JP5754568B2 - 4−ジメチルアミノ−フェニルで置換されているナフチリジン、及び医薬としてのその使用 - Google Patents
4−ジメチルアミノ−フェニルで置換されているナフチリジン、及び医薬としてのその使用 Download PDFInfo
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- JP5754568B2 JP5754568B2 JP2011521515A JP2011521515A JP5754568B2 JP 5754568 B2 JP5754568 B2 JP 5754568B2 JP 2011521515 A JP2011521515 A JP 2011521515A JP 2011521515 A JP2011521515 A JP 2011521515A JP 5754568 B2 JP5754568 B2 JP 5754568B2
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- phenyl
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Description
R1は、−O−R3、−NR3R4、−CR3R4R5、−(エチン)−R3、−S−R3、−SO−R3及びSO2−R3から選択される基Aを表すか、又は
R1は、
− C6〜10−アリール、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜10員単環式もしくは二環式ヘテロアリール(ここで、このヘテロアリールは、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、3〜10員単環式もしくは二環式飽和もしくは部分飽和複素環基(ここで、この複素環基は、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、ならびに
− N、O及びSから互いに独立して選択されるヘテロ原子1、2もしくは3個を場合により含んでいてもよい、5〜11員スピロ基(ここで、このスピロ基は、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、
から選択される基Bを表し、
ここで、この基Bは、請求項1記載のとおり場合により置換されていてもよく、そして
R3、R4、R5、R6及びmは、請求項1に示された意味を有していてもよい)で示される新規な置換ナフチリジン、及びその薬理学的に許容しうる塩、ジアステレオマー、鏡像異性体、ラセミ化合物、水和物又は溶媒和物、ならびにこれらの化合物を含む医薬に関する。
R1は、−O−R3、−NR3R4、−CR3R4R5、−(エチン)−R3、−S−R3、−SO−R3及びSO2−R3から選択される基Aであるか、又は
R1は、
− C6〜10−アリール、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜10員単環式もしくは二環式ヘテロアリール(ここで、このヘテロアリールはC原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、3〜10員単環式もしくは二環式飽和もしくは部分飽和複素環基(ここで、この複素環は、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、ならびに
− N、O及びSから互いに独立して選択されるヘテロ原子1、2もしくは3個を場合により含んでいてもよい、5〜11員スピロ基(ここで、このスピロ環は、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、
から選択される基Bであり、
ここで、この基Bは、H、ハロゲン、−C1〜3−アルキル、−NH(C1〜4−アルキル)、−N(C1〜4−アルキル)2、−NH2、−C1〜3−アルキル−OH、−OH、オキソ、−CO−NH2、−C1〜3−アルキレン−CO−NH2、−CO−NH−(C1〜3−アルキル)、−C1〜3−アルキレン−CO−NH(C1〜3−アルキル)、−CO−NH(C3〜5−シクロアルキル)、−C1〜3−アルキレン−CO−NH(C3〜5−シクロアルキル)、−NH−CO−NH2、−NH−CO−NH(C1〜3−アルキル)、−NH−CO−N(C1〜3−アルキル)2、O−C1〜3−アルキル、−(C1〜3−アルキレン)−NH2、−フェニル及び−CO−(C1〜5−アルキル)から互いに独立して選択される基1個以上で場合により置換されていてもよく、
R3は、Hであるか、又は
−C1〜6−アルキル、−C1〜6−フルオロアルキル、−(C1〜5−アルキル)−OH、−C6〜10−アリール、−(C1〜4−アルキレン)−(C6〜10−アリール)、エテニル、−(C1〜4−アルキレン)−(エテン)、−エチニル、−(C1〜4−アルキレン)−(エチン)、−(C1〜4−アルキレン)−(エチン)−NH2、−(C1〜4−アルキレン)−(エチン)−(C1〜4−アルキレン)−NH2、−NH(C1〜3−アルキル)、−(C1〜4−アルキレン)−NH(C1〜3−アルキル)、−CHOH−(C1〜4−アルキレン)−NH2、−(C1〜4−アルキレン)−CHOH−(C1〜4−アルキレン)−NH2、−(C1〜4−アルキレン)−CHOH−NH2、−CHOH−NH2、単環式もしくは二環式飽和もしくは部分飽和−C3〜10−シクロアルキル、単環式もしくは二環式飽和もしくは部分飽和−(C1〜4−アルキレン)−C3〜10−シクロアルキル、−(Het)、−(C1〜4−アルキレン)−(Het)、−(ヘタリール)、及び−(C1〜4−アルキレン)−(ヘタリール)から選択される基であり、
この基は、H、−OH、−オキソ、−COOH、−ハロゲン、−C1〜3−アルキル、−C1〜3−ハロアルキル、−C1〜3−アルキル−OH、−C3〜7−シクロアルキル、−O−(C1〜4−アルキル)、−NH(C1〜4−アルキル)、−(C1〜4−アルキレン)−NH(C1〜4−アルキル)、−N(C1〜4−アルキル)2、−(C1〜4−アルキレン)−N(C1〜4−アルキル)2、−NH−CO−NH2、−(C1〜4−アルキレン)−NH−CO−NH2、−CO−NH2、−(C1〜4−アルキレン)−CO−NH2、−CO−NH(C1〜3−アルキル)、−(C1〜4−アルキレン)−CO−NH(C1〜3−アルキル)、−CO−N(C1〜3−アルキル)2、−(C1〜4−アルキレン)−CO−N(C1〜3−アルキル)2、−NH−(CO)m−NH2、−NH−(C1〜4−アルキレン)−(CO)m−NH2、−NH−(CO)m−NH(C1〜3−アルキル)、−NH−(C1〜4−アルキレン)−(CO)m−NH(C1〜3−アルキル)、−NH−(CO)m−N(C1〜3−アルキル)2、−NH−(C1〜4−アルキレン)−(CO)m−N(C1〜3−アルキル)2、−O−(C2〜4−アルキレン)−NH2、−O−(C2〜4−アルキレン)−NH(C1〜3−アルキル)、−O−(C2〜4−アルキレン)−N(C1〜3−アルキル)2、−NH−CO−(C1〜3−アルキル)、−(C1〜4−アルキレン)−NH−CO−(C1〜3−アルキル)、−C3〜5−シクロアルキル、−SO2−(C1〜4−アルキル)、−SO2−(C3〜5−シクロアルキル)、−SO2−NH2、−SO2−NH−C1〜3−アルキル、−SO2−N(C1〜3−アルキル)2、−SO2−(Het)、−O−(Het)、−O−(C1〜4−アルキレン)−(Het)、−NH−(Het)、−NH−(C1〜4−アルキレン)−(Het)、−NH−(ヘタリール)、−NH−(C1〜4−アルキレン)−(ヘタリール)、−(Het)及び−(C1〜4−アルキレン)−(Het)から互いに独立して選択される基1個以上で場合により置換されていてもよく、
(Het)は、C1〜3−アルキル、ハロゲン、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1〜3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1、2又は3個含む3〜10員飽和又は部分飽和単環式又は二環式複素環基を表し、
(ヘタリール)は、C1〜3−アルキル、ハロゲン、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1、2又は3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む5〜10員単環式又は二環式ヘテロアリールを表し、
m=0又は1であり、
R4及びR5は、H、メチル又はエチルを表し、そして
R6は、メチル、エチル、プロピル、−O−メチル、−O−エチル、−O−プロピル、Br、Cl、F又はフェニルを表す)で示される化合物、ならびにその薬学的に許容しうる塩、ジアステレオマー、鏡像異性体、ラセミ化合物、水和物及び溶媒和物に関する。
(Het)が、メチル、エチル、プロピル、イソプロピル、F、Cl、Br、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1〜3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1、2又は3個含む、3〜7員飽和又は部分飽和単環式複素環基を表し、そして
(ヘタリール)が、メチル、エチル、プロピル、イソプロピル、F、Cl、Br、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1、2又は3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜6員単環式ヘテロアリールを表す、
式1で示される化合物、ならびにその薬学的に許容しうる塩、ジアステレオマー、鏡像異性体、ラセミ化合物、水和物及び溶媒和物に関する。
ここで、R1が、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含み、その1〜3個のヘテロ原子の少なくとも1個がN原子である、5〜10員単環式もしくは二環式ヘテロアリール、ならびに
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含み、その1〜3個のヘテロ原子の少なくとも1個がN原子である、3〜10員単環式もしくは二環式飽和もしくは部分飽和複素環基、
から選択され、
ここで、上述のヘテロアリール及び複素環が、それぞれ少なくとも1個のN原子によって式1で示される構造に結合しているか、又は
R1が、N、O及びSから互いに独立して選択されるヘテロ原子1、2もしくは3個を含む、5〜11員スピロ基(ここで、このスピロ基の1〜3個のヘテロ原子の少なくとも1個はN原子であり、そしてそのスピロ基はこのN原子を介して式1で示される構造に結合している)である、式1で示される化合物、ならびにその薬学的に許容しうる塩、ジアステレオマー、鏡像異性体、ラセミ化合物、水和物及び溶媒和物に関する。
ここで、R1が、
X1が、R1の、式1で示される構造への結合点を表し、
R6が、メチルである、式1で示される化合物、ならびにその薬学的に許容しうる塩、ジアステレオマー、鏡像異性体、ラセミ化合物、水和物及び溶媒和物に関する。
Yは、−H、−MgBr、−B(OH)2であり、そして
R1及びR2は、本明細書の先に定義されたとおりである)
更なるジメチルアミン10.0g(220mmol)を供給し、その後、混合物を85℃で4時間、そして110℃で一晩撹拌した。
冷水500mlを反応混合物に添加し、その後、酢酸エチル250mlで3回抽出して、有機相を乾燥させてろ過し、そして溶媒をろ液から排出した。
収量:12.0g(75mmol=理論値の101%)
分析:HPLC−MS(方法D):Rt:0.94分、(M+H)+:161
Kralj, David; Groselj, Uros; Meden, Anton; Dahmann, Georg; Stanovnik, Branko; Svete, Jurij. A simple synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles. Tetrahedron (2007), 63 (45), 11213-11222。
収量:2.00g(9.42mmol=理論値の96%)
2-メチルニコチン酸4.40g(31mmol)を、テトラヒドロフラン75mlに懸濁させて、混合物を−80℃に冷却した。リチウムジイソプロピルアミド49ml(98mmol)(テトラヒドロフラン中に2.0mol/l)を30分以内で滴下し、混合物を−60℃で2時間撹拌した。
その後、−60℃で、テトラヒドロフラン中の4−ジメチルアミノ−3−メチルベンゾニトリル5.0g(31mmol)の溶液を、再度30分以内で滴下した。その後、反応混合物を0℃で4時間撹拌した。
懸濁液を水100mlと混和し、溶媒を留去した。水性残渣を酢酸エチル20mlと混合して20分間撹拌し、その後、沈殿を吸引ろ過して乾燥させた。
収量:3.0g(10.70mmol=理論値の34%)
分析:HPLC(方法D):Rt:0.96分、ESI−MS(M+H)+:280
反応混合物を蒸発させて、残渣を水約50mlと混合して、NaHCO3溶液で中和して、ジクロロメタンで抽出した。有機相をMgSO4で乾燥させ、蒸発させた。
収量:1.90g油状物(4.7mmol=理論値の44%)
分析:HPLC(方法D):Rt:1.25分、ESI−MS(M+H)+:298/300(Cl)
その後、別のトリフルオロメタンスルホン酸無水物1.5ml及びピリジン3mLを添加した。1時間後に、混合物を冷水100mLで希釈して、有機相をNaCl溶液で洗浄し、MgSO4で乾燥させ、蒸発させた。残渣をトルエンに更に2回取り出し、その後、蒸発させた。
収量:4.70g(8.4mmol=理論値の69%)
分析:HPLC(方法D):Rt:1.40分、ESI−MS(M+H)+:412
シス及びトランス5−(4−ヒドロキシシクロヘキシル)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
収量 実施例1:9mg(0.018mmol=理論値の5.5%)
分析:HPLC−MS(方法D):Rt:1.13分、(M+H)+:378
収量 実施例2:42mg(0.085mmol=理論値の25%)
分析:HPLC−MS(方法D):Rt:1.15分、(M+H)+:378
5−(アミノメチルピロリジン−1−イル)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
収量:120mg(0.33mmol=理論値の99%)
分析:HPLC−MS(方法D):Rt:1.00分、(M+H)+:362
5−(ピロリジン−3−イル−メトキシ)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
トリフルオロ酢酸1mLを添加して、混合物を25℃で2日間撹拌した。反応混合物をクロマトグラフィー(RP−HPLC−MS)により精製した。対応する分画を凍結乾燥させた。
収量:110mg(0.23mmol=理論値の98%)
分析:HPLC−MS(方法D):Rt:1.05分、(M+H)+:363
5−(3−ピラゾリル−エチルアミノ)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
混合物をクロマトグラフィー(RP−HPLC−MS)により精製した。対応する分画を凍結乾燥させた。
収量:70.00mg(0.14mmol=理論値の81%)
分析:HPLC−MS(方法D):Rt:1.05分、(M+H)+:373
混合物をアセトニトリル、水及びトリフルオロ酢酸で希釈して、クロマトグラフィー(RP−HPLC)により精製した。
収量:50mg(0.11mmol=理論値の31%)
分析:HPLC−MS(方法D):Rt:1.45分、(M+H)+:474
tert−ブチル−2−{1−[7−(4−ジメチルアミノ−3−メチル−フェニル)−[1,6]ナフチリジン−5−イル]−1H−ピラゾール−4−イル}−カルボナート 50mg(0.11mmol)を、ジオキサン塩酸2ml(8mmol)(4mol/l)に溶解して、50℃で2時間撹拌した。反応混合物を蒸発させて、残渣をクロマトグラフィー(RP−HPLC−MS)により精製し、対応する分画を凍結乾燥させた。
収量:30mg(0.08mmol=理論値の76%)
分析:HPLC−MS(方法D):Rt:1.17分、(M+H)+:374
5−メトキシ−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
収量:120mg(0.29mmol=理論値の88%)
分析:HPLC−MS(方法D):Rt:1.14分、(M+H)+:294
5−(シクロプロピルアミノ)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
収量:40mg(0.131mmol=理論値の40%)
分析:HPLC−MS(方法D):Rt:1.07分、(M+H)+:319
5−(ピロリジン−2−オン−4−イル−メチルヒドロキシ)−7−(4−ジメチルアミノ−3−メチルフェニル)−[1,6]ナフチリジン
収量 120mg(0.32mmol=理論値の95%)
分析:HPLC−MS(方法D):Rt:1.09分、(M+H)+:377
A:0.10%TFAを含む水
B:0.10%TFAを含むアセトニトリル
0.00 95 5 2.80
0.30 95 5 2.80
1.60 2 98 2.80
1.90 2 98 2.80
2.00 95 5 2.50
用いられた固定相は、Merk Chromolith(商標)Flash RP-18eカラム、3mm×100mm(カラム温度:一定に25℃)
以下の実施例は、先に記載された合成方法と同様にして製造した(表1の表示と同様)。これらの化合物は、SYK阻害剤として適しており、1μmol以下のIC50値を有する。各実施例の物質1μMでの阻害剤(%)を、以下の実施例の表に示すが、それは以下のとおり測定した。
ヒト組換えSykを、N−末端GSTタグを含む融合タンパク質として発現させて、アフィニティー精製を行い、使用するまで、検査緩衝液(25mM HEPES pH7.5;25mM MgCl2;5mM MnCl2;50mM KCl;0.2%BSA;0.01% CHAPS;100μM Na3VO4;0.5mM DTT)及び10%グリセロール中、約50〜100μMの濃度で−80℃で急速冷凍した。GST−Sykキナーゼ融合タンパク質の触媒活性を、Messrs PromegaのKinase Glo(登録商標)Luminescence Kinase検査を用いて測定した。この均一な検査では、キナーゼ反応を実施した後に残留するATPの量を、ルミネッセンスを用いたルシフェリン−ルシフェラーゼ反応により定量した。得られたルミネッセンスシグナルは、なおも存在するATPの量に相関しており、つまりプロテインキナーゼの活性と逆相関している。
検査物質を10mMの濃度で100%DMSOに溶解し、DMSOで1mMの濃度に希釈した。濃度が最終検査濃度(該物質の最終濃度:通常の場合30μM〜1nM)の7.5倍に至るまで、該物質の更なる希釈全てを、検査緩衝液中の7.5%DMSOで実施した。これらの希釈物のアリコット2μlを、384穴Optiplate(Perkin Elmer, #6007290)に移し入れた。GST−Sykを検査緩衝液に6.0nMに希釈して、この希釈物10μlをキナーゼ検査に用いた(Sykの最終濃度=総容量15μl中に4nM)。周囲温度で15分間インキュベーションした後、検査緩衝液中の750nM ATPと100μg/ml ポリ(L−グルタミン酸、L−チロシン4:1)、Fulka #81357)との混合物3μlを各ウェルに添加し、その後、インキュベーションを周囲温度で更に60分間継続した。
陽性対照は、検査物質を含まない反応混合物であり、陰性対照は、キナーゼを含まない反応混合物であった。
60分後に、Kinase-Glo(登録商標)溶液(Promega, Cat.# V6712)(周囲温度まで加熱)10μlを各ウェルに添加して、インキュベーションを周囲温度で更に15分間継続した。その後、プレートをMicroplate Scintillation and Luminescence Couter(PerkinElmer/Wallac: MicroBeta TRILUX 1450 LSC & Luminescence Counter)で読み取った。
「MicroBeta TRILUX」の出力ファイルは、ウェル番号及び得られた測定値を含むテキストファイルである。評価のために、陰性対照の測定値を100%阻害と設定し、陽性対照の測定値を0%阻害と設定した。その後、これから、各物質濃度の測定値ごとの%固有値を、「MS-Excel-VBマクロ」を用いて計算した。通常、計算された%阻害値は、100〜0%阻害であるが、個々の場合に、これらの限界を超えた値が生じてもよい。「GraphPadPrism」ソフトウエア(バージョン5)(GraphPad Software Inc.)を用いた%阻害値から、IC50値を計算した。
・β模倣薬、コルチコステロイド、式1で示されるSYK阻害剤、EGFR阻害剤及びPDE4アンタゴニスト、
・抗コリン作動薬、β模倣薬、コルチコステロイド、式1で示されるSYK阻害剤、EGFR阻害剤及びPDE4アンタゴニスト、
・PDE4阻害剤、コルチコステロイド、EGFR阻害剤及び式1で示されるSYK阻害剤、
・EGFR阻害剤、PDE4阻害剤及び式1で示されるSYK阻害剤、
・EGFR阻害剤及び式1で示されるSYK阻害剤、
・式1で示されるSYK阻害剤、β模倣薬及び抗コリン作動薬、
・抗コリン作動薬、β模倣薬、コルチコステロイド、PDE4阻害剤及び式1で示されるSYK阻害剤、
から選択される化合物1種又は2種との併用から選択してもよい。上述の化合物の分類の一つからそれぞれ取り出した活性物質3種の併用も、本発明の目的である。
ンスルホニル−ピペリジン−4−イルオキシ)−7−エトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−メタンスルホニル−ピペリジン−4−イルオキシ)−7−(2−メトキシ−エトキシ)−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[1−(2−メトキシ−アセチル)−ピペリジン−4−イルオキシ]−7−(2−メトキシ−エトキシ)−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(シス−4−アセチルアミノ−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−[1−(tert−ブチルオキシカルボニル)−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−(テトラヒドロピラン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(シス−4−{N−[(ピペリジン−1−イル)カルボニル]−N−メチル−アミノ}−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(シス−4−{N−[(4−メチル−ピペラジン−1−イル)カルボニル]−N−メチル−アミノ}−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{シス−4−[(モルホリン−4−イル)カルボニルアミノ]−シクロヘキサン−1−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[2−(2−オキソピロリジン−1−イル)エチル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(モルホリン−4−イル)カルボニル]−ピペリジン−4−イルオキシ}−7−(2−メトキシ−エトキシ)−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−(1−アセチル−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−(1−メチル−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−(1−メタンスルホニル−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−メチル−ピペリジン−4−イルオキシ)−7−(2−メトキシ−エトキシ)−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−イソプロピルオキシカルボニル−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(シス−4−メチルアミノ−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{シス−4−[N−(2−メトキシ−アセチル)−N−メチル−アミノ]−シクロヘキサン−1−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−(ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−[1−(2−メトキシ−アセチル)−ピペリジン−4−イルオキシ]−7−メトキシ−キナゾリン、4−[(3−エチニル−フェニル)アミノ]−6−{1−[(モルホリン−4−イル)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(シス−2,6−ジメチル−モルホリン−4−イル)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(2−メチル−モルホリン−4−イル)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(S,S)−(2−オキサ−5−アザ−ビシクロ[2.2.1]ヘプタ−5−イル)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(N−メチル−N−2−メトキシエチル−アミノ)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−エチル−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(2−メトキシエチル)カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{1−[(3−メトキシプロピル−アミノ)−カルボニル]−ピペリジン−4−イルオキシ}−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[シス−4−(N−メタンスルホニル−N−メチル−アミノ)シクロヘキサン−1−イルオキシ]−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[シス−4−(N−アセチル−N−メチル−アミノ)シクロヘキサン−1−イルオキシ]−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[トランス−4−メチルアミノ−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[トランス−4−(N−メタンスルホニル−N−メチル−アミノ)−シクロヘキサン−1−イルオキシ]−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(トランス−4−ジメチルアミノ−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(トランス−4−{N−[(モルホリン−4−イル)カルボニル]−N−メチル−アミノ}−シクロヘキサン−1−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−[2−(2,2−ジメチル−6−オキソ−モルホリン−4−イル)エトキシ]−7−[(S)−(テトラヒドロフラン−2−イル)メトキシ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−メタンスルホニル−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−(1−シアノ−ピペリジン−4−イルオキシ)−7−メトキシ−キナゾリン、[4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−6−{[4−(ホモモルホリン−4−イル)−1−オキソ−2−ブテン−1−イル]アミノ}−7−[(S)−(テトラヒドロフラン−3−イル)オキシ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−(2−{4−[(S)−(2−オキソ−テトラヒドロフラン−5−イル)カルボニル]−ピペラジン−1−イル}−エトキシ)−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[2−((S)−6−メチル−2−オキソ−モルホリン−4−イル)−エトキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[4−((S)−6−メチル−2−オキソ−モルホリン−4−イル)−ブチルオキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[4−((S)−6−メチル−2−オキソ−モルホリン−4−イル)−ブチルオキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[2−{4−[(S)−(2−オキソ−テトラヒドロフラン−5−イル)カルボニル]−ピペラジン−1−イル}−エトキシ)−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[2−((S)−6−メチル−2−オキソ−モルホリン−4−イル)−エトキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[4−((R)−6−メチル−2−オキソ−モルホリン−4−イル)−ブチルオキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、4−[(3−クロロ−4−フルオロ−フェニル)アミノ]−7−[4−((S)−6−メチル−2−オキソ−モルホリン−4−イル)−ブチルオキシ]−6−[(ビニルカルボニル)アミノ]−キナゾリン、セツキシマブ、トラスツズマブ、ABX−EGF、Mab ICR−62、ゲフィチニブ、カネルチニブ及びエルロチニブから選択される化合物である。
式1で示される活性物質が、生理学的に許容しうる賦形剤と混和された状態で存在する場合、以下の生理学的に許容しうる賦形剤を用いて、本発明の吸入可能な粉末を製造してもよい:単糖類(例えば、グルコール又はアラビノース)、二糖類(例えば、ラクトース、サッカロース、マルトース)、オリゴ糖及び多糖(例えば、デキストラン)、ポリアルコール(例えば、ソルビトール、マンニトール、キシリトール)、塩(例えば、塩化ナトリウム、炭酸カルシウム)又はこれらの賦形剤の互いの混合物。好ましくは、単糖類又は二糖類が用いられるが、ラクトース又はグルコースの使用は、(排他的ではないが)特に水和物の形態は、好ましい。本発明の目的では、ラクトースが、特に好ましい賦形剤であるが、ラクトース一水和物が、最も特別に好ましい。粉砕及び微粒子化により、そして最終的に成分を共に混合することにより本発明の吸入可能な粉末を製造する方法は、先行技術から公知である。
本発明により用いられうる噴射剤含有の吸入可能なエアロゾルは、式1で示される化合物を、噴射ガスに溶解させて、又は分散形態で含んでいてもよい。本発明の吸入エアロゾルを製造するのに用いられうる噴射剤ガスは、先行技術から公知である。適切な噴射剤ガスは、炭化水素、例えば、n−プロパン、n−ブタン又はイソブタン、及びハロ炭化水素、例えば好ましくはメタン、エタン、プロパン、ブタン、シクロプロパン又はシクロブタンのフッ素化誘導体から選択される。上述の噴射ガスは、単独で、又はその混合物中で用いてもよい。特に好ましい噴射ガスは、TG134a(1,1,1,2−テトラフロオロエタン)、TG227(1,1,1,2,3,3,3−ヘプタフルオロプロパン)及びその混合物から選択されるフッ素化アルカン誘導体である。本発明の使用の範囲内で用いられる噴射剤駆動性吸入エアロゾル(propellant-driven inhalation aerosols)は、他の成分、例えば、共溶媒、安定化剤、界面活性剤、抗酸化剤、滑剤及びpH調整剤を含んでいてもよい。これらの成分は全て、当該技術分野で公知である。
本発明の式1で示される化合物は、好ましくは噴射剤を含まない吸入可能な溶液及び吸入可能な懸濁液を製造するために用いられる。この目的で用いられる溶媒としては、水性又はアルコール性、好ましくはエタノール性溶液が含まれる。溶媒は、単独の水、又は水とエタノールとの混合物であってもよい。溶液又は懸濁液を、適切な酸を用いて、pH2〜7、好ましくは2〜5に調整する。無機酸又は有機酸から選択される酸を用いて、pHを調整してもよい。特に適切な無機酸の例としては、塩酸、臭化水素酸、硝酸、硫酸及び/又はリン酸が挙げられる。特に適切な有機酸の例としては、アスコルビン酸、クエン酸、リンゴ酸、酒石酸、マレイン酸、コハク酸、フマル酸、酢酸、ギ酸及び/又はプロピオン酸などが挙げられる。好ましい無機酸は、塩酸及び硫酸である。酸付加塩を既に形成させた酸を、活性物質の一つと共に用いることもできる。有機酸のうち、アスコルビン酸、フマル酸及びクエン酸が好ましい。特に、酸性化する性質に加えて他の性質を有する酸(例えば、着香剤、抗酸化剤又は錯化剤、例えばクエン酸又はアスコルビン酸)の場合に、所望なら、上記酸の混合物を用いてもよい。本発明によれば、塩酸を用いてpHを調整するのが、特に好ましい。
Claims (12)
- 式1:
(式中、
R1は、−O−R3、−NR3R4、−CR3R4R5、−(エチン)−R3、−S−R3、−SO−R3及びSO2−R3から選択される基Aを表すか、又は
R1は、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜10員単環式もしくは二環式ヘテロアリール(ここで、このヘテロアリールは、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、ならびに
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、3〜10員単環式もしくは二環式飽和もしくは部分飽和複素環基(ここで、この複素環基は、C原子もしくはN原子のいずれかを介して式1で示される構造に結合している)、
から選択される基Bを表し、
ここで、この基Bは、H、ハロゲン、−C1〜3−アルキル、−NH(C1〜4−アルキル)、−N(C1〜4−アルキル)2、−NH2、−C1〜3−アルキル−OH、−OH、オキソ、−CO−NH2、−C1〜3−アルキレン−CO−NH2、−CO−NH(C1〜3−アルキル)、−C1〜3−アルキレン−CO−NH(C1〜3−アルキル)、−CO−NH(C3〜5−シクロアルキル)、−C1〜3−アルキレン−CO−NH(C3〜5−シクロアルキル)、−NH−CO−NH2、−NH−CO−NH(C1〜3−アルキル)、−NH−CO−N(C1〜3−アルキル)2、O−C1〜3−アルキル、−(C1〜3−アルキレン)−NH2、−フェニル及び−CO−(C1〜5−アルキル)から互いに独立して選択される基1個以上で場合により置換されていてもよく、
R3は、Hであるか、又は
−C1〜6−アルキル、−C1〜6−フルオロアルキル、−(C1〜5−アルキル)−OH、−C6〜10−アリール、−(C1〜4−アルキレン)−(C6〜10−アリール)、エテニル、−(C1〜4−アルキレン)−(エテン)、−エチニル、−(C1〜4−アルキレン)−(エチン)、−(C1〜4−アルキレン)−(エチン)−NH2、−(C1〜4−アルキレン)−(エチン)−(C1〜4−アルキレン)−NH2、−NH(C1〜3−アルキル)、−(C1〜4−アルキレン)−NH(C1〜3−アルキル)、−CHOH−(C1〜4−アルキレン)−NH2、−(C1〜4−アルキレン)−CHOH−(C1〜4−アルキレン)−NH2、−(C1〜4−アルキレン)−CHOH−NH2、−CHOH−NH2、単環式もしくは二環式飽和もしくは部分飽和−C3〜10−シクロアルキル、単環式もしくは二環式飽和もしくは部分飽和−(C1〜4−アルキレン)−C3〜10−シクロアルキル、−(Het)、−(C1〜4−アルキレン)−(Het)、−(ヘタリール)、及び−(C1〜4−アルキレン)−(ヘタリール)から選択される基であり、
この基は、H、−OH、−オキソ、−COOH、−ハロゲン、−C1〜3−アルキル、−C1〜3−ハロアルキル、−C1〜3−アルキル−OH、−C3〜7−シクロアルキル、−O−(C1〜4−アルキル)、−NH(C1〜4−アルキル)、−(C1〜4−アルキレン)−NH(C1〜4−アルキル)、−N(C1〜4−アルキル)2、−(C1〜4−アルキレン)−N(C1〜4−アルキル)2、−NH−CO−NH2、−(C1〜4−アルキレン)−NH−CO−NH2、−CO−NH2、−(C1〜4−アルキレン)−CO−NH2、−CO−NH(C1〜3−アルキル)、−(C1〜4−アルキレン)−CO−NH(C1〜3−アルキル)、−CO−N(C1〜3−アルキル)2、−(C1〜4−アルキレン)−CO−N(C1〜3−アルキル)2、−NH−(CO)m−NH2、−NH−(C1〜4−アルキレン)−(CO)m−NH2、−NH−(CO)m−NH(C1〜3−アルキル)、−NH−(C1〜4−アルキレン)−(CO)m−NH(C1〜3−アルキル)、−NH−(CO)m−N(C1〜3−アルキル)2、−NH−(C1〜4−アルキレン)−(CO)m−N(C1〜3−アルキル)2、−O−(C2〜4−アルキレン)−NH2、−O−(C2〜4−アルキレン)−NH(C1〜3−アルキル)、−O−(C2〜4−アルキレン)−N(C1〜3−アルキル)2、−NH−CO−(C1〜3−アルキル)、−(C1〜4−アルキレン)−NH−CO−(C1〜3−アルキル)、−C3〜5−シクロアルキル、−SO2−(C1〜4−アルキル)、−SO2−(C3〜5−シクロアルキル)、−NH−SO2−(C1〜4−アルキル)、−SO2−NH2、−SO2−NH−C1〜3−アルキル、−SO2−N(C1〜3−アルキル)2、−SO2−(Het)、−O−(Het)、−O−(C1〜4−アルキレン)−(Het)、−NH−(Het)、−NH−(C1〜4−アルキレン)−(Het)、−NH−(ヘタリール)、−NH−(C1〜4−アルキレン)−(ヘタリール)、−(Het)及び−(C1〜4−アルキレン)−(Het)から互いに独立して選択される基1個以上で場合により置換されていてもよく、
(Het)は、C1〜3−アルキル、ハロゲン、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1〜3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1、2又は3個含む3〜10員飽和又は部分飽和単環式又は二環式複素環基を表し、
(ヘタリール)は、C1〜3−アルキル、ハロゲン、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1、2又は3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜10員単環式又は二環式ヘテロアリールを表し、
ここで、用語「二環式」は、互いに縮合した二環(但し、スピロ環は除く)を意味し、
m=0又は1であり、
R4及びR5は、H、メチル又はエチルを表し、そして
R6は、メチルを表す)で示される化合物、ならびに薬学的に許容しうるその塩。 - R1が−O−R3又は−NR3R4である請求項1記載の式1で示される化合物、及び薬学的に許容しうるその塩。
- R1が、−O−R3又は−NR3R4であり、
(Het)が、メチル、エチル、プロピル、イソプロピル、F、Cl、Br、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1〜3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1、2又は3個含む、3〜7員飽和又は部分飽和単環式複素環基を表し、そして
(ヘタリール)が、メチル、エチル、プロピル、イソプロピル、F、Cl、Br、CH2−NH2、NH2、OH、CO−NH2及びオキソから選択される基1、2又は3個で場合により置換されていて、N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含む、5〜6員単環式ヘテロアリールを表す、
請求項2記載の式1で示される化合物、及び薬学的に許容しうるその塩。 - R1が、
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含み、その1〜3個のヘテロ原子の少なくとも1個がN原子である、5〜10員単環式もしくは二環式ヘテロアリール、ならびに
− N、O及びSから互いに独立して選択されるヘテロ原子を1〜3個含み、その1〜3個のヘテロ原子の少なくとも1個がN原子である、3〜10員単環式もしくは二環式飽和もしくは部分飽和複素環基、
から選択され、
ここで、上述のヘテロアリール及び複素環が、それぞれ少なくとも1個のN原子によって式1で示される構造に結合している、請求項1記載の式1で示される化合物、及び薬学的に許容しうるその塩。 - SYK酵素の阻害により処置されうる疾患の処置用の医薬を製造するための、請求項1〜5の1項記載の化合物の使用。
- アレルギー性鼻炎、喘息、COPD、成人性呼吸促迫症候群、気管支炎、B細胞リンパ腫、皮膚炎及び接触皮膚炎、アレルギー性皮膚炎、アレルギー性鼻結膜炎、関節リウマチ、抗リン脂質症候群、ベルガー病、エバンス症候群、潰瘍性大腸炎、アレルギー抗体に基づく糸球体腎炎、顆粒球減少症、グッドパスチャー症候群、肝炎、ヘノッホ・シェーンライン紫斑病、過敏性血管炎、免疫性溶血性貧血、特発性血小板減少性紫斑病、川崎症候群、アレルギー性結膜炎、エリテマトーデス、外套細胞リンパ腫、好中球減少症、非家族性側索硬化症、クローン病、多発性硬化症、重症筋無力症、骨髄異形成症候群、骨粗鬆症、骨溶解病、骨欠乏症、乾癬、シェーグレン症候群、強皮症、T細胞リンパ腫、じんましん/血管性浮腫、ウェゲナー肉芽腫ならびにセリアック病から選択される疾患の処置用の医薬を製造するための、請求項1〜5の1項記載の化合物の使用。
- 喘息、COPD、アレルギー性鼻炎、成人性呼吸促迫症候群、気管支炎、アレルギー性皮膚炎、接触皮膚炎、特発性血小板減少性紫斑病、関節リウマチ及びアレルギー性鼻結膜炎から選択される疾患の処置用の医薬を製造するための、請求項1〜5の1項記載の化合物の使用。
- 喘息、COPD、アレルギー性鼻炎、アレルギー性皮膚炎及び関節リウマチから選択される疾患の処置用の医薬を製造するための、請求項1〜5の1項記載の化合物の使用。
- 請求項1〜5の1項記載の式1で示される化合物を1種以上含むことを特徴とする医薬配合剤。
- β模倣薬、コルチコステロイド、PDE4阻害剤、EGFR阻害剤、LTD4アンタゴニスト、CCR3阻害剤、iNOS阻害剤及びSYK阻害剤から選択される活性物質と併用される、請求項1〜5の1項記載の式1で示される化合物を1種以上含むことを特徴とする医薬配合剤。
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