JP6748113B2 - 全身性硬化症(SSc)に付随する指潰瘍(DU)を治療するための単独のまたはPDE5阻害剤と組み合わせたsGC刺激剤、sGC活性化剤の使用 - Google Patents
全身性硬化症(SSc)に付随する指潰瘍(DU)を治療するための単独のまたはPDE5阻害剤と組み合わせたsGC刺激剤、sGC活性化剤の使用 Download PDFInfo
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- JP6748113B2 JP6748113B2 JP2017557440A JP2017557440A JP6748113B2 JP 6748113 B2 JP6748113 B2 JP 6748113B2 JP 2017557440 A JP2017557440 A JP 2017557440A JP 2017557440 A JP2017557440 A JP 2017557440A JP 6748113 B2 JP6748113 B2 JP 6748113B2
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description
全身性硬化症(SSc)の病因は依然として不明確であり、理解しづらいままである。しかしながら、強皮症は非遺伝性の非感染性疾患であり、自己免疫疾患であると考えられている。SScは、皮膚線維症をもたらす真皮への細胞外マトリックスの過剰な沈着によって誘因される広範囲の症状を有する。後の段階で、SScは、腸、肺または腎臓などの他の内臓に影響を及ぼす進行性の組織線維化によって特徴付けられる。そのため、強皮症は、例えば、肺線維症、腎線維症、心臓、腸または血管の線維化も含む疾患の特徴である。SScは、皮膚および内臓における過剰な線維化に加えて、脈管障害および微小血管障害によっても特徴付けられる。特に小血管脈管障害および付随する血管灌流障害および虚血は、レイノー現象(RP)を引き起こすことがあるが、指潰瘍(DU)の形成を引き起こすこともある。組織線維化は終末臓器不全を引き起こし、末期SScの患者の高い罹患率および死亡率をもたらす場合がある一方、DUの形成はSSc患者の生活の質を実質的に低下させ、手の機能を損ない、障害につながる。(Harrisら、2005−Kelley’s Textbook of Rhematology第7版.Elsevier Saunders、Philadelphia PA)。
環状ヌクレオチド、環状アデノシン一リン酸(cAMP)および環状グアノシン一リン酸(cGMP)は、数十年前に発見され、細胞内で最も重要な二次メッセンジャー経路の1つとなっている。細胞内cGMPプールの調節が生理学および病態生理学に実質的な影響を及ぼし、薬理学的介入の1つの基本原理であることが十分に確立されている(Evgenovら、2006、Nat.Rev.Drug.Discov.5(9):755〜768)。心血管、肺またはCNS障害の治療の他に、cGMPの増加が同様に泌尿器障害のための非常に有効な治療選択肢であるという十分な証拠がある(Sandnerら、2009−Handbook Exper.Pharmacol.191:507〜531)。PDE5阻害剤は、勃起不全(ED)の治療のためのゴールドスタンダードであるが、PDE5阻害剤が過活動膀胱(OAB)および下部尿路症状(LUTS)を特徴とする症候性BPHの治療に有用となり得ることが示された(Porstら、2008−Curr.Urol.Rep.9:295〜301;McVaryら、2007−J.Urol.177:1071〜1077、J Urol.177:1401〜1407、KaplanおよびGonzalez.2007−Rev.Urol.9:73〜77)。バルデナフィル、sGC刺激剤およびsGC活性化剤の抗線維化効果はまだ理解されていない。おそらく他の臓器でcGMPによって媒介される一酸化窒素の抗線維化効果についてのいくつかの記述があり、PDE5阻害剤またはグアニル酸シクラーゼ刺激剤は陰茎線維症(ペロニー病)(Ferriniら、2006−B.J.Urol.97:625〜633)および肝臓線維症(Knorrら、2008−Arzneimittelforschung 58:71〜80)でそれぞれ効果を示している。
・TSKマウスがWTマウスと比較して弱められた創傷治癒を有すること。
・sGC刺激剤またはsGC活性化剤、すなわち式(27)および(3)による化合物が、TSKマウスの創傷治癒を有意にかつ用量依存的に促進すること。
・sGC刺激剤またはsGC活性化剤、すなわち式(27)および(3)による化合物が、治癒時間を健常WT対照マウスに正常化すること。これらのデータは、SScにおけるsGC刺激剤およびsGC活性化剤の抗線維化効果にもかかわらず、SScにおける創傷治癒が有意に加速され、健常対照個体のレベルに標準化され得ることを示唆している。
国際公開第00/06569号パンフレットに実施例16として開示されている、2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−(4−モルホリニル)−4,6−ピリミジン−ジアミン(1)、
・国際公開第02/42301号パンフレットに実施例1として開示されている、2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−(4−ピリジニル)−4−ピリミジン−アミン(2)、
・国際公開第03/095451号パンフレットに実施例8として開示されている、メチル−4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニル−(メチル)カルバメート(3)、
・国際公開第03/095451号パンフレットに実施例5として開示されている、メチル−4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニル−カルバメート(4)、
・国際公開第01/019780号パンフレットに実施例8aとして開示されている、4−({(4−カルボキシブチル)[2−(2−{[4−(2−フェニルエチル)ベンジル]オキシ}フェニル)エチル]アミノ}メチル)カルボン酸(5)、
・国際公開第2011/147809号パンフレットに開示されている、メチル−{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}カルバメート(6)、メチル−{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}メチルカルバメート(7)、メチル−{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}(2,2,2−トリフルオロエチル)カルバメート(8)、
・国際公開第00/02851号パンフレットに開示されている、ナトリウム塩としての5−クロロ−2−(5−クロロチオフェン−2−スルホニルアミノ−N−(4−(モルホリン−4−スルホニル)−フェニル)−ベンズアミド(9)、
・国際公開第00/02851号パンフレットに開示されている、2−(4−クロロ−フェニルスルホニルアミノ)−4,5−ジメトキシ−N−(4−(チオモルホリン−4−スルホニル)−フェニル)−ベンズアミド(10)、
・国際公開第2009/032249号パンフレットに開示されている、1−{6−[5−クロロ−2−({4−トランス−4−トリフルオロメチル)シクロヘキシル]ベンジル}オキシ)フェニル]ピリジン−2−イル}−5−(トリフルオロメチル)−1H−ピラゾール−4−カルボン酸(11)、
・国際公開第2009/071504号パンフレットに開示されている、1−[6−(2−(2−メチル−4−(4−トリフルオロメトキシフェニル)ベンジルオキシ)−フェニル)ピリジン−2−イル]−5−トリフルオロメチル−ピラゾール−4−カルボン酸(12)、
・国際公開第2009/068652号パンフレットに開示されている1−[6−(3,4−ジクロロフェニル)−2−ピリジニル−5−(トリフルオロメチル)−1H−ピラゾール−4−カルボン酸(13)、
・国際公開第2009/123316号パンフレットに開示されている、1−({2−[3−クロロ−5−(トリフルオロメチル)フェニル]−5−メチル−1,3−チアゾール−4−イル}メチル)−1H−ピラゾール−4−カルボン酸(14)、4−({2−[3−(トリフルオロメチル)フェニル]−1,3−チアゾール−4−イル}メチル)安息香酸(15)および1−({2−[2−フルオロ−3−(トリフルオロメチル)フェニル]−5−メチル−1,3−チアゾール−4−イル}メチル)−1H−ピラゾール−4−カルボン酸(16)、
・国際公開第2010/065275号パンフレットに開示されている、4−アミノ−2−[5−クロロ−3−(3,3,3−トリフルオロプロピル)−1H−インダゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(17)、4−アミノ−2−[5−クロロ−3−(2,3,6−トリフルオロベンジル)−1H−インダゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(18)、4−アミノ−5,5−ジメチル−2−[3−(2,3,6−トリフルオロベンジル)1H−チエノ[3,4−c]ピラゾール−1−イル]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(19)、4−アミノ−5,5−ジメチル−2−[3−(2,3,6−トリフルオロベンジル)−1H−チエノ[2,3−d]ピラゾール−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(20)、4−アミノ−5,5−ジメチル−2−[7−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−b]ピリダジン−5−イル]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(21)、4−アミノ−2−[6−クロロ−3−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(22)、4−アミノ−2−[6−フルオロ−3−(2,3,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(23)、4−アミノ−2−[6−フルオロ−3−(2,3,6−トリフルオロベンジル)−6−フルオロイミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(24)、4−アミノ−5,5−ジメチル−2−[3−(2,4,6−トリフルオロベンジル)イミダゾ[1,5−a]ピリジン−1−イル]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(25)、4−アミノ−2−[3−(2−シクロペンチルエチル)イミダゾ[1,5−a]ピリジン−1−イル]−5,5−ジメチル−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(26)、
・国際公開第00/06568号パンフレットに実施例1として開示されている、BAY41−2272として知られている3−(4−アミノ−5−シクロプロピルピリミジン−2−イル)−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン(27)、
・国際公開第2014/131760号パンフレットに実施例1として開示されている、2−{5−フルオロ−1−[(3−フルオロピリジン−2−イル)メチル]−1H−ピラゾロ[3,4−b]ピリジン−3−イル}−5−メチル−5−(トリフルオロメチル)−4−[(3,3,3−トリフルオロプロピル)アミノ]−5,7−ジヒドロ−6H−ピロロ[2,3−d]ピリミジン−6−オン(28)。
タダラフィル((6R,12aR)−2,3,6,7,12,12a−ヘキサヒドロ−2−メチル−6−(3,4−メチレン−ジオキシフェニル)ピラジノ(1’,2’:1,6)ピリド(3,4−b)インドール−1,4−ジオン)、バルデナフィル(2−(2−エトキシ−5−(4−エチルピペラジン−1−イル−1−スルホニル)フェニル)−5−メチル−7−プロピル−3H−イミダゾ(5,1−f)(1,2,4)トリアジン−4−オン)、シルデナフィル(3−[2−エトキシ−5−(4−メチルピペラジン−1−イル)スルホニル−フェニル]−7−メチル−9−プロピル−2,4,7,8−テトラアザビシクロ[4.3.0]ノナ−3,8,10−トリエン−5−オン)、ウデナフィル5−[2−プロピルオキシ−5−(1−メチル−2−ピロリジニルエチルアミドスルホニル)フェニル]−メチル−3−プロピル−1,6−ジヒドロ−7H−ピラゾロ(4,3−d)ピリミジン−7−オン、ダサンタフィル7−(3−ブロモ−4−メトキシベンジル)−1−エチル−8−[[(1,2)−2−ヒドロキシシクロペンチル]アミノ]−3−(2−ヒドロキシエチル)−3,7−ジヒドロ−1−プリン−2,6−ジオン、アバナフィル4−{[(3−クロロ−4−メトキシフェニル)メチル]アミノ}−2−[(2S)−2−(ヒドロキシメチル)ピロリジン−1−イル]−N−(ピリミジン−2−イルメチル)ピリミジン−5−カルボキサミド、ミロデナフィル、ロデナフィル、UK369.003、UK371.800、Surface LogixのSLx2101、LAS34179トリアゾロ[1,2−]キサンチン、6−メチル−4−プロピル−2−[2−プロポキシ−5−(4−メチルピペラジノ)スルホニル]フェニルまたは塩、水和物もしくは塩の水和物。
・有機硝酸塩およびNO供与体、例えば、ニトロプルシドナトリウム、ニトログリセリン、一硝酸イソソルビド、二硝酸イソソルビド、モルシドミンまたはSIN−1、および吸入NO;
・他の血管作用薬、例えば、イロプロスト、ベラプロスト、シカプロスト、エポプロステノール、トレプロスチニルなどのプロスタノイド;
・他の血管作用薬、例えば、ファスジルなどのRhoキナーゼ阻害剤;
・他の血管作用薬、例えばボセンタン、ダルセンタン、アンブリセンタンまたはシタクスセンタン、マシテンタンなどのエンドセリン受容体拮抗薬;
・例えばおよび好ましくは、ニフェジピン、アムロジピン、ベラパミルまたはジルチアゼムなどのカルシウム拮抗薬の群の血圧を下げるための活性物質;
・例えばおよび好ましくは、アンジオテンシンAII拮抗薬ト、ACE阻害剤、レニン阻害剤、α遮断薬、β遮断薬、ミネラロコルチコイド受容体拮抗薬および利尿薬の群の血圧を下げるための活性物質;および/または
・例えばおよび好ましくは、血小板凝集阻害剤、抗凝固剤、トロンビン阻害剤または 線維素溶解促進性物質の群の抗血栓薬、;
・例えばおよび好ましくは、HMG−CoAレダクターゼまたはスクアレン合成阻害剤、ACAT阻害剤、CETP阻害剤、MTP阻害剤、PPAR−α、PPAR−γおよび/またはPPAR−δアゴニスト、コレステロール吸収阻害剤、リパーゼ阻害剤、ポリマー性胆汁酸吸着剤、胆汁酸再吸収阻害剤およびリポタンパク質(a)アンタゴニストなどの甲状腺受容体サゴニスト、コレステロール合成阻害剤の群の脂肪代謝を変化させる活性物質;
・例えばおよび好ましくは、ソラフェニブ、レゴラフェニブ、イマチニブ、ダサチニブ、ニロチニブ・ニンテダニブ、ボルテゾミブおよび/またはピルフェニドンなどのプロテインキナーゼ阻害剤の群の線維性障害に使用される活性物質;
・例えば、シクロホスファミド、メトトレキサート、ラパマイシン、アザチオプリン、トシリズマブ、インフリキシマブ、リツキシマブ、アダリムマブ、ベリムマブ、アバタセプト、SAR100842、サリドマイド誘導体などの炎症反応を変化させるおよび/または免疫応答を抑制する活性物質;
・異なる経路で作用する活性物質、例えば、ピルフェニドン、SAR100842、サリドマイド誘導体、インテグリン阻害剤。
Beyer C、Schett G、Distler O、Distler JH(2010):Animal models of systemic sclerosis: prospects and limitations.Arthritis Rheum.62(10):2831−44
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Ferrini MG、Kovanecz I、Nolazco G(2006):Effects of long−term vardenafil treatment on the development of fibrotic plaques in a rat model of Peyronie´s disease.B.J.U.97:625−633.
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Kaplan SA、Gonzalez RR(2007):Phosphodiesterase type 5 inhibitors for the treatment of male lower urinary tract symptoms.Rev. Urol.9(2):73−77
Khanna DおよびDenton CP(2010)Evidence−based management of rapidly progressing systemic sclerosis.Best.Pract.Res.Clin.Rheumatol.24:387−400
Knorr A、Hirth−Dietrich C、Alonso−Alija C.ら(2008):Nitric oxide−independent activation of soluble guanylate cyclase by BAY 60−2770 in experimental liver fibrosis.Arzneimittelforschung 58:71〜80。
MVary K K.T.McVary、W.Monnig、J.L.Camps、Jr., J.M.Young、L.J.TsengおよびG. van den Ende(2007):Sildenafil citrate improves erectile function and ur inary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: a randomized, double−blind trial.J.Urol.177:1071−1077.
McVary KT、Roehrborn CG、Kaminetsky JC、Auerbach SM、Wachs B、Young JM、Esler A、Sides GD、Denes BS(2007):Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia.J Urol.177:1401−1407.
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Spiera R、Gordon J、Mersten J、Magro C、Mehta M、Wildmann H、Kloiber S、Kirou K、Lyman S、Crow M(2011):Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1year, phse IIa, single−arm open−label clinical trial.Ann.Rheum.Dis.Epub 2011年3月11日
実施例A
Tsk−1マウス対WTマウスの創傷治癒
SScのタイトスキン(Tsk−1)マウスモデルを使用して、式(27)および(3)による化合物(BAY41−2272およびBAY63−2521)の、実質的な皮膚線維症を有するマウスの創傷治癒に対する効果を評価した。常染色体優性突然変異、すなわちフィブリリン−1遺伝子の縦列重複のために、tsk−1マウスの表現型は、皮下組織の厚さの増加を特徴とする(Beyerら、2010)。以下のプライマー:変異型フィブリリン−1/tsk−1順方向プライマー:5’−GTTGGCAACTATACCTGCAT−3’、逆方向プライマー:5’−CCTTTCCTGGTAACATAGGA−3’を用いて、PCRによりTsk−1マウスの遺伝子型判定を行った。
Tsk−1マウスで、プラセボ(=化合物のビヒクル=0.5%チロース溶液)または式(27)もしくは(3)による化合物(BAY41−2272またはBAY63−2521)の効果を試験した。Tsk−1マウスを麻酔し、創傷サイズを正確に定量化するために創傷を設定する3日前に慎重に剃毛した。動物の毎日の取り扱いによる創傷治癒への影響を避けるために、1日2回の胃管栄養処理を、食物中の薬物投与に置き換えた。マウスは、通常のマウス飼料(プラセボ)、または式(27)による化合物、(BAY41−2272)15ppmおよび45ppmを含有するマウス飼料、または式(3)による化合物、(BAY63−2521)5ppm、15ppmおよび45ppmを含有するマウス飼料をそれぞれ受けた。これらの投薬量は、適応DMPK試験によって確認されるように、それぞれ、式(27)による化合物、(BAY41−2272)1mg/kgおよび3mg/kg BIDならびに式(3)による化合物、(BAY63−2521)0.3mg/kg、1mg/kgおよび3mg/kg BIDと同様の曝露をもたらした。処理群は、1群あたり少なくとも8匹のtsk−1マウスからなる。剃毛の日に処理を開始して定常状態の曝露を達成した。剃毛の3日後、マウスを慎重に麻酔し、丸い創傷を直径4mmで打ち抜いた。打抜きの3日後、マウスを安楽死させ、創傷サイズを評価した。データの統計解析を、一方向ANOVA、引き続いてTuckeyの多重比較事後分析によって行った。
a)tsk−1マウスでの創傷治癒がWTマウスと比較して有意に弱まっている、
b)式(27)による化合物、(BAY41−2272)および/または式(3)による化合物BAY63−2521による処理によって、TSK−1マウスの創傷治癒が有意にかつ用量依存的に改善される
ことを示した。
Claims (2)
- メチル−4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニル(メチル)カルバメート(3)、メチル−{4,6−ジアミノ−2−[5−フルオロ−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]ピリミジン−5−イル}カルバメート(6)及び3−(4−アミノ−5−シクロプロピルピリミジン−2−イル)−1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン(27)からなる群から選択される少なくとも1つの化合物を含む、全身性硬化症および強皮症などの線維性疾患に付随する指潰瘍の患者の創傷治癒を促進するための組成物。
- メチル−4,6−ジアミノ−2−[1−(2−フルオロベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル]−5−ピリミジニル−(メチル)カルバメート(3)を含む、全身性硬化症および強皮症などの線維性疾患に付随する指潰瘍の患者の創傷治癒を促進するための組成物。
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IL255214A0 (en) | 2017-12-31 |
WO2016177660A1 (en) | 2016-11-10 |
TN2017000465A1 (en) | 2019-04-12 |
JP2018519259A (ja) | 2018-07-19 |
CN107580495A (zh) | 2018-01-12 |
CL2017002765A1 (es) | 2018-05-18 |
MX2017014057A (es) | 2018-04-10 |
BR112017023855A2 (pt) | 2018-07-17 |
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