JP6180420B2 - 増殖性疾患の治療のためのhsp90阻害剤と組み合わせた2−カルボキサミドシクロアミノウレア誘導体 - Google Patents
増殖性疾患の治療のためのhsp90阻害剤と組み合わせた2−カルボキサミドシクロアミノウレア誘導体 Download PDFInfo
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Description
本発明は、式(I)の2−カルボキサミドシクロアミノウレア誘導体化合物および熱ショックタンパク質90の阻害剤を含む医薬的な組合せ(pharmaceutical combination)、ならびに増殖性疾患、より具体的にはPI3K依存性疾患、より具体的にはPI3K−α依存性疾患の治療におけるこのような組合せの使用に関する。
PI3K/Akt/mTOR経路は、正常細胞のための重要で厳密に調節された生存経路である。ホスファチジルイノシトール3−キナーゼ類(PI3K)は、イノシトール脂質のD−3’位へのリン酸の移動を触媒して、ホスホイノシトール−3−リン酸(PIP)、ホスホイノシトール−3,4−二リン酸(PIP2)およびホスホイノシトール−3,4,5−三リン酸(PIP3)を生じさせる、広範に発現される脂質キナーゼである。これらのPI3Kで触媒される反応の産物は、セカンドメッセンジャーとして作用し、かつ細胞の成長、分化、移動、増殖および生存を含む鍵となる細胞内プロセスにおいて、中心的役割を有する。
本発明は、
(a)式(I)の化合物
Aは、
R1は、次の置換基:(1)非置換または置換された、好ましくは置換されたC1〜C7−アルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜9個の次の部分:重水素、フルオロ、または1〜2個の次の部分C3〜C5−シクロアルキルから独立に選択される、(2)必要に応じて置換されたC3〜C5−シクロアルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜4個の次の部分:重水素、C1〜C4−アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニルから独立に選択される、(3)必要に応じて置換されたフェニル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜2個の次の部分:重水素、ハロ、シアノ、C1〜C7−アルキル、C1〜C7−アルキルアミノ、ジ(C1〜C7−アルキル)アミノ、C1〜C7−アルキルアミノカルボニル、ジ(C1〜C7−アルキル)アミノカルボニル、C1〜C7−アルコキシから独立に選択される、(4)必要に応じてモノまたはジ置換されたアミン、ここで、前記置換基は、次の部分:重水素、C1〜C7−アルキル(これは、非置換であるか、重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1つまたは複数の置換基で置換されている)、フェニルスルホニル(これは、非置換であるか、1つまたは複数の、好ましくは1つのC1〜C7−アルキル、C1〜C7−アルコキシ、ジ(C1〜C7−アルキル)アミノ−C1〜C7−アルコキシで置換されている)から独立に選択される、(5)置換されたスルホニル、ここで、前記置換基は、次の部分:C1〜C7−アルキル(これは、非置換であるか、重水素、フルオロの群から選択される1つまたは複数の置換基で置換されている)、ピロリジノ(これは、非置換であるか、重水素、ヒドロキシ、オキソの群から選択される1つまたは複数の置換基、とりわけ1つのオキソで置換されている)から選択される、(6)フルオロ、クロロ、
のうちの1つを表し、
R2は、水素を表し、
R3は、(1)水素、(2)フルオロ、クロロ、(3)必要に応じて置換されたメチル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜3個の次の部分:重水素、フルオロ、クロロ、ジメチルアミノから独立に選択される、を表す]
であって、
ただし、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く、化合物、
またはその医薬的に許容される塩、および(b)少なくとも1種のHsp90阻害剤またはその医薬的に許容される塩を含む医薬的な組合せに関する。このような組合せは、増殖性疾患を治療するために、同時に、別個に、または逐次に使用することができる。
以下の一般的定義は、本発明のよりよい理解のために提供される:
「ハロゲン」(または「ハロ」)は、フッ素、臭素、塩素またはヨウ素、とりわけフッ素、塩素を意味する。ハロゲンで置換された基および部分、例えば、ハロゲンで置換されたアルキル(ハロアルキル)は、モノ−、ポリ−または過ハロゲン化されていてよい。
、およびそれらを含有する適切な医薬製剤は、国際公開第2010/029082号に記載されており、式(I)の化合物
Aは、
R1は、次の置換基:(1)非置換または置換された、好ましくは置換されたC1〜C7−アルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜9個の次の部分:重水素、フルオロ、または1〜2個の次の部分C3〜C5−シクロアルキルから独立に選択される、(2)必要に応じて置換されたC3〜C5−シクロアルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜4個の次の部分:重水素、C1〜C4−アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニルから独立に選択される、(3)必要に応じて置換されたフェニル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜2個の次の部分:重水素、ハロ、シアノ、C1〜C7−アルキル、C1〜C7−アルキルアミノ、ジ(C1〜C7−アルキル)アミノ、C1〜C7−アルキルアミノカルボニル、ジ(C1〜C7−アルキル)アミノカルボニル、C1〜C7−アルコキシから独立に選択される、(4)必要に応じてモノまたはジ置換されたアミン、ここで、前記置換基は、次の部分:重水素、C1〜C7−アルキル(これは、非置換であるか、重水素、フルオロ、クロロ、ヒドロキシからなる群から選択される1つまたは複数の置換基で置換されている)、フェニルスルホニル(これは、非置換であるか、1つまたは複数の、好ましくは1つのC1〜C7−アルキル、C1〜C7−アルコキシ、ジ(C1〜C7−アルキル)アミノ−C1〜C7−アルコキシで置換されている)から独立に選択される、(5)置換されたスルホニル、ここで、前記置換基は、次の部分:C1〜C7−アルキル(これは、非置換であるか、重水素、フルオロの群から選択される1つまたは複数の置換基で置換されている)、ピロリジノ(これは、非置換であるか、重水素、ヒドロキシ、オキソの群から選択される1つまたは複数の置換基、とりわけ1つのオキソで置換されている)から選択される、(6)フルオロ、クロロ、
のうちの1つを表し、
R2は、水素を表し、
R3は、(1)水素、(2)フルオロ、クロロ、(3)必要に応じて置換されたメチル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜3個の次の部分:重水素、フルオロ、クロロ、ジメチルアミノから独立に選択される、を表す]、
を含み、
ただし(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く。
式(I)の化合物の定義中で使用される基および記号は、参照によりその全体が本明細書に組み込まれる国際公開第2010/029082号において開示されている意味を有する。
(a)Sigma−Aldrich Co,LLC(ミズーリ州、St.Louis)から入手可能であり、参照により本出願に組み込まれる1981年4月14日付けの米国特許第4,261,989号に開示のゲルダナマイシン誘導体であるタネスピマイシン(17−アリルアミノ−17−デメトキシゲルダナマイシン)(KOS−953および17−AAGとしても知られている)、およびその他のゲルダナマイシン関連化合物;
(b)Sigma−Aldrich Co,LLC(ミズーリ州、St.Louis)から入手可能であるラディシコール;
(c)6−クロロ−9−(4−メトキシ−3,5−ジメチルピリジン−2−イルメチル)−9H−プリン−2−アミン・メタンスルホン酸(CNF2024としても知られている)(Conforma Therapeutics Corp.);
(d)IPI504;
(e)SNX5422;
(f)構造およびその製造方法について、参照により本出願に組み込まれる、2004年8月26日に公開のPCT出願国際公開第04/072051号に開示されている、5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922);および
(g)構造およびその製造方法について、参照により本出願に組み込まれる、2007年5月31日に公開の米国特許出願公開第2007−0123546号に開示されている、(R)−2−アミノ−7−[4−フルオロ−2−(6−メトキシ−ピリジン−2−イル)−フェニル]−4−メチル−7,8−ジヒドロ−6H−ピリド[4,3−d]ピリミジン−5−オン(HSP990);
ならびにこれらの医薬的に許容される塩が挙げられる。
実験は、処置開始時にほぼ8〜12週齢の雌性Hsd:無胸腺Nude−FoxN1nuヌードマウスで実施する。すべての動物は、Harlan(マサチューセッツ州、South Easton)から購入し、食餌および水へのアクセスを自由にしたフィルタートップ型マイクロアイソレーター・ケージ中に最適化された衛生状態下に収容される(ケージ当たり最大で5匹の動物)。
次の修正を加えて実施例1に記載の手順に従う:
500万個のHCG−27腫瘍細胞を移植して20日後の、平均腫瘍体積が316mm3(164〜485mm3)である時点で処置を開始する。動物には、(a)ビヒクル対照は、毎日10mL/kgの0.5%MCの経口投与、および週2回5mL/kgのD5Wの静脈内投与を受け入れる動物からなり、(b)週2回(2 q.w.)の静脈内での50mg/kgのAUY922、(c)1日1回(q.d.)経口での25mg/kgまたは50mg/kgのいずれかの化合物A、(d)週2回の静脈内での50mg/kgのAUY922と、1日1回の経口での25mg/kgの化合物Aとの組合せ、あるいは(e)週2回の静脈内での50mg/kgのAUY922と、1日1回の経口での50mg/kgの化合物Aとの組合せ、のいずれかを投与する。処置は14日間継続される。
実験は、処置開始時点でほぼ10〜12週齢の雌性Hsd無胸腺ヌード−nu CPBマウスで実施される。すべての動物は、Harlan(ドイツ、Winkelmann)から入手し、食餌および水へのアクセスを自由にしたMakrolon III型ケージ中に最適化された衛生状態下に収容する(ケージ当たり最大で5匹の動物)。
雌性無胸腺ヌードマウスを、1日1回の経口での50mg/kgの化合物Aの単独で、または週2回静脈内で投与される50mg/kgのAUY922と組み合わせて処置する。ビヒクル対照は、10mL/kgの5%グルコース水溶液の静脈内投与に加えて、NMP/PEG300/ソルトールHS15/水(10:30:20:40%v/v)の混合物の毎日の経口投与を受け入れる動物から構成される。
第2の有効性実験では、腫瘍モデルを第1の実験のように構成し、同一処置群を使用し、12.5mg/kgの用量での化合物Aの単剤で処置される1つの群に、AUY922(50mg/kg、静脈内で週2回)と組み合わせた同一用量の化合物Aで処置されるもう1つの群を加える。
− 12.5mg/kgで投与された化合物Aに関するClarke組合せ指標(Clarke combination index)=−0.11、
− 50mg/kgで投与された化合物Aに関する組合せ指標=−0.31。
第3の有効性実験では、腫瘍モデルを第2の実験のように構成する。
− 12.5mg/kgで投与された化合物Aに関するClarke組合せ指標=−0.45、
− 50mg/kgで投与された化合物Aに関する組合せ指標=−0.67。
実験は、処置開始時点でほぼ10〜12週齢の雌性Hsd無胸腺ヌード−nuCPBマウスで実施される。KYSE−70腫瘍は、食道扁平上皮細胞癌細胞である100μLの細胞懸濁液中の7.5×106個のKYSE−70細胞を23ゲージの注射針を用いて、マウスの右側腹部に皮下で注入することによって確立される。移植の10日後に腫瘍に達した。移植のほぼ10日後に腫瘍が確立され、約156mm3(最小86mm3、最大218mm3)に達したら、48匹の動物を選択し、6つの処置群(n=8)に無作為化する。
実験は、体重がほぼ20〜25gのHarlan雌性Hsd:Npa無胸腺ヌードマウスで実施される。A375腫瘍は、黒色腫細胞である4×106個のA375細胞をマウスの背部に皮下で注入することによって確立される。移植の10日後に腫瘍に達した。移植のほぼ30日後に、32匹の動物を選択し、4つの処置群(n=8)に無作為化する。
実験は、体重がほぼ20〜25gのHarlan雌性Hsd:Npa無胸腺ヌードマウスで実施される。A375腫瘍は、黒色腫細胞である4×106個のA375細胞をマウスの背部に皮下で注入することによって確立される。移植の10日後に腫瘍に達した。移植のほぼ30日後に、32匹の動物を選択し、4つの処置群(n=8)に無作為化する。
図9に示す。
本発明は、以下の態様を包含する。
[1]
(a)式(I)の化合物
[式中、
Aは、
からなる群から選択されるヘテロアリールを表し、
R 1 は、次の置換基:(1)非置換または置換された、好ましくは置換されたC 1 〜C 7 −アルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜9個の次の部分:重水素、フルオロ、または1〜2個の次の部分C 3 〜C 5 −シクロアルキルから独立に選択される;(2)必要に応じて置換されたC 3 〜C 5 −シクロアルキル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜4個の次の部分:重水素、C 1 〜C 4 −アルキル(好ましくはメチル)、フルオロ、シアノ、アミノカルボニルから独立に選択される;(3)必要に応じて置換されたフェニル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜2個の次の部分:重水素、ハロ、シアノ、C 1 〜C 7 −アルキル、C 1 〜C 7 −アルキルアミノ、ジ(C 1 〜C 7 −アルキル)アミノ、C 1 〜C 7 −アルキルアミノカルボニル、ジ(C 1 〜C 7 −アルキル)アミノカルボニル、C 1 〜C 7 −アルコキシから独立に選択される;(4)必要に応じてモノまたはジ置換されたアミン;ここで、前記置換基は、次の部分:重水素、C 1 〜C 7 −アルキル(これは、非置換であるか、重水素、フルオロ、クロロ、ヒドロキシの群から選択される1つまたは複数の置換基で置換されている)、フェニルスルホニル(これは、非置換であるか、1つまたは複数の、好ましくは1つのC 1 〜C 7 −アルキル、C 1 〜C 7 −アルコキシ、ジ(C 1 〜C 7 −アルキル)アミノ−C 1 〜C 7 −アルコキシで置換されている)から独立に選択される;(5)置換されたスルホニル;ここで、前記置換基は、次の部分:C 1 〜C 7 −アルキル(これは、非置換であるか、重水素、フルオロの群から選択される1つまたは複数の置換基で置換されている)、ピロリジノ(これは、非置換であるか、重水素、ヒドロキシ、オキソの群から選択される1つまたは複数の置換基、とりわけ1つのオキソで置換されている)から選択される;(6)フルオロ、クロロ;
のうちの1つを表し、
R 2 は、水素を表し、
R 3 は、(1)水素、(2)フルオロ、クロロ、(3)必要に応じて置換されたメチル、ここで、前記置換基は、1つまたは複数の、好ましくは1〜3個の次の部分:重水素、フルオロ、クロロ、ジメチルアミノから独立に選択される、を表す]
であって、
ただし、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({5−[2−(tert−ブチル)−ピリミジン−4−イル]−4−メチル−チアゾール−2−イル}−アミド)を除く、化合物
またはその医薬的に許容される塩、および
(b)少なくとも1種のHsp90阻害剤またはその医薬的に許容される塩
を含む医薬的な組合せ。
[2]
薬剤(a)が、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(「化合物A」)またはその医薬的に許容される塩から選択される、上記[1]に記載の医薬的な組合せ。
[3]
薬剤(b)が、ゲルダナマイシン誘導体であるタネスピマイシン(17−アリルアミノ−17−デメトキシゲルダナマイシン)(KOS−953および17−AAGとしても知られている);ラディシコール;6−クロロ−9−(4−メトキシ−3,5−ジメチルピリジン−2−イルメチル)−9H−プリン−2−アミン・メタンスルホン酸塩(CNF2024としても知られている);IPI504;SNX5422;5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922);および(R)−2−アミノ−7−[4−フルオロ−2−(6−メトキシ−ピリジン−2−イル)−フェニル]−4−メチル−7,8−ジヒドロ−6H−ピリド[4,3−d]ピリミジン−5−オン(HSP990)またはその医薬的に許容される塩から選択される、上記[1]に記載の医薬的な組合せ。
[4]
増殖性疾患の治療のための、同時、個別または逐次使用のための、上記[1]に記載の医薬的な組合せ。
[5]
増殖性疾患が、胃、肺および気管支、前立腺、乳房、膵臓、結腸、直腸、甲状腺、肝臓および肝内胆管、腎臓および腎盂、膀胱、子宮体、子宮頸部、卵巣、多発性骨髄腫、食道、急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、骨髄性白血病、脳、口腔および咽頭、喉頭、小腸、非ホジキンリンパ腫、黒色腫、または絨毛結腸アデノーマのがんである、上記[4]に記載の医薬的な組合せ。
[6]
上記[1]に記載の式Iの化合物またはその医薬的に許容される塩、および少なくとも1種のHsp90阻害剤またはその医薬的に許容される塩を含む、増殖性疾患の治療に使用するための医薬組成物。
[7]
増殖性疾患を治療するための医薬を調製するための、上記[1]に記載の医薬的な組合せの使用。
[8]
増殖性疾患が、胃、肺および気管支、前立腺、乳房、膵臓、結腸および直腸、甲状腺、肝臓および肝内胆管、腎臓および腎盂、膀胱、子宮体、子宮頸部、卵巣、多発性骨髄腫、食道、急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、骨髄性白血病、脳、口腔および咽頭、喉頭、小腸、非ホジキンリンパ腫、黒色腫、および絨毛結腸アデノーマである、上記[7]に記載の使用。
[9]
対象に治療有効量の上記[1]に記載の式(I)の化合物またはその医薬的に許容される塩、および少なくとも1種のHsp90阻害剤またはその医薬的に許容される塩を投与する工程を含む、治療を必要とする対象における増殖性疾患の治療方法。
[10]
増殖性疾患が、胃、肺および気管支、前立腺、乳房、膵臓、結腸および直腸、甲状腺、肝臓および肝内胆管、腎臓および腎盂、膀胱、子宮体、子宮頸部、卵巣、多発性骨髄腫、食道、急性骨髄性白血病、慢性骨髄性白血病、リンパ球性白血病、骨髄性白血病、脳、口腔および咽頭、喉頭、小腸、非ホジキンリンパ腫、黒色腫、および絨毛結腸アデノーマである、上記[9]に記載の増殖性疾患の治療方法。
[11]
式(I)の化合物が、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(化合物A)から選択される、上記[9]に記載の増殖性疾患の治療方法。
[12]
Hsp90阻害剤が、ゲルダナマイシン誘導体であるタネスピマイシン(17−アリルアミノ−17−デメトキシゲルダナマイシン)(KOS−953および17−AAGとしても知られている);ラディシコール;6−クロロ−9−(4−メトキシ−3,5−ジメチルピリジン−2−イルメチル)−9H−プリン−2−アミン・メタンスルホン酸塩(CNF2024としても知られている);IPI504;SNX5422;5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922);および(R)−2−アミノ−7−[4−フルオロ−2−(6−メトキシ−ピリジン−2−イル)−フェニル]−4−メチル−7,8−ジヒドロ−6H−ピリド[4,3−d]ピリミジン−5−オン(HSP990)から選択される、上記[9]に記載の増殖性疾患の治療方法。
[13]
式(I)の化合物およびHsp90阻害剤が、単一の医薬組成物として一緒に投与される、上記[9]に記載の方法。
[14]
式(I)の化合物およびHsp90阻害剤が、別個の組成物として、または逐次に投与される、上記[9]に記載の方法。
[15]
上記[1]に記載の式(I)の化合物またはその医薬的に許容される塩、および少なくとも1種のHsp90阻害剤またはその医薬的に許容される塩を併用投与することによって増殖性疾患を治療するための使用法を提供する添付文書またはラベルを含むキット。
Claims (7)
- (a)(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(化合物A)またはその医薬的に許容される塩、および
(b)5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922)であるHsp90阻害剤またはその医薬的に許容される塩
を含む、黒色腫を治療するための医薬的な組合せ製剤。 - 黒色腫を治療するための医薬を調製するための、請求項1に記載の医薬的な組合せ製剤の使用。
- 化合物Aまたはその医薬的に許容される塩およびHsp90阻害剤またはその医薬的に許容される塩が、単一の医薬組成物として医薬において一緒に投与される、請求項2に記載の使用。
- 化合物Aまたはその医薬的に許容される塩およびHsp90阻害剤またはその医薬的に許容される塩が、別個の組成物として、または逐次に、複数の医薬において投与される、請求項2に記載の使用。
- (1)化合物(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(化合物A)またはその医薬的に許容される塩と、
(2)使用法を提供する添付文書またはラベルと、
を含む、5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922)であるHsp90阻害剤またはその医薬的に許容される塩を併用投与することによって黒色腫を治療するためのキット。 - 黒色腫を治療するための医薬組成物であって、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(化合物A)またはその医薬的に許容される塩を含み、前記医薬組成物は、5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922)であるHsp90阻害剤またはその医薬的に許容される塩と組合せて使用される、医薬組成物。
- 黒色腫を治療するための医薬組成物であって、5−(2,4−ジヒドロキシ−5−イソプロピル−フェニル)−4−(4−モルホリン−4−イルメチル−フェニル)−イソキサゾール−3−カルボン酸エチルアミド(AUY922)であるHsp90阻害剤またはその医薬的に許容される塩を含み、前記医薬組成物は、(S)−ピロリジン−1,2−ジカルボン酸2−アミド1−({4−メチル−5−[2−(2,2,2−トリフルオロ−1,1−ジメチル−エチル)−ピリジン−4−イル]−チアゾール−2−イル}−アミド)(化合物A)またはその医薬的に許容される塩と組合せて使用される、医薬組成物。
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