JP2022502368A - アルドケトレダクターゼ阻害剤およびその使用 - Google Patents
アルドケトレダクターゼ阻害剤およびその使用 Download PDFInfo
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- JP2022502368A JP2022502368A JP2021516392A JP2021516392A JP2022502368A JP 2022502368 A JP2022502368 A JP 2022502368A JP 2021516392 A JP2021516392 A JP 2021516392A JP 2021516392 A JP2021516392 A JP 2021516392A JP 2022502368 A JP2022502368 A JP 2022502368A
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- 229960001278 teniposide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical group FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003572 thiolanes Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- ICRHORQIUXBEPA-UHFFFAOYSA-N thionitrous acid Chemical compound SN=O ICRHORQIUXBEPA-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229940094720 viagra Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- FKBHRUQOROFRGD-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2[C]3C=CC=CC3=NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC FKBHRUQOROFRGD-IELIFDKJSA-N 0.000 description 1
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- 229930003231 vitamin Natural products 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
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- 208000006542 von Hippel-Lindau disease Diseases 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
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Abstract
Description
この出願は、2018年9月21日に出願された米国仮出願第62/734,560号の優先権を主張し、その主題は参照によりその全体が本明細書に組み込まれる。
式中、X1およびX3は、それぞれ独立して、CH2、NH、またはOであり、
X2およびX4は、それぞれ独立して、直鎖もしくは分岐鎖のアルキレン、アルキリン、Oであるか、または存在せず、
R1およびR4は、それぞれ独立して、置換もしくは非置換シクロアルキル、または4〜6個の環原子を含む置換もしくは非置換ヘテロシクリルであり(前記環原子のうち1個の原子は、独立して、Oから選択される)、
R2、R3、R5、およびR6は、それぞれ独立してH、ハロ基、C1−C6アルキル、C1−C6アルコキシ、C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、
CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルである。
式中、X1は、CH2、NH、またはOであり、
R2およびR3は、それぞれ独立して、H、ハロ基、C1−C6アルキル、C1−C6アルコキシ、
C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルであり、
R7およびR8は、それぞれ独立して、H、ハロ基、またはC1−C6アルキルである。
SNO−Hbレベルの維持(または回復)を促進し(「再ニトロシル化」)、コレステロールレベルを低下させ、虚血を処置し、嚢胞性線維症、喘息、炎症性腸疾患、高血圧、心不全、急性冠動脈症候群、インポテンス、脳卒中、敗血症性ショックなどのNO/SNO欠乏に関連する障害を処置し、ならびに肝再生、幹細胞増強、抗菌活性を促進し、腎虚血および心虚血を含む虚血性損傷から保護することができる。
当該技術分野で認識されている用語であり、注射などの経腸および局所投与以外の投与方法が含まれ、静脈内、筋肉内、胸膜内、血管内、心膜内、動脈内、くも膜下腔内、嚢内、眼窩内、心臓内、皮内、腹腔内、気管内、皮下、表皮下、関節内、被膜下、くも膜下、脊髄内および胸骨内の注射および注入が含まれるが、これらに限定されない。
N−Mannich塩基、Schiff塩基および、化合物中のアミノ官能基のエナミノン、オキシム、アセタール、ケタール、およびケトンのエノールエステル、およびアルデヒド官能基など、ならびに酸化されてスルホキシドまたはスルホンを形成するスルフィドが含まれる。
式中、X1およびX3は、それぞれ独立して、CH2、NH、またはOであり、
X2およびX4は、それぞれ独立して、直鎖もしくは分岐鎖のアルキレン、アルキリン、Oであるか、または存在せず、
R1およびR4は、それぞれ独立して、置換もしくは非置換シクロアルキル、または4〜6個の環原子を含む置換もしくは非置換ヘテロシクリルであり(前記環原子のうち1個の原子は、独立して、Oから選択される)、
R2、R3、R5、およびR6は、それぞれ独立してH、ハロ基、C1−C6アルキル、C1−C6アルコキシ、C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、
CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルである。
式中、X1は、CH2、NH、またはOであり、
R2およびR3は、それぞれ独立して、H、ハロ基、C1−C6アルキル、C1−C6アルコキシ、C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルであり、
R7およびR8は、それぞれ独立して、H、ハロ基、またはC1−C6アルキルである。
例えば、ジロートンなどの5−リポキシゲナーゼ(F.J.Alvarez&R.T.Slade,Pharmaceutical Res.1992;9(11):1465−1473)を含むことができる。
ジオキサン中の化合物1(1g、3.86mmol)および化合物2(0.996g、11.53mmol)の撹拌溶液に、水(20mL:5mL)をN2雰囲気下でK2CO3(1.6g、11.58mmol)を加えた。反応混合物を窒素で15分間脱気し、次いでPd(dppf)Cl2.DCM(0.315g、0.386mmol)を添加し、再度さらに10分間脱気し、16時間80℃に加熱した。完了後、反応混合物をセライトの小さなパッドを通して濾過し、酢酸エチルで洗浄し、水を加え、酢酸エチルで抽出し、水、次いで塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下で蒸発させて粗塊を得、これをカラムクロマトグラフィー(10%EA/HEX)によって精製して、所望の化合物3(800mg、94%)を黄色のガムとして得た。
メタノール性アンモニア(5ml)中の化合物3(1g、4.54mmol)の撹拌溶液に、チタンイソプロポキシド(1.5ml、13.63mmol)を0℃密封された管内で加え、反応混合物を60℃で℃12時間撹拌した。出発物質を完全に消費した後(TLCで監視)、ろ過し、後処理なしで次のステップに転送した。
メタノール性アンモニア(10ml)中の粗化合物4(2g)の上記の撹拌溶液に、TMSCN(3.42ml、27.27mmol)をゆっくりと加え、窒素でパージし、室温で2時間撹拌し、次いで60℃で12時間密封されたチューブで加熱した。反応混合物を酢酸エチルおよび水で希釈し、得られたスラリーを、セライトパッドを通して濾過し、こうして収集した濾液を無水Na2SO4で乾燥し、濾過し、減圧下で濃縮して、粗製物(1.8g)を得て、これを次の反応に直接使用した。
キラルHPLCは、前述の方法に従って、Agilent−HPLC1200シリーズによって実施した。
カラム−Chiralpak IC(4.6×250mm)、5μ
移動相−ヘキサン/EtOH/IPamine:80/20/0.1
流量−1.0ml/分
実施時間−15分
波長−282nm
溶解度−メタノール
本発明の上記の説明から、当業者は、改善、変更および修正を認識するであろう。当業者の範囲内のそのような改善、変更および修正は、添付の特許請求の範囲によってカバーされることが意図されている。本出願で引用されるすべての参考文献、刊行物、および特許は、参照によりそれらの全体が本明細書に組み込まれる。
Claims (21)
-
式中、X1およびX3は、それぞれ独立して、CH2、NH、またはOであり、
X2およびX4は、それぞれ独立して、直鎖もしくは分岐鎖のアルキレン、アルキリン、Oであるか、または存在せず、
R1およびR4は、それぞれ独立して、置換もしくは非置換シクロアルキル、または4〜6個の環原子を含む置換もしくは非置換ヘテロシクリルであり(前記環原子のうち1個の原子は、独立して、Oから選択される)、
R2、R3、R5、およびR6は、それぞれ独立して、H、ハロ基、C1−C6アルキル、C1−C6アルコキシ、C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルである、化合物。 - 2−Cがシクロプロピルまたはシクロブチル基であり、X1がNHであり、X2が存在しない場合、前記式(I)の化合物の7−Cは、水素、シクロプロピル、フルオロからなる群から選択されるR2基を含まない、請求項1に記載の化合物。
- R1およびR4は、それぞれ独立して、置換もしくは非置換のシクロプロピル、シクロブチル、ビシクロブチル、またはオキサシクロブチルである、請求項1に記載の化合物。
- X1およびX3は、NHである、請求項1に記載の化合物。
- X2およびX4は、存在しない、請求項1に記載の化合物。
- R2、R3、R5、およびR6は、それぞれ独立して、H、ハロ基、またはC1−C6アルキルである、請求項1に記載の化合物。
- 以下の式(III):
式中、X1は、CH2、NH、またはOであり、
R2およびR3は、それぞれ独立して、H、ハロ基、C1−C6アルキル、C1−C6アルコキシ、
C1−C6アルキルスルフィド、C1−C6アルキルスルフィニル、C1−C6アルキルスルホニル、−CF3、−S−CF3、−SO2CF3、CO−N(Ra)−Rb、C1−C6アルキルアルコール、C1−C6アルキルエーテル、ニトロ、C1−C6アルキルスルフィド、C1−C6アルキルアミン、C1−C6アルキルエステル、カルボン酸、C1−C6シクロアルキル、またはC1−C6ヘテロシクリルであり、
RaおよびRbは、それぞれ独立して、HまたはC1−C6アルキルであり、
R7およびR8は、それぞれ独立して、H、ハロ基、またはC1−C6アルキルである、請求項1に記載の化合物、およびその薬学的に許容される塩。 - 前記化合物の前記7−Cが、水素、シクロプロピル、およびフルオロからなる群から選択されるR2基を含まない、請求項7に記載の化合物。
- 医薬組成物の調製における請求項1〜11のいずれかに記載の化合物の使用。
- AKR阻害剤としての請求項1〜11のいずれかに記載の化合物の使用。
- 前記化合物は、選択的または部分的に選択的なAKR1A1阻害剤である、請求項13に記載の使用。
- 前記化合物は、少なくとも約6、少なくとも約7、少なくとも約8、少なくとも約9、少なくとも約10、少なくとも約11、少なくとも約12、少なくとも約13、少なくとも約14、少なくとも約15以上のAKR1A1対AKR1B1選択性(AKR1A1/AKR1B1)を有する、請求項14に記載の使用。
- 前記化合物は、対象中のタンパク質のS−ニトロシル化を増加させるのに有効な量で、前記対象に投与される、請求項13に記載の使用。
- 前記化合物は、NO/SNO欠乏に関連する障害、または対象におけるSNOの増加から利益を得る障害を処置するために、それを必要とする対象に投与される、請求項13に記載の化合物の使用。
- 前記化合物は、それを必要とする対象の血液または組織中のSNOレベルを増加させるのに有効な量で投与される、請求項13に記載の使用。
- 前記障害は、虚血を含む、請求項17に記載の使用。
- 前記虚血は、虚血組織または虚血によって損傷を受けた組織を含む、請求項19に記載の使用。
- 前記化合物は、急性冠動脈症候群、急性肺損傷(ALI)、急性心筋梗塞(AMI)、急性呼吸困難症候群(ARDS)、動脈閉塞性疾患、動脈硬化症、関節軟骨欠損、無菌全身性炎症、アテローム性動脈硬化性心血管疾患、自己免疫疾患、骨折、骨折、脳浮腫、脳低灌流、バージャー病、火傷、癌、心血管疾患、軟骨損傷、脳梗塞、脳虚血、脳卒中発作、脳血管疾患、化学療法誘発性ニューロパチー、慢性感染症、慢性腸間膜虚血、跛行、うっ血性心不全、結合組織損傷、挫傷、冠状動脈疾患(CAD)、重症肢虚血(CLI)、クローン病、深部静脈血栓症、深部創傷、潰瘍治癒の遅延、創傷治癒の遅延、糖尿病(I型およびII型)、糖尿病性ニューロパチー、糖尿病誘発性虚血、播種性血管内凝固(DIC)、塞栓性脳虚血、移植片対宿主疾患、凍傷、遺伝性出血性末梢血管拡張症、虚血性血管疾患、高酸素損傷、低酸素症、炎症、炎症性腸疾患、炎症性疾患、損傷した腱、断続的な跛行、腸虚血、虚血、虚血性脳疾患、虚血性心臓病、虚血性末梢血管疾患、虚血性胎盤、虚血性腎疾患、虚血性血管疾患、虚血性再灌流損傷、裂傷、左主冠動脈疾患、肢虚血、下肢虚血、心筋梗塞、心筋虚血、臓器虚血、骨関節炎、骨粗鬆症、骨肉腫、パーキンソン病、アルツハイマー病、または他の神経変性疾患、末梢動脈疾患(PAD)、末梢動脈疾患、末梢虚血、末梢ニューロパチー、末梢血管疾患、前癌、肺浮腫、肺塞栓症、リモデリング障害、腎虚血、網膜虚血、網膜症、敗血症、皮膚潰瘍、固形臓器移植、脊髄損傷、脳卒中、軟骨下骨嚢胞、血栓症、血栓性脳虚血、組織虚血、一過性虚血性発作(TIA)、外傷性脳損傷、潰瘍性大腸炎、腎臓の血管疾患、血管炎症状態、von Hippel−Lindau症候群、肝損傷、または組織、皮膚、もしくは臓器の創傷のうちの少なくとも1つを処置するために対象に投与される請求項13に記載の使用。
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