JP2009504670A - 嚢胞性線維症膜コンダクタンス制御因子の調節物質 - Google Patents
嚢胞性線維症膜コンダクタンス制御因子の調節物質 Download PDFInfo
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- JP2009504670A JP2009504670A JP2008526246A JP2008526246A JP2009504670A JP 2009504670 A JP2009504670 A JP 2009504670A JP 2008526246 A JP2008526246 A JP 2008526246A JP 2008526246 A JP2008526246 A JP 2008526246A JP 2009504670 A JP2009504670 A JP 2009504670A
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- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002704 solution binder Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
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- 230000001629 suppression Effects 0.000 description 1
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- 238000001356 surgical procedure Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000033 toxigenic Toxicity 0.000 description 1
- 230000001551 toxigenic effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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Classifications
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Abstract
Description
本発明は、嚢胞性線維症膜コンダクタンス制御因子(「CFTR」)の調節物質、その組成物、およびその方法に関する。本発明は、かかる調節物質を使用して、CFTRに仲介される病気を治療する方法にも関する。
ABC輸送体は、陰イオンだけでなく、様々な薬剤、潜在的に有毒の薬物、および生体異物の輸送を制御する、膜輸送タンパク質のファミリーである。ABC輸送体は、その特定の活性のために細胞内のアデノシン三リン酸(ATP)を結合して使用する、相同膜タンパク質群である。これらの輸送体のいくつかは、悪性癌細胞を化学療法剤から守る、多剤耐性タンパク質として発見された(MDR1―P糖タンパク質、または多剤耐性タンパク質、MRP1など)。現在までに、48のABC輸送体が同定され、配列同一性および機能に基づいて7つのファミリーに分類されている。
Gregory,R.J.等(1990年)Nature 347:382―386 Rich,D.P.等(1990年)Nature 347:358―362 Riordan,J.R.等(1989年)Science 245:1066−1073 Cutting,G.R.等(1990年)Nature 346:366―369 Dean,M.等(1990年)Cell 61:863:870 Kerem,B―S.等(1989年)Science 245:1073―1080 Kerem,B―S等(1990年)Proc.Natl.Acad.Sci.USA 87:8447―8451 Quinton,P.M.(1990年),FASEB J.4:2709―2727 Dalemans等(1991年),Nature Lond.354:526―528 Pasyk and Foskett(1995年),J.Cell.Biochem.270:12347―50 Aridor M等、Nature Med.(1999年),5(7),pp745―751 Shastry,B.S.,等、Neurochem.International(2003年),43,pp1―7 Rutishauser,J.,等、SwissMed WkIy(2002年),132,pp211―222 Morello,JP等、TIPS(2000年),21,pp.466―469 Bross P.,等、Human Mut.(1999年),14,pp.186―198
本発明の化合物、およびその薬学的に受容可能な組成物は、CFTR活性の調節物質として有用であることが現在分かっている。これらの化学式Iまたは化学式II:
I.本発明の化合物の一般的説明:
本発明は、化学式Iまたは化学式IIの化合物:
Xは、CH2、CF2、CH2―CH2、またはCF2―CF2であり;
環Aは、3―7員の単環式シクロアルキル環であり;
RAAおよびRBBが、窒素原子とともに、OR´で置換されるピロリジニル環を形成し;
R´は、水素、または脂肪族の最大2つの炭素単位が、―CO―、―CS―、―COCO―、―CONR―、―CONRNR―、―CO2―、―OCO―、―NRCO2―、―O―、―NRCONR―、―OCONR―、―NRNR、―NRNRCO―、―NRCO―、―S―、―SO、―SO2―、―NR―、―SO2NR―、NRSO2―、または―NRSO2NR―により選択的に独立して置換される、C1―C6の脂肪族であり;
Rは、水素、またはC1―C6の脂肪族であり;
Zは、電子求引性の置換基であり;
qは、0―3である。
一実施形態においては、環Aは、シクロプロピル、シクロペンチル、またはシクロヘキシルである。別の実施形態においては、環Aは、シクロプロピルまたはシクロペンチルである。一定の実施形態においては、環Aは、シクロプロピルである。
二つのRXがともに環(a)を形成し;
Xは、CH2であり;
環Aは、シクロプロピルであり;
R´は、水素であり;
qは、1または2であり;
Zは、ハロ、CF3またはジフルオロメチレンジオキシである。
二つのRXがともに環(a)を形成し;
Xは、CH2であり;
Rは、水素であり;
環Aは、シクロプロピルであり;
R´は、水素であり;
qは、1または2であり;
Zは、ハロ、CF3またはジフルオロメチレンジオキシである。
二つのRXがともに環(a)を形成し;
Xは、CF2であり;
環Aは、シクロプロピルであり;
R´は、水素であり;
qは、1または2であり;
Zは、ハロ、CF3またはジフルオロメチレンジオキシである。
二つのRXがともに環(a)を形成し;
Xは、CF2であり;
Rは、水素であり;
環Aは、シクロプロピルであり;
R´は、水素であり;
qは、1または2であり;
Zは、ハロ、CF3またはジフルオロメチレンジオキシである。
RX、R、環A、Z、およびqは、上に定義したとおりであり;
Lは、C(O)、SO2より選択されるリンカーであり;
pは、0または1であり;
CAは、適切なキラル補助基である。
Xは、CH2、CF2、CH2―CH2、またはCF2―CF2であり;
環Aは、3―7員の単環式シクロアルキル環であり;
RAAおよびRBBが、窒素原子とともに、OR´で置換されるピロリジニル環を形成し;
R´は、水素、または脂肪族の最大二つの炭素単位が、―CO―、―CS―、―COCO―、―CONR―、―CONRNR―、―CO2―、―OCO―、―NRCO2―、―O―、―NRCONR―、―OCONR―、―NRNR、―NRNRCO―、―NRCO―、―S―、―SO、―SO2―、―NR―、―SO2NR―、NRSO2―、または―NRSO2NR―により選択的に独立して置換される、C1―C6の脂肪族であり;
Rは、水素、またはC1―C6の脂肪族であり;
Zは、電子求引性の置換基であり;
qは、0―3であり、
LG1は、第一の適切な離脱基である
本明細書で使用されるところの、「第一の適切な条件」という用語は、化学式I―Aの化合物と化学式R―1の化合物との間、または、化学式II―Aの化合物と化学式R―1の化合物との間に、反応をおこすために適切な条件を意味する。かかる適切な条件には、たとえば、第一の適切な溶媒、第一の適切な温度、および適切な還元剤が含まれる。化学式I―Aの化合物と化学式R―1の化合物との間、または、化学式II―Aの化合物と化学式R―1の化合物との間に反応をおこすための、このような適切な条件の様々なものが、当業者に周知である。
R、Z、およびqは、上に定義されたとおりであり;
PG1は、第二の適切な保護基であり;
[CA]は、適切なキラル補助基であり;
該方法には二つのステップが含まれ、該二つのステップのうちの一方が、適切な分離手段を用いて、該異性体混合物を分離するステップであり、該二つのステップのうちのもう一方が、第四の適切な条件で、PG1をR1に変換するステップである。
PG1は、第二の適切な保護基であり;
Mは、適切なメタルカチオンであり;
[CA]は、適切なキラル補助基であり;
該方法には、第五の適切な条件で、該化学式R―4の化合物を、該化学式R―5の化合物と反応させるステップが含まれる。
本発明の化合物は、従来技術で周知の方法により、調製されうる。本発明の化合物を調製する例示的な合成経路が、以下に示される。
スキームI―Dは、本発明の例示的な化合物の合成を示す。
下のスキームII―Aは、キラル補助基を用いて本発明の化合物を調製するための、別の例示的プロセスを示す。
薬学的に受容可能な組成物
上述のとおり、本発明は、CFTRの調節物質として有用であり、したがって嚢胞性線維症、遺伝性気腫、遺伝性ヘモクロマトーシス、プロテインCの欠損等の凝固―線溶障害、1型遺伝性血管浮腫、家族性高コレステロール血症等の脂質プロセシング障害、1型カイロミクロン血症、無β―リポたんぱく血症、I細胞病/偽ハーラー等のリソソーム蓄積症、ムコ多糖症、サンドホフ/テイサックス病、クリグラー・ナジャールII型、多腺性内分泌障害/高インスリン血症、糖尿病(インシュリン受容体による)、ラロン型小人症、ミエロペルオキシダーゼ欠損、原発性副甲状腺機能低下症、黒色腫、糖鎖欠損糖タンパク質症候群1型、遺伝性気腫、先天性甲状腺機能亢進症、骨形成不全、遺伝性線維素原減少症、ACT欠損症、尿崩症(DI)、中枢性DI、腎原発性DI、シャルコー・マリー・トゥース症候群、ペリツェウス・メルツバッハー病、アルツハイマー病等の神経変性疾患、パーキンソン病、筋萎縮性側索硬化症、進行性核上性麻痺(plasy)、ピック病、ハンティングトン病、脊髄小脳性運動失調I型、脊髄性および延髄性筋萎縮症、歯状核赤核淡蒼球ルイ体、および筋緊張性ジストロフィー等のいくつかのポリグルタミン神経疾患、ならびに遺伝性クロイツフェルト・ヤコブ病(プリオンタンパク質のプロセシング障害による)等の海綿状脳症、ファブリー病、およびストロイスラー・シャインカ症候群等の病気、疾患または状態の治療に有用な化合物を提供する。
さらに別の態様においては、本発明は、CFTRに関係する状態、病気、または疾患を治療する方法を提供する。一定の実施形態では、本発明は、CFTRの欠損に関係する状態、病気、または疾患を治療する方法を提供し、その方法には、化学式(I)の化合物を含む組成物を、それを必要とする対象、好ましくは哺乳類に投与するステップが含まれる。
1―(ベンゾ[d][1,3]ジオキソール―6―イル)―N―(5―((R)―(2―クロロフェニル)((R)―3―ヒドロキシピロリジン―1―イル)メチル)チアゾール―2―イル)シクロプロパンカルボキサミド(2)ヒドロクロリドおよび1―(ベンゾ[d][1,3]ジオキソール―6―イル)―N―(5―((S)―(2―クロロフェニル)((R)―3―ヒドロキシピロリジン―1―イル)メチル)チアゾール―2―イル)シクロプロパンカルボキサミド(1)ヒドロクロリド
1―ベンゾ[1,3]ジオキソール―5―イル―シクロプロパンカルボン酸[5―(2―クロロ―ベンゾイル)―チアゾール―2―イル]―アミド
(R)―1―((2―(1―(ベンゾ[d][1,3]ジオキソール―6―イル)シクロプロパンカルボキサミド)チアゾール―5―イル(2―クロロフェニル)メチル)ピロリジン―3―イル(1S,2R,5S)―2―イソプロピル―5―メチルシクロヘキシルカーボネート
第二溶出生成物((R)―1―((R)―(2―(1―(ベンゾ[d][1,3]ジオキソール―6―イル)シクロプロパンカルボキサミド)チアゾール―5―イル)(2―クロロフェニル)メチル)ピロリジン―3―イル(1S,2R,5S)―2―イソプロピル―5―メチルシクロヘキシルカーボネート)の保持時間は、28.6分(Chiralpak ADカラム)であった。ESI―MSm/z計算値679.3,実測値;680.5(M+1)+;保持時間3.86分。
方法B:無水THF(400mL)中の2,2―ジフルオロベンゾ[d][1,3]ジオキソール―5―カルバルデヒド(125g,0.67mol)の溶液に、NaBH4(28g,0.74mol)を、0℃で少しずつ加えた。混合物を0℃で1時間撹拌した後、500mLの水に注いだ。混合物を、酢酸エチル(200mLx3)で抽出した。有機相を、Na2SO4で乾燥させ、真空濃縮して、無色油状物としての(2,2―ジフルオロベンゾ[d][1,3]ジオキソール―5―イル)メタノールを得た(120g,95%)。
(R)―N―((R)―(2―アミノ―4―メチルチアゾール―5―イル)(2―クロロフェニル)メチル)―2―メチルプロパン―2―スルフィンアミドおよび(R)―N―((S)―(2―アミノ―4―メチルチアゾール―5―イル)(2―クロロフェニル)メチル)―2―メチルプロパン―2―スルフィンアミド
I)ΔF508―CFTRを調節する化合物の性質を分析するための膜電位の光学的測定法
光学的膜電位計測法は、GonzalezおよびTsienにより記載される、電位感受性FRETセンサ(Gonzalez,J.E.およびR.Y.Tsien(1995年)“Voltage sensing by fluorescence resonance energy transfer in single cells”Biophvs J 69(4):1272―80,およびGonzalez,J.E.およびR.Y.Tsien(1997年)“Improved indicators of cell membrane potential that use fluorescence resonance energy transfer”Chem Biol 4(4):269―77を参照)を、Voltage/Ion Probe Reader(VIPR)等の、蛍光変化を測定するための計装(Gonzalez,J.E.,K.Oades,等(1999年)“Cell―based assays and instrumentation for screening ion―channel targets”Drug Discov Today 4(9):431―439を参照)とあわせて利用した。
膜電位の光学測定には、ΔF508―CFTRを安定発現するNIH3T3マウス繊維芽細胞を使用する。細胞を、175cm2培養フラスコ中の、2mMのグルタミン、10%のウシ胎児血清、1XのNEAA、β―ME、1Xのpen/strep、および25mM HEPESを添加したダルベッコの変法イーグル培地で、5%CO2および90%湿度で37℃に維持する。すべての光学的アッセイで、細胞を、384―ウェルのマトリゲル被覆プレートに、30,000/ウェルで播種し、37℃で2時間培養した後、27℃で24時間培養した。修正アッセイでは、細胞を、27℃または37℃で、化合物を伴って、および伴わずに、16〜24時間培養した。
1.Ussingチャンバアッセイ
光学的アッセイで同定されたΔF508―CFTRの調節物質をさらに特徴づけるために、ΔF508―CFTRを発現する分極化した上皮細胞にUssingチャンバ実験を行った。Costar Snapwell細胞培養インサートで増殖させたFRTΔF508―CFTR上皮細胞を、Ussingチャンバ(Physiologic Instruments,Inc.,カリフォルニア州サンディエゴ)にマウントし、電位クランプシステム(アイオワ州アイオワ大学,Department of Bioengineering,およびPhysiologic Instruments,Inc.,カリフォルニア州サンディエゴ)を使用して単層を連続的に短絡させた。2mVのパルスを因加することにより、経上皮の電気抵抗を測定した。これらの条件下において、FRT上皮は、4KΩ/cm2以上の抵抗を示した。溶液を27℃に維持し、空気でバブリングした。電極のオフセット電位および流体の抵抗を、細胞フリーのインサートを用いて修正した。これらの条件下で、電流は、頂端膜において発現するΔF508―CFTRを通るCl−の流れを反映する。MP100A―CEインタフェースおよびAcqKnowledgeソフトウェア(v3.2.6;BIOPAC Systems,カリフォルニア州サンタバーバラ)を使用して、Iscをデジタル的に得た。
代表的なプロトコルは、側底膜から頂端膜のCl−濃度勾配を利用した。この勾配を設定するために、通常のリンゲルを側底膜に用い、他方で頂端のNaClを、等モルのグルコン酸ナトリウム(NaOHでpH7.4に滴定)で置換して、上皮を横切る大きなCl−濃度勾配を得た。すべての実験を、正常な単層で行った。ΔF508―CFTRを十分に活性化させるため、ホルスコリン(10μM)、およびPDE抑制物質のIBMX(100μM)を適用し、続いて、CFTR増強物質のゲニステイン(50μM)を加えた。
EC50:「+++」は、<2uMを意味し、「++」は、2uM〜20uMの間を意味し、「+」は、25uM〜60uMの間を意味する。
%有効性:「+」は、<25%を意味し、「++」は、25%〜100%の間を意味し、「+++」は、>100%を意味する。
Claims (66)
- 化学式Iまたは化学式IIの化合物:
両方のRXが同時に水素であることはなく、または
該二つのRXがともに環(a):
Xは、CH2、CF2、CH2―CH2、またはCF2―CF2であり;
環Aは、3―7員の単環式シクロアルキル環であり;
RAAおよびRBBが、窒素原子とともに、OR´で置換されるピロリジニル環を形成し;
R´は、水素、または脂肪族の最大二つの炭素単位が、―CO―、―CS―、―COCO―、―CONR―、―CONRNR―、―CO2―、―OCO―、―NRCO2―、―O―、―NRCONR―、―OCONR―、―NRNR、―NRNRCO―、―NRCO―、―S―、―SO、―SO2―、―NR―、―SO2NR―、NRSO2―、または―NRSO2NR―により選択的に独立して置換される、C1―C6の脂肪族であり;
Rは、水素、またはC1―C6の脂肪族であり;そして
Zは、電子求引性の置換基であり;
qは、0―3である、
化合物。 - 二つのRXがともに環(a)を形成し、XはCH2である、請求項1に記載の化合物。
- 二つのRXがともに環(a)を形成し、XはCF2である、請求項1に記載の化合物。
- 一つのRXが水素であり、もう一方のRXがハロ、CF3、C1―C4アルキル、または―OC1―C4アルキルである、請求項1に記載の化合物。
- 一つのRXが水素であり、もう一方のRXが4―メトキシである、請求項1に記載の化合物。
- 環Aが、シクロプロピル、シクロペンチル、またはシクロヘキシルである、請求項1〜5のいずれか一項に記載の化合物。
- 環Aが、シクロプロピル、またはシクロペンチルである、請求項6に記載の化合物。
- 環Aが、シクロプロピルである、請求項6に記載の化合物。
- R´が水素である、請求項1〜8のいずれか一項に記載の化合物。
- R´がC1―6アルキルである、請求項1〜8のいずれか一項に記載の化合物。
- RAAおよびRBBがともに、OH置換基を伴うピロリジニルを形成する、請求項1〜10のいずれか一項に記載の化合物。
- Zが、ハロ、CF3、またはジフルオロメチレンジオキシから選択される、請求項1〜11のいずれか一項に記載の化合物。
- qは0である、請求項1〜12のいずれか一項に記載の化合物。
- qは1である、請求項1〜12のいずれか一項に記載の化合物。
- Rは水素である、請求項1〜14のいずれか一項に記載の化合物。
- 化学式Iまたは化学式IIの化合物が、以下の特徴を一つ以上、および好ましくは全て含む、請求項1〜12または14のいずれか一項に記載の化合物であり:
二つのRXがともに環(a)を形成し;
Xは、CH2であり;
環Aは、シクロプロピルであり;
Rは、水素であり;
qは、1であり;そして
Zは、ハロ、CF3、またはジフルオロメチレンジオキシである、
化合物。 - 表1より選択される、化合物。
- (i)請求項1〜19のいずれか一項に記載の化合物、および
(ii)薬学的に受容可能な担体
を含む、医薬組成物。 - 粘液溶解剤、気管支拡張剤、抗生剤、抗感染剤、抗炎症剤、本発明の化合物以外のCFTR増強剤またはCFTR修正剤(corrector)、または栄養剤より選択される追加的薬剤を選択的にさらに含む、請求項20に記載の組成物。
- 細胞の膜内の、機能的なCFTRの数を増加させる方法であり、該細胞を、請求項1〜19のいずれか一項に記載の化合物と接触させるステップを含む、方法。
- in vitro、またはin vivoでの、生体試料中のCFTRまたはその断片の活性の測定に用いるためのキットであり、
(i)請求項1〜19のいずれか一項に記載の化合物を含む第一組成物、および
(ii)
a)該組成物を該生体試料と接触させるステップと、
b)該CFTR、またはその断片の活性を測定するステップ
のための指示
を含む、キット。 - a)追加的な組成物を、前記生体試料と接触させるステップと、
b)該追加的な化合物の存在下で、前記CFTR、またはその断片の活性を測定するステップと、
c)該追加的な化合物の存在下での、該CFTRの活性を、前記第一組成物の存在下での、該CFTRの密度と比較するステップ
のための指示をさらに含む、請求項23に記載のキット。 - 前記キットが、CFTRの密度を測定するために使用される、請求項24に記載のキット。
- CFTRに関連する患者の状態、病気、または疾患を治療する方法であり、請求項1〜19のいずれか一項に記載の化合物を、前記患者に投与するステップを含む、方法。
- 前記状態、病気、または疾患が、嚢胞性線維症、遺伝性気腫、遺伝性ヘモクロマトーシス、プロテインCの欠損等の凝固―線溶障害、1型遺伝性血管浮腫、家族性(amilial)高コレステロール血症等の脂質プロセシング障害、1型カイロミクロン血症、無β―リポたんぱく血症、I細胞病/偽ハーラー等のリソソーム蓄積症、ムコ多糖症、サンドホフ/テイサックス病、クリグラー・ナジャールII型、多腺性内分泌障害/高インスリン血症、糖尿病、ラロン型小人症、ミエロペルオキシダーゼ(myleoperoxidase)欠損、原発性副甲状腺機能低下症、黒色腫、糖鎖欠損糖タンパク質症候群(glycanosis CDG)1型、遺伝性気腫、先天性甲状腺機能亢進症、骨形成不全、遺伝性線維素原過剰症、ACT欠損症、尿崩症(DI)、中枢性(neurophyseal)DI、腎発原性DI、シャルコー・マリー・トゥース症候群、ペリツェウス・メルツバッハー(Perlizaeus Merzbacher)病、アルツハイマー病等の神経変性疾患、パーキンソン病、筋萎縮性側索硬化症、進行性核上性麻痺(plasy)、ピック病、ハンティングトン病、脊髄小脳性運動失調I型、脊髄性および延髄性筋萎縮症、歯状核赤核淡蒼球ルイ体、および筋緊張性ジストロフィー、遺伝性クロイツフェルト・ヤコブ病(プリオンタンパク質プロセシング異常による)等の海綿状脳症、ファブリー病、ストロイスラー・シャインカ病、分泌性下痢、多発性嚢胞腎、慢性閉塞性肺疾患(COPD)、ドライアイ病、またはシェーグレン症候群より選択される、請求項26に記載の方法。
- CA、L、p、およびこれに結合した酸素原子を合わせると、(+)―10―カンファースルホン酸、(1S,4R)―(−)―ω―カンファン酸エステル、(1R,2S,5R)―(−)メントールカルボナート、(1S,2R,5S)―(+)―メントールカルボナート、(1R,2R)―1―フェニル―2―シクロプロピルエステル、または(3R)―テトラヒドロフラン―3―カルボナートである、請求項28に記載の化合物。
- 第一の適切な条件下で、化学式R―1の化合物を、前記化学式Iの化合物を作るために、化学式I―Aの化合物と反応させるか、前記化学式IIの化合物を作るために、化学式II―Aの化合物と反応させるステップを含む:
式中、
両方のRXが同時に水素であることはなく;または
前記二つのRXがともに環(a):
Xは、CH2、CF2、CH2―CH2、またはCF2―CF2であり;
環Aは、3―7員の単環式シクロアルキル環であり;
RAAおよびRBBが、窒素原子とともに、OR´で置換されるピロリジニル環を形成し;
R´は、水素、または脂肪族の最大二つの炭素単位が、―CO―、―CS―、―COCO―、―CONR―、―CONRNR―、―CO2―、―OCO―、―NRCO2―、―O―、―NRCONR―、―OCONR―、―NRNR、―NRNRCO―、―NRCO―、―S―、―SO、―SO2―、―NR―、―SO2NR―、NRSO2―、または―NRSO2NR―により選択的に独立して置換される、C1―C6の脂肪族であり;
Rは、水素、またはC1―C6の脂肪族であり;
Zは、電子求引性の置換基であり;
qは、0―3であり;
LG1は、第一の適切な離脱基である、
方法。 - LG1が、アルキスルホネート、アリールスルホネート、ハライド、アルキルカルボキシレートより選択される、請求項30に記載の方法。
- 前記第一の適切な条件には、第一の適切な溶媒、第一の適切な温度、および適切な還元剤が含まれる、請求項30に記載の方法。
- 前記第一の適切な溶媒は、極性または無極性の、プロトン性または非プロトン性溶媒である、請求項32に記載の方法。
- 前記溶媒が、メタノール、エタノール、プロパノール、イソプロパノール、tert―ブタノール、ジクロロメタン、ジクロロエタン、トルエン、テトラヒドロフラン、ジオキサン、ジエチルエーテル、ジメチルエーテル、アセトニトリル、DMF、DMAC、またはNMPより選択される、請求項33に記載の方法。
- 前記第一の適切な温度が、約0℃〜約110℃の間である、請求項32に記載の方法。
- 前記適切な還元剤が、メタロ―ボロヒドリド、または接触水素化が可能な薬剤である、請求項32に記載の方法。
- 前記適切な還元剤が、適切な金属触媒の存在下における、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、水素化ホウ素リチウム、トリアセトキシ水素化ホウ素ナトリウム、水素化ホウ素カルシウム、水素より選択される、請求項36に記載の方法。
- 前記適切なキラル補助基は、アルキルスルホキシル基である、請求項38に記載の方法。
- 前記適切な第二の条件には、適切なプロトン酸および適切な第二の溶媒が含まれる、請求項38に記載の方法。
- 前記適切な第二の溶媒は、極性非プロトン性溶媒、またはプロトン性溶媒から選択される、請求項40に記載の方法。
- 前記適切な第二の溶媒は、極性非プロトン性溶媒である、請求項41に記載の方法。
- 前記極性非プロトン性溶媒は、ジオキサン、テトラヒドロフラン、ジエチルエーテル、またはジクロロメタンより選択される、請求項42に記載の方法。
- LG2が、ハライド、OC(O)アルキル、ペンタフルオロフェノキシ、アルコキシ、OCO2アルキル、またはヒドロキシより選択される、請求項44に記載の方法。
- R1が、水素である、請求項44に記載の方法。
- 前記第三の適切な条件には、適切な第三の適切なカップリング剤および第三の適切な溶媒が含まれる、請求項44に記載の方法。
- 前記適切なカップリング剤は、トリエチルアミン、ピリジン、DIEA、ルチジン、HATU、TCPH、またはHBTUより選択される、請求項47に記載の方法。
- 前記第三の適切な溶媒は、ジクロロメタン、ジオキサン、DMF、ジクロロエタン、またはテトラヒドロフランより選択される、請求項47に記載の方法。
- 前記適切な分離手段には、適切なクロマトグラフィ法が含まれる、請求項50に記載の方法。
- 前記適切なクロマトグラフィ法が、カラムクロマトグラフィ、または薄層クロマトグラフィより選択される、請求項51に記載の方法。
- 前記適切な分離手段には、結晶化法が含まれる、請求項50に記載の方法。
- 前記第四の適切な条件は、適切な脱保護剤および第四の適切な溶媒を含む、請求項50に記載の方法。
- 前記適切な脱保護剤は、トリフルオロ酢酸である、請求項54に記載の方法。
- 前記第四の適切な溶媒は、無極性非プロトン性溶媒である、請求項54に記載の方法。
- 前記極性非プロトン溶媒は、ジクロロメタンである、請求項56に記載の方法。
- 前記Mは、Li+、Na+、またはMg++より選択される、請求項58に記載の方法。
- PG1は、アルキルカルバメート、トリフルオロアセチル、トリアルキルシリル、またはピバロイルより選択される、請求項58に記載の方法。
- 前記PG1は、BOC、またはトリメチルシリルである、請求項60に記載の方法。
- 前記第五の適切な条件には、第五の適切な溶媒および第五の適切な温度が含まれる、請求項58に記載の方法。
- 前記適切な温度は、約−78℃である、請求項62に記載の方法。
- 前記第五の適切な溶媒は、テトラヒドロフランである、請求項62に記載の方法。
- 前記化学式I、または化学式IIの化合物は、表1から選択される、請求項30に記載の方法。
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EP1912983B1 (en) | 2011-06-08 |
US8586615B2 (en) | 2013-11-19 |
JP5143738B2 (ja) | 2013-02-13 |
US20120010257A1 (en) | 2012-01-12 |
NO20081280L (no) | 2008-05-09 |
EP1912983A2 (en) | 2008-04-23 |
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WO2007021982A3 (en) | 2007-05-03 |
ATE512145T1 (de) | 2011-06-15 |
US20140121381A1 (en) | 2014-05-01 |
KR20080053297A (ko) | 2008-06-12 |
CA2618057A1 (en) | 2007-02-22 |
NZ566208A (en) | 2010-09-30 |
MX2008002019A (es) | 2008-04-16 |
US9351962B2 (en) | 2016-05-31 |
WO2007021982A2 (en) | 2007-02-22 |
AU2006279810B2 (en) | 2011-10-27 |
RU2008109031A (ru) | 2009-09-20 |
JP2015127347A (ja) | 2015-07-09 |
US20080161371A1 (en) | 2008-07-03 |
US20160237079A1 (en) | 2016-08-18 |
JP2013018795A (ja) | 2013-01-31 |
US8962856B2 (en) | 2015-02-24 |
AU2006279810A1 (en) | 2007-02-22 |
US7999113B2 (en) | 2011-08-16 |
IL189178A0 (en) | 2008-06-05 |
JP2014156494A (ja) | 2014-08-28 |
US20170174675A9 (en) | 2017-06-22 |
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US20150126566A1 (en) | 2015-05-07 |
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