JP2016504343A - Pde4阻害活性を有する選ばれたマクロライド - Google Patents
Pde4阻害活性を有する選ばれたマクロライド Download PDFInfo
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- JP2016504343A JP2016504343A JP2015550082A JP2015550082A JP2016504343A JP 2016504343 A JP2016504343 A JP 2016504343A JP 2015550082 A JP2015550082 A JP 2015550082A JP 2015550082 A JP2015550082 A JP 2015550082A JP 2016504343 A JP2016504343 A JP 2016504343A
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- Prior art keywords
- pharmaceutically acceptable
- ester
- compound
- acceptable salt
- treatment
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Abstract
Description
を有し、式中、例えば、
R1は、残基−Y−X−Qであり;
Yは、S、SOまたはSO2であり;
Xは、結合、または水素原子とC、N、OおよびSから選択される1〜9個の原子(このうち2個までの原子はNであり得、1個の原子はOまたはSであり得、1個の炭素原子はCO基として現れ得、硫黄原子はSO2基として現れ得、2個の隣接するC原子は−CH=CH−または−C≡C−として存在し得る)とからなる直鎖状基であり、基Xは、非置換であるかまたは−COO−Wもしくは−CONH−Wで置換されており;
Qは、残基−V−A1−L−A2−Wであるか、またはXが結合を表さない場合は−NR10R11であり;
Vは、置換されていてもよい二価の芳香族または複素環式基であり;
Wは、置換されていてもよいアリールまたはヘテロシクリルであり;
A1およびA2は、互いに独立して、不在またはC1〜C4アルキレン基のいずれかであり;
Lは、−O−、−S−、−SO2−、−NH−、−CO−、−(CO)O−、−O(OC)−、−(CO)NH−、−NH(CO)−、−(SO2)NH−、−HN(SO2)−、−HN(CO)NH−、−O(CO)NH−、−NH(CO)O−であるか、またはA1および/もしくはA2が存在する場合は不在であることもあり得;
R2は、OR2aまたは
[式中、
は、連結結合を表す]であり;
R2aは、水素、アセチル、−(C=O)CH2NR2bR2c、または−(C=O)CH2CH2NR2bR2cであり;
R2bおよびR2cは、互いに独立して、水素またはC1〜C6アルキル(これは置換または非置換であり得、ここにおいて2個までの原子はN、OまたはSであり得、1個の炭素原子はC=Oとして現れ得る)であるか、またはそれらが連結している窒素原子と共に4〜7員の環(このうち2個までの原子はN、OまたはSであり得、1個の炭素はC=Oとして現れ得る)を形成し;
R3は、水素であるか、または
R2およびR3は、それらが連結している炭素原子と共にC=O基を表し;
R4は、水素であるか、または
R2およびR4は、それらが連結している炭素原子間の結合と共に前記炭素原子間の二重結合を表し;
Zは、
[式中、
は、連結結合を表す]であり;
R5は、水素または−OR5aもしくは−NR5bR5cであり;
R6は、水素または−OR6aもしくは−NR6bR6cであるか;または
R5およびR6は、それらが連結している炭素原子と共にC=O基を表し;
R7は、水素または−OR7aもしくは−NR7bR7cであり;
R8は、水素または−OR8aもしくは−NR8bR8cであるか;または
R7およびR8は、それらが連結している炭素原子と共にC=O基を表すか;または
R5およびR6のうちの1つは
R7およびR8のうちの1つと共に式−NR56(CO)O−または−O(CO)NR78−の基を表し;
R9は、水素であるか、または
R8およびR9は、それらが連結している炭素原子間の結合と共に前記炭素原子間の二重結合を表し;
R5a、R6a、R7aおよびR8aは、互いに独立して、水素またはC1〜C6アルキル(これは置換または非置換であり得、ここにおいて1個以上の単結合は二重結合および/または三重結合に置き換えられ得、1個の炭素原子はC=Oとして現れ得、2個までの原子はN、OまたはSであり得る)であり;
R56およびR78は、水素またはC1〜C6アルキルであり;
R5b、R5c、R6b、R6c、R7b、R7c、R8bおよびR8cは、互いに独立して、水素、C1〜C6アルキル(これは置換または非置換であり得、2個までの原子はN、OまたはSであり得、1個の炭素原子はC=Oとして現れ得る)もしくは−(C=O)ヘテロシクリルであるか、またはそれらが連結している窒素原子と共に4〜7員の環(このうち2個までの原子はN、OまたはSであり得、1個の炭素はC=Oとして現れ得る)を形成し;
R10およびR11は、水素、メチルから;アリール基;アラルキル基;ヘテロシクリル基およびヘテロシクリルアルキル基から選択される置換されていてもよい基から独立して選択され、R10およびR11のうちの一方は、基−L−A2−Wであることもあり得;および
*は、(R)または(S)形にあるキラル中心を示し;ここで、
Zは、かなりの抗菌活性を示す従来のマクロライド化合物中に存在する式
の基または前記部分のヒドロキシルが保護された変形以外の部分である。
[式中、R1は、残基−X−Qであり、X、QおよびZならびに他の残基は、国際公開第2009/106419号パンフレットにおいてと同じまたは同様の意味を有する]を有する11,12−環状カルバメート部分構造を有するマクロライド化合物を開示している。これらの化合物もまた、著しい抗菌活性を有することなく、ホスホジエステラーゼ、特にPDE4の阻害剤として有効である。
を有する国際公開第2009/106419号パンフレットの実施例9の化合物は、良好ないし中程度のPDE4阻害活性を示し、細菌の多くの病原種に対して抗菌的に不活性であり、中程度のバイオアベイラビリティを示すが、他方において、かなり強力にhERGチャネルの活性を阻害する。
を有する国際公開第2009/106419号パンフレットの実施例10の化合物は、優れたPDE4阻害活性および特に良好な経口バイオアベイラビリティを示すが、他方において、依然として特定の種類の細菌に対して強力な残存抗菌活性を示す。
を有する実施例15国際公開第2009/106419号パンフレットの化合物は、優れたPDE4阻害活性を、この場合は、広い範囲の様々な種類の細菌に対して強く低減された抗菌活性と組み合わせて示す。しかしながら、その経口バイオアベイラビリティはかなり低い。
国際公開第2006084410号パンフレットの実施例1のA]〜D]に従って調製された1.8g(2.02mmol)の化合物4および後述されるように調製された0.9g(2.02mmol)の化合物5を、20mlのDMFに溶解させ、次いで0.92g(6.06mmol)のDBUおよび121mg(0.81mmol)のNaIを添加する。溶液を室温で1.0時間にわたり撹拌する。溶媒を真空中で除去し、残渣を50mlの0.5MのKH2PO4水溶液中に注入し、結果として生じる混合物を50mlのDCMで2回抽出する。合わせた有機層を水およびブラインで洗浄し、無水Na2SO4上で乾燥させ、真空中で濃縮して粗生成物を得、これをシリカゲルカラムクロマトグラフィー(溶離液:DCM/MeOH=100/1〜50/1)によって精製して、淡黄色の泡沫体として1.7gの所望の生成物を得る。
MS(ESI):640.9[M+2H]2+
1H−NMR(CDCl3):(特徴的なシグナルのみ)8.44(s,2H);6.74(d,1H);6.59(s,1H);6.50(s,1H);6.48(dd,1H);5.68(d,1H);4.97(bs,1H);4.66−4.72(m,3H);4.60(m,1H);4.48(s,2H);4.35(bs,1H);3.78(bs,4H);3.63(bs,1H);3.56(dd,1H);3.20−3.33(m,6H);3.16(s,3H);2.66−2.76(m,3H);2.40(d,1H);2.26(bs,6H);2.14(s,3H);2.04(s,3H);0.92−0.99(m,3H);0.85(t,3H).
2.0g(1.56mmol)の化合物6を、30mlのDMFに窒素雰囲気下において溶解させ、溶液を−20℃に冷却し、54mg(1.4mmol、油中60%の分散液)のNaHを添加し、出発物質が残存していないことをHPLCが示すまで−20℃で混合物を撹拌する。次いで、100mlの水を添加し、混合物を50mlのDCMで3回抽出し、合わせた有機層を水およびブラインで洗浄し、無水Na2SO4上で乾燥させ、真空中で濃縮して、褐色の油状体として2.6gの粗生成物を得、これをDCM/MeOH(V/V、60/1)で溶離するシリカゲルカラムクロマトグラフィーによって精製して、黄色の泡沫体として1.1gの所望の生成物を得る。
MS(ESI):1282.5[MH]+および641.7[M+2H]2+
1H−NMR(CDCl3):(特徴的なシグナルのみ)8.40(s,2H);6.70(d,1H);6.46(s,1H);6.42(dd,1H);5.38(d,1H);4.93(bs,1H).
600mg(0.47mmol)の化合物7を15mlのアセトニトリルに溶解させ、次いで24mlの1Nのヒドロクロリド酸(hydrochloride acid)を添加する。反応混合物を、16時間にわたり30℃で撹拌する。水相を、2NのNaHCO3水溶液でPH=7に調整する。結果として生じる混合物を30mlのDCMで2回抽出し、合わせた有機層を水およびブラインで洗浄し、無水Na2SO4上で乾燥させ、真空中で濃縮して、黄色の泡沫体として0.5gの粗生成物を得る。
MS(ESI):1080.4[MH]+および540.9[M+2H]2+
1.5g(1.39mml)の化合物4を30mlのMeOHに溶解させ、溶液を30℃で16時間にわたり撹拌する。次いで、溶媒を真空中で除去し、残差をシリカゲル上でのフラッシュクロマトグラフィー(DCM/MeOH 60:1)によって精製して、400mgの所望の生成物を得る。
MS(ESI):1038.4[MH]+および519.9[M+2H]2+
1H−NMR(CDCl3):(特徴的なシグナルのみ)8.43(s,2H);6.75(d,1H);6.50(s,1H);6.44(dd,1H);5.52(d,1H);4.71(bs,1H);4.58−4.61(m,3H);4.40(s,1H);3.77(s,3H);3.71(s,1H);3.47−3.60(m,5H);3.37−3.42(m,1H);2.83−2.88(m,1H);2.47−2.49(m,1H);2.06−2.08(m,1H);1.44(s,3H);1.25−1.38(m,9H);1.08−1.14(m,9H);0.83(t,3H).
200mg(0.15mmol)の化合物5をMeOHとTHFとの混合物(MeOH 10ml/THF 2ml)に溶解させ、63mg(0.77mmol)の酢酸ナトリウムを添加する。混合物を30〜35℃または30分間で撹拌し、次いで177mgのI2(0.70mmol)を添加する。黒色の反応混合物を、5時間にわたり30〜35℃で撹拌する。飽和Na2S2O3水溶液を、I2の色が消えるまで添加する。溶媒を真空中で除去し、残渣を30mlの水中に注入し、50mlのDCMで2回抽出する。合わせた有機層を水およびブラインで洗浄し、無水Na2SO4上で乾燥させ、真空中で濃縮して粗生成物を得、これを、シリカゲル上でのフラッシュクロマトグラフィー(DCM/MeOH 100:1〜20:1)によって精製して、黄色の泡沫体として70mgの所望の生成物を得る。
MS(ESI):1026.4[MH]+および513.8[M+2H]2+
150mlのTHF中の10.0g(4.88mmol)の化合物9の溶液に、窒素雰囲気下において0〜5℃で1.89g(14.63mmol)のDIPEAを添加する。混合物を30分間にわたり撹拌し、1.46g(9.75mmol)の4−モルホリニルカルボニルクロリド(MCC)を添加する。混合物を20時間にわたり20℃で撹拌する。溶媒を減圧下で除去する。残渣を200mlのDCMに溶解させ、水およびブラインで洗浄し、無水Na2SO4上で乾燥させ、真空中で濃縮して粗生成物を得、これを、シリカゲル上でのフラッシュクロマトグラフィー(DCM/MeOH=200:1〜50:1)によって精製して、黄色の泡沫体として4.6gの所望の生成物を得る。
MS(ESI):1137.5[M+H]+,569.2[M+2H]2+
1H−NMR(DMSO−d6):8.59(s,1H);8.59(s,1H);6.79(d,1H);6.49(d,1H);6.44(dd,1H);5.33(dd,1H);5.23(d,1H);4.90(d,1H);4.71(m,1H);4.67(d,1H);4.62(d,1H);4.56(d,1H);4.25(s,1H);3.68(s,1H);3.65(m,1H);3.65(s,3H);3.61(m,1H);3.56(m,4H);3.52(m,1H);3.39(m,1H);3.24(dd,1H);3.20(m,1H);3.12(m,2H);3.08(m,1H);3.05(m,2H);2.93(m,1H);2.88(s,3H);2.78(m,1H);2.71(s,3H);2.59(s,1H);2.56(dd,1H);2.34(m,1H);1.90(m,1H);1.87(m,1H);1.78(m,2H);1.68(1H);1.67(m,2H);1.66(m,2H);1.63(m,1H);1.55(1H);1.52(m,2H);1.46(m,1H);1.45(m,1H);1.41(s,3H);1.17(s,3H);1.15(d,3H);1.11(d,3H);1.05(d,3H);0.98(d,3H);0.94(d,3H);0.75(t,3H);
30mlのDMF中の国際公開第2009098320号パンフレットの実施例15のA]およびB]に従って調製された2.6g(6.05mmol)の化合物5−Bの溶液に、1.38g(12.1mmol)のチオ酢酸カリウムおよび181mg(1.21mmol)のヨウ化ナトリウムを添加する。反応混合物を5時間にわたり60℃で撹拌し、次いで100mlの水を添加する。混合物を、100mlの酢酸エチルで2回抽出する。合わせた有機層を水およびブラインで洗浄し、Na2SO4上で乾燥させ、真空中で濃縮して、黄色の固体として2.8gの所望の生成物を得る。
MS(ESI):469.1[MH]+
8.0g(17.0mmol)の化合物5−Cを150mlのメタノールに溶解させ、次いで溶液中に5℃でアンモニアガスを通気する。結果として生じる溶液を、アンモニア雰囲気下においてこの温度で4時間にわたり撹拌し、次いで真空下でエバポレートして、黄色の固体として7.5gの所望の生成物を得る。生成物を、アルゴン雰囲気下で貯蔵する。
MS(ESI):427.2[MH]+
PDE4を、Thorpy et al.1992(J.Pharmacol.Exp.Ther.263:1195)に従い未分化のヒト単球細胞(U937)から部分精製する。細胞を、5%牛胎児血清(GIBCO)および100μg/mLのペニシリン−ストレプトマイシン(GIBCO)を含むIscove改変ダルベッコ培地(GIBCO)中で増殖させる。細胞を音波処理によって破壊し、PDE4をDEAE−Sepharose CL−6B(GE Healthcare)上でのアニオン交換クロマトグラフィーによって精製する。最終調製物はcAMPに特異的であり、アッセイの検出限界を超えるcGMPを加水分解しない。さらに、PDE4調製物は、PDE4特異的および非特異的PDE阻害剤を用いた阻害研究によって検証される。
PDEは、cAMPおよび/またはcGMPを特異的に加水分解し、生成物AMPおよび/またはGMPを放出する。試験化合物によるPDE阻害の効力は、市販のインビトロ酵素アッセイ(IMAP(登録商標)Fluorescence Polarizationアッセイ、Molecular Devices Corp.)を用いて測定される。蛍光標識されたcAMPまたはcGMPがPDE調製物によって加水分解され、第2の工程において、標識された生成物が大きな結合パートナーに結合することにより、蛍光偏光(FP)測定による生成物検出が可能になる。
臨床・検査標準協会(CLSI:Clinical and Laboratory Standards Institute,Wayne PA,USA)によるガイドラインに従う微量液体希釈によって全てのMIC値を決定する。スタフィロコッカス・アウレウス(Staphylococcus aureus)ATCC29213は、Mueller−Hinton寒天(MHA)(Becton Dickinson)上で増殖させ、次いでカチオン調整Mueller Hintonブロス(CaMHB)(Becton Dickinson)中で37℃にて24時間増殖させる。ストレプトコッカス・ピオゲネス(Streptococcus pyogenes)ATCC19615およびモラクセラ・カタラーリス(Moraxella catharrhalis)QK34は、2.5%の溶血ウマ血液(Oxoid)を含むMHA上で増殖させる。CaMHB+5%のウマ血清(Sigma)中の液体培養物を、5%CO2雰囲気中で35℃にて24時間にわたりインキュベートする。ヘモフィルス・インフルエンザ(Haemophilus influenzae)3168は、MHA+2.5%Fildesエキス(Oxoid)上で増殖させる。5%CO2雰囲気中において35℃にてCaMHB+5%Fildesエキス中で、液体培養物を増殖させる。
血液または血漿中の薬物濃度を、薬物動態研究において時間の関数として測定する。マウスを規定用量の試験化合物で処置した。10mg/kgを経口投与に使用し、1mg/kgを静脈内投与に用いる。血液または血漿試料を規定された時点で採取し、薬物含有量をLC−MS/MSによって測定する。薬物濃度を時間の関数としてプロットし、非静脈内(経口)および静脈内の曲線下面積(AUC)を線形台形公式を用いて算出する。次いで、経口バイオアベイラビリティを、用量正規化AUCを用い、以下の式:
F[%]=AUC経口/AUC静脈内*100
を用いて算出する。
ホールセルパッチクランプ法を、安定トランスフェクトされたHEK293細胞(B’SYS GmbH,CH−4108 Witterswil,Switzerland)からのhERG末尾電流に対する試験化合物の影響を測定するために使用する。0.1%DMSOをビヒクルとして使用し、10nMの選択的IKrブロッカーE−4031を用いてこの系を検証する。
Claims (13)
- 遊離形態にある請求項1または2に記載のマクロライド化合物。
- 請求項1〜3のいずれか一項に記載のマクロライド化合物またはその薬学的に許容可能な塩もしくはエステルと薬学的に許容可能な不活性キャリアとを含む薬学的組成物。
- 請求項1〜3のいずれか一項に記載のマクロライド化合物またはその薬学的に許容可能な塩もしくはエステルと任意選択で薬学的に許容可能な不活性キャリアとを含む経口投与のための剤形。
- 医学的治療における使用のための、特に動物および好ましくはヒトから選択される被験体における障害および/または疾患の予防および/または処置のための使用のための、請求項1〜3のいずれか一項に記載のマクロライド化合物もしくはその薬学的に許容可能な塩もしくはエステル、または請求項4に記載の薬学的組成物、または請求項5に記載の剤形であって、前記予防および/または処置は、前記被験体におけるホスホジエステラーゼ4(PDE4)の阻害に基づくものである、マクロライド化合物もしくはその薬学的に許容可能な塩もしくはエステル、または薬学的組成物、または剤形。
- 被験体における炎症疾患、アレルギー疾患または自己免疫疾患の処置における使用のための、請求項1〜3のいずれか一項に記載のマクロライド化合物もしくはその薬学的に許容可能な塩もしくはエステル、または請求項4に記載の薬学的組成物、または請求項5に記載の剤形。
- 慢性閉塞性肺疾患(COPD)、乾癬、乾癬性関節炎、狼瘡、関節リウマチ、アルツハイマー、パーキンソン病、ハンチントン病、間質性膀胱炎、喘息、慢性気管支炎、気腫、アトピー性皮膚炎、蕁麻疹、アレルギー性鼻炎、アレルギー性結膜炎、敗血症性ショック、潰瘍性大腸炎、炎症性腸疾患、例えば、クローン病、成人呼吸窮迫症候群、強直性脊椎炎、ブドウ膜炎、または多発性硬化症の処置における使用のための、請求項1〜3のいずれか一項に記載のマクロライド化合物もしくはその薬学的に許容可能な塩もしくはエステル、または請求項4に記載の薬学的組成物、または請求項5に記載の剤形。
- 慢性閉塞性肺疾患(COPD)または乾癬の処置のための処置における使用のための、請求項1〜3のいずれか一項に記載のマクロライド化合物もしくはその薬学的に許容可能な塩もしくはエステル、または請求項4に記載の薬学的組成物、または請求項5に記載の剤形。
- 炎症疾患、アレルギー疾患または自己免疫疾患の処置を必要としている動物、好ましくはヒトから選択される被験体における炎症疾患、アレルギー疾患または自己免疫疾患を処置するための方法であって、ある量の請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩エステルが前記被験体に投与され、前記量は、前記炎症疾患、アレルギー疾患または自己免疫疾患を処置するのに有効である、方法。
- 請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩エステルが、前記被験体に経口投与される、請求項10に記載の方法。
- ヒトホスホジエステラーゼ4の阻害によって改善され得る障害または疾患の処置、特に炎症疾患、アレルギー疾患または自己免疫疾患の処置のための医薬の製造のための、請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩もしくはエステルの使用。
- 前記医薬が、経口投与のための医薬である、請求項12に記載の使用。
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EP12199801.7 | 2012-12-31 | ||
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EP13158812.1 | 2013-03-12 | ||
EP13158812 | 2013-03-12 | ||
PCT/EP2013/078040 WO2014102315A1 (en) | 2012-12-31 | 2013-12-27 | Selected macrolides with pde4-inhibiting activity |
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EP2938623A1 (en) | 2015-11-04 |
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WO2014102315A1 (en) | 2014-07-03 |
HK1210618A1 (en) | 2016-04-29 |
ES2607638T3 (es) | 2017-04-03 |
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