JP2005527523A - AngII介在性疾病を処置するための4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イル−アミノ]フェニル]−ベンズアミド - Google Patents
AngII介在性疾病を処置するための4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イル−アミノ]フェニル]−ベンズアミド Download PDFInfo
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- JP2005527523A JP2005527523A JP2003575945A JP2003575945A JP2005527523A JP 2005527523 A JP2005527523 A JP 2005527523A JP 2003575945 A JP2003575945 A JP 2003575945A JP 2003575945 A JP2003575945 A JP 2003575945A JP 2005527523 A JP2005527523 A JP 2005527523A
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- hypertension
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Abstract
【化1】
の4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミド、またはその医薬的に許容される塩が、アンジオテンシンII誘導性疾病の処置で用いられ、そして、(a)PDGF受容体チロシンキナーゼ阻害剤、好ましくは、N−{5−[4−(4−メチル−ピペラジノ−メチル)−ベンゾイルアミド]−2−メチルフェニル}−4−(3−ピリジル)−2−ピリミジン−アミン、および(b)抗高血圧剤、アルドステロン拮抗剤、アルドステロン合成阻害剤、および/またはアンジオテンシン受容体遮断剤から選択される少なくとも1つの化合物、そして必要に応じて、同時、別々、または連続使用のための少なくとも1つの医薬的に許容される担体を含む組合せが、特に、高血圧および高血圧誘導性疾病の処置に用いられ得る。
Description
最近の知見は、筋細胞のアポトーシスの活性化での重要な因子である、局所レニン・アンジオテンシン系(RAS)のアップレギュレーションおよびアンジオテンシンII(AngII)の合成、およびインシュリン依存性糖尿病のモデルでの応答性肥大を指摘している(Andrea Frustaci and al.; Circulation Research (2000); 87:1123-1132)。
[式中、
R1は、4−ピラジニル;1−メチル−1H−ピロリル;アミノ−またはアミノ−低級アルキル−置換フェニル(それぞれの場合のアミノ基は、遊離であるか、アルキル化またはアシル化されている);5員環の炭素原子上で結合している1H−インドリル、または1H−イミダゾリル;または環の炭素原子上で結合し、かつ非置換または窒素原子上で酸素により置換されている、非置換または低級アルキル−置換ピリジルであり;
R2およびR3は、互いに独立して、水素または低級アルキルであり;
ラジカルR4、R5、R6、R7、およびR8のうち1個または2個が、それぞれニトロ、フルオロ−置換低級アルコキシ、または式II
(式中、R9は、水素、または低級アルキルであり、
Xは、オキソ、チオ、イミノ、N−低級アルキル−イミノ、ヒドロキシイミノ、またはO−低級アルキル−ヒドロキシイミノであり、
Yは、酸素または基NHであり、
nは、0または1であり、そして
R10は、少なくとも5個の炭素原子を有する脂肪族ラジカル、または芳香族、芳香族−脂肪族、脂環式、脂環式−脂肪族、複素環式、または複素環式−脂肪族ラジカルである)のラジカルであり、
そして、残りのラジカルR4、R5、R6、R7、およびR8は、互いに独立して、水素、非置換、または遊離またはアルキル化アミノ、ピペラジニル、ピペリジニル、ピロリジニル、またはモルホリニルで置換されている低級アルキル、または低級アルカノイル、トリフルオロメチル、遊離、エーテル化、またはエステル化ヒドロキシ、遊離、アルキル化、またはアシル化アミノ、または遊離、またはエステル化カルボキシである]のN−フェニル−2−ピリミジン−アミン誘導体、または少なくとも1個の塩形成基を有する該化合物の塩の新たな使用に関する。
アミノ−またはアミノ−低級アルキル−置換フェニルR1(それぞれの場合のアミノ基は、遊離であるか、アルキル化、またはアシル化されている)は、任意の所望の位置(オルト、メタ、またはパラ)で置換されているフェニルである(アルキル化アミノ基は、好ましくは、モノ−またはジ−低級アルキルアミノ(例えば、ジメチルアミノ)であり、そしてアミノ−低級アルキルの低級アルキル部分は、好ましくは、特にメチルまたはエチルの様な直鎖C1−C3アルキルである)。
環の炭素原子上で結合している非置換または低級アルキル−置換ピリジルは、低級アルキル−置換、または好ましくは、非置換2−、4−、または好ましくは、3−ピリジル(例えば、3−ピリジル、2−メチル−3−ピリジル、または4−メチル−3−ピリジル)である。窒素原子上で酸素により置換されているピリジルは、ピリジンN−オキシドから誘導されたラジカル、すなわち、N−オキシド−ピリジルである。
Yは、存在するなら、好ましくは基NHである。
本明細書の範囲内の用語「低級」は、7個以下、好ましくは、4個以下の炭素原子を有するラジカルを示す。
低級アルキルR1、R2、R3、およびR9は、好ましくは、メチルまたはエチルである。
置換フェニルラジカルは、フッ素の様な5個以下の置換基を有するが、特に比較的大きな置換基の場合には、一般的には、1から3個の置換基のみで置換されている。特に言及される置換フェニルの例は、4−クロロ−フェニル、ペンタフルオロ−フェニル、2−カルボキシ−フェニル、2−メトキシ−フェニル、4−フルオロ−フェニル、4−シアノ−フェニル、および4−メチル−フェニルである。
酸性および塩基性基を共に有する式Iの化合物は、分子内塩(internal salt)を形成できる。
[式中、
ラジカルR4、R5、R6、R7、およびR8の1個または2個は、それぞれニトロ、または式II
(式中、
R9は、水素、または低級アルキルであり、
Xは、オキソ、チオ、イミノ、N−低級アルキル−イミノ、ヒドロキシイミノ、またはO−低級アルキル−ヒドロキシイミノであり、
Yは、酸素、または基NHであり、
nは、0または1であり、そして
R10は、少なくとも5個の炭素原子を有する脂肪族ラジカル、または芳香族、芳香族−脂肪族、脂環式、脂環式−脂肪族、複素環式、または複素環式−脂肪族ラジカルである)のラジカルであり、
そして、残りのラジカルR4、R5、R6、R7、およびR8は、互いに独立して、水素、非置換、または遊離、またはアルキル化アミノ、ピペラジニル、ピペリジニル、ピロリジニル、またはモルホリニルで置換されている低級アルキル、または低級アルカノイル、トリフルオロメチル、遊離、エーテル化、またはエステル化ヒドロキシ、遊離、アルキル化、またはアシル化アミノ、または遊離、またはエステル化カルボキシであり、
そして、残りの置換基は、上で定義されたものである]の本発明の化合物が、好ましい。
[式中、
R1は、それぞれが炭素原子上で結合している、ピリジル、またはN−オキシド−ピリジルであり、
R2およびR3は、それぞれ水素であり、
R4は、水素、または低級アルキルであり、
R5は、水素、低級アルキル、またはトリフルオロメチルであり、
R6は、水素であり、
R7は、ニトロ、フルオロ−置換低級アルコキシ、または式II
(式中、
R9は、水素であり、
Xは、オキソであり、
nは、0であり、そして
R10は、炭素原子上で結合しているピリジル、非置換であるか、またはハロゲン、シアノ、低級アルコキシ、カルボキシ、低級アルキル、または4−メチル−ピペラジニル−メチルで置換されているフェニル、またはC5−C7アルキル、チエニル、2−ナフチル、またはシクロヘキシルである)のラジカルであり、そして
R8は、水素である]の本発明の化合物が、好ましい。
[式中、
R1は、炭素原子上で結合している、ピリジルであり、
R2、R3、R5、R6、およびR8は、それぞれ水素であり、
R4は、低級アルキルであり、
R7は、式II
(式中、
R9は、水素であり、
Xは、オキソであり、
nは、0であり、そして
R10は、4−メチル−ピペラジニル−メチルである)のラジカルである]の本発明の化合物が、中でも好ましい。
非常に好ましくは、式IのN−フェニル−2−ピリミジン−アミン誘導体は、そのモノメシル酸塩の形で用いられる。
ピロロ[3,4−c]−β−カルボリン−ジオンは、Teller S, (Eur J Med Chem 2000 Apr;35(4):413-27)に記載されている。
心臓、血管、または腎臓の肥大または肥大リモデリングは、心臓、動脈、大血管、または腎臓の大きさの増大を特徴とする。
上昇した血圧状態である高血圧は、相当数のヒト集団に影響を及ぼしている。持続性高血圧の結果は、眼、腎臓、心臓および中枢系に対する血管障害を含み、そして該合併症のリスクは血圧上昇とともに増加する。血圧制御の基本因子は、心拍出量および末梢血管抵抗性であり、後者は、様々な影響により制御される優位な共通機序である。本発明による、アンジオテンシンIIにより引き起こされる高血圧と関係する損傷は、好ましくは、心不全、心不全、高血圧患者での右心室または左心室肥大(LVH)の様な心肥大、腎動脈症、および血管疾病であるが、これらに限られない。
鬱血性心不全は、糖尿病と関係する。
用語「予防的」は、アンジオテンシンII誘導性損傷を含む、疾病の始まりまたは再発の予防を意味する。
または、プラシーボ効果をコントロールした二重盲検研究が、上記の本発明の組合せの有効性を証明するために用いられ得る。
AT1受容体拮抗剤(アンジオテンシンII受容体拮抗剤とも呼ばれる)は、アンジオテンシン受容体のAT1サブタイプと結合する有効成分であるが、該受容体の活性化を生じないことは理解される。AT1受容体の阻害の結果、該拮抗剤は、例えば、抗高血圧剤として、または鬱血性心不全を処置するために利用され得る。
市販のアルドステロン合成阻害剤、または保健機関により許可されたアルドステロン合成阻害剤が好ましい。
さらに、本発明は、高血圧誘導性疾病の予防、進行の遅延、処置、特に、心血管損傷(すなわち、高血圧誘導性心血管肥大または心血管肥大リモデリング)の処置のため、および高血圧誘導性疾病の進行の遅延、または処置、特に、心血管損傷(すなわち、高血圧誘導性心血管肥大または心血管肥大リモデリング)の処置のための医薬の製造のための、本発明の組合せの使用に関する。
最も好ましくは、該実施態様において、本発明の組合せは、アンジオテンシン受容体遮断剤、特に、バルサルタン(CAS:137862−53−4)を含む。
本発明の組合せは、組合せ製剤または医薬組成物であり得る。
ヒドロクロロチアジドは、ヒトに、約4から約40mg/日、好ましくは、約8から約20mg/日で変動する投与範囲で経口投与される。
実施例1:
動物:48匹の8週齢のオスのSprague Dawleyラットをエンフルラン(Abbott Australasia, Kurnal, NSW, Australia)で麻酔し、そして浸透圧性ミニポンプ(Alzet Model 2002, Alzet Corporation, Palo Alto)を肩胛骨間に挿入した。ラットを、既に記載(Cao Z et col. Kidney Int 58:2437-2451, 2000)の、アンジオテンシンII(58ng/分)と共にまたはなしで、ビークル(0.15M NaCl、1mmol/l 酢酸)を充填したミニポンプを有するように無作為化した。次に、該動物を、処置なし、または化合物Iを毎日、胃管栄養により60mg/kg用量で投与するようにさらに無作為化し、12日後に屠殺した。ラットに、水および標準的なラット飼料へのアクセスの制限をしなかった。既に記載(Bunag RD; Journal of Applied Physiology 34:279-282, 1973)の、事前に温めらた非麻酔動物での間接的尾切断プレチスモグラフィーにより、最大血圧(SBP)を測定した。16匹の動物それぞれの群で、8匹を組織研究に用い、そして8匹を遺伝子発現分析に用いた。後者の群では、動物を斬首で屠殺し、腸管膜血管を取り出し、既に記載(Rumble J et al.; J Hypertension 14:601-607, 1996)のように、上部の下腸管膜動脈を得るために、周囲の脂肪、結合組織、および静脈を取り除いた。該血管の重さを量り、液体窒素に簡単に凍結し、続いて−80℃で保存した。
動物データ:アンジオテンシンII注射は、ビークル処置動物と比較して、全身血圧(SBP)の上昇と関係した(141±2mmHg対202±7mmHg、ビークル対アンジオテンシンII、p<0.001)。腸管膜血管の重量も、ビークル処置を受けた対照動物(32mg、p<0.001)と比較して、アンジオテンシンII注射ラット(52mg、p<0.001)で増加した。イマチニブは、全身血圧(205±10mmHg)に作用しなかったが、アンジオテンシンIIを投与した動物の腸管膜の重量(42mg、p<0.001)は有意に減少した。
活性物質として、イマチニブ(遊離塩基)100mgに対応する表題化合物(=塩I)119.5mgを含有するカプセル剤を、次の組成で製造する。
活性物質として、化合物I(遊離塩基)100mgに対応する塩I 119.5mgを含有するカプセル剤を、次の組成で製造する。
は、本発明の組合せの使用が、AngII介在性疾病、特に、心血管系および/または腎臓でのアンジオテンシンII誘導性肥大、またはアンジオテンシンII誘導性肥大リモデリングの処置のための具体的な対象であることを意味する。
該作用は、特に、本明細書に記載の様な高血圧と関係する損傷の患者に臨床上適当であり得る。
活性物質として、イマチニブ100mg、およびバルサルタン80mgを含有するカプセル剤を、次の組成で製造する。
活性物質として、イマチニブ100mg、バルサルタン80mg、およびヒドロクロロチアジド12.5mgを含有するカプセル剤を、次の組成で製造した。
造粒/乾燥:バルサルタンおよび微結晶セルロースを、流動層造粒機にて、精製水に溶解したポピドンおよびラウリル酸ナトリウムからなる造粒溶液で、スプレー造粒した。生じた粒を、流動層で乾燥する。
Claims (27)
- AngII介在性疾病を処置するための医薬の製造のための、PDGF受容体チロシンキナーゼ阻害剤、またはその医薬的に許容される塩の使用。
- AngII介在性疾病を処置するための医薬の製造のための、式I
[式中、
R1は、4−ピラジニル;1−メチル−1H−ピロリル;アミノ−またはアミノ−低級アルキル−置換フェニル(ここで、それぞれの場合のアミノ基は、遊離であるか、アルキル化、またはアシル化されている);5員環の炭素原子上で結合している1H−インドリル、または1H−イミダゾリル;または環の炭素原子上で結合し、かつ非置換または窒素原子上で酸素により置換されている、非置換または低級アルキル−置換ピリジルであり;
R2およびR3は、互いに独立して、水素、または低級アルキルであり;
残りのラジカルR4、R5、R6、R7、およびR8の1個または2個は、それぞれニトロ、フルオロ−置換低級アルコキシ、または式II
(式中、
R9は、水素または低級アルキルであり、
Xは、オキソ、チオ、イミノ、N−低級アルキル−イミノ、ヒドロキシイミノ、またはO−低級アルキル−ヒドロキシイミノであり、
Yは、水素または基NHであり、
nは、0または1であり、そして
R10は、少なくとも5個の炭素原子を有する脂肪族ラジカル、または芳香族、芳香族−脂肪族、脂環式、脂環式−脂肪族、複素環式、または複素環式−脂肪族ラジカルである)のラジカルであり、
そして、残りのラジカルR4、R5、R6、R7、およびR8は、互いに独立して、水素、非置換、または遊離またはアルキル化アミノ、ピペラジニル、ピペリジニル、ピロリジニル、またはモルホリニルで置換されている低級アルキル、または低級アルカノイル、トリフルオロメチル、遊離、エーテル化、またはエステル化ヒドロキシ、遊離、アルキル化、またはアシル化アミノ、または遊離、またはエステル化カルボキシである]のN−フェニル−2−ピリミジン−アミン誘導体、または少なくとも1個の塩形成基を有する該化合物の塩の使用。 - アンジオテンシンII介在性疾病に罹患しているか、または罹患しそうな温血動物、好ましくは、ヒトを処置する方法であって、該動物に、PDGF受容体チロシンキナーゼ阻害剤、特に、請求項2に記載の式IのN−フェニル−2−ピリミジン−アミン誘導体、またはその医薬的に許容される塩を有効量投与することを含む、方法。
- アンジオテンシンII介在性疾病が、心臓血管系でのアンジオテンシンII誘導性肥大またはアンジオテンシンII誘導性肥大リモデリング、および腎臓での、アンジオテンシンII誘導性腎臓病、前炎症状態および前酸化状態を伴う内皮機能不全を含む、高血圧誘導性かつAngII介在性損傷、疾病から選択される、請求項1から3のいずれか1項に記載の使用または方法。
- アンジオテンシンII介在性疾病が、心臓血管系でのアンジオテンシンII誘導性肥大またはアンジオテンシンII誘導性肥大リモデリングを含む疾病から選択される、請求項1から3のいずれか1項に記載の使用または方法。
- アンジオテンシンII介在性疾病が、鬱血性心不全、心不全、心肥大、心筋梗塞後の心臓リモデリング、拡張型または肥大型心筋症での肺の鬱血および心線維症、肥大型心筋症、糖尿病性筋障害、鬱血性心不全での発作予防、左心室または右心室肥大、動脈および/または大血管での肥大性中度肥厚、腸管血管構造肥大から選択される、請求項1から3のいずれか1項に記載の使用または方法。
- アンジオテンシンII介在性疾病が、腎門部の切除後の様な腎ハイパーフィルトレーション、慢性腎疾患でのタンパク尿、高血圧の結果である腎動脈症、腎硬化症、または高血圧性腎硬化症、メサンギウム細胞肥大である、請求項1から3のいずれか1項に記載の使用または方法。
- 式Iの4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミドの医薬的に許容される酸付加塩が投与される、請求項1から3のいずれか1項に記載の使用または方法。
- 式Iの4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミドのメタンスルホン酸塩が投与される、請求項1から3のいずれか1項に記載の使用または方法。
- 1日用量である、式Iの4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミドのモノメタンスルホン酸塩200から600mgが成人に投与される、請求項1から3のいずれか1項に記載の使用または方法。
- 式Iの4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミドが、1日1回ヒト対象に投与される、請求項8から11のいずれか1項に記載の方法。
- レニン・アンジオテンシン系のアップレギュレーションを特徴とする疾病に罹患している温血動物のアテローム性動脈硬化症および/または再狭窄を処置するための医薬の製造のための、PDGF受容体チロシンキナーゼ阻害剤、特に、請求項2に記載の式IのN−フェニル−2−ピリミジン−アミン誘導体、またはその医薬的に許容される塩の使用。
- 高血圧症に罹患している温血動物のアテローム性動脈硬化症および/または再狭窄を処置するための医薬の製造のための、PDGF受容体チロシンキナーゼ阻害剤、特に、請求項2に記載の式IのN−フェニル−2−ピリミジン−アミン誘導体、またはその医薬的に許容される塩の使用。
- PDGF受容体チロシンキナーゼ阻害剤が、4−(4−メチルピペラジン−1−イルメチル)−N−[4−メチル−3−(4−ピリジン−3−イル)ピリミジン−2−イルアミノ)フェニル]−ベンズアミド、またはその医薬的に許容される酸付加塩である、請求項12または13に記載の使用。
- アテローム性動脈硬化症および/または再狭窄を有するか、またはかかりそうな高血圧の温血動物、特に、ヒトを処置する方法であって、該動物にPDGF受容体チロシンキナーゼ阻害剤、特に、式IのN−フェニル−2−ピリミジン−アミン誘導体、またはその医薬的に許容される塩を有効量投与することを含む、方法。
- 高血圧誘導性疾病を有するか、またはかかりそうな温血動物、特に、ヒトを処置する方法であって、該動物に、(a)N−{5−[4−(4−メチル−ピペラジノ−メチル)−ベンゾイルアミド]−2−メチルフェニル}−4−(3−ピリジル)−2−ピリミジン−アミン、および(b)抗高血圧剤、アルドステロン拮抗剤、アルドステロン合成阻害剤、および/またはアンジオテンシン受容体遮断剤から選択される少なくとも1つの化合物(有効成分は、互いに独立して、遊離形または医薬的に許容される塩の形で存在する)、そして必要に応じて、少なくとも1つの医薬的に許容される担体を含む、組合せ製剤または医薬組成物の様な組合せを投与することを含む、方法。
- 有効成分が、高血圧誘導性疾病に対して連帯して治療上有効な量で存在する、請求項16に記載の方法。
- (a)N−{5−[4−(4−メチル−ピペラジノ−メチル)−ベンゾイルアミド]−2−メチルフェニル}−4−(3−ピリジル)−2−ピリミジン−アミン、および(b)抗高血圧剤、アルドステロン拮抗剤、アルドステロン合成阻害剤、および/またはアンジオテンシン受容体遮断剤から選択される少なくとも1つの化合物(有効成分は、互いに独立して、遊離形または医薬的に許容される塩の形で存在する)、そして必要に応じて、同時、別々、または連続して使用するための少なくとも1つの医薬的に許容される担体を含む、組合せ。
- 化合物(a)がそのモノメタンスルホン酸塩の形で用いられる、請求項18に記載の組合せ。
- 組み合せ製剤または医薬組成物である、請求項18または19に記載の組合せ。
- 高血圧介在性疾病に対して連帯して治療上有効な量の請求項18または19に記載の組合せ、および少なくとも1つの医薬的に許容される担体を含む、医薬組成物。
- 高血圧誘介在性疾病の進行の遅延、または処置のための、請求項18から20のいずれか1項に記載の組合せの使用。
- 高血圧誘導性心血管肥大または心血管肥大リモデリングの進行の遅延、または処置のための医薬の製造のための、請求項18から20のいずれか1項に記載の組合せの使用。
- 少なくとも1つの組合せパートナー(b)が、バルサルタン、フルバスタチン、アトルバスタチン、ピタバスタチン、ベンゼプリル、エナラプリル、アムロジピン、特にそのベシル酸塩、ファドロゾールの(+)鏡像異性体、エプレレノン、オマパトリル酸塩、Z 13752A、シタキッセンタン、特にシタキッセンタンナトリウム、ダルセンタン、およびヒドロクロロチアジドからなる群から選択される、請求項16から24のいずれか1項に記載の方法、使用、または組合せ。
- 組合せパートナー(b)がバルサルタンおよび/またはヒドロクロロチアジドである、請求項16から24のいずれか1項に記載の方法、使用、または組合せ。
- (a)N−{5−[4−(4−メチル−ピペラジノ−メチル)−ベンゾイルアミド]−2−メチルフェニル}−4−(3−ピリジル)−2−ピリミジン−アミン、および(b)抗高血圧剤、アルドステロン拮抗剤、アルドステロン合成阻害剤、および/またはアンジオテンシン受容体遮断剤から選択される少なくとも1つの化合物を、高血圧介在性疾病の進行の遅延または処置で同時、別々、または連続して使用するための指示書と共に含む、市販のパッケージ。
- (a)PDGF受容体チロシンキナーゼ阻害剤、および(b)バルサルタン、そして必要に応じて、ヒドロクロロチアジド(有効成分は、互いに独立して、遊離形または医薬的に許容される塩の形で存在する)、そして必要に応じて、同時、別々、または連続して使用するための少なくとも1つの医薬的に許容される担体を含む、組合せ。
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CN1917865A (zh) * | 2004-01-22 | 2007-02-21 | 诺瓦提斯公司 | 有机化合物的组合 |
GB0401761D0 (en) * | 2004-01-27 | 2004-03-03 | Novartis Ag | Organic compounds |
MY144177A (en) * | 2004-02-04 | 2011-08-15 | Novartis Ag | Salt forms of 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide. |
MY148074A (en) * | 2005-05-10 | 2013-02-28 | Novartis Ag | Pharmaceutical compositions comprising imatinib and a release retardant |
EP1741432A1 (de) * | 2005-07-07 | 2007-01-10 | Universitätsklinikum Freiburg | Tyrosinkinase-Inhibitor Imatinib zur Behandlung von Bluthochdruck |
DE102005042544A1 (de) * | 2005-09-07 | 2007-03-08 | Ernst-Moritz-Arndt-Universität | Beeinflussung des kardialen Fc-Rezeptors zur Behandlung der dilatativen Kardiomyopathie |
WO2007084949A2 (en) * | 2006-01-18 | 2007-07-26 | The Uab Research Foundation | Modulators of cardiac cell hypertrophy and hyperplasia |
JP2009530279A (ja) * | 2006-03-13 | 2009-08-27 | エンサイシブ・ファーマシューティカルズ・インコーポレイテッド | N−(4−クロロ−3−メチル−5−イソキサゾリル)2−[2−メチル−4,5−(メチレンジオキシ)フェニルアセチル]チオフェン−3−スルホンアミド、ナトリウム塩の多形 |
MX2008011842A (es) * | 2006-03-13 | 2008-10-02 | Encysive Pharmaceuticals Inc | Procedimientos y composiciones para el tratamiento de insuficiencia cardiaca diastolica. |
MX2009002336A (es) * | 2006-09-01 | 2009-03-20 | Teva Pharma | Composiciones de imatinib. |
TW201006823A (en) * | 2008-07-14 | 2010-02-16 | Novartis Ag | Use of pyrimidylaminobenzamide derivatives for the treatment of fibrosis |
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DE60308337T2 (de) | 2007-09-20 |
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