JPWO2020009248A5

JPWO2020009248A5 -

Info

Publication number: JPWO2020009248A5
Application number: JP2020529077A
Authority: JP
Filing date: 2019-07-03
Publication date: 2022-08-09

Claims

次式I：

又は次式II：

（式中、R1～R3は独立して水素原子、メチル基又はエチル基、R4は水素原子、メチル基、エチル基、n-プロピル基、イソプロピル基、sec-ブチル基又はイソブチル基、R5～R8はそれぞれ独立して水素原子、メチル基、エチル基又はイソプロピル基、R8は水素原子、メチル基又は保護基、R10及びR11は、独立して水素原子、メチル基又は保護基を表す。）
で示されるデプシペプチド化合物又はその製薬学的に許容可能な塩を含む、眼組織の線維化抑制用医薬組成物。 Formula I:

or Formula II:

(Wherein, R1 to R3 are independently hydrogen atoms, methyl groups or ethyl groups, R4 is hydrogen atoms, methyl groups, ethyl groups, n-propyl groups, isopropyl groups, sec-butyl groups or isobutyl groups, R5 to R8 each independently represents a hydrogen atom, a methyl group, an ethyl group or an isopropyl group; R8 represents a hydrogen atom, a methyl group or a protecting group; and R10 and R11 independently represent a hydrogen atom, a methyl group or a protecting group.)
A pharmaceutical composition for suppressing fibrosis of eye tissue, comprising a depsipeptide compound represented by or a pharmaceutically acceptable salt thereof.

式Iで示されるデシペプチド化合物が、次式III：

（式中、R4はイソプロピル基、sec-ブチル基又はイソブチル基を表す。）
で示されるものである、請求項１に記載の医薬組成物。 A desipeptide compound of Formula I is represented by Formula III:

(In the formula, R4 represents an isopropyl group, a sec-butyl group or an isobutyl group.)
The pharmaceutical composition according to claim 1, which is represented by

R4がイソプロピル基である、請求項１又は２に記載の医薬組成物。 3. The pharmaceutical composition according to claim 1 or 2, wherein R4 is an isopropyl group.

眼組織の線維化抑制が、眼組織において、線維化、血管新生及び瘢痕形成の３段階の各々に係る病態増悪因子遺伝子発現のうち、各段階につき少なくも１種の遺伝子発現をin vivoで阻害することによるものである、請求項１～３のいずれか１項に記載の医薬組成物。 Suppression of ocular tissue fibrosis inhibits in vivo expression of at least one gene expression at each stage among pathology exacerbating factor gene expression associated with each of the three stages of fibrosis, angiogenesis and scar formation in ocular tissue. The pharmaceutical composition according to any one of claims 1 to 3, which is obtained by doing.

病態増悪因子遺伝子が、collagen 1A、collagen 3A1、collagen 4A1、TIMP 2、TIMP 3、TIMP 4、Thrombospondin 1、Thrombospondin 2、LOX、Loxl2、TGFb2、TGFb3、CTGF、VEGF、PDGF及びSerpinからなる群から選ばれる少なくとも１種である、請求項４に記載の医薬組成物。 disease exacerbation factor gene selected from the group consisting of collagen 1A, collagen 3A1, collagen 4A1, TIMP 2, TIMP 3, TIMP 4, Thrombospondin 1, Thrombospondin 2, LOX, Loxl2, TGFb2, TGFb3, CTGF, VEGF, PDGF and Serpin The pharmaceutical composition according to claim 4, which is at least one of

眼組織の線維化を100pg／kg～3000pg／kgの投与量で抑制する、請求項１～５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, which suppresses ocular tissue fibrosis at a dose of 100 pg/kg to 3000 pg/kg.

眼組織の線維化を2pg／eye～9000pg／eyeの投与量で抑制する、請求項１～５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, which suppresses ocular tissue fibrosis at a dose of 2 pg/eye to 9000 pg/eye.

眼組織の線維化抑制が、眼組織培養細胞の線維化様相転移の抑制、及び/又は眼組織細胞のHDAC活性の阻害によるものである、請求項１～７のいずれか１項に記載の医薬組成物。 The medicament according to any one of claims 1 to 7, wherein the suppression of ocular tissue fibrosis is due to suppression of fibrosis-like phase transition of ocular tissue cultured cells and/or inhibition of HDAC activity of ocular tissue cells. Composition.

眼組織培養細胞の線維化様相転移を10nＭ以下の濃度で抑制する、請求項８に記載の医薬組成物。 9. The pharmaceutical composition according to claim 8, which suppresses the fibrosis-like phase transition of ocular tissue cultured cells at a concentration of 10 nM or less.

眼組織細胞のHDAC活性をIC50＝10nＭ以下の濃度で阻害する、請求項８に記載の医薬組成物。 9. The pharmaceutical composition according to claim 8, which inhibits HDAC activity of ocular tissue cells at a concentration of IC50=10 nM or less.

眼組織の線維化抑制が、濾過胞維持効果、又は緑内障手術の予後向上効果をもたらす、請求項１～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, wherein the suppression of ocular tissue fibrosis provides a filtering bleb maintenance effect or an effect of improving the prognosis of glaucoma surgery.

眼組織の線維化抑制が、線維化抑制効果及び/又は血管新生抑制効果と、瘢痕形成抑制効果の両者をもたらす、請求項１～１１のいずれか１項に記載の医薬組成物。 12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the ocular tissue fibrosis inhibition provides both a fibrosis inhibitory effect and/or angiogenesis inhibitory effect and a scar formation inhibitory effect.

眼組織が、緑内障関連組織、結膜関連組織及び網膜関連組織からなる群から選ばれる少なくとも１つである、請求項１～１２のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 12, wherein the ocular tissue is at least one selected from the group consisting of glaucoma-related tissue, conjunctiva-related tissue and retina-related tissue.

緑内障関連組織が、線維柱帯、又は眼圧の制御が可能な組織である請求項１３に記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the glaucoma-related tissue is trabecular meshwork or a tissue capable of controlling intraocular pressure.

網膜関連組織が、網膜色素上皮、脈絡膜新生血管、又は加齢黄斑変性に係る組織である請求項１３に記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the retina-related tissue is retinal pigment epithelium, choroidal neovascularization, or tissue associated with age-related macular degeneration.

結膜関連組織が、濾過胞組織である請求項１３に記載の医薬組成物。 14. The pharmaceutical composition according to claim 13, wherein the conjunctiva-related tissue is filtering bleb tissue.