JP4413599B2 - 新規化合物およびそれを含む薬学的組成物 - Google Patents
新規化合物およびそれを含む薬学的組成物 Download PDFInfo
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- JP4413599B2 JP4413599B2 JP2003417356A JP2003417356A JP4413599B2 JP 4413599 B2 JP4413599 B2 JP 4413599B2 JP 2003417356 A JP2003417356 A JP 2003417356A JP 2003417356 A JP2003417356 A JP 2003417356A JP 4413599 B2 JP4413599 B2 JP 4413599B2
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Description
Hamuro Jら(1978)、Cancer Res.38:3080−3085 Mizuno Tら(1992)、Biosci.Biotechnol.Biochem.56:347−348 Ebina Tら(1986)、Jpn.J.Cancer Res 77:1034−1042 Fujimiya Yら(1998)、Cancer Immunol Immunother 46:147−159 Ebina Tら(1998)、Biotherapy 11:259−265 Mizuno Mら(1998)、Biosci.Biotechnol.Biochem.62:434−437
R2は、上記R1で定義した基と同意義の基およびC(NHR3)R3からなる群から選択される基であり、
R3は、置換または非置換の直鎖C1〜C6アルキルであり、
R4は、カルボキシル基で置換された直鎖C1〜C6アルキルであり、
nは、0〜6の整数である、化合物。
ここで、上記R1は、末端カルボキシル基で置換された直鎖C1〜C6アルキル、または末端ヒドラジノ基もしくは末端アミノ基で置換されたアミノ酸である、化合物。
ここで、上記R1およびR2は、独立して、OR4、NHR4、SR4、SO3R4、(CH2)nR3、(CH2)nR4、(CH=CH)nR4、C(=O)R4、PhR4および(CH2)nCHR3R4からなる群から選択される基であり、
R3は、置換または非置換の直鎖C1〜C6アルキルであり、
R4は、カルボキシル基で置換された直鎖C1〜C6アルキルであり、
nは、0〜6の整数である、化合物。
1.1.β−N−(γ−グルタミル)−4−フォルミルフェニルヒドラジン(式VII)の合成
フェニルヒドラジン940mgに大過剰量のグルタミン酸を加え、公知の方法を用いて縮合させ、β−N−(γ−グルタミル)−フェニルヒドラジンを形成し、この縮合反応をフェニルヒドラジンが完全に消失するまで行った。次いで、加圧CO雰囲気下にて、HCl/AlCl3の存在下でフォルミル化を行い、最終生成物1(150mg)を得た。
2−フォルミル−5−ヒドロキシメチルピロール625mgに4−クロロ−酪酸674mg及び炭酸カリウム600mgを加え、18時間加熱還流した。冷却後、反応液を濾過した後、濾液を減圧下濃縮乾固し、残留物をシリカゲルカラムクロマトグラフィー(シリカゲル:30g,溶離液:クロロホルム−メタノール2:1)にて精製し、最終生成物2(無色油状、60mg)を得た。
得られた最終生成物1および2をそれぞれ、10mg/mlの濃度になるように、mili−Q水を加えて水溶液とした後に測定に供した。測定装置として、JEOL HX110/110Aタンデム型質量分析計を用い、以下のFAB、EI、CIおよびHRFABの質量分析において、それぞれ、ポジティブ(FAB、EI、CI)、ネガティブ(FAB、CI)およびネガティブ(HRFAB)の測定モードで測定した。なお、各質量分析における分解能は、FAB、EIおよびCIについて1000、そしてHRFABについて5000で行った。
マトリックスとしてグリセロールを用いた。試料搭載台でグリセロールと試料とを1:1(v/v)で混合した直後に測定を行った。質量較正には、ポジティブモードではアルカリイオンの混合物を、ネガティブモードではヨウ化セシウム(CsI)のグリセロール溶液を使用した。
試料そのものをイオン源に導入した。CIではイオンガスとしてイソブタンを使用した。
質量較正試料としてPEG−500を使用した。試料搭載台でグリセロールと試料とを1:1(v/v)で混合した後に適量のPEG−500を添加し、直後にネガティブモードで測定を行った。質量較正は、目的ピーク([M−H]−=210)を挟む2本のPEG−500のピークを選択して行った。
Bruker DMX500核磁気共鳴装置(1H500MHz)およびJEOL JNM−A400核磁気共鳴装置(1H400MHz)を用いて行った。
最終生成物1:
FAB−MSにおいて、m/z 266で偽分子イオンMH+を観察し、EI−MSにおいて、トリフロオロ酢酸および酢酸誘導体については、それぞれ、m/z 649(C20H11F12N3O3)でM+イオンを、m/z 331で[M−H2O]+イオンを観察した。H1NMRにより、アルデヒドプロトン、p−置換芳香環およびグルタミン酸残基−CO−CH2−CH2−CH(NH2)−COOHが特徴付けられた。2個の芳香族プロトン(d7.91ppm)の脱シールド、中性溶液(313nm)およびアルカリ性溶液(385nm)でのUV吸収、m/z 136(C7H8N2O)における重要なイオンの発生は、p−フォルミルフェニルヒドラジンユニットと一致した。下記1H−NMRは、重水中、テトラメチルシランを内部標準として測定した。δ値はppmで、結合定数(J)はHzで表記した。データ中、sは一重線、dは二重線、tは三重線、mは多重線を意味する。
上記各種質量分析モードにおけるいずれのスペクトルにおいても分子量211に相当するピークが観測され、この化合物の分子量は211と決定された。次いで、ピーク感度がより良好なネガティブモードでHRFAB−MS測定を行ったところ、観測された精密質量(m/z=210.0757)がC10H12O4N(−1.0mmu)とよい一致を示したことから、最終生成物2の分子式は、C10H18O4Nと決定された。
ATO−1の合成スキームおよび合成方法を以下に示す。
4−(4−グルタミル)アミノベンズアルデヒド(ATO−1)
MS m/z 251(M++1);IR(KBr)ν3400,1670,1590,1540cm−1;1H NMR(D2O,500MHz)δ2.20(2H,ddd,J=6.8),2.60(2H,dd,J=6.8,7.3),3.79(1H,t,J=6.8),7.65(2H,d,J=8.3),7.88(2H,d,J=8.3),9.79(1H,s)。
出発物質である4−クロロ−酪酸の代わりに5−クロロ−吉草酸を用いることを除いて、上記と同様の方法でアルキル化および精製を行い、最終生成物4(無色油状、50mg)を得た。
p−ニトロベンズアルデヒド1.51gを無水エタノール20ml中に懸濁し、塩化スズ(II)11.28gを添加して還元反応を行った。得られた反応液を水50mlに添加し、水酸化ナトリウムを用いて中和した後、反応産物を酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した後濾別した。得られた濾液に1N HCl/MeOH 11mlを添加して造塩し、析出した結晶を濾別、洗浄および乾燥してp−アミノベンズアルデヒド塩酸塩0.88gを得た。
3350cm−1(−NH)、3102〜2981cm−1(−COOH)、2842cm−1付近(−CH2−)、1716cm−1(−CHO)、1664〜1525cm−1付近(−NH)、1581cm−1(−COOH)、1317cm−1付近(−CH2)、1164cm−1(Ph・N)。
N−Boc γアミノ酪酸(GABA)3.66gをTHF 10mlに溶解し、冷却した後、DCC4.1g/THF 5ml溶液を添加して一昼夜反応させた。析出した結晶(DCU)を濾別し、得られた濾液を塩化メチレンに溶媒置換することによりN−Boc GABA無水溶液を得た。このN−Boc GABA無水物溶液に、p−アミノベンズアルデヒド塩酸塩0.63g、およびトリエチレンアミン0.42gを添加してペプチドを形成させた。得られた反応液を濃縮し、残渣を酢酸エチルに溶解し、5%重炭酸ナトリウム水溶液、水、飽和食塩水の順で洗浄した後、硫酸ナトリウムを用いて乾燥した。これを、濾過した後濃縮し、シリカゲルクロマトグラフィーを用いて精製し、濃縮することにより赤褐色のoilを得た。これを塩化メチレンに溶解し、氷冷下、TFA/塩化メチレン溶液を滴下して反応させ、Boc基を除去した。得られた反応液を濃縮し、赤褐色のoilを得た。これを、NMR、IR、LC、TLCを用いて分析した結果、以下の構造式で表される4−(4−フォルミルフェニルカルバモイル)プロピルアミンであることが確認された。
上記実施例1で合成したN−(3−カルボキシプロピル)−2−フォルミル−5−ヒドロキシメチルピロール(最終生成物2)、およびβ−N−(γ−グルタミル)−4−フォルミルフェニルヒドラジン(最終生成物1)について、樹状細胞(dendritic cell)を用いて免疫賦活活性を測定した。
2.1.材料
同意を得ることのできた2人の健常人の末梢血を材料として用いた。
ヘパリン加採血された全血検体からFicoll−Paque比重遠心法によりPBMCを分離した。
上記実施例1で合成されたN−(3−カルボキシプロピル)−2−フォルミル−5−ヒドロキシメチルピロール(最終生成物2)、およびβ−N−(γ−グルタミル)−4−フォルミルフェニルヒドラジン(最終生成物1)を被験試料とした。
上記化合物の免疫賦活活性効果を、インビトロにおけるヒト末梢血単球由来樹状細胞(dendritic cell:DC)誘導能から検討した。
検討を行った被験体で、DC培養開始6日目に上記化合物を添加することによって、CD80分子の著しく強い発現誘導が認められた。その代表的パターンを示した一例を図1および図2に示す。
上記実施例1で合成したN−(3−カルボキシプロピル)−2−フォルミル−5−ヒドロキシメチルピロール(最終生成物2)、およびβ−N−(γ−グルタミル)−4−フォルミルフェニルヒドラジン(最終生成物1)について、白血病細胞株の増殖抑制作用を測定した。白血病細胞株の増殖抑制作用は、TUNEL法(terminal deoxynucleotidyl transferase(TdT)−mediated deoxyuridine triphosphate(dUTP)−biotin nick end−labeling method)を用いて測定した。
実施例1で合成したβ−N−(γ−グルタミル)−4−フォルミルアニリン(最終生成物3)およびN−(4−カルボキシブチル)−2−フォルミル−5−ヒドロキシメチルピロール(最終生成物4)についても、実施例2と同様に、免疫賦活活性を測定する。β−N−(γ−グルタミル)−4−フォルミルアニリンおよびN−(4−カルボキシブチル)−2−フォルミル−5−ヒドロキシメチルピロール存在下で培養した樹状細胞上の表面抗原を、モノクローナル抗体(抗−CD80;BD Bioscience社製)を用いたフローサイトメトリーで解析することによって、DC細胞誘導能をアッセイし免疫賦活活性を確認する。
上記実施例1.3、1.6および1.7で合成したATO−1、ATO−3、およびATO−4のそれぞれ6mgをエッペンドルフチューブに入れ、最終濃度が100μl/mlになるようにDMSOに溶解して各被験試料の溶液を作製した。得られた被験試料の溶液の各々を、さらにDMSOで希釈して各被験試料について異なる濃度の一連の希釈系列を作製した。得られた各被験試料の一連の希釈系列を、新しく採取した精製水(miliQ)で10倍希釈して被験液としてSOD活性を測定した。
SOD活性値(阻害率%)=[(Ablank1−Ablank3)−(Asample−Ablank2)]/(Ablank1−Ablank3)×100
ここで、Ablank1は阻害無しの全発色量を、Ablank2は被験液自体のブランクを、Ablank3はSOD酵素液のブランクをそれぞれ示す。
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