JPWO2007077876A1 - 新規トリハロメチオニン誘導体及びそれを含む医薬 - Google Patents
新規トリハロメチオニン誘導体及びそれを含む医薬 Download PDFInfo
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- JPWO2007077876A1 JPWO2007077876A1 JP2007552961A JP2007552961A JPWO2007077876A1 JP WO2007077876 A1 JPWO2007077876 A1 JP WO2007077876A1 JP 2007552961 A JP2007552961 A JP 2007552961A JP 2007552961 A JP2007552961 A JP 2007552961A JP WO2007077876 A1 JPWO2007077876 A1 JP WO2007077876A1
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- trifluoromethionine
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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Abstract
Description
赤痢アメーバは大腸の腸管内に寄生する嫌気性・微好気性の原虫である。人への感染は嚢子(シスト)に汚染した食物や水を口から飲み込むことで起こる。嚢子は小腸で脱嚢して、栄養型となり、大腸に達し、直腸、S状結腸、盲腸、上行結腸などの大腸粘膜面に潰瘍性病原を形成する。感染者のすべてが発症するわけではなく、症状を示すのは5-10%とされている。発症すると、粘血便、下痢、テネスムス(しぶり腹)、鼓腸、排便時の下腹部痛などの赤痢症状を示す。また、典型的症例では粘血便を排出し、数日から数週間の間隔で増悪と寛解を繰り返す。増悪例では腸穿孔を起こす。また、大腸炎の症状を示すもののうち約5%が腸管外病変を示す。特に、肝臓・肺・脳・皮膚などの臓器・組織に膿瘍を形成する。このうち肝膿瘍が最も頻繁にみられ38-40℃の発熱、季肋部痛、嘔気、嘔吐、体重減少、寝汗、全身倦怠を伴う。膿瘍が破裂すると腹膜、胸膜、心外膜にも病変が形成され、重篤な症状を呈する。大腸内で、栄養型は被嚢し、糞便中に排出され、これを別の人が経口摂取することにより感染が成立する。
赤痢アメーバ症の治療は通常メトロニダゾール(商品名、フラジール)の経口投与により行われ、有症者への治療効果は高い。しかしながら、メトロニダゾールは消化管からの吸収がよく、逆に腸管内のシストへの殺滅効果が低く、シストキャリアの集団治療などでの有効性に問題がある。キャリアの治療の際には、メトロニダゾールとともに、消化管からの吸収が低いとされるフロ酸ジロキサニドが用いられる。しかし、シストへの殺虫効果が充分に得られない症例が散見される。メトロニダゾールのその他の問題点はインビトロでの耐性が簡単に獲得されることである。マラリア原虫などの他の原虫における耐性株の出現の現状をふまえると、赤痢アメーバのメトロニダゾール耐性株の出現は時間の問題であると予想されている。赤痢アメーバ同様嫌気的原虫であるトリコモナス原虫では既にメトロニダゾール耐性臨床株が報告されている。したがって赤痢アメーバを殺滅する効果を有する新たな化合物の合成が危急に必要とされている。
(i)水素
(ii)
(iii)
(iv)炭素数1〜5のアルキル
(v)炭素数1〜5のヒドロキシアルキル
本発明はまた、上記化合物又はその塩を有効成分とする医薬を提供する。
本発明はまた、細菌又は原虫による感染症治療薬である、上記医薬を提供する。
本発明はまた、赤痢アメーバ症又はトリコモナス症の治療薬である、上記医薬を提供する。
本発明はまた、上記一般式(I)で表される化合物を患者に投与することを含む、細菌又は原虫による感染症の治療方法を提供する。
本発明はまた、上記一般式(I)で表される化合物の細菌又は原虫による感染症治療薬の製造のための使用を提供する。
一般式(I)において、Zは−(CH2)m−(mは1〜5の整数である)であり、より好ましくは、−CH2−または−(CH2)2−である。
(i)水素
炭素数1〜5のアルキルは、直鎖でも分岐鎖でもよい。
炭素数1〜5のヒドロキシアルキルのアルキル鎖は、直鎖でも分岐鎖でもよく、ヒドロキシル基の位置は特に制限されない。
また、トリフルオロメチオニンベンジルアミドの場合、トリフルオロメチオニンをベンジルアミンと反応させることによっても得ることができる。
なお、原料となるトリフルオロメチオニンは以下の文献に記載された既存の方法に従って得ることができる。
R. L. Dannley, R. G., Taborsky, J. Org. Chem. 1957, 22, 557
M. E. Houston, J. F. Honek, J. Chem. Soc. Chem. Commun. 1989, 761
Tadashi Shiraiwa, Chem. Pharm. Bull. 2002, 50, 1081.
V. Soloshonok, V. Kukhar, Y.Pustovit, V. Nazaretian, Synlett 1992, 657.
その他の化合物も実施例に記載された方法で合成することができる。
式(I)の化合物の製剤中の含有量は、製剤全体の約0.01ないし約100重量%である。
式(I)の化合物の投与量は、投与対象、対象臓器、症状、投与方法などにより異なり特に制限されないが、一般的に、患者(体重60kgとして)に対して、一日につき約0.1〜100mg、好ましくは約1.0〜50mg、より好ましくは約1.0〜20mgである。
なお、本発明の医薬はその他の感染症治療薬と併用してもよい。
合成例1.トリフルオロメチオニンアミドの合成
オートクレーブにメタノール5 mlを入れ-15 ℃に冷却後、アンモニアガスを飽和するまで吹き込み約7M アンモニアのメタノール溶液を調整した。トリフルオロメチオニンメチルエステル(50.4 mg,0.199 mmol)をメタノールに溶かし、これをアンモニアのメタノール溶液に加え封管し60℃で10時間撹拌を行った。溶媒を減圧留去し、水による再結晶を行いトリフルオロメチオニンアミド(上記一般式(II))を 35.8 mg (89%) 得た。
1H NMR δ(D2O)2.15-2.26 (m, 2H,β-CH2), 2.96 (t, 2H, J = 9.0 Hz,γ-CH2), 4.02 (t, 1H, J = 9.0 Hz, α-CH)
19F NMR δ-41.31 (s, CF3)
IR (KBr, cm-1): 3438, 2925, 1681, 1492, 1120,804
mp : 165-166℃
GCMS(m/z): 202(M+), 186, 158, 115, 101,73,56
M.W.: 303.30
Rf = 0.25 (hexane/ ethyl acetate = 60/ 40)
1H-NMR (CDCl3, 200 MHz) δ:1.46 (9H, s), 2.05-2.12 (1H, m), 2.31-2.34 (1H, m), 2.98 (2H, t, J =7.6Hz), 4.30-4.42 (1H, br), 8.45 (1H, br)
19F-NMR (CDCl3, 188 MHz) δ: −42.0 (s)
1H-NMR (CDCl3, 200 MHz) δ:1.42 (9H, s), 1.93-2.04 (1H, m), 2.21-2.28 (1H, m), 2.95 (2H, t, J =7.2Hz), 4.26 (1H, br), 4.44 (2H, br), 6.44 (1H, br), 7.25 (5H, s)
19F-NMR (CDCl3, 188 MHz) δ: −41.3 (s)
1H-NMR (CDCl3, 200 MHz) δ:1.44 (9H, s), 1.94-2.20 (1H, m), 2.21-2.40 (1H, m), 3.01 (2H, t, J =7.4Hz), 4.42 (1H, br), 7.25-7.7.49 (5H, m)
19F-NMR (CDCl3, 188 MHz) δ: −41.2 (s)
1H-NMR (D2O, 200 MHz) δ:2.13 (2H, q, J =7.2 Hz), 2.74-2.837 (2H, m), 3.94 (1H, t, J =6.6 Hz), 4.25 (2H, dd, J =12.2 Hz), 7.14-7.27 (5H, m)
19F-NMR (CDCl3, 188 MHz) δ: −39.5 (s)
EI Mass 292 (M+HCl), 91 (C7H7), 158 (M+−HCl−C8H8NO)
IR (KBr) 2977, 1668
1H-NMR (D2O, 200 MHz) δ:2.23 (2H, q, J =8.2 Hz), 2.91 (2H, t, J =8.2 Hz) 4.10 (1H, t, J =6.4 Hz), 7.03-7.07 (1H, m), 7.16-7.30 (4H, m)
19F-NMR (CDCl3, 188 MHz) δ: −39.5 (s)
EI Mass 278 (M+−HCl), 69 (CF3), 77 (C6H5), 115 (M+−HCl−C9H12N2O), 158 (C4H7F3NS)
IR (KBr) 3042, 1677
(WY-241の原料)
分子式 C16H20BrF3N2O3S
M.W.: 457.31
1H-NMR (CDCl3) δ:1.46 (9H, s), 2.03-2.12 (1H, m), 2.29-2.36 (1H, m)3.02 (2H, t, J =7.0Hz), 4.38 (1H, q, J =6.2Hz), 5.10 (1H, d, J=8.4Hz), 7.33 (4H, s), 8.42 (1H, br)
19F-NMR (CDCl3) δ: −41.8 (s)
分子式 C12H17BrClF3N2OS
M.W.: 393.37
1H-NMR (D2O) δ:2.32 (2H, q, J =6.8 Hz), 3.01 (2H, t, J =7.2 Hz), 4.14 (1H, t, J =6.4 Hz), 7.27 (2H, d, J =6.4 Hz), 7.47 (2H, d, J =6.4 Hz)
19F-NMR (D2O) δ: −42.1 (s)
IR (KBr) 2965, 1672, 1129, 683 cm-1
分子式 C16H19F5N2O3S
M.W.: 414.39
1H-NMR (CDCl3) δ:1.46 (9H, s), 2.05-2.12 (1H, m), 2.23-2.42 (1H, m), 3.02 (2H, t, J=7.2Hz), 4.43 (1H, q, J=7.2Hz), 5.10 (1H, d, J=8.4Hz), 6.85 (2H, t, J=8.4Hz)7.21 (2H, d, J=8.4Hz), 8.07-8.18 (1H, m), 8.35 (1H, br,)
19F-NMR (CDCl3) δ: −41.2 (s), 113.8 (s), 124.4 (s)
(WY-244)
分子式 C12H16ClF5N2OS
M.W.: 350.70
1H-NMR (D2O) δ:2.33 (2H, q, J =7.4 Hz), 3.02 (2H, t, J =7.2 Hz), 4.23 (1H, t, J =6.4 Hz), 6.92 (2H, q, J=8.4 Hz), 7.41 (1H, q, J=8.4Hz)
19F-NMR (D2O) δ: −42.1 (s), 111.5 (t), 119.1 (d)
IR (KBr) 2914, 1694, 1508, 1114 cm-1
ester (WY-252の原料)
分子式 C16H19F5N2O3S
M.W.: 414.39
1H-NMR (CDCl3) δ:1.46 (9H, s), 2.05-2.12 (1H, m), 2.23-2.42 (1H, m), 3.02 (2H, t, J=7.2Hz), 4.43 (1H, q, J=7.2Hz), 5.10 (1H, d, J=8.4Hz), 6.85 (2H, t, J=8.4Hz)7.21 (2H, d, J=8.4Hz), 8.07-8.18 (1H, m), 8.35 (1H, br,)
19F-NMR (CDCl3) δ: −41.2 (s), 113.8 (s), 124.4 (s)
(WY-252)
分子式 C12H16ClF5N2OS
M.W.: 350.70
1H-NMR (D2O) δ:2.33 (2H, q, J =7.4 Hz), 3.02 (2H, t, J =7.2 Hz), 4.23 (1H, t, J =6.4 Hz), 6.92 (2H, q, J=8.4 Hz), 7.41 (1H, q, J=8.4Hz)
19F-NMR (D2O) δ: −42.1 (s), 111.5 (t), 119.1 (d)
IR (KBr) 2914, 1694, 1508, 1114 cm-1
1H-NMR (CDCl3, 200 MHz) δ:1.49 (9H, s), 3.25 (1H, dd, J =6.2 Hz), 3.39 (1H, dd, J =5.8 Hz), 4.57 (q, 1H, J =8.6 Hz), 5.26 (1H, d, J =9.6 Hz), 7.09-7.51 (5H, m)
19F-NMR (CDCl3, 188 MHz) δ: −41.5 (s)
1H-NMR (D2O, 200 MHz) δ:3.34-3.58 (m, 2H), 4.30 (t, 1H, J =6.6 Hz), 7.08-7.35 (m, 5H)
19F-NMR (CDCl3, 188 MHz) δ: −39.7 (s)
EI Mass 264 (M+−HCl), 77 (C6H5), 115 (M+−HCl−C8H9N2O), 144 (M+−HCl−C7H6NO), 195 (M+−HCl−CF3)
IR (KBr) 3468, 2971, 1673, 1604, 1556, 1496, 1450
(sk-276の原料)
morpholine (0.09 ml, 0.794 mmol)を加え, 攪拌した。2分後Isobutyl chloroformate (0.10 ml, 0.794 mmol)を加え, 2分攪拌させた。最後に1-Aminoindane (0.10 ml, 0.794 mmol)を加えた。TLCにより原料消失を確認した後, 固形物をろ過し, 減圧下でTHFを留去した。カラムクロマトグラフィー (hexane/ ethyl acetate = 90/10→80/20)で精製し, 生成物 (200.4 mg, 73%)を得た。
1H-NMR (CDCl3, 200 MHz) δ1.41 (s, 9H), 1.73-1.84 (m, 1H), 2.04 (m, 1H), 2.25 (m, 1H), 2.55 (m, 1H), 2.97 (m, 4H), 4.24 (q, 1H, J =6.6 Hz), 5.17 (s, 1H), 5.42 (q, 1H, J =7.8 Hz), 7.21 (m, 4H)
19F-NMR (CDCl3, 188 MHz) δ: −41.3(s)
(sk-276)
1H-NMR (CD3OD, 200 MHz) δ:1.70-1.93 (m, 1H), 2.13-2.24 (m, 2H), 2.35-2.54 (m, 1H), 2.72-2.98 (m, 4H), 3.84 (q, 1H, J =6.2 Hz), 5.32 (t, 1H, J =7.2 Hz), 7.07-7.23 (m, 4H)
19F-NMR (CDCl3, 188 MHz) δ: −40.8 (s), −40.9 (s)
EI Mass 318 (M+−HCl), 69 (CF3), 185 (M+−HCl−C9H10N), 200 (M+−HCl−C9H9), 216 (M+−HCl−CF3S)
IR (KBr): 3289, 2929, 1656, 1558
1H-NMR (CDCl3, 200 MHz) δ:1.42 (9H, s), 3.21 (1H, dd, J =6.0 Hz), 3.33 (1H, dd, J =5.8 Hz), 4.43 (3H, J =6.0 Hz)(ダブルトリプレットとダブレット二つが重なっている。), 5.22 (1H, d, J =8.8 Hz), 6.65 (1H, s), 7.24-7.37 (5H, m)
19F-NMR (CDCl3, 188 MHz) δ: −41.4 (s)
1H-NMR (D2O, 200 MHz) δ:3.31 (m, 2H), 4.12 (t, 1H, J =6.6 Hz), 4.25 (d, J =8.8 Hz), 7.13-7.22 (5H, m)
19F-NMR (CDCl3, 188 MHz) δ: −39.9 (s)
EI Mass 278 (M+−HCl), 77 (C6H5), 91 (C7H7), 106 (C7H8N), 144 (M+−HCl−C8H8NO), 163 (M+−HCl−C2H2F3S), 177 (M+−HCl−CF3S), 187 (M+−HCl−C7H7)
IR (KBr) 3308, 2971, 1663, 1558, 1497, 1457
(sk-336の原料)
1H-NMR (CDCl3, 200 MHz) δ:1.47 (s, 9H), 1.97-2.15 (m, 1H), 2.23-2.41 (m, 1H), 3.02 (t, 2H, J =7.8 Hz), 3.78 (s, 3H), 3.81 (s, 6H), 4.40 (q, 1H, J =7.4 Hz), 5.15 (d, 1H, J =8.2 Hz), 6.76 (s, 2H), 8.43 (s, 1H)
13C-NMR (CDCl3, 188 MHz) δ: 26.9, 28.9, 33.0, 54.7, 56.4, 61.4, 81.7, 97.6, 128.1, 133.9, 134.1, 134.8, 153.2, 156.7, 169.7
19F-NMR (CDCl3, 188 MHz) δ: −41.2 (s)
mp: 60.0−62.0℃
[α]20 D: −39.7 (c=1.000, CHCl3)
EI Mass 468 (M+), 57 (C4H9), 69 (CF3), 115 (C2H2F3S), 158 (M+−C9H12NO3−C3H4F3S), 168 (C9H11O3), 183 (C9H12NO3), 353 (M+−C2H2F3S), 368 (M+−CF3S), 412 (M+−C4H9)
IR (KBr): 3309, 1674, 1614, 1509
1H-NMR (CD3OD, 200 MHz) δ:2.28 (q, 2H, J =6.2 Hz), 3.02 (t, 2H, J =7.6 Hz), 3.63 (s, 3H), 3.71 (s, 6H), 4.09 (t, 1H, J =6.4 Hz), 6.91 (s, 2H)
19F-NMR (CDCl3, 188 MHz) δ: −40.8 (s)
EI Mass 368 (M+−HCl), 69 (CF3), 115 (C2H2F3S), 129 (C3H4F3S), 158 (M+−HCl−C10H12NO4), 168 (C9H11O3), 183 (C9H12NO3), 209 (M+−HCl−C4H7F3NS), 267 (M+−HCl−CF3S)
IR (KBr): 2944, 1690
13C-NMR (CDCl3, 188 MHz) δ: 26.9, 28.9, 33.2, 54.4, 56.2, 56.5, 81.4, 104.9, 111.4, 112.3, 131.3, 146.1, 149.1, 156.6, 169.7
1H-NMR (CDCl3, 200 MHz) δ:1.43 (s, 9H), 2.02-2.37 (m, 2H), 2.98-3.07 (m, 2H), 3.75 (s, 3H), 3.81 (s, 3H), 4.51 (q, 1H, J =5.4 Hz), 5.59 (d, 1H, J =8.4 Hz), 6.65-6.69 (m, 1H), 6.83-6.88 (m, 1H), 7.17 (s, 1H), 8.80 (s, 1H)
19F-NMR (CDCl3, 188 MHz) δ: −41.2 (s)
mp: 129.5−130.0℃
[α]20 D: −40.7 (c=1.063, CHCl3)
EI Mass 438 (M+), 57 (C4H9), 69 (CF3), 138 (C8H9O2), 153 (C8H10NO2), 179 (C9H10NO3), 338 (M+−CF3S), 382 (M+−C4H9)
IR (KBr): 3303, 1665, 1612, 1516
1H-NMR (CD3OD, 200 MHz) δ:2.27 (q, 2H, J =6.2 Hz), 3.01 (t, 2H, J =7.6 Hz), 3.71 (s, 3H), 3.72 (s, 3H), 4.03 (t, 1H, J =6.4 Hz), 6.79-6.83 (m, 1H), 6.98-7.04 (m, 1H), 7.22-7.23 (m, 1H)
19F-NMR (CDCl3, 188 MHz) δ: −40.8 (s)
EI Mass 338 (M+−HCl), 69 (CF3), 115 (C2H2F3S), 129 (M+−HCl−C3H4F3S), 138 (C8H9O2), 158 (M+−HCl−C9H10NO3), 181 (C9H10NO3), 210 (M+−HCl−C10H13N2O3), 237 (M+−HCl−CF3S)
IR (KBr): 2941, 1677
トリフルオロメチオニン(TFM)、トリフルオロメチオニンアミド(WY200)、メトロニダゾール(公知の抗アメーバ薬)のそれぞれの化合物の、赤痢アメーバHM1:IMSS cl6株に対する殺滅効果を調べた。
それぞれの化合物を80 μMの濃度で添加した状態で、18時間赤痢アメーバHM1:IMSS cl6株を培養した。18時間後のHM1:IMSS cl6株の細胞数を比較したデータを図1に示す。なお、細胞数はWST-1(ロシュ・ダイアグノスティクス社)を用いて赤痢アメーバの生細胞数を決定した。
その結果、WY200がトリフルオロメチオニンよりも、更に、現在臨床の現場で用いられているメトロニダゾールよりも有効に赤痢アメーバ原虫を殺滅することがわかった。なお、WY202はトリフルオロメチオニンの別の誘導体で抗アメーバ効果を持たない化合物であり、DMSO及びnoneは陰性対照群である。
更に、トリフルオロメチオニン(TFM)、トリフルオロメチオニンアミド(WY200)、SK254、 SK258、WY241、WY244、WY252、KO10、SK276、SK316、SK336、SK337のそれぞれの化合物の、赤痢アメーバHM1:IMSS cl6株に対する殺滅効果を調べた。それぞれの化合物を0.25-20μMの濃度で添加した状態で、赤痢アメーバHM1:IMSS cl6株を96穴プレート上で嫌気
的条件下で培養した。72時間後の細胞数を実施例1と同様の方法で決定した。薬剤を加えない状態の増殖を50%阻害する濃度(IC50)を表1に示す。SK337を始めとする多くの化合物がトリフルオロメチオニンよりも10倍以上低い濃度で赤痢アメーバ原虫を殺滅することがわかった。
次いで、ハムスター肝膿瘍モデルを用いた動物感染実験において本発明の化合物を評価した。
まず、3週齢のメスのハムスターに赤痢アメーバHM1:IMSS cl6株を接種して肝膿瘍を惹起させた。表2からわかるように、これにより、コントロール群に見られるように肝膿瘍が生じ、肝の総重量は増加する。これに対し、40μmolのトリフルオロメチオニンアミド(WY200)を腹腔内投与したハムスターは、肝膿瘍が生じることはなく、肝の総重量は増加しなかった。また、この薬剤を投与されたハムスター群の体重増加はコントロール群と同様に良好であった。なお、WY202はトリフルオロメチオニンの別の誘導体で抗アメーバ効果を持たない化合物である。表2において、各群のA、B、Cは使用した個体を示す。
なお、本実施例では赤痢アメーバに対する本発明の化合物の効果を示したが、トリフルオロメチオニンやメトロニダゾールがトリコモナスなどに対しても殺滅効果を有することが知られていることからも、本発明の化合物はトリコモナスなどの原虫や細菌に対しても有効であることが容易に推定できる。
更に多くの化合物(トリフルオロメチオニン、SK254, SK258, WY241, WY244, WY252)を用いて上記実施例3と同様の方法により動物感染実験において評価した。結果を表3に示す。一頭(体重28-37g)あたり3マイクロモル(1.1-1.3mg)の化合物の腹腔内投与したハムスターは、肝膿瘍が生じることはなく、肝の総重量は増加しなかった。これにより、本発明の化合物が動物実験においても赤痢アメーバ症の治療に有効であることが示された。
Claims (6)
- 一般式(I)において、Rが前記(i)〜(iii)のいずれかである、請求項1に記載の化合物。
- 請求項1〜3のいずれか一項に記載の化合物又はその塩を有効成分とする医薬。
- 細菌又は原虫による感染症治療薬である、請求項4に記載の医薬。
- 赤痢アメーバ症又はトリコモナス症の治療薬である、請求項4に記載の医薬。
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