JP2019526567A - ヒトpde1阻害薬として有用なトリアゾロピラジノン誘導体 - Google Patents
ヒトpde1阻害薬として有用なトリアゾロピラジノン誘導体 Download PDFInfo
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- JP2019526567A JP2019526567A JP2019510969A JP2019510969A JP2019526567A JP 2019526567 A JP2019526567 A JP 2019526567A JP 2019510969 A JP2019510969 A JP 2019510969A JP 2019510969 A JP2019510969 A JP 2019510969A JP 2019526567 A JP2019526567 A JP 2019526567A
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- 102000054507 human PDE6B Human genes 0.000 description 1
- 102000050549 human PDE7B Human genes 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
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- 210000003734 kidney Anatomy 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 101150037969 pde-6 gene Proteins 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
N−ブチル−2−ニトロ−ピリジン−3−アミン
約20〜25℃のEtOH(552mL)中の3−フルオロ−2−ニトロピリジン(92g、0.65mol)を添加する。この混合物を氷浴中で0℃に冷却する。ブタン−1−アミン(118.4g、1.6187mol)を約0〜5℃で40分かけて滴下する。約20〜25℃に加温し、16時間撹拌する。この反応混合物に水(800mL)を添加し、EtOAc(2×600mL)で抽出し、層を分離し、一緒にした有機層を水(2×1L)、飽和NaCl水溶液(2×500mL)で洗浄し、Na2SO4上で乾燥させ、濾過し、35℃で減圧下で濃縮して、さらなる精製なしで使用するのに適した表題化合物(120.00g、95%収率)を深黄色の油として得る。ES/MS m/z 196.1(M+1)。
N3−ブチルピリジン−2,3−ジアミン
約20〜25℃のMeOH(1024mL)中にN−ブチル−2−ニトロ−ピリジン−3−アミン(128.0g、0.7mol)を添加する。約20〜25℃の5%湿Pd/C(64g、50%負荷)を添加する。得られた混合物を3気圧のH2の下で約20〜25℃で3時間撹拌する。この反応混合物を珪藻土で濾過し、濾過ケークをMeOH(5×500mL)で洗浄し、濾液を減圧下で濃縮して、さらなる精製なしでの使用に適した表題化合物(101.9g、収率94%)を黒色の固体として得る。ES/MS m/z 166.1(M+1)。
1−ブチル−4H−ピリド[2,3−b]ピラジン−2,3−ジオン
約20〜25℃のEtOH(550mL)中にN3−ブチルピリジン−2,3−ジアミン(81.4g、0.5mol)を添加する。約20〜25℃で、EtOH中の30重量%NaOEt(427.4g、1.0mol)を一度に添加する。シュウ酸ジエチル(87.1g、0.6mol)を約20〜30℃で滴下し、RTで2.5時間撹拌する。この反応混合物を0.5MのHCl/DCM水溶液(1600mL/1200mL)の混合物中に撹拌しながら約0〜10℃で注ぐ。2層に分離し、水層をDCM(2×800mL)で抽出し、水(2×1600mL)、飽和NaCl水溶液(1600mL)で洗浄し、Na2SO4で乾燥させる。濾過し、減圧下で濃縮する。得られた固体残渣を約20〜25℃で30分間、ACN(200mL)中でスラリーにし、得られた固体を濾過により単離して、さらなる精製なしでの使用に適した表題化合物(70.0g、収率65%)を緑色の固体として得る。ES/MS m/z 220.1(M+1)。
1−ブチル−3−ヒドラジノ−ピリド[2,3−b]ピラジン−2−オン
1‐ブチル‐3‐[2−[(1‐メチルシクロプロピル)メチレン]ヒドラジノ]ピリド[2,3−b]ピラジン−2−オン
1−ブチル−3−クロロ−ピリド[2,3−b]ピラジン−2−オン
1−ブチル−3−ヒドラジノ−ピリド[2,3−b]ピラジン−2−オン
N’−(1−ブチル−2−オキソ−ピリド[2,3−b]ピラジン−3−イル)−1−メチル−シクロプロパンカルボヒドラジド
5−ブチル−9−(1−メチルシクロプロピル)ピリド[3,2−e][1,2,4]トリアゾロ[4,3−a]ピラジン−6(5H)−オン
スキーム2のステップD:RTのHMDS(360mL)中のN’−(1−ブチル−2−オキソ−ピリド[2,3−b]ピラジン−3−イル)−1−メチル−シクロプロパンカルボヒドラジド(45.0g、0.1mol)をスラリーにする。DBU(4.34g、28.5mmol)を添加し、125℃に加熱する。得られた溶液を還流下で6時間撹拌する。この反応混合物をRTへ冷却し、この混合物を水(800mL)に注ぎ入れ、得られた固体を濾過および回収する。この固体をDCM(400mL)/H2O(100mL)中に溶解し、得られた層を分離し、有機相を飽和NaCl水溶液(100mL)で洗浄し、Na2SO4上で乾燥させ、濾過し、濾液を減圧下で濃縮して、残渣を得る。EtOAc(200mL)を用いて40〜50℃で1時間摩砕し、得られた固体(22.0g、LCMSにより決定すると純度98%)を濾過により単離する。この22.0gのバッチを別のバッチの材料(10.0g、LCMSにより決定すると純度100%)と一緒にし、DCM:EtOAc(1:1)で溶出するシリカゲル上でのクロマトグラフィーによってさらに精製して、溶媒蒸発後に残渣を得る。得られた残渣を熱EtOAcで30分間摩砕し、得られた固体を濾過により単離して、表題化合物(25.70g、収率42%)を白色の固体として得る。ES/MS m/z 298.2(M+1)。
全長ヒトPDE1A(NP_001003683.1)、PDE1C(NP_005011.1)、PDE5A(NP_001074.2)、PDE7B(NP_061818.1)およびPDE9A(NP_002597.1)をコードするヌクレオチド配列を、N末端HISタグ付きのpFastBac1(Invitrogen)ベクターに挿入する。全長ヒトPDE4D(NP_006194.2)をおよびPDE3A(NP_000912.3)の触媒ドメイン(残基641〜1141)をコードするヌクレオチド配列を、C末端HISタグ付きpFastBac1(Invitrogen)ベクターに挿入する。全長ヒトPDE8A(NP_002596.1)およびPDE11A(AAI12394.1)をコードするヌクレオチド配列を、N末端Flagタグ付きpFastBac1(Invitrogen)ベクターに挿入する。全長ヒトPDE10A(AAD32595.1)をコードするヌクレオチド配列を、C末端Flag−Hisタグ付きpFastBac1(Invitrogen)ベクターに挿入する。全長ヒトPDE6A(NP_000431.2)およびPDE6B(AAH00249.1)をコードするヌクレオチド配列を、PDE6A/6B二量体の産生のために、それぞれN末端HISタグおよびN末端Flagタグ付きのpFastBacDual(Invitrogen)ベクターに挿入する。Sf9細胞におけるバキュロウイルス生成およびタンパク質発現を、BacからBacへのバキュロウイルス発現系(Invitrogen)のプロトコルにより行う。全長ヒトPDE1B(NP_000915.1)およびPDE2A(NP_002590.1)をコードするヌクレオチド配列を、C末端HISタグ付きpIEX4(Novagen)に挿入し、Sf9細胞における両タンパク質の産生を販売元のプロトコル(Novagen)によって行う。Hisタグ付きPDEタンパク質を、Ni−NTAアガロース(Qiagen)、続いて貯蔵緩衝液(20mMのTris−HCl、pH7.5、150mMのNaCl、10%グリセロール)中のSUPERDEX(登録商標)200カラム(GE Healthcare)上でのサイズ排除クロマトグラフィーを用いて精製する。PDE6A/6Bを含むFlagタグ付きPDEタンパク質を、NiNTAカラムクロマトグラフィーによる精製後に、抗Flag M2−アガロース(Sigma)を用いて精製し、保存緩衝液(50mMのTris−HCl、pH7.5、150mMのNaCl、10%グリセロール、0.1mg/mlのFlagペプチド)中で溶出する。精製したタンパク質はすべて、小分けして−80℃で保存する。
3’,5’環状ヌクレオチドホスホジエステラーゼ(PDE)酵素活性はすべて、SPA検出システムに基づく放射分析酵素アッセイ(シンチレーション近接アッセイ)を用いて測定する。試験する化合物を、10点濃度応答曲線を用いて純粋なジメチルスルホキシド(DMSO)中に希釈する。反応混合物中の最大化合物濃度は、10μMまたは100μMのいずれかである。基質の添加により反応を開始する前に、適切な濃度の化合物をいずれかのPDE酵素と共に30分間プレインキュベートする。反応は室温で60分間進行させておく。次に、SPAビーズの添加によって反応を停止させる。試料は、12時間後にMICROBETA(商標)TRILUX(登録商標)カウンターで読み取る。「IC50」は、化合物について起こり得る最大阻害応答の50%を生じるその化合物の濃度を指す。IC50値は、正規化データ対log[化合物]をプロットし、4パラメータロジスティック方程式を用いてデータを当てはめることによって計算する。
PDE1B、PDE1A、およびPDE1Cは、標準的なタンパク質生成手順に従ってクローン化および精製する。アッセイ緩衝液は、アッセイにおいてpH7.5で、50mMのTris−HCl、50mMのMgCl2、4mMのCaCl2、0.1%ウシ血清アルブミンおよび水中で6U/mlのカルモジュリンの終濃度を与えるように調製する。酵素の終濃度は、PDE1A、PDE1BおよびPDE1Cについてそれぞれ、0.25nM、0.074nMおよび0.0012nMである。反応は、47nMの終濃度を得るために、基質[3H]cAMPの添加によって始まる。
以下のホスホジエステラーゼ、すなわちヒトPDE3A(触媒ドメイン)、ヒトPDE4D、ヒトPDE7BおよびヒトPDE8Aの活性は、反応基質として[3H]cAMPを用いて測定する。これらの酵素はすべて、標準的な手順に従ってクローン化および精製する。アッセイ緩衝液は、アッセイ中の終濃度がpH7.5で50mMのTris−HCl、8.3mMのMgCl2、1.7mMのエチレンジアミン四酢酸(EDTA)および0.1%のウシ血清アルブミンとなるように調製する。酵素の終濃度は、PDE3A、PDE4D、PDE7BおよびPDE8Aについてそれぞれ、0.008nM、0.021nM、0.5nMおよび0.06nMである。反応は、47nMの終濃度を得るために、基質[3H]cAMPの添加によって始まる。
以下のホスホジエステラーゼ、すなわちヒトPDE2A、ヒトPDE5A、ヒトPDE6A/6B、ヒトPDE9A、ヒトPDE10AおよびヒトPDE11Aの活性は、反応基質として[3H]cGMPを用いて測定する。ヒトPDE6の触媒活性形態は、α(ヒトPDE6A)とβサブユニット(ヒトPDE6B)とからなる二量体である。ヒトPDE6A/6Bの二量体は、2つの精製ステップ、すなわち、NiNTAおよび抗FLAGセファロースクロマトグラフィーを使用して、発現および精製の戦略によって産生する。残りの酵素は、標準的な手順に従って実験室内でクローン化および精製する。アッセイ緩衝液は、pH7.5の50mMのトリス−HCl、8.3mMのMgCl2、1.7mMのEDTAおよび0.1%のウシ血清アルブミンの終濃度を得るように調製する。酵素の終濃度は、ヒトPDE2A、ヒトPDE5A、ヒトPDE6AB、ヒトPDE9A、ヒトPDE10AおよびヒトPDE11Aについてそれぞれ、0.2nM、0.002nM、5nM、1nM、0.03nMおよび0.03nMである。ヒトPDE2A、ヒトPDE10A、ヒトPDE5A、ヒトPDE6ABおよびヒトPDE11Aのアッセイの場合には80nMの終濃度を得るために、基質[3H]cGMPを添加して反応を開始させるのに対し、ヒトPDE9Aについては20nMの[3H]cGMPを使用する。
Claims (14)
- 以下の式の化合物
- 以下である、請求項1に記載の化合物。
- 慢性腎臓病を治療することを必要とする患者へ、有効量の請求項1に記載の化合物またはその薬学的に許容される塩を投与することを含む、患者の慢性腎臓病を治療する方法。
- 糖尿病性腎臓病を治療することを必要とする患者へ、有効量の請求項1に記載の化合物またはその薬学的に許容される塩を投与することを含む、患者の糖尿病性腎臓病を治療する方法。
- 療法における使用のための、請求項1に記載の化合物またはその薬学的に許容される塩。
- 慢性腎臓病の治療における使用のための、請求項1に記載の化合物またはその薬学的に許容される塩。
- 糖尿病性腎臓病の治療における使用のための、請求項1に記載の化合物またはその薬学的に許容される塩。
- 請求項1に記載の化合物またはその薬学的に許容される塩を、1種以上の薬学的に許容される担体、希釈剤、または賦形剤と共に含む、医薬組成物。
- 請求項1に記載の化合物またはその薬学的に許容される塩を1種以上の薬学的に許容される担体、希釈剤、または賦形剤と混合することを含む、医薬組成物を調製するためのプロセス。
- 慢性腎臓病を治療することを必要とする患者へ、有効量の請求項2に記載の化合物を投与することを含む、患者の慢性腎臓病を治療する方法。
- 糖尿病性腎臓病を治療することを必要とする患者へ、有効量の請求項2に記載の化合物を投与することを含む、患者の糖尿病性腎臓病を治療する方法。
- 慢性腎臓病の治療における使用のための、請求項2に記載の化合物。
- 糖尿病性腎臓病の治療における使用のための、請求項2に記載の化合物。
- 請求項2に記載の化合物またはその薬学的に許容される塩を、1種以上の薬学的に許容される担体、希釈剤、または賦形剤と共に含む、医薬組成物。
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AR112457A1 (es) * | 2017-08-02 | 2019-10-30 | Lilly Co Eli | Derivados de [1,2,4]triazolo[4,3-a]pirazin-6(5h)-ona |
AR112346A1 (es) | 2017-08-10 | 2019-10-16 | Lilly Co Eli | Derivados de [1,2,4]triazolo |
US11453673B2 (en) | 2018-02-06 | 2022-09-27 | Eli Lilly And Company | Substituted [1,2,4]triazolo[4,3-a]pyrazines as phosphodiesterase inhibitors |
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