。また、R111は、水素又はアルカニルであってもよく、水素又はメチルであってもよい。また、R101は、水素、ヒドロキシル、ハロ、アルキル又は−NR108R109でああってもよく、水素、アルキル又は−NR108R109であってもよいまた、R101は、メチル、NH2又は−NR108R109であってもよく、−OR104、−SR105、−NR106NH2又は−NR107NHSO2Meであってもよい。また幾つかの実施形態では、R104、R105、R106又はR107は、メチルである。さらに他の実施形態では、R102は、水素である。さらに他の実施形態では、R103は水素である。
他の実施形態では、Bは以下の構造:
また他の実施形態では、Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである。
さらに他の実施形態では、Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
Bは以下の構造:
他の実施形態では、R3はn−C16H33O(CH2)3−であり、
Bは以下の構造:
R2はメチル又はフルオロである。
また他の実施形態では、R3はn−C16H33O(CH2)3−であり、
Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである。
さらに他の実施形態では、R3はn−C16H33O(CH2)3−であり、
Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
Bは以下の構造:
式中、R101は、−OR104、−SR105、−NR106NH2、−NR107NHSO2Meであり、R102は、水素、アルキル、ハロ、−NR108R109であり、R103は、水素又はアルキルであり、R104、R105、R106、R107、R108、R109はそれぞれ独立して、水素又はアルキルであり、R1及びR2は水素である。他の実施形態では、R104、R105、R106、R107はアルキルであり、R102は、−NR108R109である。また他の実施形態では、R104、R105、R106、R107はアルキルであり、R102は−NR108R109であり、R103は水素である。さらに他の実施形態では、R104、R105、R106、R107はメチル又はエチルであり、R102は−NH2であり、R103は水素である。さらに他の実施形態では、R104はメチル又はエチルであり、R105、R106、R107はメチルであり、R102は−NH2であり、R103は水素である。
上記の実施形態の幾つかでは、R1とR2は水素である。また上記の実施形態の幾つかでは、R1及びR2は、式(I)に示す化合物中の水素である。上記の実施形態の幾つかでは、R2はメチル又はフルオロである。上記の実施形態の幾つかでは、R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである。上記の実施形態の幾つかでは、R1及びR2は、それらを構成する原子が相互に結合してなる、シクロプロピル又は置換シクロプロピルである。上記の実施形態の幾つかでは、R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
上記の実施形態の幾つかでは、R1及びR2は、それらを構成する原子が相互に結合してなる、シクロヘテロアルキル又は置換シクロヘテロアルキルを形成する。上記の実施形態の幾つかでは、R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
R2はアルキル又はハロである。
他の実施形態では、Bは以下の構造:
R2はアルキル又はハロである。
また他の実施形態では、Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである。
さらに他の実施形態では、Bは以下の構造:
R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
Bは以下の構造:
他の実施形態では、R2はメチル又はフルオロである。
また他の実施形態では、R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである。さらに他の実施形態では、R1及びR2は、それらを構成する原子が相互に結合してなる、シクロプロピル又は置換シクロプロピルである。さらに他の実施形態では、R1及びR2は、それらを構成する原子が相互に結合してなる、以下の構造:
他の実施形態では、Bが以下の構造:
また他の実施形態では、R3がn−C16H33O(CH2)3−であり、Bが以下の構造:
さらに他の実施形態では、Bは以下の構造:
さらに他の実施形態では、Bが以下の構造:
さらに他の実施形態では、R3がn−C16H33O(CH2)3−であり、Bが以下の構造:
さらに他の実施形態では、R3がn−C16H33O(CH2)3−であり、Bが以下の構造:
ここで、式中、R220は、水素、ヒドロキシル、ハロ、アルキル、−OR224、−SR225、−NR226NH2若しくは−NR227NHSO2Me、−NR228R229であり、R221は、水素、アルキル、ハロ、−NR228R229であり、R222は、水素又はアルキルであり、R224、R225、R226、R227、R228、R229は、水素又はアルキルであり、Xは−(R202)C(R202’)−であり、Lは、原子価結合又は式:−J−(CR230)t−G−(ここで、式中、tは1〜24の整数であり、J及びGはそれぞれ独立して、−O−、−S−、−C(O)O−又はNH−であり、R230は、水素、アルキル又は置換アルキルである。)で表される二官能性分子であり、mは0〜6の整数であり、nは0又は1である。幾つかの実施形態では、R201及びR201’は、何れも水素ではない。
ここで開示される組成物及び該組成物の使用方法に用いられる、ヌクレオシドホスホネート及びそのエステルの典型的な調製方法を以下に記載するが、かかる具体例には限定されない。ここで開示されるヌクレオシドホスホネート及びそのエステルの調製には、当該技術分野において従来公知の種々の方法を適宜用いることができる。
’を付加して)アルコールE’を得ることができる。かかるアルコールE’を酸化して、カルボニル化合物F’を得る。そして、Horner
Emmons反応によって、例えばビニルホスホネートG’(R’及びR’’はアルキル又はアリールである。)を得、これを水素化することで飽和ホスホネートH’を得る。かかる飽和ホスホネートH’から、保護基P’’を除去してアルコールI’を得、これを例えばプリン塩基誘導体で置換して、ホスホネートJ’を得ることができ(ここで、同様の手法を用いてピリミジン誘導体を結合させてもよい。)、これを加水分解することによりリン酸K’を得る。そして、かかるリン酸K’の親油性側鎖を選択的に結合させてホスホネートL’を得、これを加水分解してプリンホスホネートM’を得ることができる。
本明細書で提供される医薬組成物は、ウイルス感染及び異常な細胞増殖に関連する疾患又は障害の1つ若しくは複数の症状の予防、処置又は軽減に有用な量のここで開示される1種又はそれ以上の化合物を、治療有効量含んでいる。かかる医薬組成物は、また、薬学的に許容されるビヒクルを含んでいる。ここで開示される化合物の投与に好適な医薬ビヒクルは、特定の投与方法に好適であることが従来公知な担体を任意に含み得る。
Edition(1999)を参照されたい)。
form)で製剤化して投与してもよい。なお、本明細書において、単位用量形態とは、ヒト及び動物被検体に好適であり、当該技術分野において従来公知な単位で物理的に分離し、個別に包装された形態を指す。単位用量には、各々、所望の治療効果を発揮するのに十分な量の治療活性化合物と共に必要とされる医薬ビヒクルが含まれる。単位用量形態としては、例えば、アンプル剤、シリンジ剤、個別包装された錠剤又はカプセル剤が挙げられる。かかる単位用量形態は、分割して投与しても、分割したものを複数投与してもよい。また、本明細書において複数回投与量形態とは、単位用量形態を分離して、投与する複数の同一の単位剤形を単一容器に収めされたものを指す。かかる複数回投与量形態としては、例えば、バイアル、錠剤若しくはカプセル剤のビン、パイントビン、ガロンビンが挙げられる。このため、複数回投与量形態は分離包装されていない単位用量の倍数である。
Easton, Pa., 15th Edition, 1975又はその新版を参照されたい。
Ed., Marcel Dekker, NY, 1995, pp.379-80を参照されたい。)。実際に、水分や熱は、一部の化合物の分解を加速させ得る。製剤の製造、取扱い、包装、保管、輸送、及び使用の際の環境には、通常、水分及び/又は湿気が存在するため、製剤に対する水分の作用を考慮することは、殊に重要である。
かかる結合剤としては、例えば、微結晶性セルロース、トラガントゴム、グルコース溶液、アラビアゴム液、ゼラチン溶液、糖蜜、ポリビニルピロリジン、ポビドン、クロスポビドン、スクロース、デンプン糊が挙げられる。潤滑剤としては、例えば、タルク、デンプン、ステアリン酸マグネシウム若しくはステアリン酸カルシウム、石松子、ステアリン酸が挙げられる。希釈剤としては、例えば、ラクトース、スクロース、デンプン、カオリン、塩、マンニトール、リン酸二カルシウムが挙げられる。流動促進剤としては、例えば、コロイド状の二酸化ケイ素が挙げられる。崩壊剤としては、例えば、クロスカルメロースナトリウム、デンプングリコール酸ナトリウム、アルギン酸、コーンスターチ、ポテトスターチ、ベントナイト、メチルセルロース、寒天、カルボキシメチルセルロースが挙げられる。着色剤としては、例えば、認可された水溶性FD及びC色素、それらの混合物;アルミナ水和物で懸濁した水不溶性FD及びC色素;が挙げられる。甘味剤としては、例えば、スクロース、ラクトース、マンニトール、サッカリン等の人工甘味剤、ならびに様々な噴霧乾燥香味料が挙げられる。着香剤としては、例えば、果実等の植物から抽出された天然香味料、爽快感を与える化合物(例えば、ペパーミントやサリチル酸メチルの合成ブレンド)が挙げられる。湿潤剤としては、例えば、プロピレングリコールモノステアレート、ソルビタンモノオレエート、ジエチレングリコールモノラウレート、ポリオキシエチレンラウリルエーテルが挙げられる。催吐コーティング剤としては、例えば、脂肪酸、油脂、ワックス、セラック、アンモニア処理セラック、セルロースアセテートフタレートが挙げられる。フィルムコーティング剤としては、例えば、ヒドロキシエチルセルロース、カルボキシメチルセルロースナトリウム、ポリエチレングリコール4000、セルロースアセテートフタレートが挙げられる。
液体経口剤形に再構成された非発泡顆粒剤に使用され得る薬学的に許容される物質としては、例えば、希釈剤、甘味剤、湿潤剤が挙げられる。液体経口剤形に再構成された発泡顆粒剤に使用され得る薬学的に許容される物質としては、例えば、有機酸や二酸化炭素源が挙げられる。また、着色剤や着香剤は、上記の剤形の全てで使用され得る。
かかる剤形によれば、例えば、ヒドロキシプロピルメチルセルロース、他のポリマーマトリックス、ゲル、透過性膜、浸透圧システム、多層コーティング、微小粒子、リポソーム、ミクロスフェア、又はこれらの組合せを用いて、1種又は2種以上の活性成分の放出速度を遅らせる等、放出速度を自由に調節することができる。このように、かかる剤形を用いることで、任意の放出制御を行うことができる。ここで開示される活性成分を使用する際には、従来公知の放出制御製剤を適宜選択し得る。
かかる装置では、活性成分を、例えばポリメチルメタクリレート、ポリブチルメタクリレート、可塑化又は無可塑化ポリ塩化ビニル、可塑化ナイロン、可塑化ポリエチレンテレフタレート、天然ゴム、ポリイソプレン、ポリイソブチレン、ポリブタジエン、ポリエチレン、エチレン−ビニルアセテートコポリマー、シリコンゴム、ポリジメチルシロキサン、シリコンカーボネートコポリマー、親水性ポリマー(例えば、アクリル酸やメタクリル酸のエステルのヒドロゲル)、コラーゲン、架橋ポリビニルアルコール、及び部分的に加水分解された架橋ポリビニルアセテート分散し、これを体内で溶解しない高分子膜、例えば、ポリエチレン、ポリプロピレン、エチレン/プロピレンコポリマー、エチレン/アクリル酸エチルコポリマー、エチレン/ビニルアセテートコポリマー、シリコンゴム、ポリジメチルシロキサン、ネオプレンゴム、塩素化ポリエチレン、ポリ塩化ビニル、塩化ビニルと酢酸ビニルとのコポリマー、塩化ビニリデン、エチレン及びプロピレン、イオノマーポリエチレンテレフタレート、ブチルゴム、エピクロロヒドリンゴム、エチレン/ビニルアルコールコポリマー、エチレン/酢酸ビニル/ビニルアルコールターポリマー、エチレン/ビニルオキシエタノールコポリマー等で包んだ形態であり得る。かかる構成によれば、高分子膜に内包された化合物は、制御された放出速度で段階的に拡散し得る。こうした非経口組成物に含有させる該活性化合物の割合は、例えば、その性質や化合物の活性、被検体の必要量等によって大きく異なり得る。
ヒトの治療では、被検体の年齢、体重、疾患の段階等に基づき、最も適切な投与量を医師が決定する。医薬組成物の投与量は、例えば体重1キログラム当たりの化合物の投与量が、1日約0.001mg〜約2000mgとなるよう調節する。また、投薬単位剤形は、例えば1投薬単位剤形当たりの活性成分が、約0.01mg以上(例えば0.1mg以上、例えば1mg以上)であって、2000mg以下(例えば1000mg以下、例えば約500mg以下)となるよう調製することができる。或いは、1投薬単位剤形当たりの活性成分又は必須成分が、約10mg〜約500mgとなるように調製することもできる。
化合物の抗ウイルス活性は、当該技術分野において一般的なアッセイにより測定することができる。かかるアッセイとしては、例えば、HFF細胞を用いたプラーク減少アッセイ、MRC−5細胞を用いたDNA減少アッセイ、MT−2細胞を用いたp24減少アッセイ、HFF細胞を用いたCPEアッセイ、Daudi細胞を用いたEBV Elisaアッセイ等が挙げられるが、これらに限定されるものではない。
ここで開示される化合物及びその組成物を用いて、ウイルス感染又は異常な細胞増殖に関連する疾患の1つ又はそれ以上の症状を治療、予防又は軽減する方法を提供する。かかる方法を実施する際は、被検体に治療有効濃度の化合物を含む化合物又は組成物を有効量投与する。本明細書で提供される方法は、特に限定されないが、例えば、インフルエンザ;B型及びC型肝炎ウイルス;サイトメガロウイルス(CMV);疱疹感染症、例えば水痘帯状疱疹ウイルス、単純ヘルペスウイルス1型及び2型、エプスタインバーウイルス、ヘルペス6型6(HHV−6)及び8型(HHV−8);水痘帯状疱疹ウイルス感染症、例えば帯状疱疹又は水痘;エプスタインバーウイルス感染症、例えば伝染性単核球症/腺熱;レトロウイルス感染症、例えばSIV、HIV−1及びHIV−2;エボラウイルス;アデノウイルス及びパピローマウイルス;等のウイルス感染に関連する疾患の1つ又はそれ以上の症状を、治療、予防又は軽減する方法である。
ここで開示される化合物及びその組成物はまた、1種又はそれ以上の他の活性成分と組合せて使用してもよい。例えば、化合物を別の治療剤と組合せて、又は連続的して、投与し得る。かかる(別の)治療剤としては、ウイルス感染又は異常な細胞増殖に関する1つ又はそれ以上の症状を治療、予防又は軽減し得るとして知られたものが挙げられる。具体的には、例えば抗ウイルス薬や抗腫瘍薬が挙げられるが、これらに限定されるものではない。
278:9489-9495;Love, et al., 2003, J. Virol.
77:7575-7581;Gu et al., 2003, J. Biol. Chem.
278:16602-16607;Tomei et al., 2004, J. Virol.
78:938-946;Nguyen et al., 2003, Antimicrob. Agents
Chemother. 47:3525-3530に記載されている。
Drug Discov. Dev.7:204-210;Takeda et al., 2003, Annu.
Rev. Immunol. 21:335-376;Lee et al., 2003, Proc. Natl
Acad. Sci. USA 100:6646-6651;Hosmans et al., 2004,
Hepatology 40 (Suppl.1), 282A;米国特許第6,924,271号明細書等に記載されている。
ここで開示される化合物はまた、酵素治療剤、インターフェロン、インターロイキン、腫瘍壊死因子、マクロファージコロニー刺激因子、コロニー刺激因子等の免疫系モジュレーターと組合せて使用しすることもできる。
1H NMR(400MHz,CHLOROFORM−d)δ ppm 1.32−1.44(m,15H);1.84−1.96(m,5H);2.67−2.79(m,5H);4.09−4.21(m,10H);4.76−4.81(m,2H);4.81−4.94(m,3H);5.28(dt,J=19.23,8.06Hz,3H);6.07(br.s.,4H);7.78−7.89(m,3H)。
1H NMR(400MHz,CHLOROFORM−d)δ ppm 0.91−1.03(m,16H);1.72−1.82(m,5H);2.21−2.33(m,4H);3.10(t,J=7.18Hz,3H);4.03−4.15(m,4H);5.04−5.16(m,2H);7.25−7.37(m,10H);7.55−7.67(m,7H)。
Claims (35)
- 下記式(I)又は式(II)で表される化合物、又は該化合物の塩、溶媒和物若しくは水和物。
Bは、プリン塩基若しくはピリミジン塩基、又はそれらの類似体(アナログ)であり;
R1及びR2は、それぞれ独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、R4CO2−、R5O−、−R6S(O)k、ハロ、ヘテロアルキル、−N3、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル若しくは置換ヘテロアリールアルキルである。あるいは、式(I)の化合物においては、R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル又は置換シクロヘテロアルキルであってもよく;
Xは、−CH2−であり;
nは、0又は1であり;
kは、0、1又は2であり;
R3は水素、1価のカチオン又は親油基であり;
R4、R5及びR6は、それぞれ独立して、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル又は置換ヘテロアリールアルキルである。;
ただし、R1及びR2の少なくとも1つが水素ではないか、あるいは、R1及びR2のいずれもが水素である場合、
Bは以下の構造:
R1及びR2が、それらを構成する原子同士が相互に結合してなる、シクロアルキル、置換シクロアルキル、シクロヘテロアルキル又は置換シクロヘテロアルキルである場合は、R1とR2とを結合する炭素結合は二重結合であり得;
R1及びR2が、それぞれ独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、R4CO2−、R5O−、R6S(O)k−、ハロ、ヘテロアルキル、−N3、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル又は置換ヘテロアリールアルキルである場合は、R1とR2とを結合する炭素結合は二重結合であり得る。 - R3は、n−C14H29O(CH2)3−、n−C15H31O(CH2)3−、n−C16H33O(CH2)3−、n−C17H35O(CH2)3−又はn−C18H37O(CH2)3−である、請求項1に記載の化合物。
- R2は、アルキル又はハロである、請求項1に記載の化合物。
- R2は、メチル又はフルオロである、請求項1に記載の化合物。
- R1及びR2は、それらを構成する原子が相互に結合してなる、シクロアルキル又は置換シクロアルキルである、請求項1に記載の化合物。
- R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロプロピル又は置換シクロプロピルである、請求項1に記載の化合物。
- R3は、n−C16H33O(CH2)3−であり、
R2は、アルキル又はハロである、請求項1に記載の化合物。 - R3は、n−C16H33O(CH2)3−であり、
R2は、メチル又はフルオロである、請求項1に記載の化合物。 - R3は、n−C16H33O(CH2)3−であり、
R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロアルキル又は置換シクロアルキルである、請求項1に記載の化合物。 - R104、R105、R106、R107はアルキルであり、R102は−NR108R109である、請求項21に記載の化合物。
- R104、R105、R106、R107はアルキルであり、R102は−NR108R109であり、R103は水素である、請求項21に記載の化合物。
- R104、R105、R106、R107はメチル又はエチルであり、R102は−NH2であり、R103は水素である、請求項21に記載の化合物。
- R104はメチル又はエチルであり、R105、R106、R107はメチルであり、R102は−NH2であり、R103は水素である、請求項21に記載の化合物。
- R2はメチル又はフルオロである、請求項22〜26の何れか1項に記載の化合物。
- R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロアルキル又は置換シクロアルキルである、請求項22〜26の何れか1項に記載の化合物。
- R1及びR2は、それらを構成する炭素原子同士が相互に結合してなる、シクロプロピル又は置換シクロプロピルである、請求項22〜26の何れか1項に記載の化合物。
- 請求項1に記載の化合物及びと薬学的に許容されるビヒクルとを含む、医薬組成物。
- 又は治療を必要とする被検体に治療有効量の請求項1に記載の化合物を投与することを含む、ウイルス感染の治療方法。
- 又は治療を必要とする被検体に治療有効量の請求項1に記載の化合物を投与することを含む、新生物(腫瘍)の治療方法。
- 治療を必要とする被検体に治療有効量の請求項1に記載の化合物を投与することを含む、悪性腫瘍の治療方法。
- 細胞増殖を調節する方法であって、治療を必要とする被検体に治療有効量の請求項1に記載の化合物を投与することを含む、細胞増殖の調整方法。
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JP (1) | JP2013503197A (ja) |
KR (1) | KR20120124383A (ja) |
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AU (1) | AU2010292500A1 (ja) |
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JPS6157584A (ja) * | 1984-08-24 | 1986-03-24 | メルク エンド カムパニー インコーポレーテツド | 抗ウイルス化合物 |
WO2006137953A1 (en) * | 2005-04-01 | 2006-12-28 | The Regents Of The Univerisity Of California | Phosphono-pent-2-en-1-yl nucleosides and analogs |
WO2007130783A2 (en) * | 2006-05-03 | 2007-11-15 | Chimerix, Inc. | Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates |
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EP0338168A1 (en) * | 1988-04-19 | 1989-10-25 | Merrell Dow Pharmaceuticals Inc. | Phosphonoalkylpurine derivatives |
US5302585A (en) * | 1990-04-20 | 1994-04-12 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents |
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CN1921867B (zh) * | 2004-02-17 | 2010-05-05 | 株式会社Lg生命科学 | 用于治疗hiv感染的膦酸核苷衍生物 |
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JPS6157584A (ja) * | 1984-08-24 | 1986-03-24 | メルク エンド カムパニー インコーポレーテツド | 抗ウイルス化合物 |
WO2006137953A1 (en) * | 2005-04-01 | 2006-12-28 | The Regents Of The Univerisity Of California | Phosphono-pent-2-en-1-yl nucleosides and analogs |
WO2007130783A2 (en) * | 2006-05-03 | 2007-11-15 | Chimerix, Inc. | Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates |
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CN102781462A (zh) | 2012-11-14 |
CA2772261A1 (en) | 2011-03-17 |
KR20120124383A (ko) | 2012-11-13 |
US20130018018A1 (en) | 2013-01-17 |
WO2011031567A1 (en) | 2011-03-17 |
ZA201202032B (en) | 2012-12-27 |
IL218276A0 (en) | 2012-04-30 |
AU2010292500A1 (en) | 2012-03-15 |
EP2470194A4 (en) | 2013-03-06 |
RU2012106469A (ru) | 2013-11-10 |
MX2012002368A (es) | 2012-07-25 |
EP2470194A1 (en) | 2012-07-04 |
BR112012008050A2 (pt) | 2017-07-04 |
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