JP5430552B2 - ベンゾ[a]フェノキサチン化合物を有効成分として含有する原虫疾患予防又は治療用医薬組成物 - Google Patents
ベンゾ[a]フェノキサチン化合物を有効成分として含有する原虫疾患予防又は治療用医薬組成物 Download PDFInfo
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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Description
1.下記一般式(1)で示されるベンゾ[a]フェノキサチン化合物又はその塩を有効成分として含有する原虫疾患予防又は治療用医薬組成物。
2.一般式(1)において、R1及びR2それぞれ独立に水素原子、炭素数が1〜8のアルキル基、炭素数が3〜8のアルケニル基、炭素数が6〜10のアリール基又は炭素数が1〜10のヘテロ環残基であり、R3は炭素数が3〜8のアルケニル基、炭素数が6〜10のアリール基又は炭素数が1〜10のヘテロ環残基であり、R4およびR5はそれぞれ独立にハロゲン原子又は炭素数が1〜8のアルキル基であり、m及びnはそれぞれ独立に0又は1を表し、X-で表される陰イオンが、塩素原子、臭素原子、硝酸イオン、硫酸イオン、P-トルエンスルホン酸イオン又はシュウ酸イオンである、請求項1記載の医薬組成物。
3.一般式(1)において、R1及びR2はそれぞれ独立にメチル基、エチル基、プロピル基、2−ヒドロキシエチル基、又は2−メタンスルホンアミドエチル基であり、R3はヘテロ環残基を表す、上記1又は2記載の医薬組成物。
4.R3はピリジル基、ピリミジル基、イミダゾリル基、テトラゾリル基又はチアゾリル基である、上記3記載の医薬組成物。
5.R4はフッ素原子、塩素原子、メトキシ基、エトキシ基、又はメチル基である、上記1〜4のいずれか一項に記載の医薬組成物。
6.R4の置換位置が11位を含む、上記5記載の医薬組成物。
7.R5はフッ素原子、塩素原子又はメチル基である、上記1〜6のいずれか一項に記載の医薬組成物。
8.R5の置換位置が3位を含む、上記7記載の医薬組成物。
9.以下の構造式1A〜1T及び1a〜1hのいずれかで示される化合物又はその塩を有効成分として含有する原虫疾患予防又は治療用医薬組成物。
11.原虫寄生感染症がマラリア症、リーシュマニア症、アフリカ睡眠病、又はシャーガス病である、上記10に記載の医薬組成物。
12.上記の構造式1A〜1T及び1a〜1hのいずれかで示される化合物。
以下の反応式において、一般式1で表されるベンゾ[a]フェノキサチン化合物およびその塩は、一般式3で示される4−ニトロソアニリン誘導体又は5で示されるp−フェニレンジアミン類と一般式4で示される2−ナフトール誘導体をHNO3等の酸化剤の存在下に反応させることにより2を得た後、第一級アミンと酸素を含む酸化剤の存在下にエタノール中で反応させるとベンゾ[a]フェノキサチン1が、遊離塩基として安定な物質として得られた。これらの構造は1Hおよび13C NMR、IR、UV、マススペク1トルさらに元素分析によって決定した。また、これらは塩酸塩としても精製が可能である。なお、1A-1T は総て新規化合物である。
Benzo[a]phenoxazine 1A-1Tの合成
硝酸ベンゾ[a]フェノキサチニウム 2(非特許文献3)(1 mmol)をエタノール (5 mL)に溶解し、相当するアミン (3 mmol) を撹拌下に一気に加え、この混合物を一晩加熱還流し、さらに室温で1日撹拌する。溶媒を留去後、残留物をシリカゲルクロマトグラフィーにて2回精製する。溶出液はCHCl3: MeOH (10:1, v/v) ついで CHCl3: MeOH (10:0.3, v/v)を用いる。溶媒を留去後、生成物をAcOEt ついで Et2Oで洗浄して ベンゾ[a]フェノキサチン 1A-T を得た。
Yield 55 %, mp 169-170℃; IRν(neat, cm-1): 2975, 1645, 1590, 1580, 1490, 1455, 1270, 1220, 1110; UV-vis (CHCl3): λ (nm) (log ε/L mol-1cm-1): 532 (4.57); 1H NMR (400 MHz, CDCl3 )δ ppm 1.20 (t, J = 7.1 Hz, 6H), 3.39 (q, J = 7.1 Hz, 4H), 6.27 (d, J = 2.7 Hz, 1H), 6.43 (s, 1H), 6.54 (dd, J = 9.0, 2.7 Hz, 1H), 6.99-7.03 (m, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.60-7.72 (m, 3H), 8.50-8.51 (m, 1H), 8.60-8.64 (m, 2H); 13C NMR (101 MHz, CDCl3 )δ ppm 12.6, 44.9, 96.3, 99.1, 108.6, 117.0, 118.6, 123.7, 124.7, 125.3, 129.8, 130.1, 130.3, 131.6, 132.8, 137.6, 141.9, 146.6, 148.9, 149.0, 149.9, 157.9, 163.8; MS (EI+): m/z: 394 [M×]+; HRMS (EI+) 394.1793 [M×]+, found 394.1767; Anal. Calcd. For C25H22N4O ×0.75H2O: C, 73.60; H, 5.81; N, 13.73; Found: C, 73.68; H, 5.57; N, 13.43.
Yield 38 %, mp 247-248℃; IR ν (neat, cm-1): 2975, 1640, 1595, 1575, 1490, 1455, 1270, 1220, 1110; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):713 (4.48), 537 (4.49); 1H NMR (400 MHz, CDCl3)δ ppm 1.21 (t, J = 7.1 Hz, 6H), 3.41 (q, J = 7.1 Hz, 4H), 6.13 (s, 1H), 6.29 (d, J = 2.7 Hz, 1H), 6.57 (dd, J = 9.0, 2.7 Hz, 1H), 6.85-6.86 (m, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.61-7.69 (m, 2H), 8.50-8.52 (m, 2H), 8.54 (dd, J = 7.9, 1.4 Hz, 1H), 8.62 (dd, J = 7.9, 1.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)δppm 12.6, 44.9, 96.3, 97.7, 108.8, 116.0, 123.9, 124.7, 125.1, 129.9, 130.3, 130.5, 131.6, 132.2, 141.5, 146.6, 149.1, 150.0, 150.4, 156.8, 159.4; MS (EI+): m/z: 394 [M×]+; HRMS (EI+) 394.1793 [M×]+, found 394.1807; Anal. Calcd. For C25H22N4O×0.25H2O: C, 75.26; H, 5.68; N, 14.04; Found: C, 75.31; H, 5.10; N, 13.88.
1B・HCl mp > 300; IR ν (neat, cm-1): 2920, 2850, 1638, 1579, 1518, 1318, 1251, 1162, 1077; UV-vis (EtOH): λ(nm) (logε/L mol-1cm-1): 602 (4.64), 213 (4.63); 1H NMR (400 MHz, CD3OD) δ ppm 1.47 (t, J = 7.2 Hz, 6H), 4.02 (dd, J = 20.5, 7.1 Hz, 4H), 7.38 (d, J = 2.6 Hz, 1H), 7.60 (d, J = 7.5 Hz, 2H), 7.93-7.87 (m, 1H), 7.97 (dd, J =10.0, 2.6 Hz, 1H), 8.02 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 8.15 (d, J = 10.0 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 7.5 Hz, 2H), 9.17 (d, J = 8.1 Hz, 1H); MS (ESI+): m/z: 395.2 [M-Cl]+; Anal Calcd. For C25H23ClN4O×2.5H2O: C, 63.09; H, 5.93; N, 11.77; Found: C, 62.66; H, 5.42; N, 11.57.
Yield 44 %, mp 217-218 ℃; IR ν (neat, cm-1): 2954, 2887, 1628, 1592, 1577, 1447, 1442, 1359, 1200, 1111, 1002, 746; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):546 (4.42), 236 (4.21); 1H NMR (400 MHz, CDCl3)δ ppm 3.07 (s, 6H), 6.14 (s, 1H), 6.33 (d, J = 2.9 Hz, 1H), 6.61 (dd, J = 9.0, 2.7 Hz, 1H), 6.85-6.87 (m, 2H), 7.48 (d, J = 9.0 Hz, 1H), 7.53-7.55 (m, 2H), 7.66-7.7 (m, 2H), 8.53 (dd, J = 7.9, 1.4 Hz, 1H), 8.64 (dd, J = 7.9, 1.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)δppm 40.3, 96.9, 97.9, 109.1, 112.9, 116.9, 123.9, 125.1, 129.2, 130.1, 130.4, 131.5, 132.2, 142.1, 146.2, 149.08, 152.2, 156.8, 159.4;MS (EI+): m/z: 367.1 [M+1]+; HRMS (EI+) 366.1478 [M×]+, found 366.1480.
Yield 39 %, mp 215-216℃; IR ν (neat, cm-1): 2962, 2876, 1635, 1580, 1547, 1483, 1458, 1361, 1238, 1112, 772; UV-vis (CHCl3):λ(nm) (logε/L mol-1cm-1):716 (4.97), 550 (5); 1H NMR (400 MHz, CDCl3)δ ppm 1.051 (t, J = 7.2 Hz, 6H), 1.57(m,4H), 3.5 (t, J = 7.1 Hz, 4H), 6.31 (s, 1H), 6.6 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 8.9, 2.7 Hz, 1H),7.14-7.16 (m, 2H) 7.71-7.77 (m, 2H), 7.8 (d, J = 9.0 Hz, 1H), 8.45 (dd, J = 7.9, 1.4 Hz, 1H), 8.72-8.76 (m, 2H), 8.9 (dd, J = 7.9, 1.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 11.3, 20.5, 53.1, 96.4, 97.2, 109.6, 116.8, 123.9, 125.1, 125.3, 129.9, 130.6, 130.7, 131.7, 132.4, 140.7, 146.6, 149.7, 150.9, 151.7, 152.2, 157.4; MS (EI+): m/z: 422 [M×+1]+; HRMS (EI+) 422.2106 [M×]+, found 422.2128.
Yield25 %, mp 188-189℃; IR ν (neat, cm-1): 2950, 2872, 1626, 1581, 1514, 1457, 1365, 1324, 1285, 1218, 772; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):545 (4.06), 222(3.92); 1H NMR (400 MHz, CDCl3)δ ppm 0.97 (t, J = 7.3 Hz, 6H), 1.37(m,4H), 1.6 (m,4H), 3.3 (t, J = 7.2 Hz, 4H), 6.13 (s, 1H), 6.27 (d, J = 2.7 Hz, 1H), 6.55 (dd, J = 9, 2.7 Hz, 1H),7.39-7.34 (m, 2H) 7.62-7.7 (m, 2H), 7.84-7.89 (m, 2H), 8.2 (d, J = 9.0 Hz, 1H), 8.5 (dd, J = 7.9, 1.4 Hz, 1H), 8.6 (dd, J = 7.9, 1.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 13.9, 20.2, 29.4, 50.9, 51.1, 96.3, 97.3, 109.4, 116.6, 123.8, 123.9, 124.0, 125.0, 125.3, 127.3, 128.3, 129.9, 130.1, 130.5, 130.6, 131.0,146.6, 149.5, 150.7, 157.2; MS (EI+): m/z: 451 [M×+1]+;HRMS (EI+) 450.2406 [M×]+, found 450.2409
Yield 73 %, mp 204-205℃; IR ν (neat, cm-1): 2980, 1640, 1590, 1580, 1490, 1455, 1320, 1250, 1115; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 544 (4.62); 1H NMR (400 MHz, CDCl3)δ ppm 1.21 (t, J = 7.1 Hz, 6H), 3.40 (q, J = 7.1 Hz, 4H), 6.26 (d, J = 2.6 Hz, 1H), 6.47 (s, 1H), 6.55 (dd, J = 9.0, 2.7 Hz, 1H), 7.04 (t, J = 6.3 Hz, 2H), 7.46 (d, J = 9.0 Hz, 1H), 7.70-7.74 (m, 2H), 8.44 (d, J = 8.6 Hz, 1H), 8.50-8.51 (m, 1H), 8.78 (d, J = 2.0 Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 45.0, 96.3, 99.1, 108.9, 117.2, 118.9, 124.7, 124.8, 125.5, 128.2, 130.4, 133.1, 134.1, 137.7, 140.8, 146.7, 148.9, 149.0, 150.2, 156.7, 163.2; MS (CI+): m/z: 473 [MH]+;HRMS (CI+) 473.0976 [MH]+, found 473.0981; Anal. Calcd. For C25H21BrN4O×3H2O: C, 56.93; H, 5.16; N, 10.62; Found: C, 57.41; H, 4.35; N, 10.01.
Yield 28 %, mp 269-271℃; IR ν (neat, cm-1): 2980, 1635, 1590, 1575, 1490, 1410, 1355, 1250, 1115; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 720 (4.44), 547 (4.43); 1H NMR (400 MHz, CDCl3)δ ppm 1.22 (t, J = 7.1 Hz, 6H), 3.41 (q, J = 7.1 Hz, 4H), 6.08 (s, 1H), 6.27 (d, J = 2.6 Hz, 1H), 6.56 (dd, J = 9.0, 2.7 Hz, 1H), 6.84-6.86 (m, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 8.6, 2.1 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.53-8.55 (m, 2H), 8.63 (d, J = 2.0 Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 45.0, 96.2, 97.5, 109.1, 116.0, 124.81, 124.85, 125.6, 128.0, 130.3, 130.6, 133.3, 133.5, 140.4, 146.6, 149.1, 150.2, 150.3, 155.7, 159.2; MS (CI+): m/z: 473 [MH]+; HRMS (CI+) 473.0976 [MH]+, found 473.1017; Anal. Calcd. For C25H21BrN4O×4H2O: C, 73.86; H, 5.77; N, 11.88; Found: C, 73.16; H, 5.29; N, 11.67.
Yield 71 %, mp 234-236℃; IR ν(neat, cm-1): 2980, 1635, 1585, 1540, 1510, 1340, 1265, 1220, 1110; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 691 (4.30), 539 (4.57); 1H NMR (400 MHz, CDCl3)δ ppm 1.19 (t, J = 7.1 Hz, 6H), 3.39 (q, J = 7.1 Hz, 4H), 6.26 (d, J = 2.7 Hz, 1H), 6.47 (s, 1H), 6.57 (dd, J = 9.0, 2.7 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.44-7.48 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.63-7.70 (m, 3H), 7.79-7.83 (m, 1H), 8.03 (d, J = 8.4 Hz, 1H), 8.14-8.16 (m, 1H), 8.62-8.72 (m, 2H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 44.9, 96.3, 99.3, 108.9, 117.6, 123.7, 124.8, 124.9, 125.6, 125.7, 127.4, 128.5, 129.5, 129.8, 130.3, 130.4, 130.5, 131.7, 132.5, 137.8, 146.7, 148.0, 149.2, 150.0, 156.4, 158.2; MS (EI+): m/z: 444 [M×]+; HRMS (EI+) 444.1950 [M×]+, found 444.1931; Anal. Calcd. For C29H24N4O×1.5H2O: C, 73.86; H, 5.77; N, 11.88; Found: C, 73.16; H, 5.29; N, 11.67.
Yield 45 %, mp 229-231℃; IR ν (neat, cm-1):2975, 1640, 1585, 1545, 1510, 1460, 1420, 1320, 1220, 1110; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 583 (4.62); 1H NMR (400 MHz, CDCl3)δppm 1.24 (t, J = 7.1 Hz, 6H), 3.44 (q, J = 7.1 Hz, 4H), 6.40 (d, J = 2.6 Hz, 1H), 6.64 (dd, J = 9.1, 2.6 Hz, 1H), 7.37 (dd, J = 8.6, 2.1 Hz, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.59 (s, 1H), 7.62-7.71 (m, 2H), 7.75 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 8.64-8.66 (m, 2H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 45.1, 96.2, 100.4, 109.9, 120.7, 122.5, 123.7, 125.7, 125.9, 126.4, 129.0, 129.8, 130.6, 131.0, 131.6, 132.1, 136.2, 140.4, 146.9, 150.5, 150.7, 151.4, 157.9, 160.3; MS (CI+): m/z: 485 [MH]+;HRMS (CI+) 485.1203 [MH]+, found 485.1268; Anal. Calcd. For C27H21ClN4OS×0.5H2O: C, 65.64; H, 4.49; N, 11.34; Found: C, 65.39; H, 4.42; N, 10.97.
Yield 34 %, mp 195-196℃; IR ν (neat, cm-1): 2975, 1635, 1590, 1560, 1490, 1275, 1110; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 539 (4.65); 1H NMR (400 MHz, CDCl3)δppm 1.23 (t, J = 7.1 Hz, 6H), 2.45 (s, 3H), 3.42 (q, J = 7.1 Hz, 4H), 5.92 (s, 1H), 6.33 (d, J = 2.7 Hz, 1H), 6.58 (dd, J = 9.0, 2.7 Hz, 1H), 6.77 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.60-7.68 (m, 2H), 8.59-8.63 (m, 2H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 12.7, 44.9, 96.3, 99.1, 99.6, 109.0, 123.7, 125.0, 125.5, 129.8, 130.3, 130.5, 131.5, 132.3, 141.3, 146.7, 149.2, 150.1, 160.3, 168.8, 169.6; MS (EI+): m/z: 398 [M×]+; HRMS (EI+) 398.1742 [M×]+, found 398.1721; Anal. Calcd. For C24H22N4O2×2H2O: C, 66.34; H, 6.03; N, 12.89; Found: C, 66.54; H, 5.43; N, 12.67.
Yield 10 %, mp 192-193℃; IR ν (neat, cm-1): 2980, 1640, 1590, 1555, 1420, 1275, 1210, 1115; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 547 (4.67); 1H NMR (400 MHz, CDCl3)δ ppm 1.22 (t, J = 7.1 Hz, 6H), 3.43 (q, J = 7.1 Hz, 4H), 6.34 (d, J = 2.6 Hz, 1H), 6.42 (s, 1H), 6.61 (dd, J = 9.0, 2.5 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.63-7.71 (m, 2H), 7.78 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.63-8.69 (m, 2H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 45.0, 96.3, 98.8, 109.3, 123.7, 124.6, 125.2, 125.6, 125.8, 129.9, 130.4, 130.7, 131.6, 132.0, 137.3, 141.1, 145.4, 146.7, 149.4, 150.3, 158.5, 158.8; MS (EI+): m/z: 462 [M×]+; HRMS (EI+) 462.1014 [M×]+, found 462.0958; Anal. Calcd. For C25H20Cl2N4O×0.5H2O: C, 63.57; H, 4.48; N, 11.86; Found: C, 63.48; H, 4.30; N, 11.72.
Yield 24 %, mp 208-210℃; IR ν (neat, cm-1): 2975, 1640, 1590, 1550, 1395, 1275, 1110; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1): 543 (4.62); 1H NMR (400 MHz, CDCl3)δ ppm 1.23 (t, J = 7.1 Hz, 6H), 3.43 (q, J = 6.9 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 6.58 (s, 1H), 6.63 (dd, J = 9.0, 2.3 Hz, 1H), 7.02 (t, J = 4.8 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.61-7.70 (m, 2H), 8.63 (d, J = 7.7 Hz, 1H), 8.67 (d, J = 8.1 Hz, 1H), 8.74 (d, J = 4.8 Hz, 2H); 13C NMR (101 MHz, CDCl3)δ ppm 12.6, 45.01, 96.2, 99.3, 109.6, 115.6, 123.6, 125.4, 125.7, 129.8, 130.5, 130.8, 131.6, 131.9, 140.9, 146.7, 149.4, 150.4, 158.6, 159.0, 168.1; MS (EI+): m/z: 395 [M×]+; HRMS (CI+) 396.1824 [MH]+, found 396.1850; Anal. Calcd. For C24H21N5O×1.5H2O: C, 68.23; H, 5.73; N, 16.58; Found: C, 68.60; H, 5.29; N, 16.34.
Yield 43 %, mp 198-199℃; IR ν (neat, cm-1): 2971, 1636, 1589, 1564, 1488, 1469, 1408,1352, 1271, 1218, 1109, 1014; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):533 (4.46), 240 (4.36); 1H NMR (400 MHz, CDCl3)δ ppm 1.21 (t, J = 7.1 Hz, 6H), 3.42 (q, J = 7.1 Hz, 4H), 6.24 (s, 1H), 6.29 (d, J = 2.7 Hz, 1H), 6.57 (dd, J = 9.0, 2.7 Hz, 1H), 7.29-7.31(m, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.63-7.69 (m, 2H), 8.28 (d, J = 1.47 HZ,1H), 8.37(dd, J = 4.33, 1.80 HZ), 8.57 (d, J = 7.62 Hz, 1H), 8.64 (dd, J = 7.9, 1.3 Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 12.58, 44.92, 96.3, 97.7, 108.8, 123.6, 123.8, 124.8, 125.07, 128.1, 129.9, 130.2, 130.4, 131.5, 132.4, 141.8, 142.4, 144.5, 146.6, 149.1, 150.02; MS (EI+): m/z: 395.1 [M+1]+; HRMS (EI+) 394.1793 [M×]+, found 394.1792.
Yield 39 %, mp 235-236℃; IR ν(neat, cm-1): 3066 2962, 2855, 1636, 1592, 1585,1551, 1488, 1462 1423, 1332, 1307, 1237, 1123, 772; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):525 (4.38), 225 (4.33); 1H NMR (400 MHz, CDCl3)δ ppm 3.38 (t, J = 7.2 Hz, 4H), 3.87 (t, J = 7.1 Hz, 4H), 6.6 (s, 1H), 6.89 (dd, J = 8.9, 2.7 Hz, 1H), 7.12 (t, J = 7.8 Hz, 2H), 7.6 (d, J = 9.0 Hz, 1H), 7.72-7.74 (t, J = 7.3Hz, 2H), 7.81(t, J = 7.3Hz, 2H), 8.35 (dd, J = 7.9, 1.4 Hz, 1H), 8.5 (d, J = 6.7 Hz, 1H), 8.69 (t, J = 7.9, Hz, 1H); 13C NMR (101 MHz, CDCl3)δ ppm 47.7, 66.4, 99.5, 99.8, 106.4, 111.7, 117.6, 119.2, 124.0, 125.8, 127.3, 130.4, 130.5, 130.6, 131.2, 131.6, 138.0, 146.1, 148.5, 148.9, 153.1, 157.5; MS (EI+): m/z: 409.1 [M×+1]+; HRMS (EI+) 408.1586 [M×]+, found 408.1568.
Yield 38 %, mp 229-230℃; IR ν (neat, cm-1): 3059, 2973, 2930, 1637, 1590, 1552, 1489, 1463, 1407, 1352, 1271, 1252, 1113, 770; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):683 (4.10), 537 (4.24); 1H NMR (400 MHz, CDCl3)δppm 1.18 (t, J = 7.1 Hz, 6H), 3.43 (q, J = 7.1 Hz, 4H), 2.88 (s, 3H), 6.03 (s, 1H), 6.28 (d, J = 2.6 Hz, 1H), 6.58-6.69 (dd, J = 8.9, 2.7 Hz, 1H), 6.78 (s, 1H), 7.41-7.74 (m, 6H), 8.2 (d, J = 9.0 Hz, 1H), 8.63-8.70 (m, 2H) ; 13C NMR (101 MHz, CDCl3)δ ppm 12.5, 25.4, 44.9, 96.3, 98.2, 108.8, 110.0, 121.1, 122.2, 123.8, 123.9, 124.7, 124.8, 125.3, 126.2, 126.5, 126.9, 127.9, 128.4, 129.6, 130.0, 130.3, 130.5, 131.2, 131.6, 132.1, 141.5, 146.6, 149.1, 150.0, 157.3, 159.3, 159.7; MS (EI+): m/z: 459.1 [M×+1]+; HRMS (EI+) 458.2106 [M×]+, found 458.2125.
Yield 37 %, mp 175-176℃; IR ν (neat, cm-1): 3312, 3066, 2978, 2934, 1734, 1637, 1586, 1515, 1444, 1409, 1376,1354, 1272, 1252, 1170, 1014; UV-vis (CHCl3): λ(nm) (logε/L mol-1cm-1):539 (4.41), 387 (4.04); 1H NMR (400 MHz, CDCl3)δ ppm 1.22 (t, J = 7.1 Hz, 6H), 1.37 (t, J = 7.13 Hz, 3H), 3.43 (q, J = 7.1 Hz, 4H), 4.82 (q, J = 7.1 Hz, 2H), 6.17 (s, 1H), 6.30 (d, J = 2.7 Hz, 1H), 6.55-658 (dd, J = 8.95, 2.58 Hz, 1H), 6.76 (d, J = 8.46 Hz, 2H), 6.99 (d, J = 8.43 Hz, 2H), 7.49-7.50 (m, 2H), 7.67-7.81 (m, 2H),, 8.63-8.69 (dd, J = 8.95, 2.58 HZ, 1H), 9.87 (s, 1H), 13C NMR (101 MHz, CDCl3)δ ppm 12.5, 14.2, 36.9, 44.5, 53.8, 61.9, 96.2, 98.6, , 109.5, 122.3, 123.9, 123.8, 125.02, 125.7, 128.8, 129.9, 130.2, 130.5, 131.3, 132.5, 146.6, 148.3, 150.4, 155.3, 156.1, 170.4; MS (EI+): m/z: 510 [M.]+; HRMS (EI+) 510.2393 [M×]+, found 510.2413.
Yield 38 %, mp 235-236℃; IR ν(neat, cm-1): 3633, 3023, 2972, 1639, 1605, 1581, 1556, 1491, 1412, 1370, 1313, 1219, 1136; 1H NMR (400 MHz, CDCl3)δ ppm 1.21 (t, J = 7.01 Hz, 3H), 2.6 (s, 3H ), 2.97 (s, 3H ), 3.35 (q, J = 6.62 Hz, 2H), 3.47 (q, J = 7.0 Hz, 2H), 3.58 (t, J = 6.62 Hz, 2H), 6.13 (s, 1H), 6.24 (d, J = 2.41 Hz, 1H), 6.51 (s, 1H), 6.86 (d, J = 5.58 Hz, 1H), 7.65-7.69 (m, 2H), 8.51-8.54 (m, 3H), 8.68 (dd J = 7.46, Hz, 1H); MS (EI+): m/z: 502.3 [M×+1]+
1R・HCl mp > 300; IR ν (neat, cm-1): 3062, 2979, 2864, 1639, 1580, 1512, 1444, 1364, 1320, 1236, 1194, 1079; 1H NMR (400 MHz, CDCl3) δppm 1.21 (t, J = 7.01 Hz, 3H), 2.6 (s, 3H ), 2.87 (s, 3H ), 3.14 (q, J = 6.62 Hz, 2H), 3.49 (t, J = 6.62 Hz, 2H), 5.99 (s, 1H), 6.42 (d, J = 2.41 Hz, 1H), 6.67 (s, 1H), 6.91 (d, J = 5.58 Hz, 1H), 7.19-7.2 (t, J = 6.24 Hz, 1H), 7.69-7.81 (m, 2H), 8.45 (dd J = 7.96, 1.11 Hz, 1H), 8.51(dd J = 4.56, 157, Hz, 2H), 8.59 (dd J = 7.96, 0.99 , Hz, 1H); MS (EI+): m/z: 503.2 [M×+1]+.
Yield 41 %, mp 221-222℃; IR ν (neat, cm-1): 3632, 3065, 2979, 1634, 1593, 1580, 1549, 1488, 1462, 1370, 1320, 1272, 1147, 772; 1H NMR (400 MHz, CDCl3)δ ppm 1.14(t, J = 7.1 Hz, 3H), 2.53 (s, 3H ), 2.96 (s, 3H ), 3.32 (q, J = 6.7 Hz, 2H), 3.38 (q, J = 7.12 Hz, 2H), 3.51 (t, J = 6.76 Hz, 2H), 6.31 (s, 1H), 6.5 (d, J = 8.27Hz, 1H), 6.64 (t, J = 7.27 Hz, 1H), 6.96 (d, J = 8.01 Hz, 1H), 7.01-7.06 (t, J = 7.1 Hz, 1H), 7.44 (t, J = 7.01 Hz, 1H), 7.64-7.7 (m, 2H), 8.06 (d, J = 4.15 Hz, 1H), 8.51-8.6 (m, 2H) ; MS (EI+): m/z: 502.3 [M×+1]+
Yield 45 %, mp 227-228℃; IR ν(neat, cm-1): 3620, 3065, 2975, 1634, 1591, 1554, 1488, 1411, 1319, 1272, 1218, 1147, 772; 1H NMR (400 MHz, CDCl3)δ ppm 1.2 (t, J = 7.02 Hz, 3H), 2.6 1 (s, 3H ), 2.97 (s, 3H ), 3.35 (q, J = 6.62 Hz, 2H), 3.46 (q, J = 7.0 Hz, 2H), 3.57 (t, J = 6.56 Hz, 2H), 6.2 (m, 2H), 6.49 (d, J = 1.98 Hz, 1H), 7.29-7.31 (m, 2H), 7.65-7.67 (m, 2H), 8.25 (d, J = 1.59 Hz, 1H), 8.37 (dd, J = 4.36, 1.66 Hz, 1H), 8.61 (dd, J = 7.9, 1.3 Hz, 1H), 8.684 (dd J = 7.46, 1.3 Hz, 1H); MS (EI+): m/z: 502.3 [M×+1]+
Yield 13.8 %, 1a・HCl mp 167.2-168.4 oC; IR n (neat, cm-1): 2978, 1638, 1594, 1577, 1530, 1446, 1245, 1196, 1124, 870, 780; UV-vis (MeOH): l (nm) (log e/L mol-1cm-1): 668 (4.85); 1H NMR (400 MHz, MeOD) d ppm 8.86 (d, J = 8.0 Hz, 1H), 8.62 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 4.6 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.84 (t, J = 7.5, 1H), 7.78 (t, J = 7.5, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.30-7.19 (m, 1H), 6.89 (d, J = 2.4, 1H), 3.80 (q, J = 7.1 Hz, 4H), 2.73 (s, 3H), 1.39 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, MeOD) d ppm 159.5, 153.0, 151.5, 147.4, 146.7, 145.6, 145.2, 142.4, 141.4, 132.6, 131.9, 131.2, 130.0, 126.8, 124.6, 124.3, 122.4, 119.3, 117.5, 107.5, 97.3, 36.7, 17.5, 13.6; MS (ESI+): m/z: 409.1 [M+]; Anal. Calcd. For C26H25ClN4O×4.5H2O: C, 59.37; H, 6.51; N, 10.65;Found: C, 59.24; H, 5.66; N, 10.55.
Yield 18.2 %, 1b・HCl mp 161.6-163.1 oC; IR n (neat, cm-1): 2978, 1639, 1585, 1546, 1449, 1381, 1321, 1249, 1198, 1125, 1089, 988; UV-vis (MeOH): l (nm) (log e/L mol-1cm-1): 656 (4.64); 1H NMR (400 MHz, MeOD) d ppm 9.13 (d, J = 8.4 Hz, 1H), 9.02 (d, J = 2.4 Hz, 1H), 8.68 (d, J = 5.0 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.12 (dd, J = 8.4, 5.0 Hz, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.91 (m, 1H), 7.57 (m, 1H), 7.54 (s, 1H), 7.05 (d, J = 2.4 Hz, 1H), 3.87 (q, J = 7.2 Hz, 4H), 2.86 (s, 3H), 1.40 (t, J = 7.2 Hz, 6H); 13C NMR (101 MHz, MeOD) d ppm 158.6, 151.7, 151.6, 149.9, 146.3, 141.9, 169.6, 139.4, 138.8, 137.4, 133.0, 132.4, 131.2, 130.0, 129.4, 125.4, 125.0, 124.3, 120.9, 99.0, 96.5, 39.8, 17.4, 13.6; MS (ESI+): m/z: 409.1 [M+]; Anal. Calcd. For C26H25ClN4O×4.5H2O: C, 59.37; H, 6.51; N, 10.65; Found: C, 59.63; H, 5.36; N, 10.56.
Yield 26.6 %, 1c・HCl mp >300 oC; IR n (neat, cm-1): 2977, 1639, 1579, 1513, 1443, 1324, 1249, 1199, 1072, 946, 823, 780; UV-vis (MeOH): l (nm) (log e/L mol-1cm-1): 594 (4.22); 1H NMR (400 MHz, MeOD) d ppm 9.16 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 7.4 Hz, 2H), 8.31 (d, J = 8.4 Hz, 1H), 8.06-7.96 (m, 2H), 7.86-7.90 (m, 1H), 7.79 (s, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.25 (d, J = 2.5 Hz, 1H), 4.0 (q, J = 7.0 Hz, 4H), 2.89 (s, 3H), 1.46 (t, J = 7.0 Hz, 6H); 13C NMR (101 MHz, MeOD) d ppm 160.2, 158.7, 152.0, 147.3, 146.5, 144.6, 144.4, 142.5, 132.9, 131.9, 131.5, 130.0, 127.9, 124.8, 124.7, 123.4, 112.9, 110.5, 97.6, 39.5, 17.5, 14.1; MS (ESI+): m/z: 394 [M+];Anal. Calcd. For C26H25ClN4O×4.5H2O: C, 59.37; H, 6.51; N, 10.65;Found: C, 58.51; H, 5.57; N, 10.52.
Yield 14.1 %, mp >300 oC; IR n (neat, cm-1): 1641, 1599, 1579, 1486, 1401, 1366, 1337, 1263, 1201, 1133, 1114, 986, 809, 769; UV-vis (CHCl3): l (nm) (log e/L mol-1cm-1): 532 (4.67); 1H NMR (400 MHz, CDCl3) d ppm 8.64 (dd, J = 7.8, 1.6Hz, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 2H), 8.52 (d, J = 1.6 Hz, 1H), 7.77-7.59 (m, 2H), 7.55 (d, J = 9.0 Hz, 1H), 6.86 (dd, J = 4.8, 1.5 Hz, 2H), 6.60 (dd, J = 9.0, 2.7 Hz, 1H), 6.33 (d, J = 2.7 Hz, 1H), 6.15 (s, 1H), 3.07 (s, 6H); 13C NMR (101 MHz, CDCl3) d ppm 159.9, 156.9, 152.3, 149.7, 149.2, 146.3, 142.0, 132.2, 131.5, 130.5, 130.3, 130.1, 125.2, 125.1, 124.0, 116.2, 109.3, 97.9, 96.9, 40.3; MS (ESI+): m/z: 367.1 [M+H]+; Anal. Calcd. For C23H18N4O×0.5H2O: C, 73.58; H, 5.10; N, 14.92;Found: C, 73.27; H, 4.85; N, 14.62.
Yield 14.5 %, mp >300 oC; IR n (neat, cm-1): 2968, 2835, 1635, 1595, 1578, 1510, 1488, 1239, 1121, 1110, 1043, 1003, 827, 755; UV-vis (CHCl3): l (nm) (log e/L mol-1cm-1): 502 (4.49); 1H NMR (400 MHz, CDCl3) d ppm 8.69-8.62 (m, 1H), 8.54 (dd, J = 4.8, 1.5 Hz, 2H), 8.51 (d, J = 2.2 Hz, 1H), 7.77-7.63 (m, 2H), 7.58 (d, J = 8.9, 1H), 6.85 (dd, J = 4.8, 1.5 Hz, 2H), 6.78 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (d, J = 2.6, 1H), 6.15 (s, 1H), 3.86 (t, J = 4.8 Hz, 4H), 3.29 (t, J = 4.8 Hz, 4H);13C NMR (101 MHz, CDCl3) d ppm 159.1, 156.5, 152.8, 150.2, 148.7, 145.8, 144.0, 132.4, 131.2, 130.5, 130.4, 130.1, 126.6, 125.2, 124.1, 115.9, 111.2, 99.7, 98.4, 66.4, 47.6; MS (ESI+): m/z: 409.2 [M+H]+; Anal. Calcd. For C25H20N4O2×0.5H2O: C, 71.93; H, 5.07; N, 13.42; Found: C, 72.15; H, 5.08; N, 12.23.
Yield 1.5 %, mp 266.8-268.2 oC; IR n (neat, cm-1): 2931, 2850, 1635, 1595, 1577, 1485, 1239, 1112, 1000, 827, 756; UV-vis (CHCl3): l (nm) (log e/L mol-1cm-1): 530 (4.52); 1H NMR (400 MHz, CDCl3) d ppm 8.68-8.61 (m, 1H), 8.54 (dd, J = 4.6, 1.5 Hz, 2H), 8.51 (d, J = 1.8 Hz, 1H), 7.71-7.63 (m, 2H), 7.53 (d, J = 9.0 Hz, 1H), 6.86 (dd, J = 4.6, 1.5 Hz, 2H), 6.78 (dd, J = 9.0, 2.7 Hz, 1H), 6.51 (d, J = 2.7 Hz, 1H), 6.14 (s, 1H), 3.35 (t, J = 5.0 Hz, 4H), 1.71-1.65 (m, 6H); 13C NMR (101 MHz, CDCl3) d ppm 159.7, 156.9, 153.0, 149.8, 149.1, 146.1, 142.6, 132.1, 131.3, 130.5, 130.3, 130.1, 125.7, 125.1, 124.0, 116.3, 111.6, 99.3, 97.9, 48.8, 25.2, 24.2; MS (ESI+): m/z: 407.1 [M+H]+;Anal. Calcd. For C26H22N4O: C, 76.83; H, 5.46;N, 13.78; Found: C, 76.15; H, 5.47; N, 13.77.
1.クロロキン耐性熱帯熱マラリア原虫の培養
本実験では、Plasmodium falciparum K1株の原虫を用いた。実験に用いた培地は、ろ過滅菌したRPMI−1640培地で、ヒト血清を5%となるように添加した。マラリア原虫の培養はO2濃度3%、CO2濃度4%、N2濃度93%、温度は37℃で行った。
試験に用いる本発明化合物又は陽性対象薬(クロロキン)はDMSOに溶解し、所定濃度の試験液とした。培養したマラリア原虫感染赤血球を遠心分離で集め、非感染赤血球で希釈し、初期感染率0.15%とした。このときのヘマトクリット値は 2.5%とした。
96穴培養プレートのウェルに、200μLのマラリア感染培養液を加え、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加え調整した。試験液はduplicateにとった。
37℃で48時間培養した後、0.5μCiの放射性のトリチウム(3H)標識されたヒポキサンチンを各ウェルに加えた。さらに24時間同条件で培養した後、グラスファイバーフィルター上に採取し蒸留水で洗浄した。ベータプレート液体シンチレーションカウンター(Wallac社製)で放射線強度を計測し、試験液添加群及びコントロールのマラリア原虫感染率を算出した。
増殖阻害率(%)={1−(b−a)/(c−a)}×100
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
ラット由来L6細胞(rat skeletal myoblast cell)を用いた。培地はRPMI1640培地に、L−グルタミン(200mM)が1%、胎児牛血清が10%となるように添加し、CO2濃度5%、37℃で培養した。
試験に用いる本発明化合物又は対照薬をDMSOに溶解し、所定濃度の試験液とした。
前培養を行い、対数増殖期に入った細胞を含む培地を96穴培養プレートのウェルにとり、次に所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はduplicateにとった。
培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。それぞれのウェルに10μLのAlamar Blue水溶液を加え、さらに2時間培養した。次に、培養プレートを蛍光マイクロプレートリーダー(Spectramax Gemeni XS;米国モレキュラー・デバイス社製)に装着し、536nmの励起波長で照射し、588nmの蛍光強度を測定し、試験液添加群及びコントロールのL6細胞の残存率を算出した。
増殖阻害率(%)={(C−A)/(B−A)}×100
A:初期細胞数
B:3日後のコントロールの細胞数
C:サンプル添加した3日後の細胞数
クロロキン耐性熱帯熱マラリア原虫とラットL6細胞に対するサンプルのEC50値からサンプルの抗マラリア作用を評価する。クロロキン耐性マラリア原虫に対する選択毒性の指標として用いられる化学療法係数を下記式により算出し、薬効判定を行った。選択毒性の値は大きいほど副作用の危険性が少ないことを意味する。
÷(クロロキン耐性熱帯熱マラリア原虫に対するサンプルのEC50値)
本実験ではローデントマラリア原虫(Plasmodium berghei NK65株)を用いた。
感染血液はICR系雌性SPFマウス4〜6週齢(20-26g)に腹腔内または尾静脈投与で感染させ継体したものを使用している。マラリア感染マウスの尾静脈から採血し感染率を求め適度に感染(10-20%の感染率)しているのを確認した後、マウス心臓からヘパリン入り注射器でマラリア感染血液を採血した。その後、赤血球数(cells/ml)と原虫感染率から、投与量1mlあたり5.0×10-6のマラリア原虫となるように血液を生理食塩水にて希釈した。これを未感染マウス(ICR系雌性5週齢)の体重20gあたり0.2mlずつ尾静脈より感染させた(Day-0)。試験に用いる化合物は10%DMSO溶液(DMSOを1mlと5%Glucose solutionを9mlの混合液)に溶解した。
治癒率:Suppression(%)=(B−A)/B×100
A:本試験化合物を投与したマウスの原虫感染率
B:コントロール(化合物非投与)マウスの原虫感染率
延命日数:MSD(day)= C−D C:本試験化合物を投与したマウスのマラリア感染日から死亡日までの日数の平均
D:コントロール(化合物非投与)マウス4匹のマラリア感染日から死亡日までの日数の平均
本実験では、Trypanosoma brucei rhodensiense(STIB900株)の原虫の血流棲息型トリポマスチゴート体を用いた。実験に用いた培地は、ろ過滅菌したMEM培地に、25mMのN−2−ヒドロキシエチルピペラジン−2−エタンスロホン酸(HEPES)、1g/Lのグルコース、1%のMEM非必須アミノ酸、0.2mMの2−メルカプトエタノール、2mMのピルビン酸ナトリウム塩、0.1mMのヒポキサンチン及び15%熱処理ウマ血清を加えたものを用いた。原虫の培養はCO2濃度を5%とした空気中で、温度は37℃で行った。
試験に用いる本発明化合物、または陽性対象薬(メラルソプロール)はジメチルスルホキシド(DMSO、以下同じ)に溶解し、所定濃度の試験液とした。
96穴培養プレートのウェルに、原虫の個数が8x103個を含む培地と、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加え、それぞれ100μLになるよう培地を加え調整した。試験液はduplicateにとった。
培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。それぞれのウェルに10μLのAlamar Blue水溶液を加え、さらに2時間培養した。次に、培養プレートを蛍光マイクロプレートリーダー(Spectramax Gemeni XS;米国モレキュラー・デバイス社製)に装着し、536nmの励起波長で照射し、588nmの蛍光強度を測定し、試験液添加群及びコントロールのトリパノソーマ原虫感染率を算出した。
本実験では、Trypanosoma cruzi (Tulahuen C2C4株)の原虫のラットL6細胞に感染したアマスチゴート体及びトリポマスチゴート体を用いた。実験に用いた培地は、L6細胞を含むRPMI1640培地に、L−グルタミン(200mM)が1%、胎児牛血清が10%となるように添加し、CO2濃度5%、37℃で培養した。
試験に用いる本発明化合物、または陽性対象薬(ベンズニダゾール)はDMSOに溶解し、所定濃度の試験液とした。
96穴培養プレートのウェルに、原虫の個数が5x103個を含む培地を加え48時間前培養を行った。培地を交換後、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はduplicateにとった。
培養プレートをインキュベーター中で96時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。それぞれのウェルに50μLのCPRG/Nonidetを加え、さらに2〜6時間放置した。次に、培養プレートを吸光マイクロプレートリーダーに装着し、540nmの吸光度を測定し、試験液添加群及びコントロールのトリパノソーマ原虫感染率を算出した。
本実験では、Leishmania donovani (MHOM/ET/67/L82株)を用いた。原虫はSyrian Goldenハムスターで継代し、そこからアマスチゴート体を得た。実験には10%の加熱処理したウシ胎児血清を加えたSM培地を用い、pH5.4に調整しCO2濃度5%の空気下、37℃で培養した。
試験に用いる本発明化合物、または陽性対象薬(ミルテフォシン)はDMSOに溶解し、所定濃度の試験液とした。
96穴培養プレートのウェルに所定の個数の原虫を含む培地を加え前処理をほどこした後、CASYセル分析システム(ドイツ・Scharfe社製)でアマスチゴートの濃度を計測した。その後、所定濃度の薬剤を含む試験液又は薬剤を含まないDMSОを加えた。試験液はduplicateにとった。
培養プレートをインキュベーター中で72時間培養した後、増殖阻害活性を検定した。検定は以下のように行った。それぞれのウェルに10μLのAlamar Blue水溶液を加え、さらに2時間培養した。次に、培養プレートを蛍光マイクロプレートリーダー(Spectramax Gemeni XS;米国モレキュラー・デバイス社製)に装着し、536nmの励起波長で照射し、588nmの蛍光強度を測定し、試験液添加群及びコントロールのリーシュマニア原虫感染率を算出した。
増殖阻害率(%)={1−(b−a)/(c−a)}×100
a:初期感染率
b:試験液添加時の感染率
c:コントロールの感染率
Claims (5)
- 以下の構造式1Bで示される化合物又はその塩を有効成分として含有する、原虫疾患予防又は治療用医薬組成物。
- 以下の構造式1C〜1H、1J〜1M、1P、1R〜1T、1a〜1c及び1e〜1hのいずれかで示される化合物又はその塩を有効成分として含有する、原虫疾患予防又は治療用医薬組成物。
- 前記原虫疾患がマラリア症、リーシュマニア症、アフリカ睡眠病、シャーガス病、トキソプラズマ症、リンパフィラリア症、バベシア症、又はコクシジウム症である、請求項1または2に記載の医薬組成物。
- 前記原虫疾患がマラリア症、リーシュマニア症、アフリカ睡眠病、又はシャーガス病である、請求項3に記載の医薬組成物。
- 以下の構造式1B〜1G、1J〜1K、1M、1P、1R〜1T、1a〜1c及び1e〜1hのいずれかで示される化合物。
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