JP5213448B2 - 末梢血管疾患の処置のための方法および組成物 - Google Patents
末梢血管疾患の処置のための方法および組成物 Download PDFInfo
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Description
(下付1)...13,14−不飽和−15−OH
(下付2)...5,6−および13,14−ジ不飽和−15−OH
(下付3)...5,6−、13,14−および17,18−トリ不飽和−15−OH。
本発明者は鋭意研究を行った結果、11-デオキシ-プロスタグランジン化合物が末梢血管疾患に対して選択的に有意な効果を有することを見いだし、本発明を完成するに至った。
図1Aは、ET-1によって誘導されたラットにおける末梢微小循環の低下に対する化合物A (11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1)の効果を示すグラフである。グラフにおいて、データは平均± S.E.として表し、*p<0.05は、媒体処理対照との比較である。CTBF: 皮膚組織血流。
本発明において、「11-デオキシ-プロスタグランジン化合物」(以下、「11-デオキシ-PG化合物」と称する)は、5員環の配置、二重結合の数、置換基の存在または非存在、あるいはαまたはω鎖のその他の修飾に関わりなく、プロスタン酸骨格の11位に置換基を有さない化合物のあらゆる誘導体またはアナログ (置換誘導体を含む)を含みうる。
LおよびNは、水素、ヒドロキシ、ハロゲン、低級アルキル、ヒドロキシ(低級)アルキル、低級アルカノイルオキシまたはオキソ、ここで、5員環は少なくとも1つの二重結合を有していていてもよい;
Aは、−CH3、−CH2OH、−COCH2OH、−COOH またはそれらの官能性誘導体;
R1は、非置換またはハロゲン、アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された飽和または不飽和の二価の低〜中級脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は酸素、窒素または硫黄によって置換されていてもよい;および、
R0は、非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基で置換された飽和または不飽和の低〜中級脂肪族炭化水素残基; 低級アルコキシ; 低級アルカノイルオキシ; シクロ(低級)アルキル; シクロ(低級)アルキルオキシ; アリール; アリールオキシ; 複素環基; 複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は酸素、窒素または硫黄によって置換されていてもよい]。
LおよびNは、水素、ヒドロキシ、ハロゲン、低級アルキル、ヒドロキシ(低級)アルキル、低級アルカノイルオキシまたはオキソ、ここで、5員環は少なくとも1つの二重結合を有していてもよい;
Aは、−CH3、−CH2OH、−COCH2OH、−COOH またはそれらの官能性誘導体;
Bは、単結合、−CH2−CH2−、−CH=CH−、−C≡C−、−CH2−CH2−CH2−、−CH=CH−CH2−、−CH2−CH=CH−、−C≡C−CH2−または−CH2−C≡C−;
Zは、
R1は、非置換またはハロゲン、アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された飽和または不飽和の二価の低〜中級脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は、酸素、窒素または硫黄によって置換されていてもよい;および、
Raは、非置換またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基で置換された飽和または不飽和の低〜中級脂肪族炭化水素残基; 低級アルコキシ; 低級アルカノイルオキシ; シクロ(低級)アルキル; シクロ(低級)アルキルオキシ; アリール; アリールオキシ; 複素環基; 複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は酸素、窒素または硫黄によって置換されていてもよい]。
Lは、水素、ヒドロキシ、ハロゲン、低級アルキル、ヒドロキシ(低級)アルキル、低級アルカノイルオキシまたはオキソ、ここで5員環は少なくとも1つの二重結合を有していてもよい;
Aは、−CH3、−CH2OH、−COCH2OH、−COOH またはそれらの官能性誘導体;
Bは、単結合、−CH2−CH2−、−CH=CH−、−C≡C−、−CH2−CH2−CH2−、−CH=CH−CH2−、−CH2−CH=CH−、−C≡C−CH2−または−CH2−C≡C−;
Zは、
X1およびX2は、水素、低級アルキル、またはハロゲン;
R1は、非置換またはハロゲン、アルキル、ヒドロキシ、オキソ、アリールまたは複素環基で置換された飽和または不飽和の二価の低〜中級脂肪族炭化水素であり、脂肪族炭化水素における少なくとも1つの炭素原子は、酸素、窒素または硫黄によって置換されていてもよい;および、
R2は、単結合または低級アルキレン;および、
R3は、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基であり、脂肪族炭化水素における少なくとも1つの炭素原子は、酸素、窒素または硫黄によって置換されていてもよい]。
−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH(CH3)−CH2−、
−CH2−CH2−CH2−CH2−O−CH2−、
−CH2−CH=CH−CH2−O−CH2−、
−CH2−C≡C−CH2−O−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH(CH3)−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH=CH−CH2−CH2−CH2−CH2−CH2−、
−CH2−CH2−CH2−CH2−CH2−CH2−CH=CH−、
−CH2−C≡C−CH2−CH2−CH2−CH2−CH2−、および、
−CH2−CH2−CH2−CH2−CH2−CH2−CH(CH3)−CH2−。
、メニエル病、メニエル症候群、知覚麻痺、感覚低下、感覚消失、休息痛、灼熱痛(やけつく痛み)、末梢循環機能障害、神経機能障害、運動機能障害、運動麻痺、糖尿病性末梢循環障害、腰部脊柱管狭窄症、糖尿病性神経障害、ショック、自己免疫疾患、例えば、エリテマトーデス、リウマチ性疾患および関節リウマチ、自律神経障害、糖尿病性自律神経障害、自律神経失調、起立性低血圧、***機能障害、女性生殖機能障害、逆行性***、膀胱機能障害、過敏膀胱、膣の潤滑不全、運動不耐性、心臓除神経、高熱不耐性、味覚性発汗、糖尿病合併症、高血糖、無自覚性低血糖、無応答性低血糖; 緑内障、血管新生緑内障、白内障、網膜症、糖尿病性網膜症、糖尿病性黄斑症、網膜動脈閉塞、網膜中心動脈閉塞、網膜静脈閉塞、黄斑浮腫、加齢性黄斑変性症、加齢性円板状黄斑変性症、嚢胞様黄斑浮腫、眼瞼浮腫、網膜浮腫、脈絡網膜症、血管新生黄斑症、ブドウ膜炎、虹彩炎、網膜血管炎、眼内炎、全眼球炎、転移性眼炎、脈絡膜炎、網膜色素上皮炎、結膜炎、毛様体炎、強膜炎、上強膜炎、視神経炎、眼球後視神経炎、角膜炎、眼瞼炎、滲出性網膜剥離、角膜潰瘍、結膜潰瘍、慢性貨幣状角膜炎、タイジェソン角膜炎、進行性モーレン潰瘍、皮膚傷害、皮膚潰瘍、例えば、足部潰瘍、糖尿病性潰瘍、火傷潰瘍、下腿潰瘍、手術後潰瘍、外傷性潰瘍、帯状疱疹後潰瘍、放射線性潰瘍、薬物誘導性潰瘍、凍傷 (寒冷傷害)、霜焼け、壊疽および突発性壊疽、狭心症、異型血管炎、冠動脈硬化症 (慢性虚血性心疾患、無症候性虚血性心疾患、動脈硬化性心血管疾患)、心筋梗塞、心不全、うっ血性心不全および無痛性虚血性心疾患、肺水腫、高血圧、肺高血圧; 門脈圧亢進症; 糖尿病性腎障害; 褥瘡、腎不全が挙げられる。
被験化合物A: 11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1
被験化合物B: 11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1 イソプロピルエステル
被験化合物A: 11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1
およそ 2.5-3.5 kg の体重の8匹の雄性ニホンシロウサギ (Std:JW/CSK)を本研究に用いた。研究にわたって一貫して各動物の同じ側の眼を被験化合物で処理し、他方の眼を媒体で処理し、各処理の間にウォッシュアウト期間を設けた。30μlの各被験化合物溶液をマイクロピペット (Pipetman、Gilson、Inc.、France)を用いて各動物の一方の眼に局所適用した。反対側の対照眼には等体積の媒体を与えた。動物には毎朝ほぼ同じ時間に投薬した。動物をホルダーに拘束した後、1滴の局所麻酔薬 (0.4% 塩酸オキシブプロカイン)を両眼に適用し、IOPを投薬前および投薬の1、2、4、6、および8 時間後に圧平眼圧計 (Model 30 ClassicTM、Mentor O & O、Inc.、USA)を用いて測定した。
化合物A: 11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1
糖尿病を、7-週齡雄性 Crl: CD(SD) ラットにおいて50 mg/kg ストレプトゾトシン (STZ)の単回静脈内注射によって誘導した。STZ処理の19日後の血漿グルコースレベルが 400 mg/dL 以上の動物を本研究に用いた。STZ 注射の3週間後、動物をナトリウムチオブタバルビタールの腹腔内注射により麻酔した。動物の体温 (直腸温)を加温パッドにより実験の間およそ 37℃に維持した。脱毛クリームによる右後足の前側の脱毛後、皮膚組織血流 (CTBF)を非接触型レーザードップラー血流計 (FLO-N1、Omegawave Inc.、Japan)を用いて連続的に測定した。血圧および心拍数を同時にモニターした。化合物Aまたは媒体を動物に10 分間かけて静脈内投与した。
表 2.ストレプトゾトシン-誘導糖尿病ラットにおける皮膚組織血流に対するSAG-017の効果
化合物A: 11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1
4ヶ月齢雄性 Kbs: J. W. ウサギを、室温 (23-24℃)、相対湿度 (55-74%)、換気速度(10-20回/時間)および12-時間明暗周期 (照明:午前 7:00 -午後 7:00)について制御した動物室中のアルミニウムケージで飼育した。動物にウサギ用固形飼料(120 g/動物/日)および水を自動給水装置から自由に与えた。動物を少なくとも 6 日間検疫および順化に供した。この期間中に、体重測定および全身健康観察を行い、健康状態が良好であると判断された動物を本研究に用いた。
**: P<0.01;媒体対照からの有意差(ダネット多重比較検定)
雄性 Crl: CD(SD) ラットをナトリウムチオブタバルビタールの腹腔内注射により麻酔した。動物の体温 (直腸温)を実験の間加温パッドによりおよそ 37℃に維持した。脱毛クリームによる右後足の前側の脱毛後、皮膚組織血流 (CTBF)を化合物C (11-デオキシ-13,14-ジヒドロ-16,16-ジフルオロ-PGE1)または媒体の静脈内投与の前および30 分後に非接触型レーザードップラー血流計 (FLO-N1、Omegawave Inc.、Japan)を用いて測定した。血圧および心拍数もモニターした。
ヒト血管内皮細胞培養を経内皮電気抵抗 (TEER)により測定して集密にさせた。細胞培養から窒素雰囲気中でのインキュベーションにより30 分間酸素を枯渇させた。細胞を次いで0.1% DMSOまたは5 nM 化合物Aと0.1% DMSOとの組合せ(終濃度)のいずれかにより処理した。細胞密度を示された時点においてTEERにより測定した。
ヒト微小血管内皮細胞(成人) (HMVEC-AD)を集密まで培養した。細胞を窒素雰囲気に30 分間曝し、通常の空気雰囲気に戻した。示された時点でルシフェリン-ルシフェラーゼアッセイシステム (ATPlite、Perkin Elmer)を用いてATPレベルをモニターした。
インスリン非依存性糖尿病の自然モデルである雄性 GK/Jcl ラットをナトリウムチオブタバルビタールの腹腔内注射により麻酔した。動物の体温 (直腸温)を加温パッドにより実験の間およそ 37℃に維持した。脱毛クリームによる右後足の前側の脱毛後、皮膚組織血流 (CTBF)を非接触型レーザードップラー血流計 (FLO-N1、Omegawave Inc.、Japan)を用いて化合物Aまたは媒体の静脈内投与の前(ベースライン)および20分後に測定した。データはベースライン皮膚組織血流と比較しての%として表す。
16,16-ジフルオロ-PGE1 ベンジルエステル (1) (457.8 mg、0.95 mmol) を酢酸 (13.7 mL、0.24 mol)に溶解し、溶液を80℃で18 時間撹拌した。反応混合物を室温まで冷却した。10 mLのトルエンを溶液に添加し、減圧下で濃縮した。 この操作を5回繰り返して酢酸を除去した。残渣をシリカゲルカラムクロマトグラフィー (シリカゲル: FL60D (70 g)、Fuji Silysia、ヘキサン/酢酸エチル (2:1))で精製して化合物 (2)を黄色油状物として得た。収率: 391.6 mg (88.9%)
16,16-ジフルオロ-PGA1 ベンジルエステル (化合物 (2)) (382.5 mg、0.83 mmol)を酢酸エチル (10 mL)中、10% パラジウム-炭素 (57.4 mg、50% w/wの水で湿っている) の存在下で室温、大気圧で2 時間水素化した。反応混合物をセライトパッドでろ過し、フィルターケーキを酢酸エチルで洗浄し、次いでろ液を減圧下で濃縮した。残渣をシリカゲルカラムクロマトグラフィー (シリカゲル BW-300SP (50 g、15% w/w の水で湿っている)、Fuji Silysia、ヘキサン/酢酸エチル (1:1)) で精製し、粗化合物 (3) (298.5 mg、95.7%)を得た。
1H-NMR (200MHz、CDCl3) δ
0.94 (3H、t、J=7.1Hz)、1.22-2.29 (28H、m)、2.34 (2H、t、J=7.3Hz)、3.65-3.81 (1H、m)
13C-NMR(50MHz、CDCl3) δ
13.70、22.40、23.25、24.32、26.28、26.63)、27.18、27.58、28.49、29.09、30.39、31.77 (t、J=24.4Hz)、33.67、37.63、41.05、54.76、72.73 (t、J=29.0Hz)、124.09 (t、J=244.3Hz)、179.07、220.79
化合物 (6)の1H-NMR (200MHz、CDCl3)および 13C-NMR(50MHz、CDCl3)をそれぞれ図 3 および4に示す。
化合物 (9)の1H-NMR (200MHz、CDCl3)および 13C-NMR(50MHz、CDCl3)をそれぞれ図 5 および6に示す。
化合物 (12) の1H-NMR (200MHz、CDCl3) および13C-NMR(50MHz、CDCl3)をそれぞれ図 7および8に示す。
化合物 (15)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)をそれぞれ図 9および10に示す。
化合物 (18)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)をそれぞれ図 11および12に示す。
化合物 (21)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)をそれぞれ図 13および14に示す。
化合物 (23)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)を図 15 および16に示す。
化合物 (25)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)をそれぞれ図 17 および 18に示す。
化合物 (34)の 1H-NMR (200MHz、CDCl3)および13C-NMR(50MHz、CDCl3)をそれぞれ図 19および20に示す。
Claims (13)
- 有効量の11-デオキシ-プロスタグランジン化合物を含む、哺乳類対象における末梢血管疾患を処置するための組成物であって、11−デオキシ−プロスタグランジン化合物が下記一般式(III):
Lは、ヒドロキシまたはオキソ;
Aは、−COOHまたはその塩、エステルまたはアミド;
Bは、−CH2−CH2 −;
Zは、
X1およびX2は、水素またはハロゲンであって、X 1 およびX 2 の少なくとも一方はハロゲンである;
R1 は、飽和または不飽和の二価のC1−10脂肪族炭化水素;
R2は、単結合;および、
R3は、直鎖または分岐鎖C1−6アルキル]
で表される化合物である、組成物。 - 有効量の11-デオキシ-プロスタグランジン化合物を含む、哺乳類対象における損傷を受けた末梢血管壁を処置するための組成物であって、11−デオキシ−プロスタグランジン化合物が下記一般式(III):
Lは、ヒドロキシまたはオキソ;
Aは、−COOHまたはその塩、エステルまたはアミド;
Bは、−CH2−CH2−;
Zは、
X1およびX2は、水素またはハロゲンであって、X 1 およびX 2 の少なくとも一方はハロゲンである;
R1 は、飽和または不飽和の二価のC1−10脂肪族炭化水素;
R2は、単結合;および、
R3は、直鎖または分岐鎖C1−6アルキル]
で表される化合物である、組成物。 - 有効量の11-デオキシ-プロスタグランジン化合物を含む、哺乳類対象における損傷を受けた末梢血管内皮細胞を処置するための組成物であって、11−デオキシ−プロスタグランジン化合物が下記一般式(III):
Lは、ヒドロキシまたはオキソ;
Aは、−COOHまたはその塩、エステルまたはアミド;
Bは、−CH2−CH2 −;
Zは、
X1およびX2は、水素またはハロゲンであって、X 1 およびX 2 の少なくとも一方はハロゲンである;
R1 は、飽和または不飽和の二価のC1−10脂肪族炭化水素;
R2は、単結合;および、
R3は、直鎖または分岐鎖C1−6アルキル]
で表される化合物である、組成物。 - 該11-デオキシ-プロスタグランジン化合物が11-デオキシ-13,14-ジヒドロ-15-ケト-16-モノまたはジハロゲン-プロスタグランジン化合物である請求項1から3いずれかの組成物。
- 該11-デオキシ-プロスタグランジン化合物が11-デオキシ-13,14-ジヒドロ-15-ケト-16-モノまたはジフルオロ-プロスタグランジン化合物である請求項1から3いずれかの組成物。
- 該11-デオキシ-プロスタグランジン化合物が11-デオキシ-13,14-ジヒドロ-15-ケト-16-モノまたはジハロゲン-プロスタグランジンEまたはF化合物である請求項1から3いずれかの組成物。
- 該プロスタグランジン化合物が11-デオキシ-13,14-ジヒドロ-15-ケト-16-モノまたはジフルオロ-プロスタグランジンEまたはF化合物である請求項1から3いずれかの組成物。
- 該プロスタグランジン化合物が11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-プロスタグランジンE1化合物である請求項1から3いずれかの組成物。
- 該末梢血管疾患が末梢動脈疾患である請求項1または4から8いずれかの組成物。
- 該末梢動脈疾患が動脈硬化症である請求項9の組成物。
- 該プロスタグランジン化合物が、11-デオキシ-13,14-ジヒドロ-16,16-ジフルオロ-PGEまたはPGF化合物、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGEまたはPGF化合物、2-デカルボキシ-2-(2-カルボキシエチル)-11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGEまたはPGF化合物、または11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-20-エチル-PGEまたはPGF化合物である、請求項1から3いずれかの組成物。
- 該プロスタグランジン化合物が、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1、11-デオキシ-13,14-ジヒドロ-16,16-ジフルオロ-PGE1、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1イソプロピルエステル、2-デカルボキシ-2-(2-カルボキシエチル)-11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1イソプロピルエステル、2-デカルボキシ-2-(2-カルボキシエチル)-11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-20-メチル-PGE1イソプロピルエステル、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-20-メチル-PGE1、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-20-エチル-PGE1、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGE1メチルエステル、11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-20-エチル-PGE1イソプロピルエステルまたは11-デオキシ-13,14-ジヒドロ-15-ケト-16,16-ジフルオロ-PGF1αイソプロピルエステルである、請求項1から3のいずれかの組成物。
- 該プロスタグランジン化合物が、11−デオキシ−13,14−ジヒドロ−15−ケト−16,16−ジフルオロ−PGE1である、請求項1から3のいずれかの組成物。
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