JP7434278B2 - ラニフィブラノールの重水素化誘導体 - Google Patents
ラニフィブラノールの重水素化誘導体 Download PDFInfo
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- JP7434278B2 JP7434278B2 JP2021504431A JP2021504431A JP7434278B2 JP 7434278 B2 JP7434278 B2 JP 7434278B2 JP 2021504431 A JP2021504431 A JP 2021504431A JP 2021504431 A JP2021504431 A JP 2021504431A JP 7434278 B2 JP7434278 B2 JP 7434278B2
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- derivative according
- deuterated derivative
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Description
APCI=大気圧化学イオン化法
DCM=ジクロロメタン
DMSO=ジメチルスルホキシド
eq.=当量
EtOAc=酢酸エチル
EtOH=エタノール
h=時間
HPLC=高速液体クロマトグラフィー
LCMS=液体クロマトグラフィー/質量分析法
MeOH=メタノール
min=分
Pd(PPh3)4=テトラキス(トリフェニルホスフィン)パラジウム(0)
pTsOH=p-トルエンスルホン酸
NMR=核磁気共鳴
THF=テトラヒドロフラン
調製例1:2-ジュウテリオ-1,3-ベンゾチアゾール
n-BuLi(37.0mL、92.5mmol、2.5eq;2.5Mヘキサン溶液)を1,3-ベンゾチアゾール(5.0g、36.9mmol、1.0eq.)のTHF(80mL)溶液に滴下し、-78℃まで冷却した。滴下終了後、-78℃で反応混合物にD2O(4mL、222mmol、6.0eq.)を添加した。全体を30分間攪拌後、室温に戻した。反応をLCMS分析によりモニタリングした。その後、反応混合物を飽和NH4Cl水溶液で処理し、全体をDCMで3回抽出した。有機層を合わせてMgSO4で乾燥し、次いでろ過し、減圧留去して得た粗生成物をフラッシュクロマトグラフィー(溶離液:0から40%のEtOAcのn-ヘプタン溶液)によって精製して、調製例1の化合物(3.22g、収率64%)を茶色油状物として得た。APCI MS m/z 137[M+H]+;HPLC-MS(220-254nm)純度:99%。1H NMR(300MHz DMSO-d6):δ7.46-7.58(2H,m);8.08-8.19(2H,m)。
2-ジュウテリオ-1,3-ベンゾチアゾール(調製例1、2.9g、21.3mmol、1.0eq.)を硫酸溶液(13mL)に0℃でゆっくりと添加し、次いで、温度を0℃未満に保ちながら硝酸(6.4mL)を滴下した。その後、反応混合物を室温に戻し、12時間攪拌してから、氷水混合物上で加水分解させた。黄色沈殿物をろ別し、水で洗浄し、エタノールから結晶化させて、所望の生成物(調製例2、1.4g、収率37%)を黄色結晶として得た。APCI MS m/z 182[M+H]+;HPLC-MS(220-254nm)純度>99%。1H NMR(300MHz DMSO-d6):δ8.27-8.38(2H,m);9.25(1H,d,J=2.3Hz)。
塩化スズ粉末(7.3g、38.6mmol、3.5eq.)を調製例2の化合物(2.0g、11.0mmol、1.0eq.)のEtOH/EtOAc(1:1)混合物(60mL)溶液に添加し、この溶液を室温で4時間攪拌した。反応終了時に反応混合物をCelite(登録商標)カートリッジでろ過し、飽和Na2CO3溶液で抽出した。有機層を合わせてMgSO4で乾燥し、次いでろ過し、減圧留去して得られた粗生成物をフラッシュクロマトグラフィー(溶離液:0から20%のMeOHのDCM溶液)によって精製して、所望の化合物(調製例3、970mg、収率58%)を茶色結晶として得た。APCI MS m/z 152[M+H]+;HPLC-MS(220-254nm)純度:97%。1H NMR(300MHz DMSO-d6):δ5.38(2H,s);6.8(1H,dd,J=8.7Hz及びJ=2.2Hz);7.11(1H,d,J=2.2Hz);7.7(1H,d,J=8.7Hz)。
塩化チオニル(1.1mL)水溶液(4.5mL)を0℃で調製し、4℃で一晩保管した。この水溶液に塩化銅(I)(0.05eq.)を-10℃で添加した。調製例3の化合物(450mg、2.9mmol、1.0eq.)を温度を25℃未満に保ちながら塩酸(3.5mL)に溶解させ、この溶液を-10℃まで冷却してから亜硝酸ナトリウム溶液(3.3mmol、0.7mL、1.1eq.)を温度が-2℃を超えないように添加した。得られた混合物を-2℃で15分間攪拌し、最初の塩化チオニル水溶液に-5℃で滴下した。その後、反応混合物を-5℃で3時間攪拌し、次いで水中で加水分解させた。形成された沈殿物をろ過してから水で洗浄して、所望の生成物(調製例4、255mg、収率37%)を薄茶色結晶として得た。この化合物を精製せずに次の工程で使用した。HPLC-MS(220-254nm)純度:94%。
アルゴン下、4-クロロ-2-ヨードアニリン(564mg、2.2mmol、1.0eq.)を無水ピリジン(8mL)に溶解させ、調製例4の化合物(600mg、2.5mmol、1.15eq.)を添加した。次いで、この溶液を室温で2時間攪拌した。溶媒を蒸発させ、粗反応物をフラッシュクロマトグラフィー(溶離液:0から30%のEtOAcのn-ヘプタン溶液)によって精製して、所望の生成物(調製例5、0.73g、収率73%)を茶色結晶として得た。APCI MS m/z 452[M+H]+;HPLC-MS(220-254nm)純度:94%。1H NMR(300MHz DMSO-d6):δ7.01(1H,d,J=8.5Hz);7.4(1H,dd,J=8.5Hz及びJ=2.3Hz);7.82(1H,dd,J=8.7Hz及びJ=1.8Hz);7.88(1H,d,J=2.4Hz);8.26(1H,d,J=8.7Hz);8.6(1H,d,J=1.5Hz);10.03(1H,s)。
アルゴン下、調製例5の化合物(1.31g、2.9mmol、1.0eq.)を無水DMF(30mL)に溶解させた後、5-ヘキシン酸(360mg、3.2mmol、1.1eq.)、ヨウ化銅(56mg、0.3mmol、0.1eq.)、Pd(PPh3)4(168mg、0.15mmol、0.05eq.)、及びトリエチルアミン(606μL、4.4mmol、1.5eq.)を添加し、反応混合物を80℃で2時間攪拌した。反応終了時にこの混合物を1N塩酸水溶液に取り、酢酸エチルで2回抽出した。有機層を合わせてMgSO4で乾燥し、次いでろ過し、減圧留去して得た粗生成物をフラッシュクロマトグラフィー(溶離液:0から5%のMeOHのDCM溶液)によって精製して、所望の生成物(実施例1、1.05g、収率83%)を茶色結晶として得た。APCI MS m/z 452[[M+H]+;HPLC-MS(220-254nm)純度:94%。1H NMR(300MHz DMSO-d6):δ1.86-2.01(2H,m);2.29-2.41(2H,m);3.08(2H,t,J=7.2Hz);6.61(1H,s);7.31(1H,dd,J=8.7Hz及びJ=2.0Hz);7.51(1H,d,J=2.0Hz);7.84(1H,dd,J=8.7Hz及びJ=1.8Hz);8.08(1H,d,J=8.7Hz);8.19(1H,d,J=8.7Hz);8.97(1H,d,J=1.8Hz);12.13(1H,s)。500MHz NMR分析による重水素導入率:98%。
調製例7:2-(1,1,2,2,3,3,4,4-オクタジュウテリオ-4-ヨード-ブトキシ)テトラヒドロピラン
ヨードトリメチルシラン(25g、125mmol、1eq.)を0℃でTHF-D8(10g、125mmol、1eq.)に添加した。0℃で2時間攪拌後、エーテル(80mL)及び水(20mL)を添加した。この混合物を3時間攪拌し、その後デカンテーションした。次いで、有機層をMgSO4で乾燥し、ろ過し、減圧濃縮した。得られた粗反応物を0℃でDCM(100mL)に取り、その後ジヒドロピラン(12.5mL、150mmol、1.2eq.)及びpTsOH(50mg、0.2mmol、0.002eq.)を添加した。その後、反応混合物を0℃で一晩攪拌した。この溶液をNaHCO3飽和溶液(3×15mL)、次いで塩水で順に洗浄してから、Na2SO4で乾燥した後、減圧濃縮した。粗反応物をフラッシュクロマトグラフィー(溶離液:1:20から1:5のEtOAc:ヘキサン)によって精製して、所望の生成物(調製例7、23g、収率62%)を無色油状物として得た。この生成物をそのまま次の工程で使用した。
新たに蒸留したDMSO(60mL)にリチウムアセチリド(19.94g、186.3mmol、1eq.)を溶解させた溶液を5℃で調製例7の化合物(30g、102.7mmol、0.55eq.)のDMSO(30mL)溶液に滴下した。得られた溶液を2時間攪拌してから、NH4Cl溶液で0℃で加水分解させた。次いで、この混合物をヘキサンで抽出し、硫酸銅(5%、20mL)溶液、次いで塩水(20mL)で洗浄した。有機層を合わせてNa2SO4で乾燥した後、減圧濃縮して、所望の生成物(調製例8、10.7g、収率55%)を黄色油状物として得た。この生成物を精製せずにそのまま次の工程で使用した。
調製例8の化合物(10.7g、56.2mmol、1eq.)を0℃でTHF(12.5mL)及びMeOH(350mL)の混合物に溶解させた溶液にpTsOH(360mg、1.82mmol、0.03eq.)を小分けにして添加し、得られた反応混合物を一晩攪拌した。次いで、この混合物をNaHCO3飽和溶液(3×15mL)及び塩水(15mL)で洗浄してから、Na2SO4で乾燥した後、減圧濃縮した。粗反応物をフラッシュクロマトグラフィー(溶離液:1:20から1:5のEtOAc:ヘキサン)によって精製して、所望の生成物(調製例9、5g、収率82%)を無色油状物として得た。この生成物をそのまま次の工程で使用した。
調製例9の化合物(9.25g、87mmol、1eq.)のアセトン(87mL)溶液に攪拌下、Jones試薬(CrO3(17.45g、174.5mmol、2eq.)の10N H2SO4(218mL)溶液)を0℃で5分かけて添加した。次いで、反応混合物を1時間攪拌後、減圧濃縮した。直ちにエーテル(130mL)及び水(4mL)を添加した。得られた固体をろ別し、ろ液をエーテル(6×100mL)で抽出した。有機層を合わせて水で洗浄してから、Na2SO4で乾燥した後、ろ過し、減圧濃縮して、所望の生成物(調製例10、9.17g、収率89%)を橙色油状物として得た。この生成物を精製せずにそのまま次の工程で使用した。
ベンゾチアゾール-6-スルホン酸(4-クロロ-2-ヨード-フェニル)-アミド(16g、35.5mmol、1eq.)、ヘキサ-5-イン酸(調製例10、5.2g、44mmol、1.24eq.)、ヨウ化銅(335mg、1.75mmol、0.05eq.)、ジクロロビス(トリフェニルホスフィン)パラジウム(1.24g、1.72mmol、0.05eq.)、トリエチルアミン(130mL)、及びN,N-ジメチルホルムアミド(130mL)の混合物を窒素下、110℃で1時間攪拌した。次いで、反応混合物を1M HCl溶液で希釈し、酢酸エチルで抽出した。不溶物をろ別し、ろ液をNa2SO4で乾燥した後、減圧濃縮した。粗反応物をフラッシュクロマトグラフィーによって精製してから、DCMから再結晶させて、所望の生成物(実施例2、2.3g、収率15%)を白色固形物として得た。500MHz NMR分析による重水素導入率:>99%。1H NMR(400MHz,DMSO-d6)δ 6.62(1H,d,J=0.6Hz),7.32(1H,dd,J=8.9及び2.2Hz),7.57(1H,d,J=2.1Hz),7.85(1H,dd,J=8.7及び2.1Hz),8.10(1H,d,J=8.9Hz),8.20(1H,d,J=8.7Hz),8.99(1H,s),9.66(1H,s),12.15(1H,s)。
本発明の化合物を生物学的試験に供して、特定の症状を治療又は予防できる可能性を評価した。まず、これらの化合物が核内受容体PPARの活性化因子として作用する能力を測定した。
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Claims (10)
- 少なくとも上記R1はDである、請求項1に記載の重水素化誘導体。
- 4-(1-(2-ジュウテリオ-1,3-ベンゾチアゾール-6-イル)スルホニル)-5-クロロ-1H-インドール-2-イル)ブタン酸である請求項2に記載の重水素化誘導体。
- 上記R2~R7のうち少なくとも1つの基はDである、請求項1に記載の重水素化誘導体。
- 上記R2及びR3のうち少なくとも1つの基、及び/又は上記R4及びR5のうち少なくとも1つの基、及び/又は上記R6及びR7のうち少なくとも1つの基はDである、請求項4に記載の重水素化誘導体。
- 4-[1-(1,3-ベンゾチアゾール-6-イルスルホニル)-5-クロロ-インドール-2-イル]-2,2,3,3,4,4-ヘキサジュウテリオブタン酸である請求項5に記載の重水素化誘導体。
- 請求項1~6のいずれか一項に記載の重水素化誘導体又はその塩若しくは溶媒和物と、適切な担体とを含む組成物。
- 請求項1~6のいずれか一項に記載の重水素化誘導体又はその薬学的に許容される塩若しくは溶媒和物と、薬学的に許容される担体とを含む医薬組成物。
- 治療に使用される請求項1~6のいずれか一項に記載の重水素化誘導体又はその薬学的に許容される塩若しくは溶媒和物。
- 線維性疾患、特に、肝線維症、脂肪肝、非アルコール性脂肪肝炎、慢性腎臓病、特発性肺線維症等の肺線維症、及び全身性強皮症から選択される線維性疾患の治療に使用される請求項1~6のいずれか一項に記載の重水素化誘導体又はその薬学的に許容される塩若しくは溶媒和物。
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2018
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2019
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2009506099A (ja) | 2005-08-30 | 2009-02-12 | ラボラトワール フルニエ エス・アー | 新規インドール化合物 |
Non-Patent Citations (4)
Title |
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Glob J Pharmaceu Sci,2017年,1(4),79-90 |
J.Med.Chem.,2018年,61,2246-2265 |
MEDCHEM NEWS ,2014年,41(2),8-22 |
NATURE MEDICINE ,2013年,19(6),656 |
Also Published As
Publication number | Publication date |
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FI3830085T3 (fi) | 2024-01-17 |
DK3830085T3 (da) | 2024-01-22 |
FR3084254A1 (fr) | 2020-01-31 |
PT3830085T (pt) | 2024-01-24 |
CN112638911A (zh) | 2021-04-09 |
SI3830085T1 (sl) | 2024-03-29 |
JP2024036611A (ja) | 2024-03-15 |
WO2020021215A1 (fr) | 2020-01-30 |
LT3830085T (lt) | 2024-02-12 |
JP2021533101A (ja) | 2021-12-02 |
RS65095B1 (sr) | 2024-02-29 |
HRP20240157T1 (hr) | 2024-04-12 |
EP4331584A1 (fr) | 2024-03-06 |
EP3830085A1 (fr) | 2021-06-09 |
EP3830085B1 (fr) | 2023-11-08 |
US20210300913A1 (en) | 2021-09-30 |
FR3084254B1 (fr) | 2020-10-23 |
HUE065045T2 (hu) | 2024-04-28 |
PL3830085T3 (pl) | 2024-04-15 |
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