JP4523154B2 - Use of cyclosporines in the treatment of inflammatory autoimmune diseases - Google Patents
Use of cyclosporines in the treatment of inflammatory autoimmune diseases Download PDFInfo
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- JP4523154B2 JP4523154B2 JP2000551796A JP2000551796A JP4523154B2 JP 4523154 B2 JP4523154 B2 JP 4523154B2 JP 2000551796 A JP2000551796 A JP 2000551796A JP 2000551796 A JP2000551796 A JP 2000551796A JP 4523154 B2 JP4523154 B2 JP 4523154B2
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Description
【０００１】
本発明は、サイクロスポリン(cyclosporins)の類の新規使用、および、特に、非免疫抑制性、シクロフィリン結合サイクロスポリン類の新規薬学的使用に関する。
【０００２】
非免疫抑制性、シクロフィリン結合サイクロスポリン類ならびにAIDSおよびAIDS−関連疾患の処置および予防におけるそれらの使用は、欧州特許第４８４２８１号に記載され、それはサイクロスポリンのクラスの化合物、それらの命名法および作用形態の一般的記載を含む。EP0,484,281Bの記載、特に、上記に関する一般的記載および以下に関連する記載の他の部分を、本発明の教示に引用して包含させる。
【０００３】
驚くべきことに、シクロフィリンに結合するが、免疫抑制性ではないサイクロスポリン類が炎症性自己免疫疾患およびその状態に阻害作用を示すことが判明した。
【０００４】
サイクロスポリン化合物は、Quesniaux, Eur. J. Immunol. 1987, 17, 1359-1365に記載の競合ELISA試験において、シクロスポリン(Ciclosporin)(サイクロスポリンＡとも呼ぶ)と同様に、その少なくとも５分の１がヒト組換えシクロフィリンに結合する場合に、シクロフィリンに結合すると考えられる。本試験において、試験するサイクロスポリン化合物を、シクロフィリンの被覆ＢＳＡ−シクロスポリンとのインキュベーション中に添加し、競合剤なしでコントロール反応の５０％阻害をもたらすのに必要な濃度を計算する(ＩＣ50)。結果は結合比(ＢＲ)として示し、これは試験化合物のＩＣ50と、試験するサイクロスポリンの代わりにシクロスポリンを使用した同様の試験のＩＣ50の比率の基底１０に対する対数である。即ち、１.０のＢＲは、試験化合物がシクロフィリンにシクロスポリンよりも１×１０倍低く結合することを示し、負の値はシクロスポリンよりも強い結合を示す。
【０００５】
炎症性自己免疫疾患の阻害剤として働くサイクロスポリンは、０.７より低いＢＲ(log10５＝約０.７のため)を有し、好ましくは０かそれ以下である。
【０００６】
サイクロスポリンは、混合リンパ球反応(ＭＲＬ)においてシクロスポリンよりも５％より多くない、好ましくは２％より多くない活性を有するとき、非免疫抑制性であるとみなされる。混合リンパ球反応は、T. Meo "Immunological Methods", L. Lefkovits and B. Peris, Eds., Academic Press, N.Y. pp. 227-239 (1979)により記載されている。Balb/cマウス(雌、８−１０週齢)からの脾臓細胞(０.５×１０6)を、５日間、ＣＢＡマウス(雌、８−１０週齢)由来の０.５×１０6照射(２０００ラド)またはマイトマイシンＣ処理脾臓細胞と共インキュベートする。照射同種異系細胞はBalb/c脾臓細胞に増殖反応を誘発し、それはＤＮＡに取りこまれる標識前駆体により測定できる。刺激細胞が照射(またはマイトマイシンＣ処理)されているため、それらはBalb/c細胞に増殖により応答しないが、抗原性は保持する。ＭＲＬにおける試験化合物で見られるＩＣ50を、平行実験でシクロスポリンで見られたものと比較する。
【０００７】
上記ＭＬＲで非免疫抑制性と判断された化合物が、しばしば、IL-2 Reporter Gene Assayで不活性であり、したがって、IL-2 Reporter Gene Assayを、本発明で使用するための非免疫抑制性、シクロフィリン結合サイクロスポリン化合物の選択、例えば、一次スクリーニングに使用し得る。
【０００８】
炎症性自己免疫状態の阻害剤として活性な非免疫抑制性、シクロフィリン結合サイクロスポリン化合物を、以後、活性化合物と呼ぶ。
【０００９】
活性化合物は、特に、自己免疫疾患および炎症状態、特に、関節炎(たとえば、関節リウマチ、慢性進行性関節炎および変形性関節炎)およびリウマチ疾患のような、病因が自己免疫要素を含む炎症性状態の処置、予防、または軽減に有用である。活性化合物を用い得る具体的自己免疫疾患は、自己免疫血液学的疾患(例えば、溶血性貧血、無形成性貧血、真正赤血球性貧血および特発性血小板減少症)、全身性エリテマートーデス、ポリコンドリティス、スクレロドーマ、ヴェグナー肉芽腫症、皮膚筋炎、慢性活動性肝炎、重症筋無力症、乾癬、スティーブン−ジョンソン症候群、特発性スプルー、自己免疫性炎症性大腸疾患(例えば、潰瘍性大腸炎およびクローン病を含む)、膵臓炎、内分泌性眼科疾患、グレーヴズ病、サルコイドーシス、多発性硬化症、原発性胆汁性肝硬変、糖尿病、例えば、若年性糖尿病(Ｉ型糖尿病)、ブドウ膜網膜炎(uveoretinitis)(ベーチェット病)、ブドウ膜炎(前部および後部)、乾性角結膜炎およびを春季角結膜炎、間質性肺繊維症、乾癬性関節炎および糸球体腎炎(ネフローゼ症候群ありおよびなし、例えば、特発性ネフローゼ症候群または最小変化ネフローゼを含む)、喘息および自己免疫要素を含む他の炎症性気道疾患、甲状腺炎(橋本Ghoto病)、脳脊髄炎、中枢神経系の炎症性状態および類似の自己免疫疾患を含む。
【００１０】
サイクロスポリンの炎症性自己免疫状態の阻害剤としての活性は、以下の試験系で証明し得る：
実験的自己免疫ブドウ膜炎
雌ルイスラット、１２週齢(ＢＲＬ、Basel)に右足肉趾に５０μgの精製ウシ網膜Ｓ−抗原を注射する。抗原をリン酸緩衝化食塩水で希釈し、フロインド完全アジュバントおよびBactgo M Tuberculosis H37 RA(DiFco)で５０：５０(v/v)に乳化する。注射する用量は０.１mlであり、５０μl完全アジュバントおよび１.１４mg Mycobacterium tuberculosisを含む。注射１０日後に開始して、目を毎日細隙灯を使用して検査する。目の炎症の程度を、０−４のスケールを使用した半定量的方法で採点する：
０ 可視的変化なし
１ 脈管構造にわずかな変化、虹彩および結膜血管の一定の拡張
２ 中程度の変化、血管透明性の欠失、拡張した虹彩および血管、濁った中膜
３ 著しい変化、目の突出、濁った瞳孔、血管構造の明らかな損失、一定の凝血
４ 重篤な変化、著しい目の突出、構造の完全な損失、拡散した凝血
参考文献：Wacker W. B., Donoso L. A., Kalsow C. M., Yakeelov J. A. Jr., Organisciak D. T.: Experimental Allergic Uveitis. Isolartion, Characterisation and Locallization of a soluble Uveitopathogenic antigen from bovine retina. J. Immunol. 119 (1977) 1949-1958
【００１１】
ラットにおける実験的自己免疫脳脊髄炎(ＥＡＥ)
雄ウィスターラットに、後足にウシ脊髄および完全フロインドアジュバントの混合物を注射する。疾病の症状(尾および両後足の麻痺)が通常１６日以内に発症する。疾病の動物の数および疾病の発症の時間を記録する。上記試験モデルにおける疾病発症の阻害は薬学的有用性の指標である。
参考文献：Levine et al., Am. J. Path. 47 (1965) 61; McFarlin et al., J. Immunol. 113 (1974) 712; Borel, Transplant. & Clin. Immunol. 13 (1981) 3]。
【００１２】
フロインドアジュバント誘発関節炎
ＯＦＡおよびウィスタ−ラット(雄または雌、体重１５０ｇ)に、尾の付け根または後足に、０.６mgの凍結乾燥加熱殺菌Mycobacterium smegmatisを含む０.１mlのミネラル油をi.c.注射する。関節炎の発症のモデルにおいて、処置をアジュバント注射直後に開始する(日１−１８)；確立した関節炎モデルにおいて、処理を、２次炎症が十分に発症した１４日目に開始する(日１４−２０)。実験の最後に、関節の腫脹をマイクロキャリパーの手段で測定する。開発中のまたは確立したテストモデルにおいて、疾患進行の予防または阻害は薬学的有用性の指標である。
参考文献：Winter & Nuss, Arthritis and Rheumatism 9 (1966) 394; Billingham & Davies, Handbook of Experimental Pharmacology (Vane & Ferreira Eds, Springer Verlag, Berlin) 50/II, (1979) 108-144]
【００１３】
コラーゲン誘発関節炎
ラットを、尾の付け根の回りに皮内投与したタイプIIコラーゲンで免疫化する。１０−１２日後、関節炎の発症が起こり、紅斑および関節の腫脹により類型化する。動物の、通常、二つの異なる投与量の１日２回の試験化合物のp.o.による処置を腫脹の発症の直後に開始し、１０日まで続ける。コントロール関節炎動物および登録商標COX阻害剤で処理するラットを実験に包含させる。後足の腫脹を定期的に評価する。実験の最後に、動物を殺し、関節を組織学的パラメーターの評価のために調製する。腫脹の良好な阻害、例えば、登録商標COX阻害剤の約５０％またはそれ以上の効果を示す試験化合物を更なる実験のために選択する。
【００１４】
インビトロ走化性(例えば、ボイデンチャンバーを使用した)およびシクロフィリン誘発好中球浸潤および類似のアッセイも使用し得る。
多くの活性化合物が、シクロスポリンと、特に４および／または５位で異なる構造を有することが判明した。活性化合物の構造がシクロスポリンのものと異なり得る他の位置は６位および７位である。
【００１５】
活性化合物の他のグループは、４位のMeLeu基が異なるＮ−メチル化アミノ酸、例えば、γ−ヒドロキシ−MeLeu、MeIle、MeVal、MeThr、MeAla、MeTyrまたはMeTyr(O-PO(OH)2)またはProで置換されているサイクロスポリン類である。MeIleおよびMeThrに加えて、アロ形のMeaIleおよびMeaThrも使用し得る。アロ形において、β位の立体化学は、天然アミノ酸ものと逆の配置になっており、正常形およびアロ形はジアステレオ異性体の対を成す。
【００１６】
活性化合物の更なるグループは、５位のValがＮ−アルキル−、好ましくはＮ−メチル−、アミノ酸で置換されているものである。好ましくは、Ｎ−アルキル化されているアミノ酸はValまたはLeuである。好ましくは、[Val]５ のイミノ基の水素は非分枝鎖Ｃ１−６アルキル基、好ましくはメチル、エチル、またはｎ−プロピル、特にメチルで置換されている。後者の活性化合物の好ましいグループは全て新規である。
【００１７】
加えてまたは代替として、ある活性化合物は、シクロスポリンと１、２、３および／または６位が異なり得る。
【００１８】
本発明で使用する活性化合物の特定のクラスは、式Ａ
【化５】
【化６】
ｂは４位におけるＣ残基への結合を意味する；
Alkは２から６個の炭素原子を含む直鎖または分枝鎖アルキレンまたは３から６個の炭素原子を含むシクロアルキレン、および
Ｒは
カルボキシまたはアルキルオキシカルボニル残基；
基−ＮＲ１Ｒ２
(式中、Ｒ１およびＲ２は同じまたは異なって水素、アルキル、Ｃ２−４アルケニル、Ｃ３−６シクロアルキル、フェニル(所望によりハロゲン、アルコキシ、アルコキシカルボニル、アミノ、アルキルアミノまたはジアルキルアミノで置換されていてもよい)またはベンジルまたは、５または６個の環原子および１から３個のヘテロ原子を含む飽和または不飽和へテロ環式基、またはＲ１およびＲ２は、それらが結合している窒素原子と共に４から６個の環原子を含み、所望により窒素、酸素または硫黄からなる群から選択される更なるヘテロ原子を含んでいてもよく、所望によりアルキル、フェニルまたはベンジルで置換されていてもよい飽和または不飽和ヘテロ環を意味する)；
式
【化７】
および、式中、アルキルは、１から４個の炭素原子を含む直鎖または分枝鎖アルキルを意味する。
の基〕
のアミノ酸残基である；
ＣはMeLeuまたは４−ヒドロキシ−MeLeuである]
のシクロスポリン誘導体およびその薬学的に許容される塩である。
【００１９】
このクラスのシクロスポリン誘導体は、更に、公開国際特許出願WO98/28328、WO98/28329およびWO98/28330に記載されている。このクラスの特に好ましい化合物は、式中Ｂがアミノ酸残基Ｂ'
【化８】
【００２０】
活性化合物の特に好ましいグループは、式Ｉ：
【化９】
ＸはαAbu、Val、Thr、NvaまたはＯ−メチルスレオニン(MeOThr)；
ＲはSarまたは(Ｄ)−MeAla；
ＹはMeLeu、γ−ヒドロキシ−MeLeu、MeIle、MeVal、MeThr、MeAla、MeTyr、MeTyr(O-PO(OH)２ )、MeaIleまたはMeaThrまたはPro；
ＺはVal、Leu、N-Alk-ValまたはN-Alk-Leu
(式中、AlkはMeまたは、所望によりフェニル、または６環員を含むＮ、ＳまたはＯヘテロアリール、または所望によりハロゲンで置換されていてもよいフェニルで置換されていてもよいビニルで置換されているMeである) および、
ＱはMeLeu、γ−ヒドロキシ−MeLeuまたはMeAlaである〕
の化合物およびその薬学的に許容される塩から成る。
【００２１】
基Ｗ、Ｘ、Ｙ、ＺおよびＱは、独立して以下の好ましい意味を有する：
Ｗは好ましくはＷ'であり、Ｗ'はMeBmtまたはジヒドロ−MeBmtである；
Ｘは好ましくはＸ'であり、Ｘ'はαAbuまたはNvaであり、より好ましくはＸ"であり、Ｘ"はαAbuである；
Ｙは好ましくはＹ'であり、Ｙ'はγ−ヒドロキシ−MeLeu、MeVal、MeThr、MeAlaまたはMeTyr(O-PO(OH)２)である；
Ｚは好ましくはＺ'であり、Ｚ'はValまたはMeValである；そして
Ｑは好ましくはＱ'であり、Ｑ'はMeLeuである。
【００２２】
活性化合物の一つの特に好ましいグループは、式中、ＷがＷ'、ＸがＸ'、ＹがＹ'、ＺがＺ'およびＱがＱ'である式Ｉの化合物である。
【００２３】
特に好ましい式Ｉの活性化合物は：
ａ)[ジヒドロ−MeBmt]1−[γ−ヒドロキシ−MeLeu]4−シクロスポリン、
ｂ)[MeVal]4−シクロスポリン、
ｃ)[MeIle]4−シクロスポリン、
ｄ)[MeThr]4−シクロスポリン、
ｅ)[γ−ヒドロキシ−MeLeu]4−シクロスポリン、
ｆ)[Nva]2−[γ−ヒドロキシ−MeLeu]4−シクロスポリン、
ｇ)[γ−ヒドロキシ−MeLeu]4−[γ−ヒドロキシ−MeLeu]6−シクロスポリン、
ｈ)[MeVal]5−シクロスポリン、
ｉ)[MeOThr]2−[(D)MeAla]3−[MeVal]5−シクロスポリン、
ｊ)[８'−ヒドロキシ−MeBmt]1−シクロスポリン、
ｋ)[MeAla]6−シクロスポリン、
ｌ)[DMeAla]3−[MeTyr(OPO(OH)2)]4−シクロスポリン、
ｍ)[Ｎ−ベンジル−Val]5−シクロスポリン、
ｎ)[Ｎ−５−フルオロ−ベンジル−Val]5−シクロスポリン、
ｏ)[Ｎ−アリル−Val]5−シクロスポリン、
ｐ)[Ｎ−３−フェニル−アリル−Val]5−シクロスポリン、
ｑ)[Pro]4−シクロスポリンである。
【００２４】
特に好ましい活性化合物は、[MeIle]4−シクロスポリンおよび[γ−ヒドロキシ−MeLeu]4−シクロスポリン、最も特には[MeIle]4−シクロスポリンである。
式Ｉの化合物に加えて、好ましい活性化合物は、例えば
ｒ)[γ−ヒドロキシ−MeLeu]9−シクロスポリンを含む。
【００２５】
活性化合物は：
１)発酵
２)バイオトランスフォーメーション
３)誘導体化
４)部分合成
５)全合成
を含む方法により得られ得る。
【００２６】
これらの方法は、EP0484281Bの実施例１から１０に一般的におよびより具体的に記載される。この一般的記載およびこれらの実施例の教示は、本発明に引用して包含させる。EP0484281Bの実施例１１は、シクロスポリンに対する代表的活性化合物の免疫抑制およびシクロフィリン結合活性の測定を記載し、この実施例の教示もまた本発明の記載に包含させる。
【００２７】
活性化合物は、患者の炎症性自己免疫状態および疾患の予防および処置の両方への使用が指示される。
このように、本発明は、炎症性自己免疫疾患または状態の処置または予防のための医薬の製造における非自己免疫、シクロフィリン結合サイクロスポリンの使用を提供する。
【００２８】
本発明は、更に、有効量の本発明の活性化合物を投与することを含む、炎症性自己免疫状態および疾患の、このような疾患または状態に罹患しているまたは危険のある患者の処置または予防のための方法を提供する。
【００２９】
活性化合物は、慣用の経路で、特に、経腸的に、例えば、経口的に、例えば、飲用溶液、錠剤またはカプセルの形で、または非経腸的に、例えば、注射用溶液または懸濁液の形で投与し得る。静脈内経路により指示される一日量は１から２０mg／kg、好ましくは３から１０mg／kg、経口投与では１から５０mg／kg、好ましくは１０から３０mg／kgであり得る。
【００３０】
活性化合物の毒性は、シクロスポリンより低いと考えられる。活性化合物が免疫抑制性でないため、免疫抑制に関連するシクロスポリンの副作用は避けられる。シクロスポリンに付随する他の副作用、特に長期間使用による腎臓毒性および中枢神経系毒性は、簡便にはシクロスポリンより低い。
【００３１】
活性化合物は、炎症性自己免疫疾患の処置および予防に、単独でまたは他の治療剤、例えば、抗炎症性化合物および／または免疫抑制化合物と組合わせて使用し得る。特に好ましい態様において、活性化合物は、カルシニューリン活性を阻害しない免疫抑制性、シクロフィリン結合化合物の最近同定されたクラスであるサングリフェーリンと組合わせて使用する。サングリフェーリン、および、これらの調製の方法は、ＷＯ９７０２２８５およびＷＯ９８０７７４３に記載されている。活性化合物と組合わせた使用に特に好ましいサングリフェーリンは、サングリフェーリンAからL、特にサングリフェーリンA、B、CおよびDである。
【００３２】
このように、好ましい態様において、本発明は、有効量の本発明の活性化合物およびサングリフェーリンを含む組合わせを投与することを含む、炎症性自己免疫状態および疾患の、このような疾患または状態に罹患しているまたは危険のある患者の処置または予防のための方法を提供する。
【００３３】
本発明は、本発明の活性化合物およびサングリフェーリンを含む、例えば、炎症性自己免疫疾患または状態の処置または予防のための医薬組成物も提供する。 本発明の医薬組成物は、簡便には治療における同時、別々または連続した使用のための組合わせ製剤の形である。このように、活性化合物およびサングリフェーリンは、固定された組成物の形で一緒に投与し得、または別々に異なる時間に投与し得る。典型的に、組成物は有効量の組合わせ製剤を含む単位投与形であり得る。
【００３４】
活性剤のための好ましいガレヌス製剤は、局所および経口形を含む、英国特許出願第2222770Aに記載のようなマイクロエマルジョンに基づくものである；また英国特許出願第2209671Aに記載のような、脂肪酸サッカライドモノエステル、例えば、サッカロースモノラウレートを含む固体溶液から得る経口および注射用形を含む。経口投与用の適当な単位投与形は、例えば、調剤当たり２５から２００mgの活性化合物を１回量当たりに含む。
【００３５】
EP0484281Bの製剤実施例Ａ、Ｂ、ＣおよびＤは引用して本明細書に包含させる：
これらの製剤の個々の成分およびその製造法は、その内容を本明細書に引用して包含させる英国特許出願2222770に完全に記載されている。
【００３６】
活性化合物を他の化合物、例えば、サングリフェーリンと共に投与する場合、活性剤と他の化合物の適当な比率の類似の製剤を使用し得る。このように、例えば、活性化合物とサングリフェーリンは、好ましくは、投与量当たり約１０から約１００mg／kgの活性化合物で、約５：１から約５０：１(活性化合物po：サングリフェーリン sc)の範囲の重量比で使用する。
【００３７】
代表的活性化合物の活性は、動物モデル生物学的活性アッセイＡ、ＢおよびＣで試験し、これは添付の図面を参照する：
図１は、免疫化９−１８日後(ｘ軸)のコントロール動物(Ａ．黒色棒)および[MeIle]4−Cs処理動物(Ｂ．灰色棒)に関するＥＡＥにおける疾病得点(ｙ軸)のグラフである；
図２はＡ．−３０mg／kg [MeIle]4−Cs p.o.；Ｂ．１mg／kg サングリフェーリン A s.c.；およびＣ． −３０mg／kg [MeIle]4−Cs p.o.＋１mg／kg サングリフェーリン A s.c.で処置した動物のグループのアジュバント関節炎アッセイの発症における腫脹(ｙ軸)の阻害の割合を示すグラフである；
図３は、１２日目に免疫化し、０から９日目に処置した(ｘ軸)、媒体(−□−；EtOH １０％／コーン油／５mg／kg p.o.、６匹の動物)、[MeIle]4−Cs(−○−；２×１２.５mg／kg／日 p.o.、７匹の動物)、[MeIle]4−Cs(−△−；２×２５mg／kg／日 p.o.、７匹の動物)および登録商標COX阻害剤(−▼−；２×２.５mg／kg／日 p.o.、４匹の動物)で処置したラットにおけるコラーゲン誘発関節炎アッセイにおける後足の腫脹(mm −ｙ軸)を示すグラフである。
【００３８】
生物学的活性アッセイ
Ａ．ラットにおける実験的自己免疫脳脊髄炎(ＥＡＥ)
本発明の代表的活性化合物である[MeIle]４−シクロスポリンを、３０mg／kgの投与量で上記のような急性ＥＡＥアッセイで試験し、この疾患の発症を有意に阻害することが判明する。得られる結果を図１に記載し、これは免疫化後９から１８日のコントロール動物および活性化合物処理動物の疾病の重症度を示すグラフである。コントロール動物は１１日目に０.５を超える得点を有し、１５および１６日目に得点は２.０に近づく；一方、[MeIle]４−Cs処理動物は１２日目まで測定可能な得点はなく、１５日から１７日目に約０.５の最大得点となり、その後減少する。
【００３９】
Ｂ．ラットにおける実験的自己免疫ブドウ膜網膜炎(ＥＡＵ)
ｉ)[MeIle]４−シクロスポリンおよびサングリフェーリン Aを、それ自体およびサングリフェーリン Aとの組合わせで、また上記の様にＥＡＵアッセイで試験する。得られる結果は下記表Ｉに示す。
【表１】
ii)[MeIle]4−シクロスポリン、[γ−ヒドロキシ−MeLeu]4−シクロスポリンおよび[Ｎ−ベンジル−Val]5−シクロスポリンおよび、プラセボとしてのコーン油中のエタノールをまた本質的に上記のような本ＥＡＵアッセイで試験する。得られる結果を下記表IIに示す。
【表２】
[MeIle]４−シクロスポリンおよびサングリフェーリン Aをまたそれ自体および組合わせで、上記のような発症した関節炎アッセイで試験する。得られる結果は図２に示し、これは３０mg／kg p.o.の[MeIle]４−シクロスポリン、１mg／kg s.c.のサングリフェーリン A、または３０mg／kg p.o.の[MeIle]４−シクロスポリンと１mg／kg s.c.のサングリフェーリン Aの組合わせで処置した５匹の動物のグループで得られた腫脹の阻害の平均のグラフである。
【００４２】
Ｃ．コラーゲン誘発関節炎
非免疫抑制性サイクロスポリンである[MeIle]４−シクロスポリン(NIM 811とも呼ぶ)を、ラットコラーゲン誘発関節炎モデルにおける治療的プロトコールにおいて調査する。ラットを、尾の付け根の回りに皮内投与したタイプIIコラーゲンで免疫化する。１０−１２日後、関節炎の発症が起こり、紅斑および関節の腫脹により類型化する。動物の１日２回の[MeIle]４−シクロスポリン(エタノール１０％／コーン油媒体中、２つの異なる量)のp.o.による処置を腫脹の発症の直後に開始し、１０日まで続ける。コントロール関節炎動物および登録商標COX阻害剤で処理するラットを実験に包含させる。後足の腫脹を定期的に評価する。実験の最後に、動物を殺し、関節を組織学的パラメーターの評価のために調製する。
【００４３】
[MeIle]4−シクロスポリンは使用した２つの投与量(１日２回 p.o. １２.５および２５mg／kg)で、９日に登録商標COX阻害剤(１日２回 p.o. ２.５mg／kg)の効果の６０％までの腫脹の良好な阻害を示す(図３)。シクロスポリン(CyA、有効ＥＤ50 １０−１５mg／kg p.o.付近 − Smith R. J. and Sly L. M., J. Pharmacol. Exp. Ther., June 1996; 277(3): 1801-1813参照)とのデータの比較は、関節リウマチのこのモデルにおける[MeIle]4−シクロスポリンと同様の効果を示す。
【図面の簡単な説明】
【図１】 免疫化９−１８日後(ｘ軸J)のコントロール動物(Ａ．黒色棒)および[MeIle]4−Cs処理動物(Ｂ．灰色棒)に関するＥＡＥにおける疾病得点(ｙ軸)のグラフである；
【図２】 Ａ．−３０mg／kg [MeIle]4−Cs p.o.；Ｂ．１mg／kg サングリフェーリン A s.c.；およびＣ． −３０mg／kg [MeIle]4−Cs p.o.＋１mg／kg サングリフェーリン A s.c.で処置した動物のグループのアジュバント関節炎アッセイの発症における腫脹(ｙ軸)の阻害の割合を示すグラフである；
【図３】 １２日目に免疫化し、０から９日目に処置した(ｘ軸)、媒体(−□−；EtOH １０％／コーン油／５mg／kg p.o.、６匹の動物)、[MeIle]4−Cs(−○−；２×１２.５mg／kg／日 p.o.、７匹の動物)、[MeIle]4−Cs(−△−；２×２５mg／kg／日 p.o.、７匹の動物)および登録商標COX阻害剤(−▼−；２×２.５mg／kg／日 p.o.、４匹の動物)で処置したラットにおけるコラーゲン誘発関節炎アッセイにおける後足の腫脹(mm −ｙ軸)を示すグラフである。[0001]
The present invention relates to a novel use of a class of cyclosporins and in particular to a new pharmaceutical use of a non-immunosuppressive, cyclophilin-bound cyclosporine.
[0002]
Non-immunosuppressive, cyclophilin-conjugated cyclosporines and their use in the treatment and prevention of AIDS and AIDS-related diseases are described in EP 484281, which is a cyclosporine class of compounds, their nomenclature And a general description of the mode of action. The description of EP0,484,281B, in particular the other general descriptions relating to the above and other parts related to the following, is incorporated by reference in the teachings of the present invention.
[0003]
Surprisingly, it has been found that cyclosporines that bind to cyclophilin but are not immunosuppressive have an inhibitory effect on inflammatory autoimmune diseases and conditions.
[0004]
Cyclosporine compound is at least 5 minutes as well as Cyclosporin (also called Cyclosporin A) in the competitive ELISA test described in Quesniaux, Eur. J. Immunol. 1987, 17, 1359-1365. When 1 binds to human recombinant cyclophilin, it is considered to bind to cyclophilin. In this test, the cyclosporine compound to be tested is added during the incubation of cyclophilin with coated BSA-cyclosporine and the concentration required to give 50% inhibition of the control reaction without competitor is calculated (IC 50 ). . The results are shown as coupling ratio (BR), which is the IC 50 of the test compound, the logarithm of the
[0005]
Cyclosporine, which acts as an inhibitor of inflammatory autoimmune disease, has a BR lower than 0.7 (because
[0006]
Cyclosporine is considered non-immunosuppressive when it has no more than 5%, preferably no more than 2%, activity in a mixed lymphocyte reaction (MRL) than cyclosporine. The mixed lymphocyte reaction is described by T. Meo “Immunological Methods”, L. Lefkovits and B. Peris, Eds., Academic Press, NY pp. 227-239 (1979). Spleen cells (0.5 × 10 6 ) from Balb / c mice (female, 8-10 weeks old) were irradiated for 0.5 days with 0.5 × 10 6 from CBA mice (female, 8-10 weeks old). Co-incubate with (2000 rads) or mitomycin C treated spleen cells. Irradiated allogeneic cells induce proliferative responses in Balb / c spleen cells, which can be measured by labeled precursors that are incorporated into DNA. Because stimulator cells are irradiated (or treated with mitomycin C), they do not respond to proliferation to Balb / c cells but retain antigenicity. The IC 50 seen with test compounds in MRL is compared to that seen with cyclosporine in parallel experiments.
[0007]
Compounds that are determined to be non-immunosuppressive by the MLR are often inactive in the IL-2 Reporter Gene Assay, and therefore the IL-2 Reporter Gene Assay is non-immunosuppressive for use in the present invention, It can be used for selection of cyclophilin-linked cyclosporine compounds, for example for primary screening.
[0008]
Non-immunosuppressive, cyclophilin-bound cyclosporine compounds that are active as inhibitors of inflammatory autoimmune conditions are hereinafter referred to as active compounds.
[0009]
The active compounds are in particular the treatment of autoimmune diseases and inflammatory conditions, in particular inflammatory conditions whose etiology includes autoimmune components, such as arthritis (e.g. rheumatoid arthritis, chronic progressive arthritis and osteoarthritis) and rheumatic diseases. Useful for prevention, prevention or reduction. Specific autoimmune diseases that can use active compounds include autoimmune hematological diseases (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polycones Doritisu, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steve emissions - Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and (Including Crohn's disease), pancreatitis, endocrine ophthalmic diseases, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, diabetes, e.g., juvenile diabetes (type I diabetes), uveoretinitis (Behcet's disease), uveitis (anterior and posterior), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis ( Furoze syndrome and without, for example, including idiopathic nephrotic syndrome or minimal change nephropathy) and other inflammatory airways diseases including asthma and autoimmune component, thyroiditis (Hashimoto Ghoto disease), encephalomyelitis, CNS Includes inflammatory conditions and similar autoimmune diseases.
[0010]
The activity of cyclosporine as an inhibitor of inflammatory autoimmune conditions can be demonstrated in the following test systems:
Experimental autoimmune uveitis female Lewis rats, 12 weeks old (BRL, Basel) are injected with 50 μg of purified bovine retina S-antigen in the right footpad. Antigen is diluted with phosphate buffered saline and emulsified 50:50 (v / v) with Freund's complete adjuvant and Bactgo M Tuberculosis H37 RA (DiFco). The injected dose is 0.1 ml and contains 50 μl complete adjuvant and 1.14 mg Mycobacterium tuberculosis. Starting 10 days after injection, the eyes are examined daily using a slit lamp. The degree of eye inflammation is scored in a semi-quantitative manner using a scale of 0-4:
0 No visible change 1 Slight change in vasculature, constant dilation of iris and
[0011]
Experimental autoimmune encephalomyelitis (EAE) in rats
Male Wistar rats are injected with a mixture of bovine spinal cord and complete Freund's adjuvant in the hind paw. Symptoms of the disease (tail and paralysis of both hind legs) usually develop within 16 days. Record the number of diseased animals and the time of onset of the disease. Inhibition of disease onset in the above test model is an indicator of pharmaceutical utility.
Reference: Levine et al., Am. J. Path. 47 (1965) 61; McFarlin et al., J. Immunol. 113 (1974) 712; Borel, Transplant. & Clin. Immunol. 13 (1981) 3] .
[0012]
Freund's adjuvant-induced arthritis OFA and Wistar rats (male or female, body weight 150 g) are injected ic with 0.1 ml mineral oil containing 0.6 mg lyophilized heat-sterilized Mycobacterium smegmatis at the base of the tail or hind paw. In models of arthritis development, treatment begins immediately after adjuvant injection (days 1-18); in established arthritis models, treatment begins on
Reference: Winter & Nuss, Arthritis and Rheumatism 9 (1966) 394; Billingham & Davies, Handbook of Experimental Pharmacology (Vane & Ferreira Eds, Springer Verlag, Berlin) 50 / II, (1979) 108-144]
[0013]
Collagen-induced arthritic rats are immunized with type II collagen administered intradermally around the base of the tail. After 10-12 days, arthritis develops and is typified by erythema and swollen joints. Treatment of animals with two different doses of test compound po, usually twice daily, starts immediately after the onset of swelling and continues for up to 10 days. Control arthritic animals and rats treated with registered COX inhibitor are included in the experiment. Regularly assess hind paw swelling. At the end of the experiment, animals are sacrificed and joints are prepared for evaluation of histological parameters. Test compounds that show good inhibition of swelling, eg, about 50% or more of the registered COX inhibitor, are selected for further experiments.
[0014]
In vitro chemotaxis (eg, using a Boyden chamber) and cyclophilin-induced neutrophil infiltration and similar assays can also be used.
Many active compounds have been found to have structures that differ from cyclosporine, especially at the 4 and / or 5 positions. Other positions where the structure of the active compound may differ from that of cyclosporine are the 6 and 7 positions.
[0015]
Other groups of active compounds are N-methylated amino acids that differ in the MeLeu group at the 4-position, for example γ-hydroxy-MeLeu, MeIle, MeVal, MeThr, MeAla, MeTyr or MeTyr (O—PO (OH) 2 ) or Cyclosporines substituted with Pro. In addition to MeIle and MeThr, allo-shaped MeaIle and MeaThr may also be used. In allo-shaped, beta-position stereochemistry of natural amino acids she is also reversed arrangement Noto, normal form and allo form pairs of diastereoisomers.
[0016]
A further group of active compounds are those in which the 5-position Val is substituted with N-alkyl-, preferably N-methyl-, an amino acid. Preferably, the N-alkylated amino acid is Val or Leu. Preferably, the hydrogen of the imino group of [Val] 5 is substituted with an unbranched C 1-6 alkyl group, preferably methyl, ethyl, or n-propyl, especially methyl. All preferred groups of the latter active compounds are novel.
[0017]
In addition or alternatively, certain active compounds may differ from cyclosporine in
[0018]
A particular class of active compounds used in the present invention is of formula A
[Chemical formula 5]
[Chemical 6]
b means binding to the C residue at position 4 ;
Alk is a linear or branched alkylene containing 2 to 6 carbon atoms or a cycloalkylene containing 3 to 6 carbon atoms, and R is a carboxy or alkyloxycarbonyl residue;
The group -NR 1 R 2
Wherein R 1 and R 2 are the same or different and are hydrogen, alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl (optionally halogen, alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino Optionally substituted) or benzyl or a saturated or unsaturated heterocyclic group containing 5 or 6 ring atoms and 1 to 3 heteroatoms, or R 1 and R 2 are Containing 4 to 6 ring atoms together with a nitrogen atom, optionally further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, optionally substituted with alkyl, phenyl or benzyl Meaning a saturated or unsaturated heterocycle which may be
Formula
And in the formula, alkyl means straight-chain or branched alkyl containing 1 to 4 carbon atoms.
Base of]
Amino acid residues of
C is MeLeu or 4-hydroxy-MeLeu]
Cyclosporine derivatives and pharmaceutically acceptable salts thereof.
[0019]
This class of cyclosporine derivatives is further described in published international patent applications WO98 / 28328, WO98 / 28329 and WO98 / 28330. Particularly preferred compounds of this class are those in which B is the amino acid residue B ′
[Chemical 8]
[0020]
A particularly preferred group of active compounds is of formula I:
[Chemical 9]
X is αAbu, Val, Thr, Nva or O-methylthreonine (MeOThr);
R is Sar or (D) -MeAla;
Y is MeLeu, γ-hydroxy-MeLeu, MeIle, MeVal, MeThr, MeAla, MeTyr, MeTyr (O—PO (OH) 2 ) , MeaIle or Me a Thr or Pro;
Z is Val, Leu, N-Alk-Val or N-Alk-Leu
Wherein Alk is substituted by Me or optionally phenyl, or N, S or O heteroaryl containing 6 ring members, or vinyl optionally substituted with phenyl optionally substituted with halogen. And Me)
Q is MeLeu, γ-hydroxy-MeLeu or MeAla]
And a pharmaceutically acceptable salt thereof.
[0021]
The groups W, X, Y, Z and Q independently have the following preferred meanings:
W is preferably W ′, W ′ is MeBmt or dihydro-MeBmt;
X is preferably X ′, X ′ is αAbu or Nva, more preferably X ″, X ″ is αAbu;
Y is preferably Y ′, Y ′ is γ-hydroxy-MeLeu, MeVal, MeThr, MeAla or MeTyr (O—PO (OH) 2 );
Z is preferably Z ′, Z ′ is Val or MeVal; and Q is preferably Q ′ and Q ′ is MeLeu.
[0022]
One particularly preferred group of active compounds are those compounds of formula I, wherein W is W ′, X is X ′, Y is Y ′, Z is Z ′ and Q is Q ′.
[0023]
Particularly preferred active compounds of the formula I are:
a) [dihydro-MeBmt] 1- [γ-hydroxy-MeLeu] 4 -cyclosporine,
b) [MeVal] 4 -cyclosporine,
c) [MeIle] 4 -cyclosporine,
d) [MeThr] 4 -cyclosporine,
e) [γ-hydroxy-MeLeu] 4 -cyclosporine,
f) [Nva] 2 - [ γ- hydroxy-MeLeu] 4 - cyclosporine,
g) [.gamma.-hydroxy -MeLeu] 4 - [γ- hydroxy-MeLeu] 6 - cyclosporin,
h) [MeVal] 5 -cyclosporine,
i) [MeOThr] 2 -[(D) MeAla] 3- [MeVal] 5 -cyclosporine,
j) [8′-hydroxy-MeBmt] 1 -cyclosporine,
k) [MeAla] 6 -cyclosporine,
l) [DMeAla] 3- [MeTyr (OPO (OH) 2 )] 4 -cyclosporine,
m) [N-benzyl-Val] 5 -cyclosporine,
n) [N-5-fluoro-benzyl-Val] 5 -cyclosporine,
o) [N-allyl-Val] 5 -cyclosporine,
p) [N-3-phenyl-allyl-Val] 5 -cyclosporine,
q) [Pro] 4 -cyclosporine.
[0024]
Particularly preferred active compounds are [MeIle] 4 -cyclosporine and [γ-hydroxy-MeLeu] 4 -cyclosporine, most particularly [MeIle] 4 -cyclosporine.
In addition to the compounds of formula I, preferred active compounds include, for example, r) [γ-hydroxy-MeLeu] 9 -cyclosporine.
[0025]
The active compounds are:
1) Fermentation 2) Biotransformation 3) Derivatization 4) Partial synthesis 5) It can be obtained by methods involving total synthesis.
[0026]
These methods are described generally and more specifically in Examples 1 to 10 of EP0484281B. This general description and the teachings of these examples are incorporated herein by reference. Example 11 of EP0484281B describes the measurement of immunosuppression and cyclophilin binding activity of representative active compounds against cyclosporine and the teaching of this example is also included in the description of the present invention.
[0027]
The active compounds are indicated for use in both the prevention and treatment of inflammatory autoimmune conditions and diseases in patients.
Thus, the present invention provides the use of non-autoimmune, cyclophilin-conjugated cyclosporine in the manufacture of a medicament for the treatment or prevention of inflammatory autoimmune diseases or conditions.
[0028]
The present invention further includes the treatment or prevention of inflammatory autoimmune conditions and diseases, patients suffering from or at risk of such diseases or conditions, comprising administering an effective amount of an active compound of the present invention. Provide a way for.
[0029]
The active compounds are administered by customary routes, in particular enterally, for example orally, for example in the form of drinking solutions, tablets or capsules or parenterally, for example injectable solutions or suspensions. Can be administered. The daily dose indicated by the intravenous route can be 1 to 20 mg / kg, preferably 3 to 10 mg / kg, for oral administration 1 to 50 mg / kg, preferably 10 to 30 mg / kg.
[0030]
The toxicity of the active compound is considered lower than cyclosporine. Since the active compound is not immunosuppressive, the side effects of cyclosporine associated with immunosuppression are avoided. Other side effects associated with cyclosporine, especially nephrotoxicity and central nervous system toxicity after prolonged use, are conveniently lower than cyclosporine.
[0031]
The active compounds may be used alone or in combination with other therapeutic agents, such as anti-inflammatory compounds and / or immunosuppressive compounds, for the treatment and prevention of inflammatory autoimmune diseases. In a particularly preferred embodiment, the active compound is immunosuppressive that does not inhibit calcineurin activity, in combination with Sanguriferi down a recent class identified cyclophilin binding compounds used. Sanglifehrin and methods for their preparation are described in WO 9702285 and WO 9807743. Particularly preferred Sanguriferi in to use in combination with the active compound, L from Sanguriferi down A, especially Sanguriferi down A, B, C and D.
[0032]
Thus, in a preferred embodiment, the invention provides for such diseases or diseases of inflammatory autoimmune conditions and diseases comprising administering a combination comprising an effective amount of an active compound of the invention and sanglifehrin. Methods are provided for the treatment or prevention of patients suffering from or at risk for a condition.
[0033]
The invention also provides a pharmaceutical composition comprising, for example, an active compound of the invention and sanglifehrin, for example for the treatment or prevention of inflammatory autoimmune diseases or conditions. The pharmaceutical composition of the present invention is conveniently in the form of a combined preparation for simultaneous, separate or sequential use in therapy. Thus, the active compound and sanglifehrin can be administered together in the form of a fixed composition or can be administered separately at different times. Typically, the composition may be in unit dosage form containing an effective amount of the combined preparation.
[0034]
Preferred galenical formulations for active agents are based on microemulsions as described in UK patent application 2222770A, including topical and oral forms; also as fatty acid saccharide monos, as described in UK patent application 2209671A Oral and injectable forms obtained from solid solutions containing esters such as saccharose monolaurate. Suitable unit dosage forms for oral administration contain, for example, 25 to 200 mg of active compound per dosage form per dose.
[0035]
Formulation examples A, B, C and D of EP0484281B are incorporated herein by reference:
The individual components of these formulations and their methods of manufacture are fully described in British Patent Application 2222770, the contents of which are incorporated herein by reference.
[0036]
The active compounds of other compounds, for example, when administered Sanguriferi ting both may use similar formulations suitable ratio of active agent and another compound. Thus, for example, the active compound and sangliferin preferably are from about 10 to about 100 mg / kg active compound per dose, from about 5: 1 to about 50: 1 (active compound po: sanglifer Use at a weight ratio in the range of phosphorus sc).
[0037]
The activity of representative active compounds was tested in animal model biological activity assays A, B and C, which refer to the accompanying drawings:
FIG. 1 is a graph of disease scores (y axis) in EAE for control animals (A. black bars) and [MeIle] 4 -Cs treated animals (B. gray bars) 9-18 days after immunization (x axis). is there;
FIG. -30 mg / kg [MeIle] 4 -Cs po; 1 mg / kg sanglifehrin A sc; -30 mg / kg [MeIle] 4 -Cs po + 1 mg / kg Sanglifehrin A sc is a graph showing the percentage of inhibition of swelling (y-axis) in the development of an adjuvant arthritis assay in a group of animals;
FIG. 3 shows immunization on
[0038]
Biological Activity Assay A.1 . Experimental autoimmune encephalomyelitis in rats (EAE)
[MeIle] 4 -cyclosporine, a representative active compound of the present invention, is tested in an acute EAE assay as described above at a dose of 30 mg / kg and is found to significantly inhibit the onset of this disease. The results obtained as described in Figure 1, this is a graph showing the severity of disease in control animals and the active compound-treated
[0039]
B. Experimental autoimmune uveoretinitis (EAU) in rats
i) [MeIle] 4 - Ciclosporin and San glyceraldehyde phosphate phosphorus A, in combination with itself and San glyceraldehyde phosphate phosphorus A, also tested in EAU assay as described above. The results obtained are shown in Table I below.
[Table 1]
ii) [MeIle] 4 -cyclosporine, [γ-hydroxy-MeLeu] 4 -cyclosporine and [N-benzyl-Val] 5 -cyclosporine and ethanol in corn oil as a placebo is also essentially as described above. Test in EAU assay. The results obtained are shown in Table II below.
[Table 2]
[MeIle] 4 -cyclosporine and sanglifehrin A are also tested in themselves and in combination in the onset arthritis assay as described above. The results obtained are shown in FIG. 2, which is 30 mg / kg po of [MeIle] 4 -cyclosporine, 1 mg / kg sc of sanglifehrin A, or 30 mg / kg po of [MeIle] 4 -cyclosporine and 1 mg / kg. Figure 6 is a graph of the mean inhibition of swelling obtained with groups of 5 animals treated with the sc sanglifehrin A combination.
[0042]
C. Is collagen-induced arthritis non-immunosuppressive cyclosporin [MeIle] 4 - Ciclosporin (also referred to as NIM 811), is investigated in a therapeutic protocol in the rat collagen-induced arthritis model. Rats are immunized with type II collagen administered intradermally around the base of the tail. After 10-12 days, arthritis develops and is typified by erythema and swollen joints. Treatment of the animals with [MeIle] 4 -cyclosporine (10% ethanol / two different amounts in corn oil medium) po twice daily starts immediately after the onset of swelling and continues to 10 days. Control arthritic animals and rats treated with registered COX inhibitor are included in the experiment. Regularly assess hind paw swelling. At the end of the experiment, animals are sacrificed and joints are prepared for evaluation of histological parameters.
[0043]
[MeIle] 4 -cyclosporine is the two doses used (twice a day po 12.5 and 25 mg / kg) of the registered COX inhibitor (twice a day po 2.5 mg / kg) It shows good inhibition of swelling up to 60% of the effect (FIG. 3). Comparison of data with cyclosporine (CyA, effective ED 50 around 10-15 mg / kg po-Smith RJ and Sly LM, J. Pharmacol. Exp. Ther., June 1996; 277 (3): 1801-1813) It shows the same effect as [MeIle] 4 -cyclosporine in this model of rheumatoid arthritis.
[Brief description of the drawings]
FIG. 1 is a graph of disease score (y axis) in EAE for control animals (A. black bars) and [MeIle] 4 -Cs treated animals (B. gray bars) 9-18 days after immunization (x axis J). Is
FIG. -30 mg / kg [MeIle] 4 -Cs po; 1 mg / kg sanglifehrin A sc; -30 mg / kg [MeIle] 4 -Cs po + 1 mg / kg Sanglifehrin A sc is a graph showing the percentage of inhibition of swelling (y-axis) in the development of an adjuvant arthritis assay in a group of animals;
FIG. 3. Immunization on
Claims (2)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9811854.0A GB9811854D0 (en) | 1998-06-02 | 1998-06-02 | Organic compounds |
| GB9811854.0 | 1998-06-02 | ||
| PCT/EP1999/003770 WO1999062540A1 (en) | 1998-06-02 | 1999-05-31 | Use of cyclosporins in the treatment of inflammatory autoimmune diseases |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2009252882A Division JP2010059177A (en) | 1998-06-02 | 2009-11-04 | Use of cyclosporins in treatment of inflammatory autoimmune disease |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2002516873A JP2002516873A (en) | 2002-06-11 |
| JP2002516873A5 JP2002516873A5 (en) | 2006-07-20 |
| JP4523154B2 true JP4523154B2 (en) | 2010-08-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000551796A Expired - Fee Related JP4523154B2 (en) | 1998-06-02 | 1999-05-31 | Use of cyclosporines in the treatment of inflammatory autoimmune diseases |
| JP2009252882A Pending JP2010059177A (en) | 1998-06-02 | 2009-11-04 | Use of cyclosporins in treatment of inflammatory autoimmune disease |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2009252882A Pending JP2010059177A (en) | 1998-06-02 | 2009-11-04 | Use of cyclosporins in treatment of inflammatory autoimmune disease |
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| EP (1) | EP1082130A1 (en) |
| JP (2) | JP4523154B2 (en) |
| KR (1) | KR20010043969A (en) |
| CN (1) | CN1304315A (en) |
| AU (1) | AU750422B2 (en) |
| BR (1) | BR9910860A (en) |
| CA (1) | CA2333315A1 (en) |
| GB (1) | GB9811854D0 (en) |
| HU (1) | HUP0102142A3 (en) |
| ID (1) | ID27576A (en) |
| IL (1) | IL139589A0 (en) |
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| PL (1) | PL344451A1 (en) |
| SK (1) | SK18142000A3 (en) |
| TW (2) | TWI250022B (en) |
| WO (1) | WO1999062540A1 (en) |
| ZA (1) | ZA200006464B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1123001A (en) | 1999-10-27 | 2001-05-08 | Alexandra Lucas | Compositions and methods for preventing and treating transplant rejection |
| DE60140960D1 (en) * | 2000-09-29 | 2010-02-11 | Viron Therapeutics Inc | USE OF SERP-1 IN COMBINATION WITH AN IMMUNOSUP PRESSOR FOR THE TREATMENT OF ARTHRITIS |
| GB0320638D0 (en) * | 2003-09-03 | 2003-10-01 | Novartis Ag | Organic compounds |
| US20080194470A1 (en) * | 2004-04-08 | 2008-08-14 | Novartis Ag | Nim811 In Cerebral Ischemia and Brain and Spinal Cord Injury |
| JP2008506648A (en) | 2004-07-14 | 2008-03-06 | ノバルティス アクチエンゲゼルシャフト | Use of a combination of cyclosporine and pegylated interferon for the treatment of hepatitis C (HCV) |
| AU2005290984B2 (en) * | 2004-10-01 | 2010-09-09 | Debiopharm Sa | Use of [D-MeAla]3-[EtVal]4-cyclosporin for the treatment of hepatitis C infection and pharmaceutical composition comprising said [D-MeAla]3-[EtVal]4-cyclosporin |
| US7285530B2 (en) | 2004-10-21 | 2007-10-23 | Viron Therapeutics, Inc. | Use of SERP-1 as an antiplatelet agent |
| BRPI0519345A2 (en) * | 2004-12-23 | 2009-01-20 | Novartis Ag | hcv treatment composition |
| CN101084005A (en) * | 2004-12-23 | 2007-12-05 | 诺瓦提斯公司 | Compounds for flaviviridae treatment |
| MX2007016068A (en) | 2005-06-17 | 2008-03-10 | Novartis Ag | Use of sanglifehrin in hcv. |
| JP2007112775A (en) * | 2005-10-24 | 2007-05-10 | Hamamatsu Univ School Of Medicine | Use of cyclosporines in the treatment of cytomegalovirus infection |
| US20090306033A1 (en) * | 2008-06-06 | 2009-12-10 | Keqiang Li | Novel cyclic peptides |
| US9090671B2 (en) | 2008-06-06 | 2015-07-28 | Scynexis, Inc. | Macrocyclic peptides |
| CA2748389A1 (en) | 2008-12-31 | 2010-07-08 | Scynexis, Inc. | Derivatives of cyclosporin a |
| US20110144005A1 (en) * | 2009-12-09 | 2011-06-16 | Scynexis, Inc. | Novel cyclic peptides |
| EP2900684A2 (en) | 2012-09-29 | 2015-08-05 | Novartis AG | Cyclic peptides and use as medicines |
| EP2908841A4 (en) * | 2012-10-19 | 2016-05-25 | Scynexis Inc | NEW ANTIVIRAL MACROCYCLES |
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| DK0484281T4 (en) * | 1990-11-02 | 2001-02-05 | Novartis Ag | cyclosporines |
| AR006514A1 (en) * | 1995-07-04 | 1999-09-08 | Sandoz Ag | A MACROLID, ITS USES, A PROCESS TO PRODUCE IT, A BIOLOGICALLY PURE ISOLATE CAPABLE OF PRODUCING IT, AND A PHARMACEUTICAL COMPOSITION THAT IT INCLUDES |
| US6124453A (en) * | 1995-07-04 | 2000-09-26 | Novartis Ag | Macrolides |
| CZ288631B6 (en) * | 1996-01-18 | 2001-08-15 | Galena, A. S. | Therapeutic preparations containing cyclosporin |
| CZ288739B6 (en) * | 1996-08-01 | 2001-08-15 | Galena, A. S. | Cyclosporin containing medicinal preparations |
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1998
- 1998-06-02 GB GBGB9811854.0A patent/GB9811854D0/en not_active Ceased
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1999
- 1999-05-31 BR BR9910860-7A patent/BR9910860A/en not_active IP Right Cessation
- 1999-05-31 WO PCT/EP1999/003770 patent/WO1999062540A1/en not_active Application Discontinuation
- 1999-05-31 CN CN99806904A patent/CN1304315A/en active Pending
- 1999-05-31 HU HU0102142A patent/HUP0102142A3/en unknown
- 1999-05-31 JP JP2000551796A patent/JP4523154B2/en not_active Expired - Fee Related
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- 1999-05-31 AU AU43724/99A patent/AU750422B2/en not_active Ceased
- 1999-05-31 EP EP99926489A patent/EP1082130A1/en not_active Withdrawn
- 1999-05-31 CA CA002333315A patent/CA2333315A1/en not_active Abandoned
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| Publication number | Publication date |
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| JP2010059177A (en) | 2010-03-18 |
| JP2002516873A (en) | 2002-06-11 |
| AU750422B2 (en) | 2002-07-18 |
| ZA200006464B (en) | 2002-03-11 |
| ID27576A (en) | 2001-04-12 |
| CA2333315A1 (en) | 1999-12-09 |
| PL344451A1 (en) | 2001-11-05 |
| AU4372499A (en) | 1999-12-20 |
| NO20006113D0 (en) | 2000-12-01 |
| GB9811854D0 (en) | 1998-07-29 |
| SK18142000A3 (en) | 2001-06-11 |
| CN1304315A (en) | 2001-07-18 |
| EP1082130A1 (en) | 2001-03-14 |
| HUP0102142A2 (en) | 2001-11-28 |
| TWI250022B (en) | 2006-03-01 |
| TW200522975A (en) | 2005-07-16 |
| HUP0102142A3 (en) | 2001-12-28 |
| WO1999062540A1 (en) | 1999-12-09 |
| NO20006113L (en) | 2001-01-25 |
| KR20010043969A (en) | 2001-05-25 |
| IL139589A0 (en) | 2002-02-10 |
| BR9910860A (en) | 2001-03-06 |
| TWI250021B (en) | 2006-03-01 |
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