JP4954877B2 - 抗hiv薬剤としてのヌクレオシドホスホネート結合体 - Google Patents
抗hiv薬剤としてのヌクレオシドホスホネート結合体 Download PDFInfo
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- JP4954877B2 JP4954877B2 JP2007523866A JP2007523866A JP4954877B2 JP 4954877 B2 JP4954877 B2 JP 4954877B2 JP 2007523866 A JP2007523866 A JP 2007523866A JP 2007523866 A JP2007523866 A JP 2007523866A JP 4954877 B2 JP4954877 B2 JP 4954877B2
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Classifications
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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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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Description
本発明は一般に、HIV阻害性活性を有する化合物に関する。
細胞および組織を標的するために薬物および他の因子の送達を改善することは、長年にわたってかなりの研究の焦点であった。インビボおよびインビトロの両方で細胞に対して生物学的に活性な分子を輸送するために有効な方法を開発する多くの試みがなされてきたが、全体的な満足は証明されていない。阻害性薬物の細胞間の、例えば近隣の細胞への再分布を最小限にしたままで、細胞内標的とのその阻害性薬物の会合を最適化することはしばしば、困難であるか不十分である。
細胞内標的化は、細胞内の生物学的に活性な因子の蓄積または保持を可能にする方法および組成物によって達成され得る。本発明は、HIVの阻害またはHIVに対する治療活性のための組成物および方法を提供する。
1つ以上の基A0で置換される、結合体、そのエナンチオマーまたは、その薬学的に受容可能な塩もしくは溶媒和化合物を提供し、
ここで:
A0は存在しないか、Hであるか、結合であるか、A1、A2またはW3であって、ただしこれはこの結合体が少なくとも1つのA1を含むという条件下であり;
A1は:
Y1は独立して、O、S、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、またはN(N(RX)(RX))であり;
Y2は独立して、存在しないか、結合であるか、O、C(RX)(RX)、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、N(N(RX)(RX))、−S(O)M2−、または−S(O)M2−S(O)M2−であり;かつY2が2つのリン原子を結合する場合、Y2はまたC(R2)(R2)であってもよく;
RXは独立して、存在しないか、結合であるか、H、R1、R2、W3、保護基、または式:
ここで:
Ryは独立してH、W3、R2または保護基であり;
R1は独立してHまたは1〜18個の炭素原子のアルキルであり;
R2は独立してH、R1、R3またはR4であり各々のR4は独立して0〜3個のR3基で置換されるか、または炭素原子で一緒になって、2つのR2基が3〜12個の炭素、窒素および必要に応じて酸素原子の環または縮合環を形成し、そしてこの環系は0〜3個のR3基で置換されてもよく;
R3は、R3a、R3b、R3cまたはR3dであり、ただしこれはR3がヘテロ原子に結合する場合はR3が、R3cまたはR3dであるという条件下であり;
R3aは、F、Cl、Br、I、−CN、N3、−NO2、−OR1または−OR6aであり;
R3bは、Y1であり;
R3cは、−RX、−N(RX)(RX)、−SRX、−S(O)RX、−S(O)2RX、−S(O)(ORX)、−S(O)2(ORX)、−OC(Y1)RX、−OC(Y1)ORX、−OC(Y1)(N(RX)(RX))、−SC(Y1)RX、−SC(Y1)ORX、−SC(Y1)(N(RX)(RX))、−N(RX)C(Y1)RX、−N(RX)C(Y1)ORX、または−N(RX)C(Y1)(N(RX)(RX))であり;
R3dは、−C(Y1)RX、−C(Y1)ORX、または−C(Y1)(N(RX)(RX))であり;
R4は、H、1〜18個の炭素原子のアルキル、2〜18個の炭素原子のアルケニル、または2〜18個の炭素原子のアルキニルであり;
R5は、R4であり、各々のR4が0〜3個のR3基で置換され;
W3は、W4またはW5であり;
W4は、R5、−C(Y1)R5、−C(Y1)W5、−SOM2R5、または−SOM2W5であり;
W5は、炭素環または複素環であり、ここでW5は独立して、0〜3個のR2基で置換され;
W6は、0、1、2または3個のA3基で独立して置換されたW3であり;
KおよびK’は独立して、存在しないか、結合であるかまたは必要に応じて置換されたRyであり;
M2は0、1または2であり;
M12aは1、2、3、4、5、6、7、8、9、10、11または12であり;
M12bは0、1、2、3、4、5、6、7、8、9、10、11または12であり;
M1a、M1cおよびM1dは独立して0または1であり;かつ
M12cは0、1、2、3、4、5、6、7、8、9、10、11または12である。
[薬物]−(A0)nn
の化合物、そのエナンチオマーまたはその薬学的に受容可能な塩を提供し、ここで
薬物は式Aの化合物であって;
nnは1、2または3であり;
KおよびK’は上記のとおりであり;
A0は、A1、A2またはW3であり、ただしこれはこの結合体が少なくとも1つのA1を含む条件下であって
A1は:
Y1は独立して、O、S、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、またはN(N(RX)(RX))であり;
Y2は独立して、結合であるか、O、C(RX)(RX)、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、N(N(RX)(RX))、−S(O)M2−、または−S(O)M2−S(O)M2−であり;かつY2が2つのリン原子を結合する場合、Y2はまたC(R2)(R2)であってもよく;
RXは独立して、H、R1、R2、W3、保護基、または式:
ここで:
Ryは独立してH、W3、R2または保護基であり;
R1は独立してHまたは1〜18個の炭素原子のアルキルであり;
R2は独立してH、R1、R3またはR4であり、各々のR4は独立して0〜3個のR3基で置換されるか、または炭素原子で一緒になって、2つのR2基が3〜8個の炭素の環を形成し、そしてこの環は0〜3個のR3基で置換されてもよく;
R3は、R3a、R3b、R3cまたはR3dであり、ただしこれはR3がヘテロ原子に結合される場合はR3が、R3cまたはR3dであるという条件下であり;
R3aは、F、Cl、Br、I、−CN、N3、−NO2、−OR1または−OR6aであり;
R3bは、Y1であり;
R3cは、−RX、−N(RX)(RX)、−SRX、−S(O)RX、−S(O)2RX、−S(O)(ORX)、−S(O)2(ORX)、−OC(Y1)RX、−OC(Y1)ORX、−OC(Y1)(N(RX)(RX))、−SC(Y1)RX、−SC(Y1)ORX、−SC(Y1)(N(RX)(RX))、−N(RX)C(Y1)RX、−N(RX)C(Y1)ORX、または−N(RX)C(Y1)(N(RX)(RX))であり;
R3dは、−C(Y1)RX、−C(Y1)ORX、または−C(Y1)(N(RX)(RX))であり;
R4は、1〜18個の炭素原子のアルキル、2〜18個の炭素原子のアルケニル、または2〜18個の炭素原子のアルキニルであり;
R5は、R4であり、各々のR4が0〜3個のR3基で置換され;
W3は、W4またはW5であり;
W4は、R5、−C(Y1)R5、−C(Y1)W5、−SOM2R5、または−SOM2W5であり;
W5は、炭素環または複素環であり、ここでW5は独立して、0〜3個のR2基で置換され;
W6は、0、1、2または3個のA3基で独立して置換されたW3であり;
M2は0、1または2であり;
M12aは1、2、3、4、5、6、7、8、9、10、11または12であり;
M12bは0、1、2、3、4、5、6、7、8、9、10、11または12であり;
M1a、M1cおよびM1dは独立して0または1であり;かつ
KおよびK’は上記のとおりであり;
M12cは0、1、2、3、4、5、6、7、8、9、10、11または12である。
Y1は独立して、O、S、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、またはN(N(RX)(RX))であり;
Y2は独立して、存在しないか、結合であるか、O、C(RX)(RX)、N(RX)、N(O)(RX)、N(ORX)、N(O)(ORX)、N(N(RX)(RX))、−S(O)M2−、または−S(O)M2−S(O)M2−であり;かつY2が2つのリン原子を結合する場合、Y2はまたC(R2)(R2)であってもよく;
RXは独立して、H、R2、W3、保護基、または式:
Ryは独立してH、W3、R2または保護基であり;
R1は独立してHまたは1〜18個の炭素原子のアルキルであり;
R2は独立してH、R3またはR4であり、各々のR4は独立して0〜3個のR3基で置換され;
R3は、R3a、R3b、R3cまたはR3dであり、ただしこれはR3がヘテロ原子に結合される場合はR3が、R3cまたはR3dであるという条件下であり;
R3aは、F、Cl、Br、I、−CN、N3、−NO2、−OR1または−OR6aであり;
R3bは、Y1であり;
R3cは、−RX、−N(RX)(RX)、−SRX、−S(O)RX、−S(O)2RX、−S(O)(ORX)、−S(O)2(ORX)、−OC(Y1)RX、−OC(Y1)ORX、−OC(Y1)(N(RX)(RX))、−SC(Y1)RX、−SC(Y1)ORX、−SC(Y1)(N(RX)(RX))、−N(RX)C(Y1)RX、−N(RX)C(Y1)ORX、または−N(RX)C(Y1)(N(RX)(RX))であり;
R3dは、−C(Y1)RX、−C(Y1)ORX、または−C(Y1)(N(RX)(RX))であり;
R4は、1〜18個の炭素原子のアルキル、2〜18個の炭素原子のアルケニル、または2〜18個の炭素原子のアルキニルであり;
R5は、R4であり、各々のR4が0〜3個のR3基で置換され;
R5aは、独立して、1〜18個の炭素原子のアルキレン、2〜18個の炭素原子のアルケニレン、または2〜18個の炭素原子のアルキニレンであり、そのアルキレン、アルケニレンまたはアルキニレンのうちいずれか1つが0〜3個のR3基で置換され;
W3は、W4またはW5であり;
W4は、R5、−C(Y1)R5、−C(Y1)W5、−SO2R5、または−SO2W5であり;
W5は、炭素環または複素環であり、ここでW5は独立して、0〜3個のR2基で置換され;
W6は、0、1、2または3個のA3基で独立して置換されたW3であり;
KおよびK’は上記のとおりであり;
M2は0、1または2であり;
M12aは1、2、3、4、5、6、7、8、9、10、11または12であり;
M12bは0、1、2、3、4、5、6、7、8、9、10、11または12であり;
M1a、M1cおよびM1dは独立して0または1であり;かつ
M12cは0、1、2、3、4、5、6、7、8、9、10、11または12である。
引用文献はここで、本発明の実施形態を確実にするために詳細になされており、その実施例は添付の構造および式に図示される。本発明は、列挙された実施形態と組み合わせて記載されるが、それらは本発明をこれらの実施形態に限定するものではないと理解される。逆に、本発明は、この実施形態によって規定されるような本発明の範囲内に包含され得る全ての代替、改変および等価物を包含するものとする。
他に言及しない限り、以下の用語および句は本明細書において用いる場合、以下の意味を有するものとする。
本発明の状況では、保護基とははプロドラッグ部分および化学的保護基を含む。
エステル形成基としては:(1)ホスホン酸エステル形成基、例えば、ホスホンアミデートエステル、ホスホロチオエートエステル、ホスホネートエステルおよびホスホン−ビス−アミデート;(2)カルボキシルエステル形成基、および(3)イオウエステル形成基、例えば、スルホン酸塩、硫酸塩およびスルフィン酸塩が挙げられる。
R1はHまたはC1−C12アルキルであってもよく;m1は1、2、3、4、5、6、7または8であり、そしてフェニル炭素環は、0〜3個のR2基で置換される。Y1がOである場合、乳酸エステルが形成され、そしてY1がN(R2)、N(OR2)またはN(N(R2)2である場合、ホスホンアミデートエステルが生じる。
C3−C12複素環(上記)またはアリール。これらの芳香族基は必要に応じて多環式または単環式である。例としては、フェニル、スピリル、2−および3−ピロリル、2−および3−チエニル、2−および4−イミダゾリル、2−、4−および5−オキサゾリル、3−および4−イソキサゾリル、2−、4−および5−チアゾリル、3−、4−および5−イソチアゾリル、3−および4−ピラゾリル、1−、2−、3−および4−ピリジニル、ならびに1−、2−、4−および5−ピリミジニル、C3−C12複素環またはハロで置換されたアリール、R1、R1−O−C1−C12アルキレン、C1−C12アルコキシ、CN、NO2、OH、カルボキシ、カルボキシエステル、チオール、チオエステル、C1−C12ハロアルキル(1−6ハロゲン原子)、C2−C12アルケニルまたはC2−C12アルキニルが挙げられる。このような基としては、2−、3−および4−アルコキシフェニル(C1−C12アルキル)、2−、3−および4−メトキシフェニル、2−、3−および4−エトキシフェニル、2,3−、2,4−、2,5−、2,6−、3,4−および3,5−ジエトキシフェニル、2−および3−カルボエトキシ−4−ヒドロキシフェニル、2−および3−エトキシ−4−ヒドロキシフェニル、2−および3−エトキシ−5−ヒドロキシフェニル、2−および3−エトキシ−6−ヒドロキシフェニル、2−、3−および4−O−アセチルフェニル、2−、3−および4−ジメチルアミノフェニル、2−、3−および4−メチルメルカプトフェニル、2−、3−および4−ハロフェニル(2−、3−および4−フルオロフェニルおよび2−、3−および4−クロロフェニルを含む)、2,3−、2,4−、2,5−、2,6−、3,4−および3,5−ジメチルフェニル、2,3−、2,4−、2,5−、2,6−、3,4−および3,5−ビスカルボキシエチルフェニル、2,3−、2,4−、2,5−、2,6−、3,4−および3,5−ジメトキシフェニル、2,3−、2,4−、2,5−、2,6−、3,4−および3,5−ジハロフェニル(2,4−ジフルオロフェニルおよび3,5−ジフルオロフェニル)を含む、2−、3−および4−ハロアルキルフェニル(1〜5個のハロゲン原子、4−トリフルオロメチルフェニルを含むC1−C12アルキル)、2−、3−および4−シアノフェニル、2−、3−および4−ニトロフェニル、2−、3−および4−ハロアルキルベンジル(1〜5ハロゲン原子、C1−C12アルキルであってこれには4−トリフルオロメチルベンジルおよび2,3−および4−トリクロロメチルフェニルならびに2−、3−および4−トリクロロメチルフェニルを含む)、4−N−メチルピペリジニル、3−N−メチルピペリジニル、1−エチルピペラジニル、ベンジル、アルキルサリチルフェニル(C1−C4アルキルであってこれには2,3−および4−エチルサリチルフェニルを含む)、2−、3−および4−アセチルフェニル、1,8−ジヒドロキシナフチル(−C10H6−OH)およびアリールオキシエチル[C6−C9アリール(フェノキシアチルを含む)]、2,2’−ジヒドロキシビフェニル、2−、3−および4−N,N−ジアルキルアミノフェノール、−C6H4CH2−N(CH3)2、トリメトキシベンジル、トリクトキシベンジル(tricthoxybenzyl)、2−アルキルピリジニル(C1−4アルキル);
5または6個の炭素の単糖類、二糖類またはオリゴ糖(3〜9個の単糖残基);
トリグリセリド、例えば、トリグリセリドのグリセリル酸素を通じて本明細書における親の化合物のアシルに結合されたα−D−β−ジグリセリド(ここでグリセリド脂質からなる脂肪酸は一般に、天然に存在する飽和または不飽和のC6−26、C6−18、C6−10脂肪酸、例えば、リノール酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、パルミトレイン酸、リノレン酸などの脂肪酸である);
リン脂質のリン酸塩を通じてカルボキシル基に結合されたリン脂質;
フタリジル(Claytonら、Antimicrob.Agents Chemo.(1974)5(6):670〜671の図1に示される);
環状の炭酸塩、例えば(5−Rd−2−オキソ−1,3−ジオキソレン−4−イル)メチルエステル(Sakamotoら、Chem.Pharm.Bull.(1984)32(6)2241〜2248)であって、ここでRdはR1、R4またはアリールであるもの;そして
CH(CH2CH2OCH3)OC(O)C(CH3)3、
・エーテル(メチル、t−ブチル、アリル);
・置換メチルエーテル(メトキシメチル、メチルチオメチル、t−ブチルチオメチル、(フェニルジメチルシリル)メトキシメチル、ベンジルオキシメチル、p−メトキシベンジルオキシメチル、(4−メトキシフェノキシ)メチル、グアイアコールメチル、t−ブトキシメチル、4−ペンテニルオキシメチル、シロキシメチル、2−メトキシエトキシメチル、2,2,2−トリクロロエトキシメチル、ビス(2−クロロエトキシ)メチル、2−(トリメチルシリル)エトキシメチル、テトラヒドロピラニル、3−ブロモテトラヒドロピラニル、テトラヒドロチオピラニル(tetrahydropthiopyranyl)、1−メトキシシクロヘキシル、4−メトキシテトラヒドロピラニル、4−メトキシテトラヒドロチオピラニル、4−メトキシテトラヒドロチオピラニル(Methoxytetrahydropthiopyranyl)、S,S−ジオキシド、1[(2−クロロ−4−メチル)フェニル]−4−メトキシピペリジン−4−イル、1,4−ジオキサ−2−イル、テトラヒドロフラニル、テトラヒドロチオフラニル、2,3,3a,4,5,6,7,7a−オクタヒドロ−7,8,8−トリメチル−4,7−メタノベンゾフラン−2−イル));
・置換エチルエーテル(1−エトキシエチル、1−(2−クロロエトキシ)エチル、1−メチル−1−メトキシエチル、1−メチル1−1−ベンジルオキシエチル、1−メチル−1−ベンジルオキシ−2−フルオロエチル、2,2,2−トリクロロエチル、2−トリメチルシリルエチル、2−(フェニルセレニル)エチル、
・p−クロロフェニル、p−メトキシフェニル、2,4−ジニトロフェニル、ベンジル);
・置換ベンジルエーテル(p−メトキシベンジル、3,4−ジメトキシベンジル、o−ニトロベンジル、p−ニトロベンジル、p−ハロベンジル、2,6−ジクロロベンジル、p−シアノベンジル、p−フェニルベンジル、2−、および4−ピコリル、3−メチル−2−ピコリル N−オキシド、ジフェニルメチル、p,p’−ジニトロベンズヒドリル、5−ジベンゾスベリル、トリフェニルメチル、α−ナフチルジフェニルメチル、p−メトキシフェニルジフェニルメチル、ジ(p−メトキシフェニル)フェニルメチル、トリ(p−メトキシフェニル)メチル、4(4’−ブロモフェナシルオキシ)フェニルジフェニルメチル、4,4’,4”−トリス(4,5−ジクロロフタルイミドフェニル)メチル、4,4’,4”−トリス(レブリノイルオキシフェニル)メチル、4,4’,4”−トリス(ベンゾイルオキシフェニル)メチル、3−(イダゾール−1−イルメチル)ビス(4’,4”−ジメトキシフェニル)メチル、1,1−ビス(4−メトキシフェニル)−1’−ピレニルメチル、9−アントリル、9−(9−フェニル)キサンテニル、9−(9−フェニル−10−オキソ)アントリル、1,3−ベンゾジチオラン−2−イル、ベンゾイソチアゾリル S,S−ジオキシド);
・シリルエーテル(トリメチルシリル、トリエチルシリル、トリイソプロピルシリル、ジメチルイソプロピルシリル、ジエチルイソプロピルシリル、ジメチルテキシルシリル、t−ブチルジメチルシリル、t−ブチルジフェニルシリル、トリベンジルシリル、トリ−p−キシリルシリル、トリフェニルシリル、ジフェニルメチルシリル、t−ブチルメトキシフェニルシリル);
・エステル(ギ酸塩、ギ酸ベンゾイル、酢酸塩、クロロアセテート、ジクロロ酢酸、トリクロロアセテート、トリフルオロアセテート、メトキシアセテート、トリフェニルメトキシアセテート、フェノキシアセテート、p−クロロフェノキシアセテート、p−ポリ−フェニルアセテート、3−フェニルプロピオネート、4−オキソペンタノエート、(レブリネート)、4,4−(エチレンジチオ)ペンタノエート、ピバロエート(pivaloate)、アダマントエート(adamantoate)、クロトネート、4−メトキシクロトネート、安息香酸塩、p−フェニルベンゾエート、2,4,6−トリメチルベンゾエート(メシトエート));
・炭酸塩((メチル、9−フルオレニルメチル、エチル、2,2,2トリクロロエチル、2−(トリメチルシリル)エチル、2−(フェニルスルホニル)エチル、2−(トリフェニルホスホニオ)エチル、イソブチル、ビニル、アリル、p−ニトロフェニル、ベンジル、p−メトキシベンジル、3,4−ジメトキシベンジル、o−ニトロベンジル、p−ニトロベンジル、S−ベンジルチオカーボネート、4−エトキシ−1−ナチフル、メチルジチオカーボネート);
・切断補助基(2−インドベンゾエート、4−アジドブチラート、4−ニトロ−4−メチルペンタノエート、o−(ジブロモメチル)ベンゾエート、2−ホルミルベンゼンスルホナート、2−(メチルチオメトキシ)エチルカーボネート、4−(メチルチオメトキシ)ブチラート、2−(メチルチオメトキシメチル)安息香酸塩);雑多なエステル(2,6−ジクロロ−4−メチルフェノキシアセテート、2,6−ジクロロ−4−(1,1,3,3テトラメチルブチル)フェノキシアセテート、2,4−ビス(1,1−ジメチルプロピル)フェノキシアセテート、クロロジフェニルアセテート、イソブチレート、モノスクシネート、(E)−2−メチル−2−ブテノアート(チグロエート(tigloate))、o(メトキシカルボニル)ベンゾエート、p−ポリ−ベンゾエート、α−ナフトエート、硝酸塩、アルキルN,N,N’,N’−テトラメチルホスホロジアミデート、N−フェニルカルバメート、ホウ酸塩、ジメチルホスフィノチオイル、2,4−ジニトロフェニルスルフェナート);ならびに
・スルホン酸塩(硫酸塩、メタンスルホン酸(メシレート)、ベンジルスルホナート、トシラート)。
別のセットの保護基としては、Greeneの第315〜385頁に記載される任意の代表的なアミノ保護基が挙げられる。それらとしては、以下が挙げられる:
・カルバメート(メチルおよびエチル、9−フルオレニルメチル、9(2−スルホ)フルオレニルメチル、9−(2,7−ジブロモ)フルオレニルメチル、2,7−ジ−t−ブチル−[9−(10,10−ジオキソ−10,10,10,10−テトラヒドロチオキサンチル)]メチル、4−メトキシフェナシル);
・置換エチル(2,2,2−トリクロロエチル、2−トリメチルシリルエチル、2−フェニルエチル、1−(1−アダマンチル)−1−メチルエチル、1,1−ジメチル−2−ハロエチル、1,1−ジメチル−2,2−ジブロモエチル、1,1−ジメチル−2,2,2−トリクロロエチル、1−メチル−1−(4−ビフェニルイル)エチル、1−(3,5−ジ−t−ブチルフェニル)−1−メチルエチル、2−(2’−および4’−ピリジル)エチル、2−(N,N−ジシクロヘキシルカルボキサミド)エチル、t−ブチル、1−アダマンチル、ビニル、アリル、1−イソプロピルアリル、シンナミル、4−ニトロシンナミル、8−キノリル、N−ヒドロキシピペリジニル、アルキルジチオ、ベンジル、p−メトキシベンジル、p−ニトロベンジル、p−ブロモベンジル、p−クロロベンジル、2,4−ジクロロベンジル、4−メチルスルフィニルベンジル、9−アントリルメチル、ジフェニルメチル);
・切断補助基:(2−メチルチオエチル、2−メチルスルホニルエチル、2−(p−トルエンスルホニル)エチル、[2−(1,3−ジチアニル)]メチル、4−メチルチオフェニル、2,4−ジメチルチオフェニル、2−ホスホニオエチル、2−トリフェニルホスホニオイソプロピル、1,1−ジメチル−2−シアノエチル、m−クロロ−p−アシルオキシベンジル、p−(ジヒドロキシボリル)ベンジル、5−ベンズイソキサゾリルメチル、2−(トリフルオロメチル)−6−クロモニルメチル);
・光分解性切断可能な基:(m−ニトロフェニル、3,5−ジメトキシベンジル、o−ニトロベンジル、3,4−ジメトキシ−6−ニトロベンジル、フェニル(o−ニトロフェニル)メチル);尿素型誘導体(フェノチアジニル−(10)−カルボニル、N’−p−トルエンスルホニルアミノカルボニル、N’−フェニルアミノチオカルボニル);
・雑多なカルバメート(t−アミル、S−ベンジル チオカルバメート、p−シアノベンジル、シクロブチル、シクロヘキシル、シクロペンチル、シクロプロピルメチル、p−デシルオキシベンジル、ジイソプロピルメチル、2,2−ジメトキシカルボニルビニル、o−(N,N−ジメチルカルボキサミド)ベンジル、1,1−ジメチル−3−(N,N−ジメチルカルボキサミド)プロピル、1,1−ジメチルプロピニル、ジ(2−ピリジル)メチル、2−フラニルメチル、2−インドエチル、イソボルニル、イソブチル、イソニコチニル、p−(p’−メトキシフェニルアゾ)ベンジル、1−メチルシクロブチル、1−メチルシクロヘキシル、1−メチル−1−シクロプロピルメチル、1−メチル−1−(3,5−ジメトキシフェニル)エチル、1−メチル−1−(p−フェニルアゾフェニル)エチル、1−メチル−1−フェニルエチル、1−メチル−1−(4−ピリジル)エチル、フェニル、p−(フェニルアゾ)ベンジル、2,4,6−トリ−t−ブチルフェニル、4−(トリメチルアンモニウム)ベンジル、2,4,6−トリメチルベンジル);
・アミド(N−ホルミル、N−アセチル、N−クロロアセチル、N−トリクロロアセチル、N−トリフルオロアセチル、N−フェニルアセチル、N−3−フェニルプロピオニル、N−ピコリノイル、N−3−ピリジルカルボキサミド、N−ベンゾイルフェニルアラニル、N−ベンゾイル、N−p−フェニルベンゾイル);
・切断補助アミド(N−o−ニトロフェニルアセチル、N−o−ニトロフェノキシアセチル、N−アセトアセチル、(N’−ジチオベンジルオキシカルボニルアミノ)アセチル、N−3−(p−ヒドロキシフェニル)プロピオニル、N−3−(o−ニトロフェニル)プロピオニル、N−2−メチル−2−(o−ニトロフェノキシ)プロピオニル、N−2−メチル−2−(o−フェニルアゾフェノキシ)プロピオニル、N−4−クロロブチリル、N−3−メチル−3−ニトロブチリル、N−o−ニトロシンナモイル、N−アセチルメチオニン、N−o−ニトロベンゾイル、N−o−ベンゾイルオキシメチル)ベンゾイル、4,5−ジフェニル−3−オキサゾリン−2−オン);
・環状イミド誘導体(N−フタルイミド、N−ジチアスクシノイル、N−2,3−ジフェニルマレオイル、N−2,5−ジメチルピロリル、N−1,1,4,4−テトラメチルジシリルアザシクロペンタン付加物、5−置換1,3−ジメチル−1,3,5−トリアザシクロヘキサン−2−オン、5−置換1,3−ジベンジル−1,3−5−トリアザシクロヘキサン−2−オン、1−置換3,5−ジニトロ−4−ピリドニル);
・N−アルキルおよびN−アリールアミン(N−メチル、N−アリル、N−[2−(トリメチルシリル)エトキシ]メチル、N−3−アセトキシプロピル、N−(1−イソプロピル−4−ニトロ−2−オキソ−3−ピロリン−3−イル)、四級アンモニウム塩、N−ベンジル、N−ジ(4−メトキシフェニル)メチル、N−5−ジベンゾスベリル、N−トリフェニルメチル、N−(4−メトキシフェニル)ジフェニルメチル、N−9−フェニルフルオレニル、N−2,7−ジクロロ−9−フルオレニルメチレン、N−フェロセニルメチル、N−2−ピコリルアミンN’−オキシド);
・イミン誘導体(N−1,1−ジメチルチオメチレン、N−ベンジリデン、N−p−メトキシベニリデン、N−ジフェニルメチレン、N−[(2−ピリジル)メシチル]メチレン、N,(N’,N’−ジメチルアミノメチレン、N,N’−イソプロピリデン、N−p−ニトロベンジリデン、N−サリチリデン、N−5−クロロサリチリデン、N−(5−クロロ−2−ヒドロキシフェニル)フェニルメチレン、N−シクロヘキシリデン);
・エナミン誘導体(N−(5,5−ジメチル−3−オキソ−1−シクロヘキセニル));
・N−金属誘導体(N−ボラン誘導体、N−ジフェニルボロン酸誘導体、N−[フェニル(ペンタカルボニルクロミウム−または−タングステン)]カルベニル、N−銅またはN−亜鉛キレート);
・N−N誘導体(N−ニトロ、N−ニトロソ、N−酸化物);
・N−P誘導体(N−ジフェニルホスフィニル、N−ジメチルチオホスフィニル、N−ジフェニルチオホスフィニル、N−ジアルキル ホスホリル、N−ジベンジル ホスホリル、N−ジフェニルホスホリル);
・N−Si誘導体;N−S誘導体;およびN−スルフェニル誘導体(N−ベンゼンスルフェニル、N−o−ニトロベンゼンスルフェニル、N−2,4−ジニトロベンゼンスルフェニル、N−ペンタクロロベンゼンスルフェニル、N−2−ニトロ−4−メトキシベンゼンスルフェニル、N−トリフェニルメチルスルフェニル、N−3−ニトロピリジンスルフェニル);およびN−スルホニル誘導体(N−p−トルエンスルホニル、N−ベンゼンスルホニル、N−2,3,6−トリメチル−4−メトキシベンゼンスルホニル、N−2,4,6−トリメトキシベンゼンスルホニル、N−2,6−ジメチル−4−メトキシベンゼンスルホニル、N−ペンタメチルベンゼンスルホニル、N−2,3,5,6,−テトラメチル−4−メトキシベンゼンスルホニル、N−4−メトキシベンゼンスルホニル、N−2,4,6−トリメチルベンゼンスルホニル、N−2,6−ジメトキシ−4−メチルベンゼンスルホニル、N−2,2,5,7,8−ペンタメチルクロマン−6−スルホニル、N−メタンスルホニル、N−β−トリメチルシリルエタンスルホニル、N−9−アントラセンスルホニル、N−4−(4’,8’−ジメトキシナフチルメチル)ベンゼンスルホニル、N−ベンジルスルホニル、N−トリフルオロメチルスルホニル、N−フェナシルスルホニル)。
本発明の化合物のアミノ酸またはポリペプチド保護基は、構造R15NHCH(R16)C(O)−を有し、R15はH、アミノ酸またはポリペプチド残基であり、またはR5およびR16は以下に規定される。
グリシン;
アミノポリカルボン酸、例えば、アスパラギン酸、β−ヒドロキシアスパラギン酸、グルタミン酸、β−ヒドロキシグルタミン酸、β−メチルアスパラギン酸、β−メチルグルタミン酸、β,β−ジメチルアスパラギン酸、γ−ヒドロキシグルタミン酸、β,γ−ジヒドロキシグルタミン酸、β−フェニルグルタミン酸、γ−メチレングルタミン酸、3−アミノアジピン酸、2−アミノピメリン酸、2−アミノスベリン酸および2−アミノセバシン酸;
アミノ酸アミド例えば、グルタミンおよびアスパラギン;
ポリアミノ−または多塩基−モノカルボン酸、例えば、アルギニン、リジン、β−アミノアラニン、γ−アミノブチリン、オルニチン、シトルリン、ホモアルギニン、ホモシトルリン、ヒドロキシリジン、アロヒドロキシリジン、およびジアミノ酪酸;
他のアミノ酸残基、例えば、ヒスチジン;
ジアミノジカルボン酸、例えば、α,α’−ジアミノコハク酸、α,α’−ジアミグルタル酸、α,α’−ジアミアジピン酸、α,α’−ジアミピメリン酸、α,α’−ジアミノ−β−ヒドロキシピメリン酸、α,α’−ジアミスベリン酸、α,α’−ジアミノアゼライン酸、およびα,α’−ジアミセバシン酸;
イミノ酸、例えば、プロリン、ヒドロキシプロリン、アロヒドロキシプロリン、γ−メチルプロリン、ピペコリン酸、5−ヒドロキシピペコリン酸、およびアゼチジン−2−カルボン酸;
モノ−またはジ−アルキル(代表的にはC1−C8分枝または正常)アミノ酸、例えば、アラニン、バリン、ロイシン、アリルグリシン、ブチリン、ノルバリン、ノルロイシン、ヘプチリン、α−メチルセリン、α−アミノ−α−メチル−γ−ヒドロキシ吉草酸、α−アミノ−α−メチル−δ−ヒドロキシ吉草酸、α−アミノ−α−メチル−ε−ヒドロキシカプロン酸、イソバリン、α−メチルグルタミン酸、α−アミノイソ酪酸、α−アミノジエチル酢酸、α−アミノジイソプロピル酢酸、α−アミノジ−n−プロピル酢酸、α−アミノジイソブチル酢酸、α−アミノジ−n−ブチル酢酸、α−アミノエチルイソプロピル酢酸、α−アミノ−n−プロピル酢酸、α−アミノジイソアミル酢酸、α−メチルアスパラギン酸、α−メチルグルタミン酸、1−アミノシクロプロパン−1−カルボン酸;イソロイシン、アロイソロイシン、tert−ロイシン、β−メチルトリプトファンおよびα−アミノ−β−エチル−β−フェニルプロピオン酸;
β−フェニルセリニル;
α−アミノ−β−ヒドロキシ脂肪酸、例えば、セリン、β−ヒドロキシロイシン、β−ヒドロキシノルロイシン、β−ヒドロキシノルバリン、およびα−アミノ−β−ヒドロキシステアリン酸;
α−アミノ、α−、γ−、δ−またはε−ヒドロキシ酸、例えば、ホモセリン、δ−ヒドロキシノルバリン、γ−ヒドロキシノルバリンおよびε−ヒドロキシノルロイシン残基;カナバイン(canavine)およびカナリン(canaline);γ−ヒドロキシオルニチン;
2−ヘキソサミン酸、例えば、D−グルタミン酸またはD−ガラクトサミン酸;
α−アミノ−β−チオール、例えば、ペニシラミン、β−チオールノバリンまたはβ−チオールブチリン;
他のイオウ含有アミノ酸残基であって、これには、システイン;ホモシステイン、β−フェニルメチオニン、メチオニン、S−アリル−L−システインスルホキシド、2−チオールスチジン、シスタチオニン、およびシステインまたはホモシステインのチオールエステルを含む;
フェニルアラニン、トリプトファンおよび環−置換αアミノ酸、例えば、フェニル−またはシクロヘキシルアミノ酸α−アミノフェニル酢酸、α−アミノシクロヘキシル酢酸およびα−アミノ−β−シクロヘキシルプロピオン酸;フェニルアラニンアナログおよび誘導体であって、これにはアリール、低級アルキル、ヒドロキシ、グアニジノ、オキシアルキルエーテル、ニトロ、イオウまたはハロ−置換フェニル(例えば、チロシン、メチルチロシンおよびo−クロロ−、p−クロロ−、3,4−ジクロロ、o−、m−またはp−メチル−、2,4,6−トリメチル−、2−エトキシ−5−ニトロ、2−ヒドロキシ−5−ニトロおよびp−ニトロ−フェニルアラニン);フリル−、チエニル−、ピリジル−、ピリミジニル−、プリニル−、またはナフチルアラニン;およびトリプトファンアナログおよび誘導体であって、これにはキヌレニン、3−ヒドロキシキヌレニン、2−ヒドロキシトリプトファンおよび4−カルボキシトリプトファンを含む;
α−アミノ置換アミノ酸であって、これにはサルコシン(N−メチルグリシン)、N−ベンジルグリシン、N−メチルアラニン、N−ベンジルアラニン、N−メチルフェニルアラニン、N−ベンジルフェニルアラニン、N−メチルバリンおよびN−ベンジルバリンを含む;そして
α−ヒドロキシおよび置換α−ヒドロキシアミノ酸であって、これにはセリン、トレオニン、アロトレオニン、ホスホセリンおよびホスホトレオニンを含む。
AA、AR、AN、AD、AC、AE、AQ、AG、AH、AI、AL、AK、AM、AF、AP、AS、AT、AW、AY、AV、RA、RR、RN、RD、RC、RE、RQ、RG、RH、RI、RL、RK、RM、RF、RP、RS、RT、RW、RY、RV、NA、NR、NN、ND、NC、NE、NQ、NG、NH、NI、NL、NK、NM、NF、NP、NS、NT、NW、NY、NV、DA、DR、DN、DD、DC、DE、DQ、DG、DH、DI、DL、DK、DM、DF、DP、DS、DT、DW、DY、DV、CA、CR、CN、CD、CC、CE、CQ、CG、CH、CI、CL、CK、CM、CF、CP、CS、CT、CW、CY、CV、EA、ER、EN、ED、EC、EE、EQ、EG、EH、EI、EL、EK、EM、EF、EP、ES、ET、EW、EY、EV、QA、QR、QN、QD、QC、QE、QQ、QG、QH、QI、QL、QK、QM、QF、QP、QS、QT、QW、QY、QV、GA、GR、GN、GD、GC、GE、GQ、GG、GH、GI、GL、GK、GM、GF、GP、GS、GT、GW、GY、GV、HA、HR、HN、HD、HC、HE、HQ、HG、HH、HI、HL、HK、HM、HF、HP、HS、HT、HW、HY、HV、IA、IR、IN、ID、IC、IE、IQ、IG、IH、II、IL、IK、IM、IF、IP、IS、IT、IW、IY、IV、LA、LR、LN、LD、LC、LE、LQ、LG、LH、LI、LL、LK、LM、LF、LP、LS、LT、LW、LY、LV、KA、KR、KN、KD、KC、KE、KQ、KG、KH、KI、KL、KK、KM、KF、KP、KS、KT、KW、KY、KV、MA、MR、MN、MD、MC、ME、MQ、MG、MH、MI、ML、MK、MM、MF、MP、MS、MT、MW、MY、MV、FA、FR、FN、FD、FC、FE、FQ、FG、FH、FI、FL、FK、FM、FF、FP、FS、FT、FW、FY、FV、PA、PR、PN、PD、PC、PE、PQ、PG、PH、PI、PL、PK、PM、PF、PP、PS、PT、PW、PY、PV、SA、SR、SN、SD、SC、SE、SQ、SG、SH、SI、SL、SK、SM、SF、SP、SS、ST、SW、SY、SV、TA、TR、TN、TD、TC、TE、TQ、TG、TH、TI、TL、TK、TM、TF、TP、TS、TT、TW、TY、TV、WA、WR、WN、WD、WC、WE、WQ、WG、WH、WI、WL、WK、WM、WF、WP、WS、WT、WW、WY、WV、YA、YR、YN、YD、YC、YE、YQ、YG、YH、YI、YL、YK、YM、YF、YP、YS、YT、YW、YY、YV、VA、VR、VN、VD、VC、VE、VQ、VG、VH、VI、VL、VK、VM、VF、VP、VS、VT、VW、VYおよびVVである。
ラジカル、置換基および範囲について記載された特定の値、ならびに本明細書において記載された本発明の特定の実施形態は、例示のみのためである;それらは、他の規定された値も、または規定の範囲内の他の値も除外しない。
ここで:
Ryは、独立してH、W3、R2または保護基であり;
R1は、独立してHまたは1〜18個の炭素原子のアルキルである;
R2は、独立してH、R1、R3またはR4であり、各々のR4が独立して0〜3個のR3基で置換されるか、または炭素原子と一緒になって、2つのR2基が3〜8個の炭素の環を形成し、そしてその環は0〜3個のR3基で置換されてもよく;
ここでR3は本明細書に規定のとおりである。
ここで:
m1a、m1b、m1c、m1dおよびm1eは独立して0または1であり;
m12cは0、1、2、3、4、5、6、7、8、9、10、11または12であり;
RyはH、W3、R2または保護基である;
ここでW3、R2、Y1およびY2は本明細書に記載のとおりであり;
ただしこれは:
m1a、m12c、およびm1dが0であるならば、m1b、m1cおよびm1eは0であり;
m1aおよびm12cが0でありm1dが0でないならば、m1bおよびm1cは0であり;
m1aおよびm1dが0でありかつm12cが0でないならば、m1bならびにm1cおよびm1eの少なくとも1つは0であり;
m1aが0でありかつm12cおよびm1dが0でないならば、m1bは0であり;
m12cおよびm1dが0でありかつm1aが0でないならば、m1b、m1cおよびm1eのうち少なくとも2つが0であり;
m12cが0でありかつm1aおよびm1dが0でないならば、m1bおよびm1cのうち少なくとも1つが0であり;そして
m1dが0でありかつm1aおよびm12cが0でないならば、m1cおよびm1eのうち少なくとも1つが0である;
という条件下である。
本発明は、直接(例えば、共有結合を通じて)または連結基(すなわちリンカー)を通じて1つ以上のホスホン酸基に必要に応じて連結されるHIV阻害化合物を含む結合体を提供する。このリンカーの性質は、ホスホン酸含有化合物が治療剤として機能する能力を妨害しないならば重要ではない。ホスホン酸またはリンカーは、このホスホン酸塩またはリンカーの結合のための開放原子価を提供するためにこの化合物の水素または任意の部分を除去することによって、この化合物の上の任意の合成上実行可能な位置で化合物(例えば式Aの化合物)に連結され得る。
本発明の化合物の必要に応じて組み込まれたホスホン酸基は、それらが所望の作用部位、すなわち細胞の内側に達した後の段階でインビボで切断し得る。細胞の内側の作用の1機序は、負に荷電された「閉じ込められた(locked−in)」中間体を提供するために、例えば、エステラーゼによる第一の切断を必要とし得る。従って、本発明の化合物における末端エステル基の切断は、負に荷電された「閉じ込められた」中間体を放出する不安定な中間体を提供する。
本発明の化合物としては、HIV阻害性活性を有する化合物が挙げられる。本発明の化合物は必要に応じて、プロドラッグ部分であってもよい、1つ以上の(例えば、1、2、3または4つの)ホスホン酸基を保有する。
1実施形態では、本発明は、ヒトPBMC(末梢血単核球)において蓄積し得る化合物を提供する。PBMCとは、丸いリンパ球および単球を有する血球をいう。生理学的には、PBMCは、感染に対する機構の重要な成分である。PBMCは、正常な健常ドナーのヘパリン処理全血またはバフィーコートから、標準的な密度勾配遠心分離によって単離されて、界面から回収され、洗浄(例えば、リン酸緩衝化生理食塩水)され、そして凍結培地に保管され得る。PBMCは、マルチウェルのプレート中で培養され得る。培養の種々の時点で、上清は、評価のために取り出されてもよいし、または細胞は回収されて分析されてもよい(Smith R.ら(2003)Blood 102(7):2532〜2540)。本実施形態の化合物はさらに、ホスホン酸塩またはホスホン酸プロドラッグを含んでもよい。さらに代表的には、このホスホン酸塩またはホスホン酸プロドラッグは、本明細書において記載されるような構造A3を有し得る。
本発明の化合物は、不斉中心、例えば、不斉炭素またはリン原子を有し得る。従って、本発明の化合物は、エナンチオマー、ジアステレオマーおよびアトロプ異性体を含む全ての立体異性体のラセミ混合物を包含する。さらに本発明の化合物は、任意のまたは全ての非対称性の不斉原子で富化されるかまたは分解された光学異性体を含む。換言すれば、この描写とは異なる不斉中心は、キラル異性体またはラセミ混合物として提供される。ラセミ混合物およびジアステレオマー混合物の両方、ならびに実質的にそのエナンチオマーもジアステレオマーパートナーも含まない、単離または合成された個々の光学異性体は全て本発明の範囲内である。このラセミ混合物は、例えば、光学的に活性な補助剤、例えば酸または塩基で形成されたジアステレオマー塩の分離、その後に光学的に活性な物質へ変換して戻すことのような周知の技術を通じて、その個々の実質的に光学的に純粋な異性体に分離される。ほとんどの場合、所望の光学異性体は、所望の出発材料の適切な立体異性体で開始して、立体特異的な反応によって合成される。
本発明の組成物は必要に応じて、例えば、Na+、Li+、K+、Ca+2およびMg+2を含む、本明細書における化合物の塩、特に薬学的に受容可能な非毒性の塩を含む。このような塩は、適切な陽イオン、例えば、アルカリおよびアルカリ土類金属イオンまたはアンモニウムおよび四級アミノイオンと、酸性の陰イオン部分、代表的にはカルボン酸との組み合わせによって誘導される塩を含んでもよい。単価の塩は水溶性の塩が所望される場合に好ましい。
本発明の別の局面は、HIVの活性を阻害する方法に関し、この方法は、HIVを含むと疑わしいサンプルを本発明の組成物で処理する工程を包含する。
本発明の組成物は、酵素活性を評価するための任意の従来の技術によって、HIVに対する阻害活性についてスクリーニングされる。本発明の状況においては、代表的には組成物は、インビトロでHIVの阻害のために最初にスクリーニングされ、次いで阻害性活性を示す組成物は、インビボで活性についてスクリーニングされる。約5×10−6M未満、代表的には約1×10−7M未満、そして好ましくは約5×10−8M未満のインビトロのKi(阻害定数)を有する組成物がインビボ使用のために好ましい。有用なインビトロスクリーニングは詳細に記載されている。
本発明の化合物は、通常の実施に従って選択される、従来のキャリアおよび賦形剤で処方される。錠剤は、賦形剤、流動促進剤、充填剤、結合剤などを含む。水性処方物は、滅菌型で調製され、そして経口投与以外による送達を意図する場合には、一般に等張性である。全ての処方物は必要に応じて、Handbook of Pharmaceutical Excipients(1986)に示される賦形剤のような賦形剤を含む。賦形剤としては、アスコルビン酸および他の抗酸化剤、キレート剤、例えば、EDTA、炭水化物、例えば、デキストリン、ヒドロキシアルキルセルロース、ヒドロキシアルキルメチルセルロース、ステアリン酸などが挙げられる。処方物のpHは、約3〜約11に及ぶが、通常は約7〜10である。
本発明の1つ以上の化合物(本明細書において活性成分と呼ばれる)は、処置される条件に適切な任意の経路によって投与される。適切な経路としては、経口、直腸、経鼻、局所的(口腔内および舌下を含む)、膣および非経口(皮下、筋肉内、静脈内、皮内、くも膜下腔内および硬膜外を含む)などが挙げられる。好ましい経路は、例えば、レシピレントの状態で変化し得ることが理解される。本発明の化合物の利点は、それらが経口的に生体利用可能であり、そして経口投与され得るということである。
本発明の活性成分はまた、他の活性成分と組み合わせて用いられる。このような組み合わせは、処置されるべき状態、成分の交差反応性および組み合わせの薬物的特性に基づいて選択される。
本明細書に記載される化合物のインビトロ代謝生成物もまた本発明の範囲内におさまる。このような生成物は、主に酵素プロセスに起因して、例えば、投与された化合物の酸化、還元、加水分解、アミド化、エステル化などから生じ得る。従って、本発明は、本発明の化合物をその代謝産物を生じるのに十分な時間哺乳動物と接触させる工程を含むプロセスによって生成される化合物を含む。このような生成物は代表的には、本発明の放射性標識(例えば、C14またはH3)化合物を調製すること、それを検出可能な用量(例えば、約0.5mg/kgより大きい)でラット、マウス、モルモット、サルのような動物に、またはヒトに非経口的に投与すること、代謝が生じるのに十分な時間(代表的には約30秒〜約30時間)おくこと、および尿、血液または他の生物学的サンプルからその変換生成物を単離することによって同定される。これらの生成物は、容易に単離される。なぜなら、それらは、標識されるからである(他は、代謝物中に存在しているエピトープに結合し得る抗体の使用によって単離される)。この代謝構造は、例えば、MSまたはNMR分析によって、従来の様式で決定される。一般には、代謝物の分析は、当業者に周知の従来の薬物代謝研究と同じ方式で行なわれる。変換生成物は、それらが別の方法においてインビボで見られない限り、それら自体のHIV阻害性活性を保有しない場合でさえ、本発明の化合物の治療投与のための診断アッセイにおいて有用である。
本発明はまた、本発明の組成物を作製する方法に関する。この組成物は、有機合成の任意の適切な技術によって調製される。このような技術の多くは当該分野で周知である。しかし、多くの公知の技術が、Compendium of Organic Synthetic Methods(John Wiley&Sons,New York)、第1巻、Ian T.HarrisonおよびShuyen Harrison,1971;第2巻、Ian T.HarrisonおよびShuyen Harrison,1974;第3巻,LouisS.Hegedus and Leroy Wade,1977;第4巻、Leroy G.Wade,Jr.,1980;第5巻、Leroy G.Wade,Jr.,1984;および第6巻,Michael B.Smith;ならびにMarch,J.,Advanced Organic Chemistry,第3版、(John Wiley&Sons,New York,1985),Comprehensive Organic Synthesis.Selectivity,Strategy & Efficiency in Modern Organic Chemistry.9巻、Barry M.Trost,Editor−in−Chief(Pergamon Press,New York,1993印刷)に詳細に述べられる。
これらの例示的な方法の一般的局面は、以下にそして実施例に記載されている。以下のプロセスの生成物のいずれかが必要に応じて引き続くプロセスにおける使用の前に分離、単離および/または精製される。
本発明の化合物の調製のための多数の例示的な方法は、本明細書において、例えば、本明細書の以下の実施例に提供される。これらの方法は、このような調製の性質を例示するものであって、適用可能な方法の範囲を限定するものではない。本発明の特定の化合物は、本発明の他の化合物の調製のための中間体として用いられ得る。例えば、本発明の種々のホスホン酸塩化合物の相互変換は下に図示される。
以下のスキーム32〜38は、一般的な構造R−リンク(link)−P(O)(OR1)2のホスホン酸塩エステルの調製を記載しており、ここでは基R1は同じであっても異なってもよい。このR1基はホスホン酸エステルに結合されるか、またはそれに対する前駆体に結合されており、これは、確立された化学的変換を用いて変化されてもよい。ホスホン酸塩の相互変換反応は、スキームS32に図示される。スキーム32におけるR基は、下部構造、すなわち、薬物の「足場(scaffold)」であって、これに対して置換リンク(link)−P(O)(OR1)2が、本発明の化合物、またはそれに対する前駆体のいずれかにおいて、結合される足場を示す。ホスホン酸相互変換を行う合成経路における時点で、Rにおける特定の官能基は保護され得る。所定のホスホン酸変換に使用される方法は、置換基R1のおよびホスホン酸基が結合される基質の性質に依存する。ホスホン酸エステルの調製および加水分解は、Organic Phosphorus Compounds,G.M.Kosolapoff,L.Maeir編、Wiley,1976、9ff頁に記載される。
ホスホン酸エステルは、カルバメート結合を含んでもよい。カルバメートの調製は、Comprehensive Organic Functional Group Transformations,A.R.Katritzky編、Pergamon,1995,第6巻、416ff頁において、およびS.R.SandlerおよびW.Karo,Academic Press,1986、p260ffによる、Organic Functional Group Preparationsに記載される。カルバミル基は、Ellis,米国特許第2002/0103378A1およびHajima,米国特許第6018049の教示を含む、当該分野で公知の方法に従ってヒドロキシル基の反応によって形成され得る。
ホスホン酸のアミデートおよびエステルへの変換には多数の方法が利用可能である。1群の方法では、ホスホン酸は、塩化ホスホリルのような単離された活性化中間体に変換されるか、またはホスホン酸は、アミンまたはヒドロキシ化合物との反応のためにインサイチュで活性化される。
スキーム38a
Tannら、JOC 1985,50,p3644
Howellら、JOC 1988,53,p85
CH2Cl2(1L)中に含まれる、DavosまたはCMS chemicalsから市販されている、1(120g、258mmol)の溶液に、33%HBr/酢酸(80mL)を添加した。この混合物を室温で16時間撹拌し、氷水で冷却して、NaHCo3(150g/1.5L溶液)を用いて1〜2時間にわたってゆっくり中和した。CH2Cl2相は減圧下で分離して濃縮した。その残基は、酢酸エチル中で溶解して、酸が存在しなくなるまでNaHCO3を用いて洗浄した。有機層をMgSO4で乾燥し、濾過し、減圧下で濃縮して黄色油状物として生成物2(約115g)を得た。
Maら、J.Med.Chem.1997,40,2750
Marquezら、J.Med.Chem.1990,33,978
Hildebrandら、J.Org.Chem.1992,57,1808
Kazimierczukら、JACS 1984,106,6379
ACETONITRILE(900mL)に含まれるNaH(14g、60%)の懸濁液に、6−クロロプリン(52.6g)を3部添加した。その混合物を室温で1.5時間撹拌した。ACETONITRILE(300mL)に含まれる2(258mmol)の溶液を滴下して加えた。得られた混合物を室温で16時間撹拌した。反応は、酢酸(3.5mL)でクエンチし、濾過して、減圧下で濃縮した。その残滓をCH2Cl2と水との間で分配した。有機相をMgSO4で乾燥させて、濾過して、濃縮した。その残滓をCH2Cl2で、次いでEtOH(約1:2全体)で処理して、黄色がかった固体として所望の生成物3を沈殿させた(83g、1から65%)。
メタノール(1L)に含まれる3(83g、167mmol)の懸濁物に0℃で、NaOMe(25重量%、76mL)を添加した。この混合物を室温で2時間撹拌し、次いで、酢酸(約11mL、pH=7)を用いてクエンチした。その混合物を減圧下で濃縮して、得られた残滓をヘキサンと水(約500mLのヘキサンと300mLの水)との間で分配した。その水層を分離して、有機層を水(約300mL)と再度混合した。その水画分を合わせて、減圧下で約100mLに濃縮した。生成物4を沈殿させて、濾過によって収集した(42g、88%)。
Mossら、J.Chem.Soc.1963,1149頁
H2O(500mL)中に含まれるPt/C(10%、15g(20〜30%モル当量)水スラリーとして)およびNaHCO3(1.5g,17.94mmol)の混合物を、H2のもとで65℃で0.5時間撹拌した。次いで、その反応混合物を冷却させて、減圧下に置いて、N2を用いて数回フラッシュして、全てのH2を完全に除去した。次いで、化合物4(5.1g、17.94mmol)を室温で添加した。その反応混合物を、LC−MSによって反応が完了するまで(代表的には24〜72時間)、65℃でO2(バルーン)下で撹拌した。その混合物を室温まで冷却して濾過した。Pt/Cを、H2Oを用いて徹底的に洗浄した。あわせた濾液を約30mLに濃縮して、0℃でHCl(4N)の添加によって酸性化(pH4)した。黒色固体を沈殿させて、これを濾過によって収集した。粗生成物を最小量のメタノール中で溶解して、シリカゲルのパッドを通じて濾過した(メタノールで溶出)。その濾液を濃縮して、水から結晶化して白色固体として化合物5(2.5g)を得た。
Zemlickaら、J.Amer.Chem.Soc.1972,94,第3213頁
DMF(400mL)中に含まれる5(22g,73.77mmol)の溶液に、DMFジネオペンチルアセタール(150ml、538mmol)およびメタンスルホン酸(9.5ml、146.6mmol)を添加した。この反応混合物を80〜93℃(内部温度)で30分間撹拌し、次いで室温まで冷却して、減圧下で濃縮した。その残滓を酢酸エチルと水との間で分配した。その有機相を分離して、NaHCO3で、続いてブラインで洗浄して、MgSO4で乾燥して、濾過して、減圧下で濃縮した。その残滓およびジエチル(ヒドロキシメチル)ホスホナート(33ml、225mmol)をCH2Cl2(250mL)中で溶解して、−40℃まで冷却した。CH2Cl2(100ml)に含まれる一臭化ヨウ素(30.5g、1.1モル)の溶液を滴下して加えた。その混合物を−20℃〜−5℃で6時間撹拌した。次いで、その反応物をNaHCO3およびNa2S2O3を用いてクエンチした。この有機相を分離して、水相をCH2Cl2を用いて抽出した。あわせた有機相をブラインで洗浄して、MgSO4で乾燥して、濾過して、減圧下で濃縮した。その残滓をシリカゲルクロマトグラフィーによって精製して生成物6を得た(6g、15.3%)。
THF(45mL)に含まれる5(2.0g、6.7mmol)の溶液を、N2下でトリフェニルホスフィン(2.3g、8.7mmol)で処理した。ジイソプロピルアゾジカルボキシレート(1.8g、8.7mmol)をゆっくり添加した。得られた混合物を室温で1時間撹拌し、次いで乾燥するまで減圧下で濃縮した。その残滓をCH2Cl2(20ml)中で溶解し、次いでジエチル(ヒドロキシメチル)ホスホナート(4.5g、27mmol)で処理した。その混合物を−60℃で冷却し、次いでCH2Cl2(10ml)に含有される一臭化ヨウ素(2g、9.6mmol)の冷溶液を添加した。この反応混合物を−10℃まで温め、次いで−10℃で1時間保持した。この反応混合物をCH2Cl2で希釈して、飽和NaHCO3水で、次いでチオスルファート水溶液で洗浄した。この有機相を分離し、MgSO4で乾燥して、乾燥するまで減圧下で濃縮した。この反応混合物をシリカゲルクロマトグラフィー(25%酢酸エチル含有CH2Cl2で溶出し、次いで、3%メタノール含有CH2Cl2に切り替える)によって精製して、生成物6(0.9g、33%)を得た。
化合物6(6g、11.3mmol)を含有する酢酸(2.5mL)およびメタノール(50mL)の溶液に、NaClO(10〜13%)(50mL)を滴下して加えた。次いで、この反応混合物を0.5時間撹拌して、減圧下で濃縮した。その残滓を酢酸エチルで処理し、次いで濾過して固体を除去した。その濾液を濃縮して、その残滓をシリカゲルクロマトグラフィーによって精製して、生成物7(4g、88%)を得た。
化合物7(2.3g、5.7mmol)を含有するメタノール(6mL)の溶液を、水酸化アンモニウム(28〜30%)(60mL)と混合させた。得られた混合物を120℃で4時間撹拌し、冷却し、次いで、減圧下で濃縮した。その残滓を減圧下で12時間乾燥した。その残滓をDMF(40mL)に溶解して、ブロモトリメチルシラン(3.5mL)を添加した。その混合物を室温で16時間撹拌し、次いで減圧下で濃縮した。その残滓を水性のNaHCO3に溶解した(100mLの水に2.3g)。その溶液をエバポレートして、その残滓をC−18(40μm)カラム上で、水で溶出して精製する。水性画分を凍結乾燥して、二ナトリウム塩8(1.22g、57%)を得た。
二ナトリウム塩8(25mg、0.066mmol)、(S)−Ala−O−シクロブチルエステルハイドロクロライド(24mg、2当量、0.133mmol)およびフェノール(31mg、0.333mmol)を、無水ピリジン(1mL)中で混合した。トリエチルアミン(111μl、0.799mmol)を添加して、得られた混合物を窒素下において60℃で撹拌した。別のフラスコ中で、2’−Aldrithiol(122mg、0.466mmol)およびトリフェニルホスフィン(103mg、0.466mmol)を無水ピリジン(0.5mL)中に溶解して、得られた黄色溶液を15〜20分間撹拌した。次いで、その溶液を8の溶液に1部で添加した。合わされた混合物を窒素下において60℃16時間で撹拌して、透明な黄色〜薄茶色の溶液を得た。次いで、この混合物を減圧下で濃縮した。得られた油状物をCH2Cl2中に溶解し、シリカゲルクロマトグラフィー(CH2Cl2に含まれる0〜5%のMeOHの線形勾配で溶出する)によって精製して、油状物を得る。得られた油状物をアセトニトリル中に溶解し、分取HPLC(水に含まれる5〜95%の直線勾配のアセトニトリル)によって精製した。純粋な画分を合わせ、凍結乾燥して、白色粉末としてモノアミデート9を得る。
二ナトリウム塩8(12mg、0.032mmol)および(S)−Ala−O−n−Prエステルハイドロクロライド(32mg、6当量、0.192mmol)を、無水ピリジン(1mL)中で混合した。トリエチルアミン(53μl、0.384mmol)を添加して、得られた混合物を窒素下において60℃で撹拌した。別のフラスコ中で、2’−Aldrithiol(59mg、0.224mmol)およびトリフェニルホスフィン(49mg、0.224mmol)を無水ピリジン(0.5mL)中に溶解して、得られた黄色溶液を15〜20分間撹拌した。次いで、その溶液を8の溶液に1部で添加した。合わされた混合物を窒素下において60℃で16時間撹拌して、透明な黄色〜薄茶色である溶液を得た。次いで、この混合物を減圧下で濃縮した。得られた油状物をCH2Cl2に溶解し、そしてシリカゲルクロマトグラフィー(CH2Cl2に含まれる0〜5%のMeOHの線形勾配で溶出する)によって精製して、油状物を得る。得られた油状物をアセトニトリルおよび水の中に溶解し、分取HPLC(水に含まれる5〜95%の直線勾配のアセトニトリル)によって精製した。純粋な画分を合わせ、凍結乾燥して、白色粉末としてビスアミダートを得る。
Claims (8)
- 以下の式:
ここで、AlaはL−アラニンを表し、PheはL−フェニルアラニンを表し、MetはL−メチオニンを表し、ABAは(S)−2−アミノ酪酸を表し、ProはL−プロリンを表し、CHAは2−アミノ−3−(S)シクロヘキシルプロピオン酸を表し、Glyはグリシンを表し;
R 1 またはR 2 のアミノ酸カルボキシル基が、表中のエステルの列に示されるとおりにエステル化され、ここで、
cPentはシクロペンタンエステルであり;Etはエチルエステルであり、3−フラン−4Hは(R)テトラヒドロフラン−3−イルエステルであり;cButはシクロブタンエステルであり;sBu(S)は(S)secブチルエステルであり;sBu(R)は(R)secブチルエステルであり;iBuはイソブチルエステルであり;CH 2 cPrはメチルシクロプロパンエステルであり、nBuはn−ブチルエステルであり;CH 2 cBuはメチルシクロブタンエステルであり;3−pentは3−ペンチルエステルであり;nPentはnペンチルエステルであり;iPrはイソプロピルエステルであり、nPrはnプロピルエステルであり;アリルはアリルエステルであり;Meはメチルエステルであり;Bnはベンジルエステルである、
化合物。 - 薬学的な賦形剤および請求項1〜3のいずれか1項に記載の化合物を含む薬学的組成物。
- 前記組成物が、他の治療成分と組み合わせて投与されることを特徴とする、請求項4に記載の組成物。
- 単位剤形である、請求項4または5に記載の組成物。
- 前記組成物が、1以上の他の活性成分と組み合わせて投与されることを特徴とする、請求項6に記載の組成物。
- 請求項1〜3のいずれか1項に記載の化合物を含む、HIVを阻害するための組成物。
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