JP2013536209A - レフルノミドおよびマロノニトリラマイドの新規の使用 - Google Patents
レフルノミドおよびマロノニトリラマイドの新規の使用 Download PDFInfo
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- JP2013536209A JP2013536209A JP2013525178A JP2013525178A JP2013536209A JP 2013536209 A JP2013536209 A JP 2013536209A JP 2013525178 A JP2013525178 A JP 2013525178A JP 2013525178 A JP2013525178 A JP 2013525178A JP 2013536209 A JP2013536209 A JP 2013536209A
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- spinal cord
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- A—HUMAN NECESSITIES
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
【選択図】なし
Description
I)レフルノミド II)テリフルノミド
III)HR325 IV)FK778/A
V)FK778/B VI)MNA279
さらに有利な実施形態において、化合物は、N−(4−トリフルオロメチルフェニル)−5−メチルイソオキサゾール−4−カルボキサミド、N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−クロトン酸アミド、1(3−メチル−4−トリフルオロメチルフェニル−カルバモイル)−2−シクロプロピル−2オキソ−プロピオノニトリルであり、N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−ヘプト−2−エン−6−イン−カルボン酸アミド、および、2−シアノ−3−シクロプロピル−3−オキソ−(4−シアノフェニル)プロピオンアミド、または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である。
Ν,Ν−ジベンジルエチレンジアミン、クロロプロカイン、コリン、ジエタノールアミン、エチレンジアミン、メグルマイン(N−メチルグルカミン)、リジン、およびプロカインを包含する。
A)レフルノミド(N−(4−トリフルオロメチルフェニル)−5−メチルイソオキサゾール−4−カルボキサミド)
B)A77−1726(テリフルノミド)(N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−クロトン酸アミド)
C)HR325(ラフルニムス)(1(3−メチル−4−トリフルオロメチルフェニル−カルバモイル)−2−シクロプロピル−2オキソ−プロピオノニトリル)
D)FK778(N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−ヘプト−2−en−6−in−カルボン酸アミド)
E)MNA279(2−シアノ−3−シクロプロピル−3−オキソ−(4−シアノフェニル)プロピオンアミド)
である。
ヒト被検者における本開示に係る化合物の臨床評価を裏付けるために、一連の非臨床の薬理学および毒性学の研究を行った。これらの研究は、研究設計についての国際的に認められたガイドラインに従って、且つ、特記しない限りは、医薬品最適研究基準(GLP)の要件を遵守して行われた。
ラットにおける重篤な脊髄挫傷損傷後の運動回復を向上するためのレフルノミド治療
<外科的方法>
生後13週のメスのルイスラット(Charles River, Sulzfeld Germany)を、12:12時間の暗/明措置の下に収容し、水および餌は自由にとらせた。1週間の順化の後、動物に、イソフルランと空気との混合物(導入:5%イソフルラン、維持:2.2%イソフルオラン)による全身麻酔を行った。硬膜を破裂させずにTh10椎弓切除術を行い、重症打撲SCI(25 gcm NYU/MASCIS II impactor){Gruner, 1992 #3}を誘発した。筋肉および皮膚を縫合した後、5mlの乳酸リンゲル液の皮下(s.c.)注射を与えた。自発的排尿が戻るまで(通常は1週間以内)、1日に2回手作業で膀胱を空にした。病変重症度を、インパクターの棒の衝撃速度および挫傷深度により検証した。衝撃速度誤差>5%であった動物は、更なる分析から排除した。損傷の後、個々のラットを、治療グループに無作為に割り当てた。以下のグループを使用した。
グループ2:SCI+7日間の強制経口投与によるビヒクルにおけるLEF(20mg/kg/日)
−BBBオープンフィールド運動評定尺度−
BBB運動評定尺度は、ラットにおける脊髄損傷後の機能回復を評価するために開発された「オープンフィールド運動スコア」である(Basso et al., 1995)。BBBスコアは、0点から21点で段階付され、0のBBBスコアは、後肢の完全な麻痺を表し、21のBBBスコアは、正常運動を表す。0点と21点との間に、機能回復のいくつかの「主要管理点」があり、重症挫傷損傷後の最も重要な主要管理点は、BBBスコア>9である。BBBスコア>9は、動物が、「体重支持足底足踏」または「歩行」のレベルに達したことを意味する。BBBスコア<9を有する動物は、歩くことができない。
プレキシグラスシリンダ(直径18cm×高さ35.0cm)に入れた場合、動物は自発的に立ち上がり、その前足が壁に接触する。立ち上がりの回数、持続期間、および種類をシリンダにおいて3分間記録した観察期間の間に分析した(Himes etal., 2006; Shumsky et al., 2003)。前足が常に見えるようにシリンダの後ろの角度に鏡を設置した。実験期間をビデオに収め、立ち上がり行動を後日無分別にスコア付けした。
−機能回復−
BBB運動評定尺度により評価されるような機能回復は、損傷後、最初の2〜3週間に亘って回復が進むパターンとなった。その後、自発的機能回復は、「定常状態」に達した。レフルノミド治療の顕著な効果は、DPO7日とDPO56日とに記録された。図1は、BBB運動評定尺度により評価した機能回復を示す。(*p<0.05)
実験の終了時に、レフルノミド治療動物は、ビヒクル対照に比べてよりよく行動した(マン・ホイットニーのU検定;p= 0.062、図2参照)。図2は、DPO63日でのレフルノミド治療動物とビヒクル治療動物との個々のBBBスコアを示す。
HR325(ラフルニムス)治療は、ラットにおける重症脊髄挫傷損傷後の運動回復を向上できる。
グループ2:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(20mg/kg/日)
BBBオープンフィールド運動評定尺度については実施例1を参照。
−機能回復−
BBB運動評定尺度により評価した通りの機能回復は、損傷後最初の2〜3週間に亘って回復が進むパターンとなった。その後、自発的機能回復は、「定常状態」に達した。しかしながら、HR325治療動物は、BBBスコアの10前後において定常状態に達したのに対し、ビヒクル治療動物は、BBBスコアの8.3で達した。この効果は、DPO7日からDPO63日での終了まで顕著であった(ANOVA-RM;治療F1;27=11,3 p=0.002)。図4は、BBB運動評定尺度により評価した通りの機能回復を示す(**p<0.01)。
様々な投薬によるHR325(ラフルニムス)治療は、ラットにおける重症脊髄挫傷損傷後の運動回復を向上することができる。
グループ2:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(3mg/kg/日)
グループ3:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(20mg/kg/日)
グループ4:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(60mg/kg/日)
BBBオープンフィールド運動評定尺度については、実施例1を参照。
−機能回復−
BBB運動評定尺度により評価される通りの機能回復は、先述の例と同様に、損傷後最初の2〜3週間に亘って回復が進むパターンとなった。その後、自発的な機能回復は、「定常状態」に達した。統計的に有意な差は、DPO56日に記録され、20mgのHR325治療動物は、ビヒクル治療動物よりも顕著によりよく行動した(one-way ANOVA;治療F2,40=4,45 p<0.05、図7参照)。DPO63日での実験の終了時に、BBBスコアにおける有意な差は依然として観察された(one-way ANOVA;治療F2,40=3,67 p<0.05、図7および図8を参照、*p<0.05)。
テリフルノミド治療は、ラットにおける重症脊髄挫傷損傷後の運動回復を向上できる。
グループ2:SCI+7日間の強制経口投与によるビヒクルにおけるテリフルノミド(3mg/kg/日)
グループ3:SCI+7日間の強制経口投与によるビヒクルにおけるテリフルノミド(10mg/kg/日)
BBBオープンフィールド運動評定尺度については、実施例1を参照。
−機能回復−
BBB運動評定尺度により評価される通りの機能回復は、先述の実施例と同様に、損傷後、最初の2〜3週間に亘って回復が進むパターンとなった。その後、自発的機能回復は、「定常状態」に達した。テリフルノミド治療動物とビヒクル対照動物との間の差は、先述の例に比べて比較的遅くに現れた。統計的に有意の差は、DPO49日で記録され、10mgテリフルノミド治療動物は、ビヒクル対照動物よりも顕著によりよく行動した(one-way ANOVA;治療F2,37=4,30 p<0.05、図10参照)。DPO63日での実験の終了時に、BBBスコアにおける有意な差は、以前として観察された(one-way ANOVA;治療F2,37=4,31 p<0.05、図10および図11参照)。実験全体を通して、3mgテリフルノミド治療動物は、ビヒクル対照動物と同等に行動した。
HR325(ラフルニムス)治療は、ラットにおける重症脊髄挫傷損傷後の運動回復を向上することができる。
グループ2:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(10mg/kg/日)
グループ3:SCI+7日間の強制経口投与によるビヒクルにおけるHR325(30mg/kg/日)
BBBオープンフィールド運動評定尺度については実施例1を参照。
−機能回復−
BBB運動評定尺度により評価された通りの機能回復は、先述の実施例と同様に、損傷後、最初の2〜3週間に亘って回復が進むパターンとなった。その後、自発的な機能回復は、「定常状態」に達した。HR325治療動物とビヒクル対照動物との間の差異は、DPO42日から実験の終了まで観察された。10mgのHR325治療動物は、DPO42日でビヒクル対照動物よりも明らかによりよく行動した(one-way ANOVA;治療F2,40=5,66 p<0.01、図12参照)。BBBスコアにおける10mgHR325治療動物とビヒクル対照との間のこの差は、実験の終了まで残った(one-way ANOVA;治療F2,40=5,80 p<0.01、図12および図13参照)。30mgHR325治療動物は、実験全体を通して、ビヒクル対照動物と同程度の行動をした。
以下のさらなる刊行物を、参照により本願に援用する。
Davis, J. P., et al.,1996. The immunosuppressive metabolite of leflunomide is a potent inhibitor ofhuman dihydroorotate dehydrogenase. Biochemistry. 35, 1270-3.
Greene, S., et al., 1995.Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agentleflunomide. Biochem Pharmacol. 50, 861-7.
Himes, B. T., et al., 2006. Recovery offunction following grafting of human bone marrow-derived stromal cells into theinjured spinal cord. Neurorehabil Neural Repair. 20, 278-96.
Kuo, E. A., et al., 1996.Synthesis, structure-activity relationships, and pharmacokinetic properties ofdihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ]propenamide and related compounds. J Med Chem. 39, 4608-21.
Shumsky, J. S., et al.,2003. Delayed transplantation of fibroblasts genetically modified to secreteBDNF and NT-3 into a spinal cord injury site is associated with limitedrecovery of function. Exp Neurol. 184, 114-30.
Williamson, R. A., et al., 1995. Dihydroorotatedehydrogenase is a high affinity binding protein for A77 1726 and mediator of arange of biological effects of the immunomodulatory compound. J Biol Chem. 270,22467-72.
Zielinski, T., et al.,1995. Leflunomide, a reversible inhibitor of pyrimidine biosynthesis? InflammRes. 44 Suppl 2, S207-8.
Claims (20)
- 中枢神経系外傷関連障害の治療において使用するための、化学式(I)
の化合物、または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体。 - 中枢神経系外傷関連障害の治療において使用するための、化学式(II)
の化合物、または、その薬学的に許容可能な塩、溶媒和物、立体異性体もしくは誘導体。 - 前記誘導体は、マロノニトリラマイドである
請求項2に記載の使用。 - 前記誘導体は、
i)(1(3−メチル−4−トリフルオロメチルフェニル−カルバモイル)−2−シクロプロピル−2オキソ−プロピオノニトリル)、
ii)N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−ヘプト−2−エン−6−イン−カルボン酸アミド、および
iii)2−シアノ−3−シクロプロピル−3−オキソ−(4−シアノフェニル)プロピオンアミドからなる群より選択されるか、
または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である
請求項2に記載の使用。 - 前記誘導体は、化学式IIIから化学式VIの以下の化合物:
からなる群より選択されるか、または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である
請求項2に記載の使用。 - 前記誘導体は、
または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である
請求項2に記載の使用。 - 前記化合物の前記立体異性体は、RまたはS鏡像異性体である
請求項1〜6のいずれか1項に記載の使用。 - 前記中枢神経系外傷関連障害は、完全脊髄損傷、不完全脊髄損傷、脊髄挫傷、脊髄圧迫、脊髄外傷、脊髄損傷、対麻痺、四肢麻痺(quadriplegia)、四肢麻痺(tetraplegia)、脊髄中心部症候群、ブラウン・セカール症候群、脊髄前部症候群、脊髄円錐症候群、馬尾症候群、外傷性脳損傷、TBI、脳損傷、脳ダメージ、頭部外傷、びまん性軸索損傷(DAI)、頭部外傷、脳振盪、脳挫傷、硬膜下血腫、硬膜外血腫、クモ膜下出血、脳内出血、またはCNS圧迫である
請求項1〜7のいずれか1項に記載の使用。 - 前記中枢神経系外傷関連障害は、脊髄損傷である、
請求項1〜7のいずれか1項に記載の使用。 - 前記中枢神経系外傷関連障害は、脊髄挫傷である
請求項1〜7のいずれか1項に記載の使用。 - 自由な形態で、または、薬学的に許容可能な塩もしくは生理学的に機能性の誘導体の形態で、請求項1に記載の化合物を含み、薬学的に許容可能な希釈剤または媒介物と共に、中枢神経系外傷関連障害の治療において使用するための医薬組成物。
- 自由な形態で、または、薬学的に許容可能な塩もしくは生理学的に機能性の誘導体の形態で、請求項2に記載の化合物を含み、薬学的に許容可能な希釈剤または媒介物と共に、中枢神経系外傷関連障害の治療において使用するための医薬組成物。
- 自由な形態で、または、薬学的に許容可能な塩もしくは生理学的に機能性の誘導体の形態で、請求項2に記載の化合物の誘導体である化合物を含み、薬学的に許容可能な希釈剤または媒介物と共に、中枢神経系外傷関連障害の治療において使用するための医薬組成物。
- 前記誘導体は、
i)(1(3−メチル−4−トリフルオロメチルフェニル−カルバモイル)−2−シクロプロピル−2オキソ−プロピオノニトリル)、
ii)N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−ヘプト−2−エン−6−イン−カルボン酸アミド、および
iii)2−シアノ−3−シクロプロピル−3−オキソ−(4−シアノフェニル)プロピオンアミドからなる群より選択されるマロノニトリラマイド、
または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である
請求項13に記載の医薬組成物。 - CNS外傷関連障害を予防および/または治療するための医薬組成物であって、
治療有効量のレフルノミドまたはその生理学的に機能性の誘導体を薬学的な許容可能な媒介物または賦形剤と混合して含む医薬組成物。 - CNS外傷関連障害を予防および/または治療するための医薬組成物であって、治療有効量のテリフルノミドまたはその誘導体を、薬学的な許容可能な媒介物または賦形剤と混合して含む医薬組成物。
- 前記誘導体は、
i)(1(3−メチル−4−トリフルオロメチルフェニル−カルバモイル)−2−シクロプロピル−2オキソ−プロピオノニトリル)、
ii)N−(4−トリフルオロメチル)−フェニル−2−シアノ−3−ヒドロキシ−ヘプト−2−エン−6−イン−カルボン酸アミド、および
iii)2−シアノ−3−シクロプロピル−3−オキソ−(4−シアノフェニル)プロピオンアミドからなる群より選択されるマロノニトリラマイド、
または、その薬学的に許容可能な塩、溶媒和物もしくは立体異性体である
請求項16に記載の医薬組成物。 - 前記枢神経系外傷関連障害は、完全脊髄損傷、不完全脊髄損傷、脊髄挫傷、脊髄圧迫、脊髄外傷、脊髄損傷、対麻痺、四肢麻痺(quadriplegia)、四肢麻痺(tetraplegia)、脊髄中心部症候群、ブラウン・セカール症候群、脊髄前部症候群、脊髄円錐症候群、馬尾症候群、外傷性脳損傷、TBI、脳損傷、脳ダメージ、頭部外傷、びまん性軸索損傷(DAI)、頭部外傷、脳振盪、脳挫傷、硬膜下血腫、硬膜外血腫、クモ膜下出血、脳内出血、またはCNS圧迫である
請求項11〜17のいずれか1項に記載の医薬組成物。 - 前記中枢神経系外傷関連障害は、脊髄損傷である
請求項11〜17のいずれか1項に記載の医薬組成物。 - 前記中枢神経系外傷関連障害は、脊髄挫傷である
請求項11〜17のいずれか1項に記載の医薬組成物。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |