JP2015508068A - 線維症の処置方法 - Google Patents
線維症の処置方法 Download PDFInfo
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- JP2015508068A JP2015508068A JP2014556085A JP2014556085A JP2015508068A JP 2015508068 A JP2015508068 A JP 2015508068A JP 2014556085 A JP2014556085 A JP 2014556085A JP 2014556085 A JP2014556085 A JP 2014556085A JP 2015508068 A JP2015508068 A JP 2015508068A
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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Abstract
Description
本願は、テキスト形式で電子的に提出された、その全体が参考としてここに援用される配列表を含む。このテキストコピーは、2013年5月21日に作成され、PS966PCT_SL.txtと命名され、そのサイズは3,284バイトである。
線維症は、通常は損傷または長期の炎症による、修復性または反応性の過程(例えば治癒)における、臓器または組織における過剰な線維性結合組織の形成である。線維症は、冒された組織を硬化および/または腫大させ、そしてこれらの組織を通る流体の流れを減らす。結果として、線維症の組織は、適切に機能できなくなる可能性がある。
例えば、本明細書中で開示される化合物を患者に投与することを含む、線維症を処置するための方法が、本明細書中で提供される。そのような方法において使用するための化合物も提供される。例えば、治療上および/または薬学的に受容可能な量の、以下によって示される化合物;およびその薬学的に受容可能な塩を投与することを含む、肝線維症および/または腸管線維症を予防または処置する必要のある、またはそれに罹患した被験体または患者において、肝線維症および/または腸管線維症を予防または処置するための方法が提供される:
R10は、HおよびC1〜C6アルキルからなる群から選択される;
R11は、H、C1〜C6アルキル、および−C(O)−C1−C6アルキルからなる群から選択される;
R5は、C1〜C6アルキルである。
本開示は、部分的には、本明細書中で開示されるある化合物は、例えば肝臓または結腸における線維症を予防または処置する能力を有するという知見に基づく。1つの局面において、本開示は、線維症、例えば肝線維症および/または腸管線維症を予防または処置する必要のある患者において、線維症、例えば肝線維症および/または腸管線維症を予防または処置する方法に関する。その開示された方法は、本明細書中で開示される化合物を投与することを含む。
1つまたはそれより多くの開示された方法における使用が企図される化合物は、式Iによって示される化合物、またはその薬学的に受容可能な塩、鏡像異性体、または立体異性体を含む:
R1およびR2はそれぞれ、HおよびC1−6アルキルからなる群から独立に選択される;またはR1およびR2は、それらが結合する窒素原子と一緒になって、5個または6個の原子を有する芳香族または脂肪族の環を形成し得る;
YおよびZは、H、OH、COOH、−OR3、−CH(OR3)COOHからなる群から独立に選択される;および
R3は、H、フェニル、ベンジル、ビニル、アリル、C1−6アルキルまたは1つまたはそれより多くのハロゲンによって置換されたC1−6アルキルから選択される。
R1およびR2は、HおよびC1−6アルキルからなる群から独立に選択される;またはR1およびR2は、それらが結合する窒素原子と一緒になって、5個または6個の原子を有する芳香族または脂肪族の環を形成し得る;
R6は、−NR9OH、OH、および−OR9からなる群から選択される;
R9は、C1−6アルキルである;
R4は、H、ハロ、フェニル、ベンジル、ビニル、アリル、C1−6アルキルおよび1つまたはそれより多くのハロゲンで置換されたC1−6アルキルからなる群から選択される;
R5およびR7は、水素またはハロゲンからなる群から独立に選択される、または
R4およびR5、またはR4およびR6は一緒になって、必要に応じてハロまたはC1−6アルキルで置換された、5個または6個の原子を有する縮合複素環を形成する;および
Aは、縮合複素環である。
R6は、OHまたは−OR9からなる群から選択され、ここでR9は上記で定義される;および
R10は、H、ハロ、またはC1−6アルキル、例えばメチルまたはエチルからなる群から、各出現に関して独立に選択される。
R1は、C1〜C6アルキル、C3〜C6シクロアルキル、C2〜C6アルケニルおよびC2〜C6アルキニルからなる群より選択され;
R2は、水素およびC1〜C6アルキルからなる群より選択され;
R3は、それぞれの出現に対して、水素、C1〜C6アルコキシ、C1〜C6アルキル、シアノ、C3〜C6シクロアルキル、ハロゲン、ヒドロキシルおよびニトロからなる群より独立して選択され;
R4は、水素およびC1〜C6アルキルからなる群より選択され;
R5は、C1〜C6アルキルである。
R2は、水素およびC1〜C6アルキルからなる群より選択され;
R3は、それぞれの出現に対して、水素、C1〜C6アルコキシ、C1〜C6アルキル、シアノ、C3〜C6シクロアルキル、ハロゲン、ヒドロキシルおよびニトロからなる群より独立して選択され;
R5は、水素またはC1〜C6アルキルである。
R3は、それぞれの出現に対して、水素、C1〜C6アルコキシ、C1〜C6アルキル、シアノ、C3〜C6シクロアルキル、ハロゲン、ヒドロキシルおよびニトロからなる群より独立して選択され;
R4は、水素およびC1〜C6アルキルからなる群より選択され;
R5は、水素またはC1〜C6アルキルであり;ならびに
Aは、縮合された5員複素環または6員複素環である。
ここでpは1または2であり;
R1は、C1〜C6アルキル、C3〜C6シクロアルキル、C2〜C6アルケニルおよびC2〜C6アルキニルからなる群より選択され;
R4およびR8は、水素およびC1〜C6アルキルからなる群よりそれぞれ独立して選択される。
R11は、H、C1〜C6アルキル、および−C(O)−C1〜C6アルキルからなる群から選択される;(例えばR11はH、メチル、−C(O)−メチル、または−C(O)−エチルであり得る)。
肝線維症および/または腸管線維症のような、線維症を予防または処置する方法が、本開示の一部を形成する。そのような方法は、その必要のある患者、またはそのリスクのある患者に、本明細書中で開示される化合物、例えば式I、IIa、またはIIb、例えば化合物17、29、34、または39のような、PPARy薬剤を含む薬学的調製物を投与することを含み得る。例えば、肝線維症を予防または処置する方法であって、その必要のある患者に、本明細書中で開示される化合物を投与することを含む、方法が提供される。あるいは、腸管線維症を予防または処置する方法であって、その必要のある患者に、本明細書中で開示される化合物を投与することを含む、方法が提供される。
オスC57bl6マウス(Charles River、l’Arbresle、France)において、四塩化炭素(CCl4)の注射によって、肝線維症を誘導した。C57bl6マウスは、体重22〜25gであり、そして実験の前に1週間、実験室の状態に維持した。動物を、ケージあたり5匹収容し、食物および水は自由に摂取可能であった。
ホルマリン固定した肝組織を処理して、そして厚さ5μmのパラフィン切片を、ヘマトキシリンおよびエオシン(H&E)ならびにピクロシリウスレッド染色(組織切片中のコラーゲンについての特異的着色)で染色して、肝臓における線維症の程度を評価した。各切片を、Metavirスコアを用いて、肝臓の各葉(5)の線維症の程度の定量のために、3人の異なる実験者によって、盲検的に分析した(Metavir Scoreチャートに関して図2Aを参照のこと)。図2Bで見られる写真を、20倍の対物レンズで得た。コントロール群は、F0スコアを有し、そしてCCl4群はF3スコアを有し、これは、肝臓の線維症を示した。化合物34(GED)は、JWH−133群よりも大きな線維症低減を示し、それぞれのスコアは、化合物34はF1、そしてJWH−133はF2であった。
化合物34(GED)および特異的CB2アゴニスト(JWH−133)の投与の影響を、定量的リアルタイムPCRによって、サイトカイン(IL−1β、TNF−α)および線維症のメカニズムに関与する遺伝子の遺伝子発現レベルで評価した。
化合物34(GED)および特異的CB2アゴニスト(JWH−133)の経口投与の影響を、マウスの血清において、異なる肝臓生化学的パラメーター:肝酵素(アラニンアミノトランスフェラーゼ(AST)およびアスパラギン酸アミノトランスフェラーゼ(ALT))、ガンマGTおよびアルカリホスファターゼについて評価した。
本実施例は、腸管線維症に対する化合物34の影響を評価するための実験を説明する。滅菌飲料水に溶解した2.5%DSS(40,000−50,000MW、TdB consultancyAB、Sweden)を5日間の後に通常の飲料水を7日間の3サイクルによって、C57bl6マウスにおいて慢性大腸炎を誘導した。
A.結腸重量/サイズ比
腸管線維症は、結腸の短縮および肥厚化ならびに付着性によって特徴付けられる。結腸の重量/サイズ比の測定は、炎症および線維症のレベルの指標である。図6Aにおいて見られるように、通常の水のみを受けたコントロールマウスと比較して、媒体を受けたDSSマウスにおいて、結腸重量/サイズ比の124%の有意な増加が観察され、それぞれ、44.98±6.31対20.11±3.91、p<0.05であった。これらの結果は、DSSマウスにおける結腸の重大な短縮によって説明される(図6B)。化合物34は、DSSの線維症促進効果の34%の低減を引き起こし、媒体を投与したDSSマウスと比較して、38.13±7.82対44.98±6.31(P<0.05)の結腸の重量/サイズ比の有意な減少を引き起こした(図6A)。よって、それは結腸の短縮および肥厚化のような、線維症の形態学的徴候を低減し、そして結腸のコラーゲン沈着を減少させる(図6B)。
結腸の横行部分の環をサンプルに取り(死後)、そして4%ホルムアルデヒド中で固定し、そして組織学的分析のために、パラフィン中に包埋した。切片(4μm)を、メイ−グリュンワルド−ギムザで染色し、そしてマルチパラメーター組織学的スコアリング(0から18)を、2人の研究者によって盲検的に行った。この染色は、炎症の定量を可能にした。炎症レベルを反映する組織学的グレードを、粘膜における細胞浸潤の強度、その粘膜下層における拡大、および上皮病変の存在に基づいて割り当てた(表5を参照のこと)。
C1.ピクロシリウスレッド染色による評価
得られた結腸のサンプルをすぐに、PBS(pH7.4)中10%の緩衝化ホルマリンで3時間固定し、段階的エタノール(graded ethanol)で脱水し、そして低温融解パラフィン中に包埋した。ホルマリン固定結腸組織を処理し、そして組織学的分析のために、5μmの厚さのパラフィン切片を、ピクロシリウスレッド染色で染色した。20倍の対物レンズで写真を得た。各切片を、0から4までのスコアを用いて、線維症の程度の定量のために、3人の異なる実験者によって盲検的に分析した。
この結腸線維症レベルの評価において、マッソントリクロームおよびコラーゲン染色を使用した。得られた結腸のサンプルをすぐに、PBS(pH7.4)中10%の緩衝化ホルマリンで3時間固定し、段階的エタノールで脱水し、そして低温融解(low−temperature−fusion)パラフィンに包埋した。連続的な3μmの切片を、メタノールおよび3%過酸化水素溶液中で40分インキュベートし、そして次いでPBS中ですすいだ。トリクローム陽性結合組織染色の密度および範囲、ならびに組織構造の破壊に依存して、腸管線維症を、なし、軽度、または重度としてスコアをつけた。
免疫組織化学的分析に関して、結腸由来の組織標本を、新しい4%パラホルムアルデヒド(PFA)/PBS溶液で、室温で3時間固定し、段階的(graded)エタノール系列で脱水し、そして低温融解パラフィンに包埋した。3μmの厚さの切片を、メタノール中で40分間、そして次いで3%過酸化水素中で5分間インキュベートした。サンプルを、線維症の主要なマーカーである、コラーゲンI〜III型(Abcam)、結合組織増殖因子(CTGF)(Abcam)、血小板由来増殖因子(PDGF)、SMAD2/3に対する特異的抗体と一晩インキュベートした。そのサンプルをPBSで5分間洗浄し、そしてストレプトアビジン−ビオチン−ペルオキシダーゼ結合二次抗体(Dako LSAB Corporation、cod K0675、Dako−Cytomation、Milano)とインキュベートした。PBS中で10分間洗浄した後、その切片を、3,3−ジアミノベンジジン−テトラヒドロクロリドと、1〜3分間インキュベートした。
この実施例は、腸管線維症の処置における化合物34(GED)の効果を評価するための実験を説明する。
インビトロ実験
Janvier(Le Genest−St−Isle、France)から購入した、全部で60匹の野生型C57BL/6マウスを研究に含めた。全てのマウスを、Pasteur Institute in Lille(France)の、特定の病原体を含まない施設で維持した。政府のガイドラインN°68/609/CEEに従って、動物実験を行った。
3サイクル(5日間DSS、7日間水)の、飲料水中2.5%(w/v)のDSSの経口投与によって、慢性大腸炎および線維症を、マウスにおいて誘導した。動物を、食物および流体の摂取に関して毎日モニターし、そして研究の最初、およびその後3日ごとに定期的に体重を測定した。
そのマウスを2つの群:i.DSSおよびii.DSS+GEDに無作為に分けた。各群は25匹のマウスから成り、そして水だけを受けた10匹のコントロールマウスと比較した。GED(30mg/kg/マウス)を、0.5%のカルボキシメチルセルロースナトリウム塩(CMC;MW:90,000Da;Sigma Aldrich)および1%のTween80を含む溶液に溶解し、そして経口経管栄養(100μl/マウス)によって毎日投与した。GEDを、2回目のサイクルの最初に投与した。
流体の摂取、体重の変化に関して毎日動物を観察し、そして体重の減少、下痢、直腸内出血および直腸脱を含む大腸炎の徴候、および立毛、嗜眠、および眼窩周囲の浸出液のような全身性炎症の徴候に関して検査した。
最後に、最後のDSSサイクルの投与の7日後に、各群の動物を、深いCO2麻酔下で、頸椎脱臼によって屠殺し、そして開腹手術を行った。結腸を見えるようにし、そして迅速に切り出した。結腸−直腸全体の長さおよび結腸−直腸の遠位8cmの重量を測定した。
拡張、厚さ、および狭窄を含む、肉眼的な結腸病変を、マウスの処置を知らない、独立した観察者によってスコアをつけた。結腸由来の組織標本を解剖し、そしてすぐに凍結したか、または新しい4%のホルムアルデヒド(FA)/PBS溶液で、室温で3時間固定し、続いてパラフィン包埋の標準的な手順を行った。3μmで横断的に切片にしたパラフィン包埋組織に、ヘマトキシリン/エオシン染色を行い、炎症の程度を評価し、そしてマッソントリクローム染色を行い、結合組織および線維症をより良く評価した。次いで染色した切片を、Olympus BX51 Light Microscope(Olympus、Optical Co.LTd.、Tokyo、Japan)の下で、2人の病理学者が盲検的に観察して、組織学的スコア評価を行った:i.潰瘍の存在(0=なし、1=小さい潰瘍、2=大きい潰瘍);ii.炎症の程度(0=なし、1=軽度、2=中程度、および3=重度);iii.病変の深さ(0=なし、1=粘膜下に広がる病変、2=固有筋層(muscolarispropria)の病変、および3=漿膜の病変);iv.線維症の程度(0=なし、1=軽度、2=中程度、および3=重度)。腸管の炎症の程度を、慢性炎症性浸潤の密度および範囲、杯細胞の喪失、および腸壁の肥厚によって評価した。顕微鏡スコアの合計を、全てのスコアの和として得る(可能な最高スコア=10)。
解剖し、そして新しい4%のホルムアルデヒド(FA)/PBS溶液で、室温で3時間固定した、結腸由来の組織標本を、段階的(graded)エタノール系列で脱水し、そして低温融解パラフィンに包埋した。3μmの厚さの切片を、メタノールおよび3%過酸化水素の溶液中で45分間インキュベートした。
0.5cmの凍結結腸サンプルを切断し、そして100mMのフッ化ナトリウム(NaF)、2mMのオルトバナジン酸ナトリウム(Na3VO4)、10mMのピロリン酸ナトリウム(NaPPi)、1mMのフェニルメタンスルホン(PMSF)、ならびに10μg/mLのロイペプチンおよびアプロチニンを含む古典的なプロテアーゼ阻害剤カクテルを補充した、50mMのTrisHCl pH7.6、150mMのNaCl、1.5mMのMgCl2、5mMのEDTA、1%のTriton−Xおよび10%のグリセロールを含むRIPA緩衝液中で機械的にホモジナイズした。
細胞培養
ヒト結腸癌細胞系統HT−29(ATCC HTB−38)および結腸腸管線維芽細胞(ATCCヒトCDD−18 co)を、それぞれ、10%の胎児ウシ血清(FBS)とともに100U/mlのペニシリンおよび100μg/mlのストレプトマイシンを補充したダルベッコ改変イーグル培地(DMEM)およびアルファ−改変イーグル培地、中で増殖させた。細胞培養を、37℃で、95%空気および5%CO2の加湿雰囲気下で維持した。
PPARγノックダウンHT29を、pSUPER.retroシステム(OligoEngine)を用いて得た。ヒトPPARγmRNAのヌクレオチド105−123(5’−GCCCTTCACTACTGTTGAC−3’(配列番号11))に対応する前方向標的配列および逆方向標的配列を、pSUPERretroベクター(pRS)のBglII/XhoI制限部位にクローニングして、ShPPAR構築物を得た。ルシフェラーゼ遺伝子を標的とした、配列5’−ACGCTGAGTACTTCGAAAT−3’(配列番号12)を含むネガティブコントロールpRSプラスミドも作製した(ShLuc構築物)。両方の構築物を、AmaxaBiosystemsのNucleofector技術を用いて、製造会社のプロトコールに従って、HT−29およびCaco−2細胞にトランスフェクトした。トランスフェクションの24時間後に、ピューロマイシン(5μg/ml)を補充した完全培養培地によって、安定にトランスフェクトされたクローンを選択した。PPARg発現のサイレンシングを、定量的RT−PCRおよびウェスタンブロット分析によってチェックした。一旦確立されたら、ShPPARおよびShLuc細胞系統を、2.5μg/mlのピューロマイシンを補充した完全培地で維持した。
hCCD−18およびHT29を、血清を含まない培地に溶解した、それぞれ、1ng/mLおよび10ng/mLのTGF−βで4日間刺激することによって、線維症の表現型を誘導した。分化期間中、1mMのGED(195.22g/mol)を投与した。それに加えて、PPARγ活性化に対する潜在的な依存を、この受容体の特異的アンタゴニストであるGW9662を用いて調査した。10−5MのGW9662を、TGFβ誘導分化の開始の4時間前に投与した。
総RNAを、Nucleospin RNAキット(Macherey−Nagel、Hoerdt、France)によって抽出した。RNAseの不活性化の後、DNAse処理によって、微量のゲノムDNAを総RNAから除去し、そしてRNAseフリー、DEPCフリーの水に溶出した。そのRNAの純度を、220から350nmで、Nanodropシステムにおいて、UV分光学によって、およびAgilent 2100 bioanalyzerにおけるプロファイリングによって評価した。1μgの総RNAを使用して、製造会社のプロトコールに従って、Roche Diagnostics(Indianapolis、IN)のLightCyclerFastStart DNA Master SYBR Green Iを用いることによって、定量的RT−PCRを行った。
インビボ実験
マウスの慢性大腸炎における臨床的所見および肉眼的所見
DSSの慢性経口投与は、全ての慢性マウスにおいて、最初のDSSサイクルの最後の日(5日目)から始まる、体重の減少を誘導した。10日目、DSSを受けたマウスは、コントロールマウスと比較して、より低い体重を示し、それぞれ23.88±0.31対25.27±0.35 p<0.05であった(図11)。
マウスにおけるDSS誘導性慢性大腸炎の推移および肉眼的所見に対するGED投与の影響を、表7にまとめる。これは、GEDが、慢性DSS誘導性大腸炎における肉眼的病変を改善し、そして線維症の形態学的徴候を低減することを示す。
いくつかの組織学的パラメーターを、粘膜における細胞浸潤の強度、粘膜下層における炎症の拡大、ならびに上皮病変およびコラーゲン沈着の存在に基づいて、スコアを付けた。通常の水を受けたコントロールマウスと比較して、DSSを受けたマウスの群において、有意なおよび強力な炎症が観察された。両方のモデルの組織学的特徴は、粘膜潰瘍および変性、杯細胞の減少、広範囲の炎症性細胞浸潤、および粘膜下浮腫を示した。これらの所見は全て、DSS誘導性慢性大腸炎においてより強調されているようであり、そして結腸壁の広範囲な肥厚化が明らかであった。それに加えて、慢性モデルは、長期治療において、陰窩の明らかな再生、および炎症程度の可能性のある自発的な回復を示した(図12)。
DSS誘導性大腸炎の慢性モデルにおける、線維症の主要なマーカーの組織レベルを、免疫組織化学的分析によって評価し、そしてイムノブロッティングによって確認した。従って、DSSのみを受けたマウスと比較して、GED処置の経口投与を受けたマウスの結腸において、線維芽細胞分化の特異的マーカーであるコラーゲンI〜III(図13a)およびα−SMA(図13b)の著しい減少が観察された。コラーゲンI〜IIIおよびα−SMAの発現レベルを、6匹のコントロールマウス、8匹のDSSマウス、および8匹のDSS+GEDマウスにおいて測定した。免疫化学およびウェスタンブロッティングはどちらも、全ての主要な線維症マーカーが、通常の水を受けたコントロールマウスと比較して、DSSを受けたマウスの群において有意に増加したこと、およびGEDの毎日の投与が、その発現の低減に関与することを示した。各タンパク質の発現レベルを、コントロール群の平均に対するパーセンテージとして表し、そして関心のある各マーカーを、GAPDHのようなハウスキーピングタンパク質によって正規化した。コントロール群と比較した、DSSマウスにおけるコラーゲンI〜IIIの発現の著しい増加(184%)、およびα−SMAの25%の中程度のアップレギュレーションが観察された。DSS誘導性慢性大腸炎を有するマウスにおけるGEDの経口投与は、これらのタンパク質の発現レベルの低減を引き起こし、コラーゲンI〜IIIに関してより有意に明白であった(GEDについて90.75%±19.9%対DSSについて284.4%±63.8%、p<0.005)。
GEDが異なるレベルでTGFβ/Smad経路をコントロールする能力を、免疫組織化学的分析によって観察し、そしてTGF−β1、Smad3、CTGFのような、この経路に関与する異なるメンバーの明白な低減を示した(データは示していない)。
本明細書中で言及される特許文書および科学論文それぞれの開示全体は、全ての目的のために参考として援用される。
本発明を、その趣旨および本質的な特徴から逸脱することなく、他の特定の形態で具体化し得る。従って、前述の実施形態は、全ての点において、本明細書中で記載される発明を制限するのではなく例示であるとみなすべきである。従って本発明の範囲は、前述の説明ではなく添付の請求項によって示され、そしてその請求項に均等な意味および範囲に入る全ての変化は、そこに含まれるべきであることが意図される。
Claims (17)
- 線維症を予防または処置するための方法であって、その必要のある患者に、治療上有効な量の、式A:
R10は、HおよびC1〜C6アルキルからなる群より選択され;
R11は、H、C1〜C6アルキルおよび−C(O)−C1〜C6アルキルからなる群より選択され;
R5は、HまたはC1〜C6アルキルである、方法。 - 前記化合物が、式A’または式A”:
- R5が、メチル、エチル、プロピルまたはイソプロピルである、請求項1または2に記載の方法。
- R5がメチルである、請求項3に記載の方法。
- R10およびR11が各々Hである、請求項4に記載の方法。
- 前記化合物が、以下:
- 線維症を予防または処置する方法であって、その必要のある患者に、化合物20、化合物21、2−メトキシ−3−(4’−アミノフェニル)プロピオン酸;2−エトキシ−3−(4’−アミノフェニル)プロピオン酸(化合物39);6−アミノ−2,2−ジメチル−4H−ベンゾ[1,3]ジオキシン−4−オン;5−アミノ−N−ヒドロキシ−2−メトキシベンズアミド;および5−アミノ−2,3−ジヒドロベンゾフラン−7−カルボン酸ならびにそれらの薬学的に受容可能な塩および立体異性体からなる群より選択される化合物の治療上有効な量を投与することを含む、方法。
- 前記線維症が、肝線維症である、請求項1〜7のいずれか一項に記載の方法。
- 前記線維症が、腸管線維症である、請求項1〜7のいずれか一項に記載の方法。
- 前記線維症が、腎線維症、心線維症、心内膜心筋線維症、特発性肺線維症、骨髄線維症、後腹膜線維症および腎性全身性線維症からなる群より選択される、請求項1〜7のいずれか一項に記載の方法。
- 肝線維症を予防または処置する方法であって、その必要のある患者に、治療上有効な量の薬学的調製物を投与することを含み、該薬学的調製物は、化合物20、化合物21、2−メトキシ−3−(4’−アミノフェニル)プロピオン酸;2−エトキシ−3−(4’−アミノフェニル)プロピオン酸;6−アミノ−2,2−ジメチル−4H−ベンゾ[1,3]ジオキシン−4−オン;5−アミノ−2,3−ジヒドロベンゾフラン−7−カルボン酸;ならびにそれらの薬学的に受容可能な塩および立体異性体からなる群より選択されるPPARγ薬剤を含む、方法。
- 前記薬学的調製物が経口投与される、請求項11に記載の方法。
- 前記患者がヒトである、請求項11または12に記載の方法。
- 前記患者が、B型肝炎またはC型肝炎に現在罹患しているかまたは罹患した、請求項11〜13のいずれか一項に記載の方法。
- 前記患者が、肝硬変である、請求項11〜14のいずれか一項に記載の方法。
- 前記患者が、クローン病、炎症性腸疾患または潰瘍性大腸炎にも罹患している、請求項11〜13のいずれか一項に記載の方法。
- 前記薬学的調製物が、2−メトキシ−3−(4’−アミノフェニル)プロピオン酸を含む、請求項11〜17のいずれか一項に記載の方法。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2009502775A (ja) * | 2005-07-22 | 2009-01-29 | ジュリアーニ インターナショナル リミテッド | Ppar受容体及びegf受容体に特異的な化合物及びそれらの塩並びに医療分野におけるそれらの使用 |
JP2010520166A (ja) * | 2007-02-28 | 2010-06-10 | ジュリアーニ インターナショナル リミテッド | 免疫保護性刺激物質としてカチオン性抗菌ペプチド発現を誘導するためのPPAR−γアゴニスト |
WO2010091892A2 (en) * | 2009-02-16 | 2010-08-19 | Giuliani International Limited | Alkylamido compounds and uses thereof |
Family Cites Families (119)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB767788A (en) | 1953-12-28 | 1957-02-06 | Schering Corp | Polyiodinated phenyl fatty acid compounds and process for their manufacture |
US3211610A (en) | 1961-09-29 | 1965-10-12 | Merck & Co Inc | Benzoic acid ester derivatives for treating coccidiosis and method of using same |
US3444232A (en) | 1966-05-18 | 1969-05-13 | Squibb & Sons Inc | O-alkyl or phenylalkyl benzohydroxamic acids |
GB1359560A (en) | 1972-02-25 | 1974-07-10 | Merck & Co Inc | Preparation of pyrrylsalicylic acid |
US4036951A (en) | 1973-03-12 | 1977-07-19 | Synergistics, Inc. | Ultra-violet filtration with certain aminosalicylic acid esters |
FR2440353A1 (fr) | 1978-11-03 | 1980-05-30 | Science Union & Cie | Nouveaux arylethanols, leurs procedes d'obtention et leur emploi comme medicament |
US4348223A (en) | 1980-12-05 | 1982-09-07 | Ppg Industries, Inc. | N-Alkyl-N-[3-(alkoxyalkyl)phenyl]-2-haloacetamide herbicides |
EP0055689B1 (de) | 1980-12-22 | 1984-07-04 | Schering Aktiengesellschaft | In 3-Stellung substituierte 2,4,6-trihalogenierte Benzamide und deren Salze, deren Herstellung und Verwendung als Ersatzstoffe für natürliche Süssstoffe sowie Süssungsmittel auf Basis dieser Verbindungen |
JPS58194814A (ja) | 1982-05-11 | 1983-11-12 | Nippon Shinyaku Co Ltd | 免疫調節作用を有する薬剤 |
IL69282A (en) | 1982-09-02 | 1988-06-30 | Euro Celtique Sa | Method for the carboxylation of potassium phenoxide with carbon dioxide |
GB8302708D0 (en) | 1983-02-01 | 1983-03-02 | Efamol Ltd | Pharmaceutical and dietary composition |
DE3786452T2 (de) | 1987-02-05 | 1993-10-21 | Kureha Chemical Ind Co Ltd | Benzylether-Verbindungen und Verfahren zu ihrer Herstellung. |
US4933330A (en) | 1987-04-01 | 1990-06-12 | Dak-Laboratoriet | Benzoic acid derivatives and use thereof |
ATE113209T1 (de) | 1988-05-05 | 1994-11-15 | Tillotts Pharma Ag | Verwendung von 5-amino-salicylsäure für die behandlung von hautkrankheiten. |
US5519014A (en) | 1990-10-22 | 1996-05-21 | Borody; Thomas J. | Treatment of non-inflammatory and non-infectious bowel disorders |
ATE256468T1 (de) | 1990-10-22 | 2004-01-15 | Gastro Services Pty Ltd | Behandlung von nicht-entzündlichen darmerkrankungen |
US5262549A (en) | 1991-05-30 | 1993-11-16 | Polaroid Corporation | Benzpyrylium dyes, and processes for their preparation and use |
US5302751A (en) | 1992-01-21 | 1994-04-12 | Ethyl Corporation | Profen resolution |
DE122005000058I1 (de) | 1992-03-17 | 2006-04-27 | Astellas Pharma Inc | Depsipeptide, Herstellung und Anwendung |
DE69331727D1 (de) | 1992-06-30 | 2002-04-25 | Howard K Shapiro | Verwendung einer kombination bestehend aus einem aminderivat oder aminverwandten derivat der benzoesäure und einem amino-polysaccharide zur herstellung eines medikaments fuer die behandlung von entzündlichen erkrankungen |
US5594151A (en) | 1994-01-28 | 1997-01-14 | Prolinx, Inc. | Phenylboronic acid complexing reagents derived from aminosalicylic acid |
AU698881B2 (en) | 1994-05-11 | 1998-11-12 | Howard K. Shapiro | Compositions for treatment of chronic inflammatory diseases |
US5594015A (en) | 1994-06-22 | 1997-01-14 | Regents Of The University Of California | Thiazolidine derivatives for the treatment of psoriasis |
JPH10511097A (ja) | 1995-03-28 | 1998-10-27 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 低薬用量リドグレル調合物および炎症性腸疾患の処置のためのそれらの使用 |
GB9600464D0 (en) | 1996-01-09 | 1996-03-13 | Smithkline Beecham Plc | Novel method |
GB9617001D0 (en) | 1996-08-13 | 1996-09-25 | Tillotts Pharma Ag | Oral composition |
DE19647582A1 (de) | 1996-11-18 | 1998-05-20 | Hoechst Ag | Verfahren zur Herstellung von aromatischen Olefinen mittels Katalyse durch Palladaphosphacyclobutane |
AU6773598A (en) | 1997-03-26 | 1998-10-20 | Institut Pasteur | Treatment of gastrointestinal disease with ppar modulators |
AU8588798A (en) | 1997-07-25 | 1999-02-16 | Institut Pasteur | Human peroxisome proliferator activated receptor gamma (ppargamma) gene re gulatory sequences and uses therefor |
AU9002798A (en) | 1997-09-19 | 1999-04-12 | Ono Pharmaceutical Co. Ltd. | Fused or nonfused benzene compounds |
EP1037624B1 (en) | 1997-12-12 | 2005-11-23 | Purdue Research Foundation | Use of conjugated linoleic acid for treating type ii diabetes |
US7015249B1 (en) | 1997-12-12 | 2006-03-21 | Purdue Research Foundation | Methods and compositions for treating diabetes |
FR2773075B1 (fr) | 1997-12-31 | 2000-05-05 | Cird Galderma | Utilisation d'activateurs de ppar-gamma en dermatologie |
US6114382A (en) | 1998-11-11 | 2000-09-05 | Moretti; Itagiba G. | Methods for treating inflammatory bowel disease |
US6326364B1 (en) | 1999-02-08 | 2001-12-04 | Cedars-Sinai Medical Center | Use of 5-aminosalicylates as antimicrobial agents |
FR2791671B1 (fr) | 1999-04-01 | 2001-05-11 | Oreal | Nouveaux composes derives d'esters d'acide benzoique, composition les comprenant et utilisation |
US20040034067A1 (en) | 1999-04-15 | 2004-02-19 | Macphee Colin Houston | Novel method of treatment |
GB9908647D0 (en) | 1999-04-15 | 1999-06-09 | Smithkline Beecham Plc | Novel compounds |
GB9914371D0 (en) | 1999-06-18 | 1999-08-18 | Smithkline Beecham Plc | Novel compounds |
TWI262185B (en) | 1999-10-01 | 2006-09-21 | Eisai Co Ltd | Carboxylic acid derivatives having anti-hyperglycemia and anti-hyperlipemia action, and pharmaceutical composition containing the derivatives |
US6369098B1 (en) | 1999-10-05 | 2002-04-09 | Bethesda Pharmaceuticals, Inc. | Dithiolane derivatives |
US7736661B1 (en) | 2000-03-07 | 2010-06-15 | Avon Products, Inc | Method of treating skin conditions |
EP1274675B1 (en) | 2000-04-19 | 2004-09-01 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
US7049342B2 (en) | 2000-05-29 | 2006-05-23 | Kyorin Pharmaceutical Co., Ltd. | Substituted phenylpropionic acid derivatives |
DK1285908T3 (da) | 2000-05-29 | 2008-12-01 | Kyorin Seiyaku Kk | Substituerede phenylpropionsyrederivater |
CA2420576C (en) | 2000-08-29 | 2005-06-14 | Nobex Corporation | Immunoregulatory compounds, derivatives thereof and their use |
EP1348698A4 (en) | 2000-12-05 | 2005-01-19 | Kyorin Seiyaku Kk | SUBSTITUTED CARBOXYLENE DERIVATIVES |
FR2822955B1 (fr) | 2001-03-27 | 2003-10-03 | Chru Lille | Methode de diagnostic de maladies inflammatoires chroniques de l'intestin |
US7312247B2 (en) | 2001-03-27 | 2007-12-25 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
EP1389044A4 (en) | 2001-04-18 | 2006-07-05 | Merck & Co Inc | PPAR-ALPHA-GAMMA AGONISTS OR LIGANDS FOR THE TREATMENT OF INFLAMMATIONS |
CA2354921A1 (en) | 2001-05-24 | 2002-11-24 | Yasuo Konishi | Drug evolution: drug design at hot spots |
CN1589258A (zh) | 2001-10-16 | 2005-03-02 | 雷迪实验室有限公司 | 新的β-苯基-α-氧取代的丙酸衍生物,它的制备方法和它们制备药学上重要的化合物的应用 |
AU2002357729A1 (en) | 2001-11-16 | 2003-06-10 | Nutrition 21, Inc. | Trans-10, cis-12 conjugated linoleic acid isomer for the treatment of diseases |
GB0127916D0 (en) | 2001-11-21 | 2002-01-16 | Rowett Res Inst | Method |
JP2005513031A (ja) * | 2001-11-26 | 2005-05-12 | アラクノーバ・セラピューティックス・リミテッド | 肺線維症の処置のためのpparアクチベーターの使用 |
UA82835C2 (en) | 2001-12-03 | 2008-05-26 | Reddys Lab Ltd Dr | ?-aryl-?-oxysubstituted propionuc acid derivatives and pharmaceutical composition based thereon |
US20030113815A1 (en) | 2001-12-19 | 2003-06-19 | Pfizer Inc. | Canine peroxisome proliferator activated receptor gamma |
WO2003053974A1 (en) | 2001-12-21 | 2003-07-03 | Dr. Reddy's Laboratories Ltd. | Novel compounds and their use in medicine, process for their preparation and pharmaceutical compositions containing them |
US20030220374A1 (en) | 2002-01-14 | 2003-11-27 | Pharmacia Corporation | Compositions and methods of treatment involving peroxisome proliferator-activated receptor-gamma agonists and cyclooxygenase-2 selective inhibitors |
US20040115127A1 (en) | 2002-04-12 | 2004-06-17 | Wright Samuel D. | Ppar-alpha-gamma ligands or agonists for the treatment of inflammation |
US8492438B2 (en) | 2002-04-26 | 2013-07-23 | Asan Laboratories Company (Cayman), Limited | Treatment skin disorders |
AU2003228744A1 (en) | 2002-04-29 | 2003-11-17 | The Ohio State University | Inhibition of protein tyrosine phosphatases and sh2 domains by a neutral phosphotyrosine mimetic |
DE10250080A1 (de) | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
GB0303609D0 (en) | 2003-02-17 | 2003-03-19 | Glaxo Group Ltd | Novel therapeutic method and compositions |
US20060159648A1 (en) | 2003-02-17 | 2006-07-20 | Davis Adrian F | Novel therapeutic method and compositions for topical administration |
JPWO2004082715A1 (ja) | 2003-03-20 | 2006-06-22 | エーザイ株式会社 | 炎症性腸疾患治療剤としての併用医薬 |
US7981915B2 (en) * | 2003-04-30 | 2011-07-19 | Beth Israel Deaconess Medical Center | Methods for modulating PPAR biological activity for the treatment of diseases caused by mutations in the CFTR gene |
AU2004261400A1 (en) | 2003-07-21 | 2005-02-10 | Laboratoires Serono Sa | Alkynyl aryl carboxamides |
WO2005039590A1 (en) | 2003-10-21 | 2005-05-06 | Inspire Pharmaceuticals, Inc. | Non-nucleotide compositions and method for treating pain |
WO2005040102A2 (en) | 2003-10-28 | 2005-05-06 | Dr. Reddy's Laboratories Ltd. | Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them |
FR2862870A1 (fr) | 2003-12-01 | 2005-06-03 | Galderma Res & Dev | Utilisation d'activateurs de recepteurs ppar en cosmetique et dermatologie. |
EP1691806A2 (en) | 2003-12-03 | 2006-08-23 | Smithkline Beecham Corporation | Novel therapeutic method and compositions |
EP1722630A4 (en) | 2004-01-20 | 2009-05-27 | Richard F Harty | COMPOSITIONS AND METHODS FOR TREATING INFLAMMATORY DISEASES |
WO2005084658A1 (en) | 2004-03-04 | 2005-09-15 | Arakis Ltd. | Derivatives of actarit and their therapeutic use |
US20050277693A1 (en) | 2004-06-10 | 2005-12-15 | Dr. Reddy's Laboratories Limited | Basic salts and monohydrates of certain alpha, beta-propionic acid derivative |
GT200500246A (es) | 2004-09-09 | 2006-04-17 | Combinacion de compuestos organicos | |
WO2006037052A2 (en) | 2004-09-27 | 2006-04-06 | Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services National Institutes Of Health | Modulating mxa expression |
US20060286046A1 (en) | 2005-01-05 | 2006-12-21 | Haber C Andrew | Skin care compositions |
EP1719543A1 (en) | 2005-05-04 | 2006-11-08 | Asan Labs., Ltd. | Use of histone deacetylase inhibitors for the treatment of gastrointestinal distress |
US20060270635A1 (en) | 2005-05-27 | 2006-11-30 | Wallace John L | Derivatives of 4- or 5-aminosalicylic acid |
ITRM20050389A1 (it) | 2005-07-22 | 2007-01-23 | Giuliani Spa | Composti e loro sali specifici per i recettori ppar ed i recettori per l'egf e loro uso in campo medico. |
US20070093524A1 (en) | 2005-10-25 | 2007-04-26 | Wyeth | 5-Lipoxygenase modulators |
DE102005061472A1 (de) | 2005-12-22 | 2007-07-05 | Saltigo Gmbh | Verfahren zur Herstellung von enantiomerenangereicherten 2-Alkoxy-3-phenylpropionsäuren |
WO2007096148A1 (en) | 2006-02-23 | 2007-08-30 | Lipid Nutrition B.V. | Immunoregulation |
US7645801B2 (en) | 2007-01-29 | 2010-01-12 | Alaven Pharmaceutical Llc | Reduced irritant enema for treatment of inflammatory bowel disease (IBD) |
US8796282B2 (en) | 2007-03-28 | 2014-08-05 | Case Western Reserve University | Method of treating dermatological disorders |
US20090054312A1 (en) | 2007-08-22 | 2009-02-26 | Wolf Dieter A | SMIPs: Small molecule inhibitors of p27 depletion in cancers and other proliferative diseases |
IE20070928A1 (en) * | 2007-12-21 | 2009-09-30 | Giuliani Int Ltd | Multi target ligands |
ITMI20072429A1 (it) | 2007-12-24 | 2009-06-25 | Giuliani Int Ltd | Composti per il trattamento selettivo della componente immuno-infiammatoria intestinale della malattia celiaca |
US8030520B2 (en) | 2008-03-31 | 2011-10-04 | Saltigo Gmbh | Process for preparing organic compounds by a transition metal-catalysed cross-coupling reaction of an aryl-X, heteroaryl-X, cycloalkenyl-X or alkenyl-X compound with an alkyl, alkenyl, cycloalkyl or cycloalkenyl halide |
US20090264520A1 (en) | 2008-04-21 | 2009-10-22 | Asha Lipid Sciences, Inc. | Lipid-containing compositions and methods of use thereof |
FR2938338B1 (fr) | 2008-11-13 | 2012-10-05 | Galderma Res & Dev | Modulateurs de l'acetyl-coenzyme a acyltransferase 1 ou 2 dans le traitement de l'acne, d'une dermatite seborrheique ou de l'hyperseborrhee |
UA107562C2 (uk) | 2008-12-05 | 2015-01-26 | Спосіб лікування псоріазу | |
EP2298321A1 (en) | 2009-08-26 | 2011-03-23 | Nordic Pharma | Novel pharmaceutical compositions for treating IBD |
EP2667900B1 (en) | 2011-01-28 | 2020-02-12 | William A. Shaver | Method, composition and package for bowel cleansing |
WO2013012662A2 (en) | 2011-07-15 | 2013-01-24 | S.L.A. Pharma Ag | Pharmaceutical compositions for rectal administration |
HRP20231679T1 (hr) | 2011-10-17 | 2024-04-12 | The Regents Of The University Of California | Postupci za ocjenjivanje kvalitete organskih materijala kod odbijanja kukaca te postupci i pripravci za odbijanje artropoda |
EP2773378B1 (en) | 2011-10-31 | 2016-08-10 | Larsen, Claus Selch | Prodrugs of non-steroid anti-inflammatory agents (nsaids) |
US9044304B2 (en) | 2011-12-23 | 2015-06-02 | Alcon Lensx, Inc. | Patient interface with variable applanation |
US9682923B2 (en) | 2012-02-09 | 2017-06-20 | Nogra Pharma Limited | Methods of treating fibrosis |
BR112014026160A2 (pt) | 2012-04-18 | 2017-07-18 | Nogra Pharma Ltd | métodos para tratar intolerância à lactose |
WO2013168438A1 (ja) | 2012-05-10 | 2013-11-14 | 国立大学法人岩手大学 | ラクターゼ活性を有するタンパク質、該タンパク質をコードする遺伝子、該遺伝子を含有する組み換えベクター、形質転換体、及びその製造方法並びに用途 |
US9013997B2 (en) | 2012-06-01 | 2015-04-21 | Broadcom Corporation | System for performing distributed data cut-through |
CN104619687A (zh) | 2012-06-01 | 2015-05-13 | 诺格拉制药有限公司 | 能够调节t-细胞应答的双环杂环及其使用方法 |
US9957247B2 (en) | 2012-06-07 | 2018-05-01 | Georgia State University Research Foundation, Inc. | SecA inhibitors and methods of making and using thereof |
CA2883836A1 (en) | 2012-09-13 | 2014-03-20 | Nogra Pharma Limited | Methods of inhibiting hair growth |
KR20150054934A (ko) | 2012-09-13 | 2015-05-20 | 노그라 파마 리미티드 | 모발 관련 상태의 치료 방법 |
WO2014150377A1 (en) | 2013-03-15 | 2014-09-25 | Embry-Riddle Aeronautical University, Inc. | Electrically coupled counter-rotation for gas turbine compressors |
AU2014243102B2 (en) | 2013-03-26 | 2018-04-26 | Lipid Therapeutics Gmbh | Pharmaceutical formulation comprising phosphatidylcholine for the treatment of ulcerative colitis |
KR101423005B1 (ko) | 2013-10-17 | 2014-07-28 | 강윤식 | 장 세정용 조성물 |
CN105566153B (zh) | 2014-10-14 | 2019-05-31 | 中国医学科学院药物研究所 | 偶氮苯衍生物及其制法和药物组合物与用途 |
WO2016154730A1 (en) | 2015-04-02 | 2016-10-06 | University Health Network | Gut anti-inflammatory agents for regulation of high blood glucose levels |
BR112017026739A2 (pt) | 2015-06-15 | 2018-08-28 | Nmd Pharma Aps | compostos para uso no tratamento de distúrbios neuromusculares |
WO2017046343A1 (en) | 2015-09-17 | 2017-03-23 | Nogra Pharma Limited | Compositions for rectal administration in the treatment of ulcerative colitis and methods of using same |
WO2017093444A1 (en) | 2015-12-01 | 2017-06-08 | Nogra Pharma Limited | Compositions for oral administration in the treatment of inflammatory bowel disease |
EP3419616A1 (en) | 2016-02-26 | 2019-01-02 | Nogra Pharma Limited | Methods of treating lactose intolerance |
US20220000818A1 (en) | 2019-01-25 | 2022-01-06 | Nogra Pharma Limited | Compositions for use in preventing acne |
WO2020161362A1 (en) | 2019-02-08 | 2020-08-13 | Nogra Pharma Limited | Process of making 3-(4'-aminophenyl)-2-methoxypropionic acid, and analogs and intermediates thereof |
US11903592B2 (en) | 2021-05-10 | 2024-02-20 | DePuy Synthes Products, Inc. | Data modules for surgical instruments |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009502775A (ja) * | 2005-07-22 | 2009-01-29 | ジュリアーニ インターナショナル リミテッド | Ppar受容体及びegf受容体に特異的な化合物及びそれらの塩並びに医療分野におけるそれらの使用 |
JP2010520166A (ja) * | 2007-02-28 | 2010-06-10 | ジュリアーニ インターナショナル リミテッド | 免疫保護性刺激物質としてカチオン性抗菌ペプチド発現を誘導するためのPPAR−γアゴニスト |
WO2010091892A2 (en) * | 2009-02-16 | 2010-08-19 | Giuliani International Limited | Alkylamido compounds and uses thereof |
Non-Patent Citations (3)
Title |
---|
CURR OPIN RHEUMATOL., vol. 22, no. 6, JPN6016032255, 2010, pages 671 - 676, ISSN: 0003384264 * |
GASTROENTEROLOGY, vol. Volume 140, Isuue 5, Supplement 1, JPN6016032252, 2011, pages 515, ISSN: 0003384263 * |
JOHNSON LAURA A, INFLAMMATORY BOWEL DISEASES MAR 2012, vol. V18 N3, JPN5015003734, 14 July 2011 (2011-07-14), pages 460 - 471, ISSN: 0003384265 * |
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