JP5130051B2 - ビオチン残基を含む抗血栓性デュアルインヒビター - Google Patents
ビオチン残基を含む抗血栓性デュアルインヒビター Download PDFInfo
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- JP5130051B2 JP5130051B2 JP2007547509A JP2007547509A JP5130051B2 JP 5130051 B2 JP5130051 B2 JP 5130051B2 JP 2007547509 A JP2007547509 A JP 2007547509A JP 2007547509 A JP2007547509 A JP 2007547509A JP 5130051 B2 JP5130051 B2 JP 5130051B2
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Description
スペーサーは、10から70原子の鎖長を有する、本質的に薬理学的に不活性な屈曲性連結残基であり;
Aは、残基−CH[NH−SO2−R1][CO−NR2−CH(4−ベンズアミジン)−CO−NR3R4]{式中、R1は、フェニル、ナフチル、1,2,3,4−テトラヒドロナフチル、(イソ)キノリニル、テトラヒドロ(イソ)キノリニル、3,4−ジヒドロ−1H−イソキノリニル、クロマニルまたは樟脳基であり、これらの基は(1−8C)アルキルまたは(1−8C)アルコキシから選択される1つ以上の置換基で場合により置換されていてよく、R2およびR3は独立してHまたは(1−8C)アルキルであり;R4は(1−8C)アルキルまたは(3−8C)シクロアルキルであり;またはR3およびR4は、それらが結合している窒素原子と一緒に、もう1つのヘテロ原子を場合により含有する非芳香族(4から8)員環を形成し、この環は(1−8C)アルキルまたはSO2−(1−8C)アルキルで場合により置換されている。}である。]
の化合物であり、ここで、前記式Iの化合物が、さらに、ビオチン残基またはこの類似体との少なくとも1つの共有結合を含む、前記化合物、またはこれらの薬学的に許容できる塩、プロドラッグまたはこれらの溶媒和物に関する。
好ましいビオチン類似体の残基は、式:−(NH−CO)n−(CH2)p−NR−BT(式中、nは0または1(特にnは、0である。)であり、pは4または5(特にpは、4である。)であり、R=Hまたは(1−4C)アルキルであり、BTは前記に定義した通りである。)を有する。好ましい実施形態において、RはHである。
スペーサーの化学的性質は、本発明の化合物の抗血栓活性にとってあまり重要ではない。スペーサーは、環構造および不飽和結合などの(いくらか)強固な要素を含むことができる。高度に屈曲性のスペーサーは、他のものよりも、より適する。適したスペーサーは、当業者により容易に設計され得る。合成上の理由により、より長いスペーサーは、より不適切と考えられるが、それでも、より長いスペーサーは、本発明の化合物において首尾よく適用することができる。好ましいスペーサーは、少なくとも1つの−(CH2CH2O)−要素を含む。
ビオチン(またはこの類似体)標識は、式Iの化合物のあらゆる部分において存在し得る。従って、本発明の実施形態は、(a)式Iの化合物のオリゴ糖残基が、ビオチン残基またはこの類似体との共有結合を含み、(b)式Iの化合物のスペーサーが、ビオチン残基またはこの類似体との共有結合を含み、および(c)式Iの化合物の残基Aがビオチン残基またはこの類似体との共有結合を含む(これは、Aの定義における水素原子または置換基がビオチン残基により置換されていることを意味する。)、化合物である。
式IIIの化合物は、本発明の1つの好ましい例である。
用語「(1−4C)アルキルおよび(1−8C)アルキル」は、各々1から4および1から8の炭素原子を有する分枝したまたは分枝していないアルキル基(例えば、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、tert−ブチル、ヘキシルおよびオクチル)を意味する。メチルおよびエチルは、好ましいアルキル基である。
用語「(1−8C)アルコキシ」は、アルキル部分が前記で定義した意味を有する、1から8の炭素原子を有するアルコキシ基を意味する。メトキシは、好ましいアルコキシ基である。
用語「(3−8C)シクロアルキル」は、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチルまたはシクロオクチルである3から8の炭素原子を有するシクロアルキル基を意味する。シクロペンチルおよびシクロヘキシルは、好ましいシクロアルキル基である。
スペーサーの長さは、スペーサーに結合しているオリゴ糖残基の酸素原子は数に入れずに、オリゴ糖残基と分子のペプチド部分との間の最も短い鎖に沿って数えたスペーサーの原子数である。
用語「プロドラッグ」は、例えばアミジノ部分のアミノ基が、例えばヒドロキシまたは(1から6C)アルコキシカルボニル基により保護された本発明の化合物を意味する。
本発明による溶媒和物は、水和物を含む。
ビオチン残基は、例えば(負荷電の)オリゴ糖残基に直接に結合させることができるし、または場合によりオリゴ糖−スペーサー残基のN−(1−4C)アルキル化アミノ官能基を介してまたは場合によりN−(1−4C)アルキル化アミノ酸残基を介して、場合により式Iの化合物のオリゴ糖残基のN−(1−4C)アルキル化アミン官能基に結合させることができる。
使用した略語
Aq.=水性の
ATIII=アンチトロンビンIII
Boc=tert−ブチルオキシカルボニル
DCM=ジクロロメタン
DiPEA=N,N−ジイソプロピルエチルアミン
DMF=N,N−ジメチルホルムアミド
Et=エチル
fmoc=9−フルオレニルメトキシカルボニル
NMM=N−メチルモルホリン
Me=メチル
sat.=飽和した
PRP=多血小板血漿
PPP=貧血小板血漿
RT=室温
TBTU=テトラフルオロホウ酸2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウム
TFA=トリフルオロ酢酸
TΗF=テトラヒドロフラン
Nε−(D−(+)−ビオチニル)−N−{4−[[4−[[(1R)−1−[[4−(1,2,4−オキサジアゾール−5−オニル)フェニル]メチル]−2−オキソ−2−(1−ピペリジニル)エチル]アミノ]−3−[[(4−メトキシ−2,3,6−トリメチルフェニル)スルホニル]アミノ]−1,4−(S)−ジオキソ−ブチル]アミノ]−ブタノイル}−L−リジン(3)
WO01/42262に記載されているようにして調製された化合物2(0.20g,0.27mmol)をDCM(10mL)中に溶解した。DiPEA(0.14mL,0.81mmol)を加え、ついでTBTU(86mg,0.27mmol)を加えた。窒素雰囲気下で1時間撹拌後、化合物1(Nε−fmoc−Lys−OH,0.27mmol,Fluka)を固体として加えた。DMF(5mL)を加えて(Nε−fmoc−Lys−OHを溶解した。混合物を16時間撹拌し、0.5N HCl溶液中に注いだ。溶液をDCM(3×)で抽出した。合わせた有機層を食塩水で洗浄し、乾燥(MgSO4)し、減圧下(850mbar,45℃)で濃縮した。粗生成物を、シリカカラムクロマトグラフィー(DCM/MeOH/AcOH,99/0/1→89/10/1,v/v/v)で精製した。残ったAcOHはトルエン中で繰り返し濃縮して除去した。さらに精製をHPLCクロマトグラフィー(ACN/H2O/0.1N TFA,20:78:3→95:2:3)で完成させて、純粋な化合物の0.15g(53%)を得た。TLC:Rf0.5(DCM/MeOH/AcOH,90/9/1,v/v/v)。LC−MS:m/z1089[M+H]1+。
fmoc保護中間体(0.15g,0.14mmol)をTHF(5mL)中に溶解し、Et2NH(2mL)を加えた。混合物を45℃で45分間撹拌した。溶液を減圧下で濃縮し、トルエン中で濃縮した。ESI−MS:m/z857[M+H]1+。
Nε−脱保護リジン誘導体(0.14mmol)をDMF(3mL)中に溶解し、窒素雰囲気下で1時間撹拌しておいたD−(+)−ビオチン(34mg,1当量)、TBTU(45mg,1当量)およびDiPEA(61uL,2.5当量)のDMF(4mL)中の溶液に加えた。得られた混合物を16時間撹拌した。溶媒を減圧下で除去した。EtOAc(30mL)を加え、撹拌した。固形生成物3を濾過により収集し、MeOHおよびEtOAcで洗浄し、真空中で乾燥した。収量86mg(57%)。Rf0.15(DCM/MeOH,9/1,v/v)。ESI−MS:1083.6[M+H]+。
カルボン酸誘導体(33μmol)(すなわち化合物3または11)を乾燥DMF(2×2mL)中で繰り返し濃縮することにより乾燥し、DMF(1mL)中に溶解し、N2雰囲気下、TBTU(11mg,33μmol)およびDiPEA(5.7μL,33μmol)の存在下で撹拌した。1時間後、五糖4(31μmol)を加えた。反応混合物を室温で16時間撹拌し、イオン交換(Mono−Q)クロマトグラフィーで分析した。反応混合物を濃縮(<50℃,15mmHg)した。(粗)生成物(10mg/mLのH2O/t−BuOH溶液,1/1,v/v)を10%Pd/C(粗生成物に対して等しい重量)上での水素化(H2)により脱保護した。16時間後、溶液を脱気し0.45μM HPLCフィルター上で濾過し、減圧下(<50℃,15mmHg)で濃縮した。この共役体をイオン交換クロマトグラフィー(Q−セファロース,緩衝液:H2O→2M NaCl)により精製し、Sephadex G25−カラム(H2O)で脱塩し、凍結乾燥した。
化合物3(86mg,81μmol)を化合物4(0.14g,80μmol)(WO01/42262に記載されているようにして調製した)と一般的手順に従って結合させることにより、化合物IIIを、調製し精製した。収量0.14g(60%)。ESI/TOF−MS:880.91[M−3H]3−,888.57[M−3H+Na]3−,660.43[M−4H]4−。
1H−NMR(D2O,600MHz);4.71ppmの基準水信号により、4.80から4.50ppmの間の信号の信頼できる積分が妨害されている。δ7.66(m,2H),7.30(m,2H),6.74(m,1H),5.36(m,1H),5.25(m,1H),5.05(m,1H),4.98(m,1H),4,84(m,1H),4.46(m,2H),4.31(m,1H),4.27−4.13(5H),4.13−3.99(5H),3.92(m,1H),3.88−3.70(8H),3.70−3.07(49H±5),3.07−2.92(4H),2.85(m,1H),2.76(m,1H),2.65(m,1H),2.51(s,3H),2.40(s,3H),2.36−2.22(m,2H),2.21−2.11(m,2H),2.08(m,1H),2.06−1.91(4H),1.83−1.03(20H±2)。
15−N−(9−フルオレニルメチルオキシカルボニル)−15−アザ−3,6,9,12−テトラオキサ−ペンタデカン酸tert−ブチル(6)
15−アミノ−3,6,9,12−テトラオキサ−ペンタデカン酸tert−ブチル(5)(0.50g,1.45mmol)をTHF(7.5mL)およびH2O(5mL)中に溶解した。4N NaOH溶液をpHが約9になるまで加えた。カルバミン酸N−9−フルオレニルメチル−コハク酸イミド(FmocOSu,0.54g,1.60mmol,1.1当量)を少量ずつ加えた。10分後、更なる4N NaOH溶液を加えて、pHを約9に調節した。3時間後、反応混合物を1N HCl溶液でpH6から7に酸性化した。H2Oを反応混合物に加え、EtOAcで3回抽出した。有機層を食塩水で洗浄し、MgSO4上で乾燥した。濾過後、溶媒を減圧下(50mbar,50℃)で除去した。粗製油をシリカカラムクロマトグラフィー(DCM/MeOH,1/0→95/5,v/v)で精製して、化合物6を黄色油(0.61g,79%)として得た。Rf0.64(DCM/MeOH,95/5,v/v)。
化合物6をDCM(3.5mL)中に溶解し、TFA(3.5mL)を窒素雰囲気下で加えた。1.5時間撹拌後、反応混合物を減圧下で濃縮した。その後、過剰のTFAをトルエン中の繰り返し濃縮により除去した。DCM/Et2O(100mL,1/2,v/v)を加え、1N HClで洗浄した。水層をDCM/Et2O(100mL,1/2,v/v)で抽出した。加え合わせた有機層を食塩水で洗浄し、MgSO4上で乾燥した。濾過後、溶媒を大気圧下(50℃)で除去した。粗製油をシリカカラムクロマトグラフィー(DCM/MeOH/AcOH,99/0/1→89/10/1,v/v/v)で精製して化合物7を得た。残ったAcOHを、粗製油状生成物をDCM/Et2O(1/2,v/v)に溶解し、H2O(3回)および食塩水で洗浄し、ついでMgSO4で乾燥して除去した。濾過後、溶媒を、大気圧下(50℃)で除去して化合物7を黄色油(0.37g,67%)として得た。Rf0.32(DCM/MeOH,89/10/1,v/v)。
化合物7(0.37mg,0.77mmol)をDCM(18mL)中に溶解した。引き続き、DIPEA(0.40μL,2.31mmol,3当量)およびTBTU(0.25g,0.77mmol)をN2雰囲気下で加え、溶液を10分間撹拌した。ついで、ε−(Z)−L−Lys−OtBu・HCl(0.29g,0.77mmol)を加え、混合物をさらに1.5時間撹拌した。反応混合物をDCMで希釈し、H2O、0.1N HCl、飽和NaHCO3溶液および食塩水で濯いだ。有機層を乾燥(MgSO4)し、大気圧下で濃縮した。精製をシリカゲルカラムクロマトグラフィー(DCM/MeOH,1/0→9/1,v/v)で行って、化合物8を黄色油(0.51g,83%)として得た。Rf0.85(DCM/MeOH,9/1,v/v)。ESI−MS:792.6[M+H]+,814.6[M+Na]+,736.4[M−tBu+H]+。
化合物8(0.26g,0.32mmol)をTHF(5mL)中に溶解した。Et2N(1mL)を加え、溶液を24時間撹拌した。過剰のEt2Nおよび溶媒を減圧下(50℃)で除去した。トルエンを加え、減圧下(50℃,65mbar)で除去しN−脱保護中間生成物(0.21g,0.32mmol)を得た。Rf0.23(DCM/MeOH,9/1,v/v)。ESI−MS:570.4[M+H]+,514.4[M−tBu+H]+。粗製生成物をDCM(3mL)中に溶解した。N2雰囲気中で、Et3N(0.11mL)を加え、ついでジ−tert−ブチルジカーボネート(73mg,0.34mmol,1.1当量)を加えた。5時間撹拌後、混合物を0.1N HCl冷(5℃)溶液に加え、EtOAcで抽出した。有機層を食塩水で洗浄し、乾燥(MgSO4)した。濾過後、溶媒を、減圧下(180mbar,50℃)で除去した。精製をシリカゲルカラムクロマトグラフィー(DCM/MeOH,1/0→95/5,v/v)で行って、9を無色油(0.17g,82%)として得た。Rf0.5(DCM/MeOH,9/1,v/v)。ESI−MS:670.6[MH+H]+,692.4[MH+Na]+,570.4[M−Boc+H]+,514.1[M−Boc−tBu+H]+。
化合物9(0.23g,0.34mmol)をEtOH(8mL)およびH2O(1.2mL)中に溶解した。溶液を窒素で5分間フラッシングした後、Pd/C10%(0.11g)を加えた。水素を溶液に4時間通過させた。窒素を溶液に10分間フラッシングして全ての水素を除去した。混合物をデカライト上で濾過し、減圧下(170mbar,50℃)で濃縮してN−L−リジン脱保護中間体を無色油(0.15g,81%)として得た。Rf0.02(DCM/EtOAc,9/1,v/v)。
D−(+)−ビオチン(75mg,0.31mmol)をDCM(7mL)中に懸濁した。引き続き、N2雰囲気下でDIPEA(0.11mL,0.62mmol,2当量)およびTBTU(0.10g,0.31mmol)を加え、溶液を1時間撹拌した。上記のN−L−リジン脱保護中間体のDCM(3mL)中の溶液を反応混合物に加えた。混合物を16時間撹拌した。H2Oを加え、DCM(3×)で抽出した。有機層を乾燥(MgSO4)し、減圧下(850mbar,50℃)でろ過および濃縮した。精製をシリカゲルカラムクロマトグラフィー(溶離液:DCM/MeOH,1/0→9/1v/v)で行って油(0.13g,60%)を得た。Rf0.48(DCM/MeOH,9/1,v/v)。ESI−MS:762.6[M+H],784.6[M+Na],662.4[M−Boc+H],606.4[M−Boc−tBu+H]。油をジオキサン中の乾燥4N HCl溶液(4mL)中に溶解し、撹拌した。1時間後、不溶性の油が出現し、その後溶媒を減圧下(100mbar,50℃)で除去し、化合物10を定量的収率で得た。ESI−MS:606.4[M+H]+,628.4[M+Na]+。
Nε−(D−(+)−ビオチニル)−N−{{4−[[4−[[(1R)−1−[[4−(1,2,4−オキサジアゾール−5−オニル)フェニル]メチル]−2−オキソ−2−(1−ピペリジニル)エチル]アミノ]−3−[[(4−メトキシ−2,3,6−トリメチルフェニル)スルホニル]アミノ]−1,4−(S)−ジオキソ−ブチル]アミノ]−ブタノイル}−15−N−(15−アザ−1−オキソ−3,6,9,12−テトラオキサ−ペンタデシル)}}−L−リジン(11)
化合物10(0.12g,0.21mmol)を、化合物3の調製で記載したように、化合物2(0.15g,0.21mmol)に結合させた。粗製生成物を調製用HPLC(C18,ACN/H2O,0.01%TFA)で精製して、化合物11を純粋な形態で得た。収量60mg(22%)。ESI−MS:1316.8[M+H]+。
一般的手順に従って化合物11を化合物4に結合させ、中間体共役体を脱保護して化合物IVを得た。収量9.2mg(7.6%)。
1H−NMR(D2O,600MHz),4.70ppmにおける基準水信号により、4.80から4.54ppmの間の信号の信頼できる積分が妨害されている。δ7.59(d,2H),7.23(d,2H),6.68(s,1H),5.32(m,1H),5.19(m,1H),4.91(m,1H),4.85(m,1H),4.76(m),4.53−4.31(3H),4.30−4.05(9H),4.04−3.90(7H),3.89−3.62(7H),3.61−3.42(42H±4),3.42−3.31(18H±2),3.31−3.14(12H),3.14−3.05(5H),3.03−2.94(3H),2.93−2.84(2H),2.81(dd,1H),2.70(dd,1H),2.59(d,1H),2.44(s,3H),2.34(s,3H),2.22−2.08(4H),2.06(t,2H),1.96(s,3H),1.72−1.01(18H±2)。
ESI/TOF−MS:m/z574.72[M−5H]5−,m/z718.66[M−4H]4−,m/z958.56[M−3H]3−。
ヒト血漿中の抗Xa因子活性および抗IIa因子活性の測定のためのインビトロ試験
ヒト血漿中の試験化合物の抗Xa因子活性および抗IIa因子活性を、基質として各々S2222またはS2238(Chromogenix,Chromogenics Ltd,Molndal,Sweden)を用いて、アミド分解活性を測定することにより測定した。手順は、TeienおよびLieにより記載されている方法(Teien AN,Lie M. Evaluation of an amidolytic heparin assay method increased sensitivity by adding purified antithrombin III.Thromb.Res.1977,10:399−410)に基づいた。両方の活性はIC−50(Mol/L)で表してある。
Org 42675の薬物動態学的特性および本発明の化合物IIIの薬物動態学的特性を、300から400gの雄のWistarラットについて研究した。ラットにO2/N2O/イソフルランの混合物の吸入により麻酔をかけ、その後右頚静脈にカニューレ処置をした。翌日、100nmol/kgの投与量でラットに皮下注射処置をした。皮下注射投与後、数回の間隔でサンプル採取を行った。ついで、血液を遠心分離した後血漿を吸い上げて、使用するまで−20℃で貯蔵した。試験化合物の濃度を、抗Xa活性または抗IIa活性を各々測定するために、基質としてS−2222またはS−2238(Chromogenix, Chromogenics Ltd, Molndal, Sweden)を用いてアミド分解活性について測定した。両方の手順は、Teien およびLieの方法(Teien AN, Lie M. Evaluation of an amidolytic heparin assay method increased sensitivity by adding purified antithrombin III. Thromb. Res. 1977, 10: 399−410)に基づいた。得られた血漿サンプル中の濃度は、試験化合物自身の原液を用いて作成した検量線に対して測定した。サンプル中の濃度をnmol/mLで表し、速度パラメーターをWinNonlinのノンコンパートメントモデルを用いて算出した(図1参照)。
100nmol/kgの投与量で本発明の化合物IIIまたはOrg42675で、皮下でラットを、処置した。t=2hの時点で血液サンプルを採取し、本発明の化合物IIIまたはOrg42675で処置したラットにアビジン(卵白由来,Sigma)の10mg/kgを静脈内投与した。続いて、0.17、0.5、1、2、3、および7時間の時点で血液をサンプル採取した。血液は薬物動態学実験に記載されているようにして処置し、サンプルの濃度は、(残存する)抗Xa活性または抗IIa活性を測定することにより測定した(図2参照)。
Claims (17)
- 式(I)の抗血栓性化合物
式(II):
スペーサーは、10から70原子の鎖長を有する、本質的に薬理学的に不活性な屈曲性連結残基であり;
Aは、残基−CH[NH−SO2−R1][CO−NR2−CH(4−ベンズアミジン)−CO−NR3R4]{R1は、フェニル、ナフチル、1,2,3,4−テトラヒドロナフチル、(イソ)キノリニル、テトラヒドロ(イソ)キノリニル、3,4−ジヒドロ−1H−イソキノリニル、クロマニルまたは樟脳基であり、これらの基は、非置換であるか、又は(1−8C)アルキルまたは(1−8C)アルコキシから選択される1つ以上の置換基で置換されており、ならびにR2およびR3は、独立してHまたは(1−8C)アルキルであり;R4は、(1−8C)アルキルまたは(3−8C)シクロアルキルであり;またはR3およびR4は、それらが結合している窒素原子と一緒に、もう1つのヘテロ原子を含有する又は含有しない非芳香族(4から8)員環であり、前記環は非置換であるか、又は(1−8C)アルキルまたはSO2−(1−8C)アルキルで置換されている}である。]
であり、ここで、前記式Iの化合物のスペーサーが、さらに、式:−(CH2)4−NR−BT(式中、RはH又は(1−4C)アルキルであり、BTは残基:
- スペーサーが、10から50原子の長さを有する請求項1から3のいずれか一項の化合物。
- スペーサーが、16から22原子の長さを有する請求項4の化合物。
- スペーサーが、19原子の長さを有する請求項4の化合物。
- スペーサーが、少なくとも1つの−(CH2CH2O)−要素を含む請求項1から6のいずれか一項の化合物。
- R1が、非置換であるか、またはメチルもしくはメトキシから選択される1つ以上の置換基で置換されているフェニルまたはナフチルである請求項1から7のいずれか一項の化合物。
- R1が、4−メトキシ−2,3,6−トリメチルフェニルである請求項8の化合物。
- NR3R4が、ピペリジニル基を表す請求項1から9のいずれか一項の化合物。
- R2が、Hである請求項1から10のいずれか一項の化合物。
- ナトリウム塩の形態である請求項12の化合物。
- 請求項1から13のいずれか一項の化合物および薬学的に適した補助剤を含む、医薬組成物。
- 残基Aにおけるベンズアミジン部分が、1,2,4−オキサジアゾリン−5−オン基である前駆体の形態であり、および続いて脱保護によりベンズアミジンに転換される段階を含む請求項1の式Iの化合物の調製方法。
- 治療において用いるための、請求項1から13のいずれか一項の化合物。
- 血栓症またはその他のトロンビン関連疾患の治療または予防のための医薬の製造のための、請求項1から13のいずれか一項の化合物の使用。
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