JP2018508474A - 血管新生阻害用c−19ステロイド - Google Patents
血管新生阻害用c−19ステロイド Download PDFInfo
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Abstract
Description
1.式1で定義される化合物であって:
R1は、水素原子又はC1〜C6のアルキル基であり;
R2は、OR5又は水素原子であり、ここで、R5は水素原子又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
R2は、OR5又は水素原子であり、R5は水素原子又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
5.再生過程を含む病理学的状態における新生血管形成阻害剤として使用する、前記いずれかの項目に記載の用途で使用するための化合物。
7.前記炎症状態が、関節炎、炎症性腸疾患、湿疹及び神経皮膚炎からなる群から選ばれるいずれかであることを特徴とする、前記いずれかの項目に記載の用途で使用するための化合物。
9.前記血管新生が、胸部組織の腫瘍、好ましくは乳癌、又は前立腺組織、好ましくは前立腺癌によって誘発されることを特徴とする、上記項目8に記載の用途で使用するための化合物。
11.前記固形癌は、腎細胞癌のような腎癌、結腸直腸癌、肺癌、脳腫瘍、及び特に卵巣癌、膵臓癌及びリンパ腫、並びにそれらの転移からなる群から選ばれる癌であることを特徴とする、項目10に記載の用途で使用するための化合物。
13.前記非固形癌が、多発性骨髄腫及びその転移であることを特徴とする、上記項目9に記載の用途で使用するための化合物。
15.眼関連疾患の予防又は治療用の、上記項目1〜7のいずれかに記載の用途で使用するための化合物。
17.正常な機能性組織から軟組織への形質転換を含む創傷修復における血管新生を阻止又は阻害するための、上記項目1〜5のいずれかに記載の用途で使用するための化合物。
19.血管奇形、特に皮膚又は肝臓、脳及び心臓といった固形臓器の血管腫を予防又は阻害するための、上記項目1〜5のいずれかに記載の用途で使用するための化合物。
21.肥満治療のための、上記項目1〜5のいずれかに記載の用途で使用するための化合物。
23.前記いずれかの請求項において定義された式で表される化合物、及び前記いずれかの請求項における医学的治療で使用するための製剤学的に許容される担体及び/又は賦形剤を含む、医薬組成物。
25.前記医薬組成物が、経口用途、皮下用途、皮膚用途、筋肉内、静脈内用途、眼内用途、経鼻用途、又は真皮(dermal)用途で調製されることを特徴とする、上記項目23又は24に記載の医薬組成物。
(i)VEGF、VEGFR又は可溶性VEGFR/VEGFRハイブリッド、及びチロシンキナーゼ阻害剤からなる群から選ばれる活性物質、及び
(ii)式1で定義される化合物を含む:
R1は、水素原子又はC1〜C6のアルキル基であり;
R2は、OR5又は水素原子であり、ここで、R5は水素又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
R4は、水素原子、C1〜C12のアルキル基、置換されていないフェニル基もしくはC1〜C12のアルキル基で置換されているフェニル基、又はCOR6のアシル基であり、
28.上記項目1〜27のいずれかで定義された化合物又は医薬組成物の医学的治療における抗血管新生剤としての使用。
29.医学的治療における抗血管新生剤としての、上記項目26又は27に記載の組み合わせの使用。
好ましい実施形態や実施例により、本願発明をより詳細に説明するが、それらは例示的な目的で示すに留まるものであり、本願発明の範囲を制限するものとして理解されるべきではない。
(ii)平滑筋細胞の分化増殖阻害
(iii)内皮細胞の遊走阻害
(iv)平滑筋細胞の遊走阻害
(vi)VEGFRタンパクの発現又は合成の減少
(vii)繊維芽細胞成長因子受容体13(FGFR13)、血小板由来成長因子(PDGFR)α細胞及び/又はβ細胞、並びにマスト細胞/幹細胞成長因子受容体(SCFR;c-Kit若しくはチロシンタンパク質キナーゼKit、又はCD117として知られている)を含む機能的に関連する成長因子のタンパク質の発現又は合成の低下。
但し、式1の構造中、aが単結合であり、bが二重結合であり、R2が水素原子でないときは、テストステロン関連効果やテストステロン様効果を示さないことが確認されている。
1.癌によって引き起こされた血管新生の効率的な阻害
2.炎症組織中への新血管の形成の阻害
3.内皮細胞腫瘍又は血管異常における病理学的変化であるため、内皮細胞及び/又は平滑筋細胞自体の異常な増殖の阻害
以下の章で記載された全ての実験は、少なくとも3回、主に2種類の細胞数にて、培養時間を変えて行った。さらに全ての実験は、異なる継代数の一つのHUVECに対して異なる調製物とともに、さらに数回繰り返して行った。
血管新生の必要条件は、内皮細胞の組織内へ遊走する能力である。この過程は、創傷被覆及び癌の増殖過程で観察される。内皮細胞はVEGFなどの因子の濃度勾配に沿って、組織内へと遊走する。この挙動は、例えば、図2Aから明らかなように、トランスウェルシステム(transwell system)を用いたin vitroの遊走モデルで調べることができる。特に、図2Aは、細胞の遊走をモニターするためのトランスウェルアッセイ用の典型的な装置を示している。
細胞遊走を検討する別の方法は、創傷治癒(スクラッチ)アッセイである。このアッセイは、急性の創傷治癒過程で生じる事象に似ている。創傷部位からファクターを取り除くことで、内皮細胞はスクラッチ領域内に遊走する。これは、血管形成による創傷治癒とその後の瘢痕形成による傷の閉塞の過程に似ている。
スクラッチ(掻き取った小片)の組織内への遊走後、HUVEC細胞は成長特性を変化させ、微小血管を形成する。この効果は、顕微鏡で評価することができる。
Claims (12)
- 式1で定義される化合物であって;
R1は、水素原子又はC1〜C6のアルキル基であり;
R2は、OR5又は水素原子であり、ここで、R5は水素原子又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
R3は、cが単結合のときには、水素原子又はC1〜C6のアルキル基であるか、又はcが二重結合であるときには、CHR5であり、ここでR5は先に定義した通りであり;
R4は、水素原子、C1〜C12のアルキル基、置換されていないフェニル基もしくはC1〜C12のアルキル基で置換されているフェニル基、又はCOR6のアシル基であり、
R6は、水素原子、C1〜C12の直鎖アルキル基もしくは分岐鎖アルキル基、フェニル基又はベンゾイル基であり、各置換基は置換されていなくてもよく、C1〜C12の直鎖アルキル基又は分岐鎖アルキル基で置換されていてもよく、又は生物学的代謝もしくは化学的な脱保護を起こすヒドロキシ基につながるいずれかの置換基であり、とりわけ、エステル、エーテル、アセタール、カルバメート、リン酸塩、ホスホン酸塩、ケタール、硫酸塩又はスルホン酸塩;及びそれらの塩である、血管新生阻害剤として医学的治療の用途で使用するための化合物。 - 式1で定義される化合物であって;
R1は、水素原子又はC1〜C6のアルキル基であり;
R2は、OR5又は水素原子であり、R5は水素原子又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
R3は、cが単結合のときは水素原子又はC1〜C6のアルキル基であり、cが二重結合のときはCHR5であり、ここでR5は先に定義した通りであり;
R4は、水素原子、C1〜C12のアルキル基、置換されていないフェニル基もしくはC1〜C12のアルキル基で置換されているフェニル基、又はCOR6アシル基であり、R6は、水素原子、C1〜C12の直鎖アルキル基もしくは分岐鎖アルキル基、フェニル基もしくはベンゾイル基であり、各置換基は置換されていなくてもよく、C1〜C12の直鎖アルキル基又は分岐鎖アルキル基で置換されていてもよく、又は生物学的代謝もしくは化学的な脱保護を起こすヒドロキシ基につながるいずれかの置換基であり、とりわけ、エステル、エーテル、アセタール、カルバメート、リン酸塩、ホスホン酸塩、ケタール、硫酸塩又はスルホン酸塩;及びそれらの塩である、血管新生阻害剤として治療に使用する化合物であり、
これらのうちのいずれか単独又は組み合わせて、内皮細胞の分化増殖、平滑筋細胞の分化増殖、内皮細胞の移動、平滑筋細胞の分化増殖、血管内皮増殖因子、血管内皮増殖因子受容体、線維芽細胞増殖因子受容体13、血小板由来増殖因子受容体α及び/又はβ、並びにマスト細胞/幹細胞増殖因子受容体の分化増殖又は合成を阻害することによって、炎症及び/又は癌の治療の用途で使用するための化合物。 - a及びcは単結合であり、bは二重結合であり、R2はOR5であり、OR5は請求項1に定義された通りであり、R5は水素原子又はC1〜C6の直鎖アルキル基又は分岐鎖アルキル基であることが好ましく、及びR4は水素原子又は炭素数1〜6のR6を有するCOR6であり、とりわけ、前記化合物は4−ヒドロキシテストステロン、その塩又はそのエステルであることを特徴とする、請求項1又は2の用途で使用するための化合物。
- 再生過程を含む病理学的状態における新生血管形成阻害剤として使用する、前記いずれかの請求項に記載の用途で使用するための化合物。
- 炎症状態における血管新生の予防又は阻害に使用される、前記いずれかの請求項に記載の用途で使用するための化合物であって、前記炎症状態は、とりわけ、関節炎、炎症性腸疾患、湿疹及び神経皮膚炎からなる群から選ばれるいずれかである、前記いずれかの請求項に記載の用途で使用するための化合物。
- 腫瘍によって誘発される血管新生の阻止又は阻害に使用する化合物であって、前記腫瘍は、好ましくは特に乳癌又は前立腺癌である、前記いずれかの請求項に記載の用途で使用するための化合物。
- 固形癌又は非固形癌の予防又は治療において使用される請求項1〜6のいずれかに記載の用途で使用するための化合物であって、前記固形癌は、好ましくは、腎癌、結腸直腸癌、肺癌、脳腫瘍、卵巣癌、膵臓癌及びリンパ腫、並びにそれらの転移からなる群から選ばれる癌であるか;又は、前記非固形癌は、好ましくは多発性骨髄腫又はその転移からなる群から選ばれる癌である、請求項1〜6のいずれかに記載の用途で使用するための化合物。
- 疾病又は病的状態を予防又は治療するために使用される請求項1〜6のいずれかに記載の用途で使用するための化合物であって、前記疾病又は病的状態は:
血管新生物又は血管増殖性新生物、好ましくは内皮細胞腫及び特に血管腫;
眼関連疾患、特に、糖尿病性網膜症、黄斑変性症、眼炎、角膜炎、角膜血管新生、硝子体への血管の進入(injection)、水晶体の血管新生からなる群から選ばれる眼関連疾患;
創傷修復、又は正常な機能性組織の軟組織への形質転換のため、特にオーバーシュートしている瘢痕形成の減少のため;
血管奇形、特に皮膚又は固形臓器における血管腫に対する血管奇形;
循環器疾患、特に、高血圧、血管の狭窄又は血管の再狭窄、動脈硬化症;
肥満;及び子宮内膜症から選ばれるいずれかのものである、請求項1〜6のいずれかに記載の用途で使用するための化合物。 - 前記いずれかの請求項において定義された式で表される化合物、及び医学的治療に使用する製剤学的に許容される担体及び/又は賦形剤を含む、医薬組成物。
- 請求項9に記載の医薬組成物であって、前記医薬組成物は、皮膚投与、粘膜投与、粘膜下投与、経皮投与、筋肉内投与、静脈内投与、皮下投与、皮内投与、経口投与、経鼻投与、眼内投与、又は坐薬投与若しくは腔内への点滴用に調製されることを特徴とする、医薬組成物。
- 以下の(i)及び(ii)を含む組合せであって、
(i) VEGF、VEGFR又は可溶性VEGFR/VEGFRハイブリッド、及びチロシンキナーゼ阻害剤からなる群から選ばれる活性物質、及び
(ii) 式1で表される化合物であり、
R1は、水素原子又はC1〜C6のアルキル基であり;
R2は、OR5又は水素原子であり、ここで、R5は水素原子又はC1〜C12の直鎖アルキル基又は分岐鎖アルキル基であり;
R3は、cが単結合のときには、水素原子又はC1〜C6のアルキル基であるか、又はcが二重結合であるときには、CHR5であり、ここでR5は先に定義した通りであり;
R4は、水素原子、C1〜C12のアルキル基、置換されていないフェニル基もしくはC1〜C12のアルキル基で置換されているフェニル基、又はCOR6のアシル基であり、
R6は、水素原子、C1〜C12の直鎖アルキル基もしくは分岐鎖アルキル基、フェニル基又はベンゾイル基であり、各置換基は置換されていなくてもよく、C1〜C12の直鎖アルキル基又は分岐鎖アルキル基で置換されていてもよく、又は生物学的代謝もしくは化学的な脱保護にを起こすヒドロキシ基につながるいずれかの置換基であり、とりわけ、エステル、エーテル、アセタール、カルバメート、リン酸塩、ホスホン酸塩、ケタール、硫酸塩又はスルホン酸塩;及びそれらの塩である、血管新生阻害剤として治療に使用する化合物。 - 前記いずれかの請求項で定義された医学的治療における、前記いずれかの請求項に記載の化合物、医薬組成物、又は組合せの使用。
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