JP7498504B2 - 脳神経または心臓保護剤としてのアミノチオール系化合物の使用 - Google Patents
脳神経または心臓保護剤としてのアミノチオール系化合物の使用 Download PDFInfo
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- JP7498504B2 JP7498504B2 JP2021573818A JP2021573818A JP7498504B2 JP 7498504 B2 JP7498504 B2 JP 7498504B2 JP 2021573818 A JP2021573818 A JP 2021573818A JP 2021573818 A JP2021573818 A JP 2021573818A JP 7498504 B2 JP7498504 B2 JP 7498504B2
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- Prior art keywords
- methylamino
- mercapto
- compound
- propanamide
- oxopropan
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- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
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Description
前記式(I)の化合物が、
ここで、
A1は、-C(O)NR8-、-S(O)2-NR8-、-S(O)NR8-、および-R7-NR8-から選択され、
A2は、カルボニル、スルホニル、スルフィニル、および置換または非置換のC1-6アルキルから選択され、
R1およびR5は、同一でも異なっていてもよく、水素、および置換または非置換のC1-C5アルキルまたはヘテロアルキルから選択され、
R2およびR6は、同一でも異なっていてもよく、置換または非置換のC1-C5アルキルまたはヘテロアルキルから選択され、
nは、0~20000の整数であり、
R3およびR4は、独立して、水素、X、および置換または非置換のC1-6アルキルから選択され、
Xは、F、Cl、BrおよびIから選択され、
R7は、置換または非置換のC1-C6アルキルから選択され、R8は、水素、および置換または非置換のC1-C6アルキルから選択され、
群(II)の化合物:(R)-2-(((R)-3-メルカプト-2-(メチルアミノ)プロピル)アミノ)-3-(メチルアミノ)プロパン-1-チオールまたはその塩酸塩(化合物1)、(R)-N-((R)-3-((2-メトキシプロパン-2-イル)チオ)-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2,2,3-トリメチルチアゾリジン-4-カルボキサミド(化合物2)および(R)-2,2,3-トリメチル-N-((6R,9R)-3,3,12,12-テトラメチル-6-(メチルカルバモイル)-8-オキソ-2,13-ジオキサ-4,11-ジチア-7-アザテトラデカン-9-イル)チアゾリジン-4-カルボキサミド(化合物3)、(R)-3-メルカプト-N-((R)-3-メルカプト-1-((2-(メチルアミノ)エチル)アミノ)-1-オキソプロパン-2-イル)-2-((2-(メチルアミノ)エチル)アミノ)プロパンアミド、(R)-N-((7R,10R)-6,9-ジオキソ-13,13,13-トリフェニル-7-(トリチルチオメチル)-12-チア-2,5,8-トリアザトリデカン-10-イル)-3-メルカプト-2-(2-(メチルアミノ)エチルアミノ)プロパンアミド、(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロパンアミドおよび(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-((R)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロピオンアミド)プロパンアミドである使用を提供する。
A1は、-C(O)NR8-、-S(O)2-NR8-、-S(O)NR8-、および-R7-NR8-から選択され、
A2は、カルボニル、スルホニル、スルフィニル、および置換または非置換のC1-6アルキルから選択され、
R1およびR5は、同一でも異なっていてもよく、水素、および置換または非置換のC1-C5アルキルまたはヘテロアルキルから選択され、
R2およびR6は、同一でも異なっていてもよく、置換または非置換のC1-C5アルキルまたはヘテロアルキルから選択され、
nは、0~20000の整数であり、
R3およびR4は、独立して、水素、X、および置換または非置換のC1-6アルキルから選択され、
Xは、F、Cl、BrおよびIから選択され、
R7は、置換または非置換のC1-C6アルキルから選択され、R8は、水素、および置換または非置換のC1-C6アルキルから選択される。
nは、0~2000の整数が好ましく、1~200の整数がより好ましく、1~200の整数がさらに好ましく、1~50の整数がなおさらに好ましく、1~10の整数(1、2、3、4、5、6、7、8、9、10を含む)がより好ましく、
好ましくは、R3およびR4は、独立して、水素、X、および置換または非置換のC1-3アルキルから選択され、より好ましくは、R3、R4は、独立して、水素、X、およびメチルから選択され、
好ましくは、Xは、F、およびClから選択され、より好ましくは、XはFであり、
好ましくは、R7は、置換または非置換のC1-C3アルキルから選択され、より好ましくは、R7はメチレンであり、
好ましくは、R8は、水素、および置換または非置換のC1-C3アルキルから選択され、より好ましくは、R8は、水素、メチル、およびエチルから選択され、さらに好ましくは、R8は、水素であり、
上記の化合物において、R3およびR4に直接に連結されたキラル炭素は、R配置またはS配置である。好ましくは、R3およびR4に直接に連結されたキラル炭素は、いずれもR配置である。
肺がん、胃がん、乳がん、直腸がん、鼻咽頭がんなど;
大腿骨壊死、前立腺炎、乳腺炎などの非細菌性炎症;
エリテマトーデス、乾癬、強皮症のような自己免疫疾患などの免疫疾患など;
関節炎、リウマチ、リウマトイドなどの変形性関節症;
白内障、硝子体混濁、緑内障、眼底黄斑変性症、若年性近視など;
糖尿病性腎症、糖尿病性眼病など;
鳥インフルエンザ感染症、敗血症、大腿骨頭壊死症、前立腺炎、乳腺炎、エリテマトーデス、乾癬、強皮症、関節炎、リウマチ、リウマトイド、白内障、硝子体混濁、緑内障、眼底黄斑変性症、若年性近視、ドライアイ症候群、糖尿病及びその合併症(糖尿病性腎症、糖尿病性眼疾患)、間質性肺疾患、特発性肺線維症、サルコイドーシス、慢性閉塞性肺疾患(COPD)、肺気腫、筋萎縮性側索硬化症(ALS)、シミ、シワ、腎移植における腎虚血再灌流障害、歯周炎、気管支喘息、アレルギー性喘息、閉塞性睡眠時無呼吸、痛み、術後筋痛、肥満、横隔膜機能障害機械的換気、サイトメガロウイルス感染、高脂血症、急性すい炎、膵臓線維症、肝炎、肝硬変、肝線維症、骨粗鬆症、ファンコニー貧血、末梢動脈閉塞性疾患、子宮外膜症、多嚢胞性卵巣症候群、精子無力症、急性高山病などの予防または治療にも用いられることができる。
実施例
健康で雄のSPFグレードのSDラット(体重250g~300g)を選択した。
選択したラットを以下のように群分けした(5群:A、B、C、D、E群、各群6匹のラット):
(1)ラットを麻酔し、頸部の皮膚を整え、体温を37±0.5℃に保った。
(2)頸部正中切開を行い、右総頸動脈、内頸動脈、外頸動脈を露出させた。6-0絹糸を用い、総頸動脈分岐部より4mmの外頸動脈遠位端を結紮し、別の6-0絹糸を外頸動脈に通し、総頸動脈分岐部の近くでスリップノットを結んだ。
(3)動脈クランプを使用して、総頸動脈をクランプした。総頸動脈分岐部から3mmの外頸動脈に小切開を入れ、1本の先端が処理された直径0.33mmのナイロン糸を小切開部から内頸動脈に挿入し、総頸動脈分岐部から約16±1mmの深さで中大脳動脈に内側に向かって挿入した。
(4)虚血後90minで糸栓子を除去し、6-0絹糸で外動脈近位端を結紮し、頸部の創を3-0絹糸で縫合し、創をバイタルヨードで消毒し、ラットを加熱パッドに乗せて覚醒後、恒温槽で飼育した。
(5)手術の24h後、ラットは神経機能を採点され、その後麻酔をかけられ、脳を採り、以下に述べるようにTTC (2,3,5-TripHenyltetrazolium chloride, sigma社)で染色された。
実験動物に対して、モデリングの前後で神経学的欠損の兆候を採点した。採点は、動物が麻酔から覚醒した24h後に実施され、得点が高いほど動物の行動障害が深刻であることを示しているLongaとBedersonの5段階評価に基づいている。
0点:神経損傷症状なし;
1点:反対側の前足を完全に伸ばすことができない;
2点:反対側へ旋回する;
3点:反対側にダンプする;
4点:自発的に歩くことができない、意識を失う。
ラットに麻酔をかけた後、ラットの脳組織を採取し、-20℃の冷蔵庫で30min凍結した。PBSで1% TTC(W/V)を準備し、TTCが溶解するまで37℃で水浴し、凍結した脳組織をスライスして10ml のTTC溶液に入れ、37℃の恒温で10minインキュベートした。脳組織を均一に染色するために時々脳スライスを回した。正常な脳組織は染色後は真っ赤になるが、梗塞部位はカラー画像では淡い白色に、または白黒画像では薄い白色に見える。また、梗塞面積の測定と統計解析には、ソフトウェアを使用した。
次の表は、各動物の行動学的採点と脳梗塞面積のデータをまとめたものである。
健康で雄のSPFグレードのSDラット(体重250g~300g)を選択した。
Conrol群:PBS
シスプラチン:5mg/kg ip
シスプラチン+化合物B群:5mg/kg ip+化合物B 200mg/kg ip、シスプラチン投与30min前に化合物Bを投与
シスプラチン+アミフォスチン群:5mg/kg ip+AMI 200mg/kg ip、シスプラチン投与30min前にAMIを投与
シスプラチン+化合物A群:5mg/kg ip+化合物A 800mg/kg po、シスプラチン投与30min前に化合物Aを投与
(1)実験で用いられるSDラットに対して、体重を測定し、ラベルを付け、3匹を1群として5群に均等に分けた。
(2)化合物B、化合物A、AMI群は、それぞれ予定濃度で投与30分後、それぞれシスプラチン群、化合物B群、化合物A群、アミフォスチン群にシスプラチン5mg/kgを、対照群にPBSを投与した。
(3)ラットに対して、毎日体重を測定して記録し、5日目にSDラットの内眼角から抗凝固チューブに採血した。
(4)各チューブから全血100 μLを採取し、SMARTerキットに入れて、全自動生化学分析装置(SMT-100V)に置き、全血中の血中クレアチニンおよび尿素窒素のレベルを測定した。
SDラットの体重の推移を図9に示す。SDラットにシスプラチンを単独で投与した場合、体重は著しく減少し、化合物Bを投与すると、体重は減少する代わりに増加し、シスプラチン群と比較して、化合物A群およびアンフォテリシン群のラットの体重は減少したものの、その減少程度はシスプラチン群より有意に優れており、これは化合物Bおよび化合物Aがラットにおけるシスプラチン誘発体重減少に対して一定の予防効果があることが示唆された。
表と図から、シスプラチンはラットの血液中のクレアチニンと尿素窒素のレベルを有意に増加させる一方、化合物A、化合物B、アンフォテリシンはいずれもシスプラチンによる血中クレアチニンと尿素窒素のレベルの増加を有意に抑え、ひいては化合物Bと化合物Aでもアンフォテリシンよりも若干活性が高いことがわかった。
C57雄マウスを、それぞれブランク対照群、照射群、化合物B(TFA)照射群、AMI照射群の4群にランダムに分け、照射30min前にすべて腹腔内注射により517mpK投与し、そして、16Gyの腹部放射線量で照射し、5日目に小腸組織を採取してHE染色を実施した。
冠動脈結紮の成功基準:心電図上、S-Tセグメントの上昇および/またはT波の増高が明らかであり、心外膜縫合部遠位端でチアノーゼが認められれば、冠動脈結紮は成功したことを判明した。
虚血後再灌流の成功基準:上昇したS-Tセグメントの50%以上が降下し、心外膜の色が元の色合いに戻った場合に、虚血後再灌流モデルが正常に構築されたことを示している。
実験的手術中の過度出血のモデル
虚血処理の前に、ラットは重度の不整脈を発症し、そのうちの67%が心室細動、心室粗動、心房細動、心房粗動、上室性頻拍、心室性頻拍、頻繁な心室性期外収縮、房室ブロック、束枝伝道ブロックを含む。
(1)モデル
(2)化合物B(iv)100mg/kg
(3)化合物A(iv)100mg/kg
(4)化合物A(経口)500mg/kg
(5)一硝酸イソソルビド注射剤(iv)1 mg/kg(臨床等価用量に相当)。
注:該実施例で用いられた化合物A、Bは、それらの塩酸塩形態であった。
モデル対照群に比べて、化合物B(iv)100mg/kg群、化合物A(iv)100mg/kg群、化合物A(経口)500mg/kg群を治療後、心筋梗塞範囲をそれぞれ25.2%(P<0.05)、24.5%(P<0.05)、28.5%(P<0.01)縮小することができ、一硝酸イソソルビド注射剤1mg/kg群の場合、25.5%(P<0.05)縮小することができた。各群と一硝酸イソソルビド注射剤群との間に有意差はなかった(P>0.05)。
モデル対照群に比べて、化合物B(iv)100 mg/kg群、化合物A(iv)100 mg/kg群、化合物A(経口)500 mg/kg群を治療後、心筋酵素LDHをそれぞれ22.2%(P<0.05)、19.9%(P<0.05)、25.8%(P<0.01)減少することができ、一硝酸イソソルビド注射剤1 mg/kg群の場合、22.4%(P<0.05)減少することができた。各群と一硝酸イソソルビド注射剤群との間に有意差はなかった(P>0.05)。結果を表2に示した。
Claims (13)
- 以下の疾患または状態:脳卒中;脳虚血再灌流障害;脳出血、心筋梗塞;ならびにショック療法、動脈バイパス術、血栓溶解療法、経皮経管冠動脈形成術、心臓外科体外循環、心肺脳蘇生術、または切断肢再移植および臓器移植に起因する虚血再灌流障害の1つ以上の予防または治療における使用のための医薬組成物であって、
当該医薬組成物が、式(I)の化合物、または以下の群(II)のいずれか1つから選択される化合物を含み、
式(I)の化合物が、
であるか、またはその立体異性体、もしくはその薬学的に許容される塩、および溶媒和物であり、
ここで、
A1は、-C(O)NR8-、-S(O)2-NR8-、-S(O)NR8-、および-R7-NR8-から選択され、
A2は、カルボニル、スルホニル、スルフィニル、および非置換のC1-6アルキルから選択され、
R1およびR5は、同一でも異なっていてもよく、水素、および非置換のC1-C5アルキルから選択され、
R2およびR6は、同一でも異なっていてもよく、非置換のC1-C5アルキルから選択され、
nは、0~10の整数であり、
R3およびR4は、独立して、水素、X、および非置換のC1-6アルキルから選択され、
Xは、F、Cl、BrおよびIから選択され、
R7は、非置換のC1-C6アルキルから選択され、R8は、水素、および非置換のC1-C6アルキルから選択され、
群(II)の化合物:(R)-2-(((R)-3-メルカプト-2-(メチルアミノ)プロピル)アミノ)-3-(メチルアミノ)プロパン-1-チオールまたはその塩酸塩(化合物1)、(R)-N-((R)-3-((2-メトキシプロパン-2-イル)チオ)-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2,2,3-トリメチルチアゾリジン-4-カルボキサミド(化合物2)、(R)-2,2,3-トリメチル-N-((6R,9R)-3,3,12,12-テトラメチル-6-(メチルカルバモイル)-8-オキソ-2,13-ジオキサ-4,11-ジチア-7-アザテトラデカン-9-イル)チアゾリジン-4-カルボキサミド(化合物3)、(R)-3-メルカプト-N-((R)-3-メルカプト-1-((2-(メチルアミノ)エチル)アミノ)-1-オキソプロパン-2-イル)-2-((2-(メチルアミノ)エチル)アミノ)プロパンアミド、(R)-N-((7R,10R)-6,9-ジオキソ-13,13,13-トリフェニル-7-(トリチルチオメチル)-12-チア-2,5,8-トリアザトリデカン-10-イル)-3-メルカプト-2-(2-(メチルアミノ)エチルアミノ)プロパンアミド、(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロパンアミドおよび(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-((R)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロピオンアミド)プロパンアミドである、医薬組成物。 - 前記式(I)の化合物が、(R)-3-メルカプト-N-((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミド、または(R)-3-メルカプト-N-((R)-3-メルカプト-1-(((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)アミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミドである、請求項1に記載の医薬組成物。
- 前記式(I)の化合物が、(R)-3-メルカプト-N-((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミドもしくはその薬学的に許容される塩、または(R)-3-メルカプト-N-((R)-3-メルカプト-1-(((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)アミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミドもしくはその薬学的に許容される塩である、請求項1に記載の医薬組成物。
- 前記式(I)の化合物が、(R)-3-メルカプト-N-((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミド トリフルオロ酢酸塩、または(R)-3-メルカプト-N-((R)-3-メルカプト-1-(((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)アミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミド トリフルオロ酢酸塩である、請求項1に記載の医薬組成物。
- 前記式(I)の化合物が、(R)-3-メルカプト-N-((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミド 塩酸塩、または(R)-3-メルカプト-N-((R)-3-メルカプト-1-(((R)-3-メルカプト-1-(メチルアミノ)-1-オキソプロパン-2-イル)アミノ)-1-オキソプロパン-2-イル)-2-(メチルアミノ)プロパンアミド 塩酸塩である、請求項1に記載の医薬組成物。
- 前記医薬組成物が、脳卒中の予防または治療に用いられる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、虚血性脳卒中または出血性脳卒中の予防または治療に用いられる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、急性虚血性脳卒中に用いられる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、心筋虚血、または心筋虚血に起因する心筋梗塞または心脳虚血再灌流障害の予防または治療に用いられる、請求項1に記載の医薬組成物。
- 前記医薬組成物が、脳出血または脳血栓症の後遺症の予防または治療に用いられる、請求項1に記載の医薬組成物。
- 前記医薬組成物中の式(I)の化合物または群(II)の化合物の用量が、約9~16200mg/kg/日である、請求項1~10のいずれか1項に記載の医薬組成物。
- (R)-N-((R)-3-((2-メトキシプロパン-2-イル)チオ)-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2,2,3-トリメチルチアゾリジン-4-カルボキサミド、(R)-2,2,3-トリメチル-N-((6R,9R)-3,3,12,12-テトラメチル-6-(メチルカルバモイル)-8-オキソ-2,13-ジオキサ-4,11-ジチア-7-アザテトラデカン-9-イル)チアゾリジン-4-カルボキサミド、(R)-3-メルカプト-N-((R)-3-メルカプト-1-((2-(メチルアミノ)エチル)アミノ)-1-オキソプロパン-2-イル)-2-((2-(メチルアミノ)エチル)アミノ)プロパンアミド、(R)-N-((7R,10R)-6,9-ジオキソ-13,13,13-トリフェニル-7-(トリチルチオメチル)-12-チア-2,5,8-トリアザトリデカン-10-イル)-3-メルカプト-2-(2-(メチルアミノ)エチルアミノ)プロパンアミド、(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロパンアミドおよび(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-((R)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロピオンアミド)プロパンアミドから選択される、化合物またはその医薬上許容される塩。
- 放射線障害または化学療法剤損傷の治療および/または予防のための医薬組成物であって、当該医薬組成物が、以下の群(II)のいずれか1つから選択される化合物を含み、
群(II)の化合物:(R)-N-((R)-3-((2-メトキシプロパン-2-イル)チオ)-1-(メチルアミノ)-1-オキソプロパン-2-イル)-2,2,3-トリメチルチアゾリジン-4-カルボキサミド(化合物2)、(R)-2,2,3-トリメチル-N-((6R,9R)-3,3,12,12-テトラメチル-6-(メチルカルバモイル)-8-オキソ-2,13-ジオキサ-4,11-ジチア-7-アザテトラデカン-9-イル)チアゾリジン-4-カルボキサミド(化合物3)、(R)-3-メルカプト-N-((R)-3-メルカプト-1-((2-(メチルアミノ)エチル)アミノ)-1-オキソプロパン-2-イル)-2-((2-(メチルアミノ)エチル)アミノ)プロパンアミド、(R)-N-((7R,10R)-6,9-ジオキソ-13,13,13-トリフェニル-7-(トリチルチオメチル)-12-チア-2,5,8-トリアザトリデカン-10-イル)-3-メルカプト-2-(2-(メチルアミノ)エチルアミノ)プロパンアミド、(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロパンアミドおよび(R)-N-((R)-3,3-ジメチル-7-オキソ-2-オキサ-4-チア-8,11-ジアザドデカン-6-イル)-3-(2-メトキシプロパン-2-イルチオ)-2-((R)-3-(2-メトキシプロパン-2-イルチオ)-2-(2,2,3-トリメチルイミダゾリジン-1-イル)プロピオンアミド)プロパンアミドである、医薬組成物。
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