JP6452711B2 - ヒトインターフェロンの誘導物質としてのピロロ[3,2]ピリミジン誘導体 - Google Patents
ヒトインターフェロンの誘導物質としてのピロロ[3,2]ピリミジン誘導体 Download PDFInfo
- Publication number
- JP6452711B2 JP6452711B2 JP2016552957A JP2016552957A JP6452711B2 JP 6452711 B2 JP6452711 B2 JP 6452711B2 JP 2016552957 A JP2016552957 A JP 2016552957A JP 2016552957 A JP2016552957 A JP 2016552957A JP 6452711 B2 JP6452711 B2 JP 6452711B2
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- Prior art keywords
- compound
- formula
- pharmaceutically acceptable
- pyrrolo
- dimethyl
- Prior art date
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
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- C07D487/04—Ortho-condensed systems
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Description
第1の態様では、本発明は式(I)の化合物及びその塩を対象とする:
第1の態様では、本発明は、式(I)の化合物及びその塩を対象とする:
R1は、水素、メチル又は-(CH2)2OR3であり、
R2は、メチル若しくは-(CH2)2OR4であり、又は
R1とR2は、それらが結合している窒素原子と共に、5又は6員のヘテロシクリルを形成するように連結され(ここで上記6員のヘテロシクリルは、場合により2つのヒドロキシ置換基で置換されていてもよい);
R3及びR4は、それぞれ独立して、水素又はメチルであり;
nは、5又は6の値を有する整数である)。
2,6-ジメチル-7-(6-(ピペリジン-1-イル)ヘキシル)-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2,6-ジメチル-7-(5-(ピロリジン-1-イル)ペンチル)-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2,2'-((5-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ペンチル)アザンジイル)ジエタノール;
2,2'-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)アザンジイル)ジエタノール;
2-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)(2-メトキシエチル)アミノ)エタノール;
7-(6-(ビス(2-メトキシエチル)アミノ)ヘキシル)-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)アミノ)エタノール;
(3R,5S)-1-(6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)ピペリジン-3,5-ジオール;
(3R,5R)-1-(6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)ピペリジン-3,5-ジオール;
7-(6-(ジメチルアミノ)ヘキシル)-2,6-ジメチル-5H-ピロロ[3,2-]ピリミジン-4-アミン;
及びそれらの塩。
式(I)の化合物及びその塩は、本明細書中以降に記載される方法論によって調製することが可能であり、本発明のさらなる態様を構成する。
の化合物の脱保護を含み、その後必要に応じて、式(I)の化合物の塩が調製される。
の化合物と、式(VII):
の化合物と、式(VII)の化合物との反応によって調製することができる。
式(I)の化合物及びその薬学的に許容される塩が有益効果を及ぼす可能性のある病態の例には、アレルギー性疾患及び他の炎症状態、例えばアレルギー性鼻炎及び喘息、感染性疾患、並びに癌が含まれる。式(I)の化合物及びその薬学的に許容される塩はまた、ワクチンアジュバントとして使用される可能性もある。
式(I)の化合物及びその薬学的に許容される塩は、必ずしもそうではないが、通常、患者に投与される前に医薬組成物に製剤化される。したがって、本発明の別の態様では、式(I)の化合物又はその薬学的に許容される塩と1種又は複数種の薬学的に許容される賦形剤とを含む医薬組成物が提供される。
分析手法
1 H NMR
1H NMRスペクトルは、Bruker DPX 400若しくはBruker Avance DRX、Varian Unity 400分光計又はJEOL Delta(すべて400MHzで動作する)で、CDCl3又はDMSO-d6中で記録した。使用した内標準は、テトラメチルシラン又は残留プロトン化溶媒(CDCl3の場合は7.25ppm、又はDMSO-d6の場合は2.50ppm)であった。
システムA
カラム:内径50mm×2.1mm、1.7μm Acquity UPLC BEH C18
流量:1mL/分
温度:40℃
UV検出範囲:210〜350nm
質量スペクトル:交互スキャン正負モードエレクトロスプレーイオン化を使用する質量分析計で記録した
溶媒: A:0.1%v/vギ酸水溶液
B:0.1%v/vギ酸アセトニトリル溶液
グラジエント: 時間(分) A% B%
0 97 3
1.5 0 100
1.9 0 100
2.0 97 3
カラム:内径50mm×2.1mm、1.7μm Acquity UPLC BEH C18
流量:1mL/分
温度:40℃
UV検出範囲:210〜350nm
質量スペクトル:交互スキャン正負モードエレクトロスプレーイオン化を使用する質量分析計で記録した。
溶媒: A:アンモニア溶液でpH10に調整した10mM炭酸水素アンモニウム水溶液
B:アセトニトリル
グラジエント: 時間(分) A% B%
0 99 1
1.5 3 97
1.9 3 97
2.0 99 1
質量分析計直結型自動分取HPLCは、以下に与える条件下で行った。UV検出は波長210nm〜350nmからの平均シグナルであり、質量スペクトルは交互スキャン正負モードエレクトロスプレーイオン化を使用する質量分析計で記録した。
方法Aを、Sunfire C18カラム(典型的には、内径150mm×30mm、充填材直径(packing diameter)5μm)で、周囲温度で行った。以下の溶媒を用いた:
A=0.1%v/vギ酸水溶液
B=0.1%v/vギ酸アセトニトリル溶液。
方法Bを、XBridge C18カラム(典型的には、内径100mm×30mm、充填材直径5μm)で、周囲温度で行った。以下の溶媒を用いた:
A=アンモニア溶液でpH10に調整した10mM炭酸水素アンモニウム水溶液。
B=アセトニトリル。
以下のリストは、本明細書で使用される場合の、特定の略語の定義を提供する。このリストは網羅的なものではないが、本明細書において以下に定義していない略語の意味は、当業者であれば容易に分かると認識される。
DCM ジクロロメタン
DMF N,N-ジメチルホルムアミド
DMSO ジメチルスルホキシド
THF テトラヒドロフラン
EtOAc 酢酸エチル
MeOH メタノール
EtOH エタノール
MeCN アセトニトリル
HCl 塩化水素酸
HPLC 高速液体クロマトグラフィー
MDAP 質量分析計直結型自動分取(Mass Directed Autopreparative)HPLC
SPE 固相抽出
MeOH メタノール
TBME tert-ブチルメチルエーテル
TFA トリフルオロ酢酸
DIPEA N,N-ジイソプロピルエチルアミン
中間体1:エチル3-アセトイミダミド-5-メチル-1H-ピロール-2-カルボキシレート
LCMS(システムB):tRET=0.45、0.47分;MH+ 210
LCMS(システムB):tRET=0.45分;MH+ 164
LCMS(システムB):tRET=0.45分;MH+ 164
LCMS(システムB):tRET=0.59分;MH+ 182/184
LCMS(システムB):tRET=0.59分;MH+ 182/184
LCMS(システムA):tRET=0.75分;MH+ 308/310
LCMS(システムA):tRET=1.18分;MH+ 428/430
LCMS(システムA):tRET=0.69分;MH+ 409
LCMS (システムA):tRET=0.67分;MH+ 409
1H NMR (400 MHz, CDCl3) δ ppm 2.31-2.52 (m, 6H) 2.18-2.26 (m, 2H) 1.92-1.96 (m, 1H) 1.40-1.72 (m, 10H)
バッチ1:透明な油状物(42mg)
LCMS(システムB):tRET=1.08分;MH+ 446
バッチ2:淡黄色の固体(117mg)
LCMS(システムB):tRET=1.11分;MH+ 446
LCMS(システムB):tRET=1.10分;MH+ 383
LCMS(システムB):tRET=1.15分;MH+ 397
実施例1:2,6-ジメチル-7-(6-(ピペリジン-1-イル)ヘキシル)-5H-ピロロ[3,2-d]ピリミジン-4-アミン
LCMS(システムB):tRET=0.80分;MH+ 330
LCMS(システムB):tRET=0.65分;MH+ 302
LCMS(システムB):tRET=0.66分;MH+ 302
LCMS(システムB):tRET=0.59分;MH+ 336
LCMS(システムB):tRET=0.64分;MH+ 350
LCMS(システムB):tRET=0.70分;MH+ 364
LCMS(システムB):tRET=0.82分;MH+ 378
LCMS(システムB):tRET=0.55分;MH+ 306
LCMS(システムB):tRET=0.60分;MH+362
LCMS(システムB):tRET=0.62分;MH+ 362
LCMS(システムB):tRET=0.66分;MH+ 290
in vitroでの生物学的活性について、本発明の化合物を以下のアッセイにしたがって試験した。
化合物の調製
化合物を、平底マイクロタイタープレート中に1.5μLの容量でDMSO中100×所要濃度に調製した。カラム1〜10は、試験化合物の連続4倍希釈液を含有していた。各プレートには、標準としてのTLR7/8アゴニストのレシキモドの連続希釈液が含まれ、カラム11は1.5μLの200μΜレシキモド(2μΜの最終濃度を与え、レシキモドに対する近似的な最大応答を定めるために使用される)を含有していた。各化合物をドナー毎に二重にアッセイした。
三人のヒトドナーからの血液試料をヘパリンナトリウム(10U/ml)中に採取した。150μLの全血を、DMSO中の試験化合物又は標準を1.5μL含有する、アッセイプレートのカラム1〜11に分注した。プレートをインキュベーター中に一晩置いた(37℃、空気95%、CO25%)。一晩のインキュベーションの後、プレートをインキュベーターから取り出し、オービタルシェーカー上でおよそ1分間混合した。100μLの0.9%生理食塩水を各ウェルに添加し、プレートをオービタルシェーカー上で再度混合した。次いでプレートを遠心し(2500rpm、10分)、その後、血漿試料をBiomek FXを使用して取り出し、MSD(Mesoscale Discovery)電気化学発光アッセイプラットフォームを使用して、IFN-αとTNF-αの両方についてアッセイした。IFN-αのアッセイは、上述のアッセイと同様に行った。TNF-αのアッセイはキットの指示書(カタログ番号K111BHB)通りに実行した。
実施例1〜10は、IFN-αについて平均pEC50が≦5.7であった。
化合物を、DMSO中100×所要濃度で分注した(平底96ウェル細胞培養プレート中、1μL/ウェル)。各化合物をドナー毎に二重にアッセイした。各プレートは、標準としてのTLR7/8アゴニストのレシキモドの希釈系列を含有しており、カラム11は1μLの200μMレシキモド(2μΜの最終濃度を与え、レシキモドに対する近似的な最大応答を定めるために使用される)を含有していた。
三人のヒトドナーからの血液試料をヘパリンナトリウム(10U/ml)中に採取した。25mL体積の全血を、Leucosepチューブ中の15mLヒストパック(Histopaque)上に重層し、これを400gで30分間遠心し、血漿/ヒストパック界面のバンドを、注意深く滅菌50mL円錐チューブに取り出した。チューブ中の体積を、滅菌DPBS(ダルベッコリン酸緩衝生理食塩水、-CaCl2/MgCl2)で50mLとし、300gで10分間遠心した。細胞ペレットを、20mLの培地(10%(v/v)ウシ胎仔血清(FCS、低エンドトキシン)、100U/mLペニシリンG、100μg/mLストレプトマイシン、10mM L-グルタミン及び1x非必須アミノ酸を添加したRPMI 1640(低エンドトキシン))中で再懸濁し、Nucleoview 3000(Chemometec社、Via-1 Cassette)を使用して細胞を計数した。PBMC濃度を調整して2x106/mLの最終濃度を得て、100μLのこの細胞懸濁液を、1μLの希釈試験化合物を含有するウェルに添加した。
細胞調製物を24時間インキュベーションし(37℃、空気95%、CO25%)、その後、上清試料をBiomek FXを使用して取り出し、MSD(Mesoscale Discovery)電気化学発光アッセイプラットフォームを使用して、IFN-αとTNF-αの両方についてアッセイした。IFN-αのアッセイは、上述のアッセイと同様に行った。TNF-αのアッセイはキットの指示書(カタログ番号K111BHB)通りに実行した。
実施例1〜9は、IFN-αについて平均pEC50が5.4〜6.3であった。
Claims (13)
- R1が水素、メチル又は-(CH2)2OR3であり、且つR2がメチル又は-(CH2)2OR4である、請求項1に記載の化合物又はその塩。
- R1とR2が、それらが結合している窒素原子と共に5又は6員のヘテロシクリルを形成するように連結されている(ここで該6員のヘテロシクリルは、2つのヒドロキシ置換基で置換されていてもよい)、請求項1に記載の化合物。
- nが5である、請求項1〜3のいずれか1項に記載の化合物。
- nが6である、請求項1〜3のいずれか1項に記載の化合物。
- 2,6-ジメチル-7-(6-(ピペリジン-1-イル)ヘキシル)-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2,6-ジメチル-7-(5-(ピロリジン-1-イル)ペンチル)-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2,2'-((5-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ペンチル)アザンジイル)ジエタノール;
2,2'-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)アザンジイル)ジエタノール;
2-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)(2-メトキシエチル)アミノ)エタノール;
7-(6-(ビス(2-メトキシエチル)アミノ)ヘキシル)-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-4-アミン;
2-((6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)アミノ)エタノール;
(3R,5S)-1-(6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)ピペリジン-3,5-ジオール;
(3R,5R)-1-(6-(4-アミノ-2,6-ジメチル-5H-ピロロ[3,2-d]ピリミジン-7-イル)ヘキシル)ピペリジン-3,5-ジオール;又は
7-(6-(ジメチルアミノ)ヘキシル)-2,6-ジメチル-5H-ピロロ[3,2-]ピリミジン-4-アミンから選択される化合物又はその塩。 - 薬学的に許容される塩の形態である、請求項1〜6のいずれか1項に記載の化合物。
- 遊離塩基の形態である、請求項1〜6のいずれか1項に記載の化合物。
- 請求項1〜6のいずれか1項に定義される化合物又は薬学的に許容されるその塩と、1つ以上の製薬上許容される賦形剤とを含む医薬組成物。
- 請求項1〜6のいずれか1項に定義される化合物又は薬学的に許容されるその塩と、抗原又は抗原組成物とを含むワクチン組成物。
- 治療において使用するための、請求項1〜6のいずれか1項に定義される化合物又は薬学的に許容されるその塩を含む医薬組成物。
- アレルギー性疾患若しくは他の炎症状態、感染性疾患又は癌の治療又は予防において使用するための、請求項1〜6のいずれか1項に定義される化合物又は薬学的に許容されるその塩を含む医薬組成物。
- アレルギー性疾患若しくは他の炎症状態、感染性疾患又は癌の治療又は予防のための医薬の製造における、請求項1〜6のいずれか1項に定義される化合物又は薬学的に許容されるその塩の使用。
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US61/942,272 | 2014-02-20 | ||
PCT/EP2015/053359 WO2015124591A1 (en) | 2014-02-20 | 2015-02-18 | Pyrrolo[3,2] pyrimidine derivatives as inducers of human interferon |
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