JP2012502107A - 4−アミノ−3−(イミダゾリル)−ピラゾロ[3,4−d]ピリミジン - Google Patents
4−アミノ−3−(イミダゾリル)−ピラゾロ[3,4−d]ピリミジン Download PDFInfo
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- JP2012502107A JP2012502107A JP2011526976A JP2011526976A JP2012502107A JP 2012502107 A JP2012502107 A JP 2012502107A JP 2011526976 A JP2011526976 A JP 2011526976A JP 2011526976 A JP2011526976 A JP 2011526976A JP 2012502107 A JP2012502107 A JP 2012502107A
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- Prior art keywords
- amino
- pyrazolo
- compound
- pyrimidin
- imidazol
- Prior art date
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract
Description
本願は、2008年9月11日出願の米国特許出願第61/096,191号の利益を主張し、その内容は本明細書に参照により組み込まれている。
該当なし。
単独又は他の置換基の一部としての用語「アルキル」は、他に言及しない限り、指定された炭素原子数を有する直鎖又は分岐鎖の炭化水素ラジカルを意味する(すなわち、C1−8は1〜8個の炭素を意味する)。アルキル基の例としては、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、t−ブチル、イソブチル、sec−ブチル、n−ペンチル、n−ヘキシル、n−ヘプチル、n−オクチル等が含まれる。
本発明は、式Iの化合物がCCR1受容体の強力なアンタゴニストとして機能するという発見に由来する。化合物はインビボ(in vivo)において抗炎症活性を有し、優れた薬物動態特性を有する。従って、本明細書で供する化合物は、CCR1介在疾患の治療のための医薬組成物、方法、及び競合的CCR1アンタゴニストの同定のためのアッセイにおけるコントロールとして有用である。
一態様において、本発明は式I:
表1
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)−2−メチルピペラジン−1−イル)エタノン
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロフェニル)−2−メチルピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)ピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)ピペラジン−1−イル)エタノン
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)−2−メチルピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−エトキシフェニル)ピペラジン−1−イル)エタノン
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロフェニル)−2−メチルピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロフェニル)ピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)−2,2−ジメチルピペラジン−1−イル)エタノン
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−エトキシフェニル)−2−メチルピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−(トリフルオロメトキシ)フェニル)ピペラジン−1−イル)エタノン
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)ピペラジン−1−イル)エタノン
以下のスキーム1及び実施例中のスキームは、本発明の一定の化合物を利用することにつながり得る一定の合成ルートを供する。他のルート又は以下に示すルートの変更は当業者が容易に理解できるものであり、本発明の範囲内である。
さらに、上記で供される化合物、ヒト及び動物でCCR1、CCR2及びCCR3活性を調節するための組成物は、典型的には医薬担体又は希釈剤を含む。
他の態様において、本発明は、このような疾患又は症状を有する対象に、上記式Iの化合物の治療上有効量を投与することによって、CCR1−、CCR2−及び/又はCCR3−介在症状又は疾患を治療する方法を供する。「対象」は、本明細書中において、例えば哺乳類、霊長類(例えば、ヒト)、ウシ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、ラット、マウス等が含まれるがこれに限定されない動物を含むものと定義する。
以下の実施例は、特許請求される発明を説明するために提供されるが、特許請求される発明を限定するものではない。
DMF、ジメチルホルムアミド;
TFA、トリフルオロ酢酸;
THF、テトラヒドロフラン;
EtOAc、酢酸エチル;
BOC2O、ジ−tertブチルジカーボネート又はBOC酸無水物;
HPLC、高圧液体クロマトグラフィー;
DIPEA、ジイソプロピルエチルアミン;
HCTU、1−[ビス(ジメチルアミノ)メチレン]−5−クロロ−1H−ベンゾトリアゾリウム−3−酸化ヘキサフルオロホスフェイト(1−);
HBTU、O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムヘキサフルオロホスフェイト;
dppf、1,1’−ビス(ジフェニルホスフィノ)フェロセン;
Pd2(dba)3、トリス(ジベンジリデンアセトン)ジパラジウム(O);
DIPEA、ジイソプロピルエチルアミン;
DMP、ジメチルフタル酸エステル;
Me、メチル;
Et、エチル;
DCM、ジクロロメタン。
この実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−メトキシフェニル)ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−メトキシフェニル)−2,2−ジメチルピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−2−フルオロ−5−メトキシフェニル)−ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−2−フルオロ−5−メトキシフェニル)−2−メチル−ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−2−フルオロフェニル)−2−メチル−ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−エトキシフェニル)−ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−メトキシフェニル)−2−メチル−ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロフェニル)−2−メチルピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロフェニル)ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−エトキシフェニル)−2−メチルピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−3−トリフルオロメトキシフェニル)ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、2−[4−アミノ−3−(1H−イミダゾール−2−イル)−ピラゾロ[3,4−d]ピリミジン−1−イル]−1−[4−(4−クロロ−2−フルオロフェニル)ピペラジン−1−イル]エタノンの調製を説明する。
本実施例は、本発明の注目の化合物と関係がある生物活性の評価を説明する。
材料及び方法
A.細胞
1.CCR1発現細胞
a)THP−1細胞
CCR1阻害剤の同定
Podolin等の上記のものに記載されるウサギLPS試験を本質的に実施することができる。メスのニュージーランドウサギ(約2キログラム)の両膝の関節内にLPS(10ng)を処置した。(例えば、1%メトセル中に製剤された)注目の化合物又はビヒクル(1%メトセル)を、5ml/kg用量で2回(関節内のLPS注射の2時間前及び関節内LPS注射の4時間後に)経口投与した。LPS注射の16時間後に、膝を灌流し、細胞カウントを行った。処理の有益な効果を、膝関節の炎症性関節液へ補充された炎症性細胞数における減少によって測定する。注目の化合物での処理は、結果として補充された炎症性細胞において顕著な減少を生じる。
関節炎が誘発された臨床上のくるぶし腫脹に対する注目の化合物の効果を評価するために、17日間進行させたII型コラーゲン関節炎試験を実施することができる。ラットコラーゲン関節炎は、多数の抗関節炎剤の前臨床試験に広く使用されている多発性関節炎の実験モデルである(Trentham, et al., J. Exp. Med.146(3):857-868 (1977), Bendele, et al., Toxicologic Pathol. 27: 134-142 (1999), Bendele, et al., Arthritis Rheum. 42:498-506 (1999)を参照されたい)。このモデルの特徴は、活発であり且つ容易に測定できる多発関節炎炎症、パンヌス形成並びに軽度から中等度の骨吸収及び骨膜骨増殖と関係する顕著な軟骨破壊の安定した発現及び進行である。
卵巣摘出誘発性骨粗しょう症のラットモデルを、Dunstan等(1999)のJ.Bone及びMin Res.14:953として本質的に実施することができる。幼齢のメスSDラット(180〜200g)を偽手術又は卵巣摘出(OVX)する。術後7日内に、CCR1アンタゴニスト又はビヒクル単独(セサミオイル)の毎日の経口投与を開始する。投薬の2週間後に、ラットを安楽死させ、破骨細胞及び骨芽細胞バイオマーカー(それぞれ、C-テロペプチド及びMIDオステオカルシン)の血清レベルを分析する。さらに、大腿骨及び脛骨を、H&E及び/又はTRAP染色法での組織病理学試験のために除去する。
骨髄腫による骨疾患は、さらにOyajobi等の、MoI Cancer Ther、2007,6:1701−1708に記載される通り試験してよい。動物試験を6〜9週齢のメスC57BL/KaLwRijHsdマウス(Harlan)を使用して実施する。骨髄腫病変は、マウスにおいて、尾静脈を介した106個の生存5TGM1−eGFP H1.1+細胞又は親の5TGM1細胞の静脈内接種によって誘発される。(例えば、100%セサミオイル中に製剤された)注目の化合物又は(100%セサミオイルである)ビヒクルを、2.5ml/kg用量体積で1日に2度を4週間経口で投与する。動物の体重をベースライン時、その後は週に一度測定する。4週間の最終日に、全マウスを撮像し、屠殺直後に、骨格及び内臓(脾臓, 肝臓, 腎臓, 生殖腺, 脳, 肺, 及び心臓)を解剖し、全身腫瘍組織量を評価するために蛍光腫瘍病巣に関して撮像する。
Claims (24)
- 前記式中、R2aがHである、請求項1に記載の化合物。
- 前記式中、R1a及びR1bがそれぞれHである、請求項1に記載の化合物。
- 前記式中、R1bがメチルであり、R1aがHである、請求項1に記載の化合物。
- 前記式中、R1a及びR1bがそれぞれCH3である、請求項1に記載の化合物。
- 前記式中、R2aが水素であり、R2dがメトキシ、エトキシ及びトリフルオロメトキシから成る群から選択される、請求項1に記載の化合物。
- 前記塩形態が塩酸塩の形態である、請求項12に記載の化合物。
- (S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)−2−メチルピペラジン−1−イル)エタノン;
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロフェニル)−2−メチルピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)ピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−2−フルオロ−5−メトキシフェニル)ピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)ピペラジン−1−イル)エタノン;
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)−2−メチルピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−エトキシフェニル)ピペラジン−1−イル)エタノン;
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロフェニル)−2−メチルピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロフェニル)ピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)−2,2−ジメチルピペラジン−1−イル)エタノン;
(S)−2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−エトキシフェニル)−2−メチルピペラジン−1−イル)エタノン;
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−(トリフルオロメトキシ)フェニル)ピペラジン−1−イル)エタノン;及び、
2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)ピペラジン−1−イル)エタノンから成る群から選択される、化合物。 - 化合物2−(4−アミノ−3−(1H−イミダゾール−2−イル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)−1−(4−(4−クロロ−3−メトキシフェニル)ピペラジン−1−イル)エタノン。
- 請求項1に記載の化合物、及び医薬的に許容される賦形剤又は担体を含んでなる医薬組成物。
- 疾患又は症状の治療のための医薬の製造における、請求項1〜15のいずれか1項に記載の化合物の使用。
- CCR1介在疾患又は症状の治療のための医薬の製造における、請求項1〜15のいずれか1項に記載の化合物の使用。
- 前記CCR1介在疾患又は症状が炎症性症状である、請求項18に記載の使用。
- 前記CCR1介在疾患又は症状が免疫調節性疾患である、請求項18に記載の使用。
- 前記CCR1介在疾患又は症状が、骨関節炎疾患、多発性骨髄腫、関節リウマチ、多発性硬化症、移植片拒絶反応、再狭窄、皮膚炎、湿疹、じん麻疹、血管炎、炎症性腸疾患、食物アレルギー、喘息、アルツハイマー病、パーキンソン病、乾癬、紅斑性狼瘡、骨関節炎、脳卒中、再狭窄及び脳脊髄炎から成る群から選択される、請求項18に記載の使用。
- 前記CCR1介在疾患又は症状が、骨関節炎疾患、多発性骨髄腫、関節リウマチ及び移植片拒絶反応から成る群から選択される、請求項18に記載の使用。
- 前記医薬が、経口、非経口、直腸、経皮、舌下、経鼻又は局所投与のために製造される、請求項18に記載の使用。
- 前記医薬が、抗炎症剤、鎮痛薬、抗増殖剤、代謝抑制剤、白血球遊走阻害剤又は免疫調節剤との組合せにおける投与のために製造される、請求項18に記載の使用。
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