JP7520822B2 - 2’-ハロゲン化-4’-チオ-2’-デオキシ-5-アザシチジンアナログおよびその使用 - Google Patents
2’-ハロゲン化-4’-チオ-2’-デオキシ-5-アザシチジンアナログおよびその使用 Download PDFInfo
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- JP7520822B2 JP7520822B2 JP2021516619A JP2021516619A JP7520822B2 JP 7520822 B2 JP7520822 B2 JP 7520822B2 JP 2021516619 A JP2021516619 A JP 2021516619A JP 2021516619 A JP2021516619 A JP 2021516619A JP 7520822 B2 JP7520822 B2 JP 7520822B2
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Description
本願は、2018年9月25日出願の米国仮特許出願第62/736,246号の先の出願日の利益を主張する。この米国仮特許出願は、その全体が参照により本明細書中に組み込まれる。
本開示は、5-アザ-2’-デオキシシチジンのハロゲン化アナログ、例えば、5-アザ-4’-チオ-2’-デオキシシチジン(5-アザ-T-dCyd)のハロゲン化アナログ、および前記ハロゲン化アナログを使用する方法に関する。
5-アザ-2’-デオキシシチジンのハロゲン化アナログおよび前記ハロゲン化アナログを使用する方法が開示される。いくつかの実施形態において、前記化合物は、式Iaに記載の構造またはその立体異性体、互変異性体もしくは薬学的に許容され得る塩を有し、
式中、Xは、ハロであり;Yは、水素、ハロまたはジュウテリウムであり;各Rは、独立して、水素またはジュウテリウムであり;Raは、水素、ジュウテリウム、アルキル、アルコキシ、アミノまたはハロである。ある特定の実施形態において、(i)Xは、Fである;または(ii)Yは、水素である;または(iii)各Rは、水素である;または(iv)Raは、水素である;または(v)(i)、(ii)、(iii)および(iv)の任意の組み合わせである。
またはそれらの任意の組み合わせである。
5-アザ-2’-デオキシシチジンのハロゲン化アナログおよび前記ハロゲン化アナログを使用する方法が開示される。いくつかの実施形態において、前記化合物は、5-アザ-4’-チオ-2’-デオキシシチジン(5-アザ-T-dCyd)のハロゲン化アナログである。開示される化合物は、新生物性細胞の存在を少なくとも部分的に特徴とする疾患(例えば、がん)の処置に有用であり得る。開示されるハロゲン化アナログのいくつかの実施形態は、ある特定のがんの処置に関して、対応する非ハロゲン化アザ化合物および/または対応する非アザのハロゲン化アナログよりも効果的であり得る。
I.定義および省略形
5-アザ-2’-デオキシシチジンのハロゲン化アナログおよびその立体異性体は、一般式Iに記載の構造:
を有し、式中、Xは、ハロ(F、Cl、BrまたはI)であり、Yは、水素、ハロ(F、Cl、BrまたはI)またはジュウテリウムであり、Zは、SまたはOであり、各Rは、独立して、水素またはジュウテリウムであり、Raは、水素、ジュウテリウム、アルキル(例えば、C1-5またはC1-3アルキル、例えば、メチル、エチル、n-プロピルまたはイソプロピル)アルコキシ、アミノまたはハロである。いくつかの実施形態において、Zは、Sである。任意のまたはすべての実施形態において、Xは、Fであり得る。任意のまたはすべての実施形態において、Yは、水素またはFであり得る。任意のまたはすべての実施形態において、各Rは、水素であり得る。任意のまたはすべての実施形態において、Raは、水素であり得る。
4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オンである。
III.薬学的組成物
IV.使用方法
実施例1
4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オンの合成
図1は、4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オンについての例示的な合成スキーム(スキーム1)である。図2は、前駆体4-オキシルオキシフェニルメタンチオールについての例示的な合成スキーム(スキーム2)である。
4-オクチルオキシフェニルメタノール(13)
1H NMR (300MHz, CDCl3/TMS) d 7.26 (d, J = 8.7 Hz,2H); 6.87 (d, J = 8.7 Hz, 2H); 4.59 (s, 2H); 3.95 (t, J = 6.6Hz, 2 H); 1.73-1.81 (m, 3 H); 1.30-1.48 (m, 10 H); 0.89 (t, J = 6.9 Hz,3 H) ppm.
4-オクチルオキシフェニルメタンチオール(14)
1H NMR (300MHz, CDCl3/TMS) d 7.23 (d, J = 8 Hz, 2 H); 6.83(d, J = 8 Hz, 2 H); 3.95 (m, 2 H); 3.72 (d, J = 7.5 Hz, 2 H);1.75 (m, 3H); 1.25 (m, 9 H); 0.87 (m, 3 H) ppm.
1H NMR (400 MHz, Chloroform-d) δ 8.07 - 8.02 (m, 1H), 8.06 - 7.99(m, 2H), 8.04 - 7.91 (m, 1H), 7.63 - 7.28 (m, 6H), 5.66 (dd, J = 10.4,0.9 Hz, 1H), 5.46 (ddd, J = 22.3, 4.5, 1.0 Hz, 1H), 5.21 - 5.06 (m, 1H),4.78 - 4.54 (m, 4H) ppm.
(2R,3R,4S)-4-フルオロ-2-ヒドロキシ-5,5-ビス((4-(オクチルオキシ)ベンジル)チオ)ペンタン-1,3-ジイルジベンゾエート(4)
1H NMR (400 MHz, Chloroform-d): δ 8.03 - 7.93 (m, 2H), 7.94 - 7.86 (m,2H), 7.61 - 7.49 (m, 2H), 7.40 (m, 4H), 7.19 - 7.10 (m, 2H), 6.97 - 6.88 (m,2H), 6.71 - 6.62 (m, 2H), 6.57 - 6.48 (m, 2H), 5.65 (ddd, J = 26.9, 7.7, 1.7Hz, 1H), 5.01 (ddd, J = 45.2, 9.1, 1.8 Hz, 1H), 4.45 (dd, J = 11.7, 2.9 Hz,1H), 4.34 - 4.17 (m, 2H), 3.97 - 3.62 (m, 8H), 2.73 (d, J = 6.2 Hz, 1H), 1.80 -1.65 (m, 4H), 1.49 - 1.32 (m, 4H), 1.37 - 1.20 (m, 17H), 0.92 - 0.81 (m, 6H).
(2S,3R,4S)-2-(2-クロロアセトキシ)-4-フルオロ-5,5-ビス((4-(オクチルオキシ)ベンジル)チオ)ペンタン-1,3-ジイルジベンゾエート(5)
1H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.86 (m, 4H), 7.63 - 7.49(m, 2H), 7.48 - 7.33 (m, 4H), 7.19 - 7.11 (m, 2H), 6.97 - 6.86 (m, 2H), 6.70 -6.60 (m, 2H), 6.63 - 6.52 (m, 2H), 5.92 (ddd, J = 25.5, 6.2, 2.4 Hz,1H), 5.54 (td, J = 6.3, 3.2 Hz, 1H), 4.78 (ddd, J = 46.0, 8.5,2.5 Hz, 1H), 4.61 - 4.44 (m, 2H), 4.37 (ddd, J = 12.5, 6.3, 1.2 Hz, 1H),4.02 - 3.64 (m, 10H), 1.81 - 1.66 (m, 4H), 1.49 - 1.36 (m, 4H), 1.41 - 1.20 (m,16H), 0.99 - 0.80 (m, 6H).
(2S,3R,4S)-4-フルオロ-2-ヒドロキシ-5,5-ビス((4-(オクチルオキシ)ベンジル)チオ)ペンタン-1,3-ジイルジベンゾエート(6)
1HNMR (400 MHz, Chloroform-d) δ 8.03 - 7.92 (m, 4H), 7.60 - 7.49 (m, 2H), 7.45 -7.34 (m, 4H), 7.12 - 6.98 (m, 4H), 6.74 - 6.59 (m, 4H), 5.72 (m, 1H), 5.02(ddd, J = 46.6, 6.3, 4.4 Hz, 1H), 4.40 - 4.28 (m, 2H), 3.94 (m, 1H), 3.89 -3.67 (m, 8H), 2.64 (d, J = 6.4 Hz, 1H), 1.71 (m, 4H), 1.49 - 1.38 (m, 4H), 1.41- 1.20 (m, 18H), 0.99 - 0.80 (m, 6H).
(2S,3R,4S)-4-フルオロ-2-((メチルスルホニル)オキシ)-5,5-ビス((4-(オクチルオキシ)ベンジル)チオ)ペンタン-1,3-ジイルジベンゾエート(7)
1H NMR (400 MHz, Chloroform-d) δ 7.99 (m, 4H), 7.70 - 7.49 (m,2H), 7.49 - 7.35 (m, 4H), 7.21 - 7.10 (m, 2H), 7.01 - 6.85 (m, 2H), 6.77 - 6.64(m, 2H), 6.62 - 6.50 (m, 2H), 5.92 (m, 1H), 5.22 - 5.14 (m, 1H), 4.85 (m, 1H),4.68 - 4.56 (m, 1H), 4.44 (m, 1H), 3.93 - 3.62 (m, 10H), 2.93 (s, 3H), 1.72 (h,J = 6.8 Hz, 4H), 1.50 - 1.18 (m, 19H), 0.98 - 0.84 (m, 6H). 19FNMR (376 MHz, Chloroform-d) δ -188.51 (ddd, J = 45.7, 25.7, 11.3Hz).
((2R,3S,4S)-3-(ベンゾイルオキシ)-4-フルオロ-5-((4-(オクチルオキシ)ベンジル)チオ)テトラヒドロチオフェン-2-イル)メチルベンゾエート(8)
1H NMR (400 MHz, Chloroform-d) δ 8.02 - 7.90 (m, 3H), 7.65 - 7.47(m, 2H), 7.47 - 7.33 (m, 4H), 7.29 - 7.19 (m, 3H), 6.86 - 6.76 (m, 2H), 5.97(ddd, J = 9.9, 5.0, 3.9 Hz, 1H), 5.15 (dt, J = 50.5, 4.7 Hz, 1H),4.69 - 4.42 (m, 3H), 3.97 - 3.82 (m, 4H), 3.80 - 3.69 (m, 1H), 1.75 (m, 2H),1.50 - 1.19 (m, 10H), 0.95 - 0.82 (m, 3H). 19F NMR (376 MHz,Chloroform-d) -187.14 (ddd, J = 50.5, 16.6, 9.9 Hz).
(2R,3S,4S)-4-フルオロ-2-(ヒドロキシメチル)-5-((4-(オクチルオキシ)ベンジル)チオ)テトラヒドロチオフェン-3-オール(9)
1H NMR (400 MHz, DMSO-d6) δ 7.24 - 7.16 (m, 2H), 6.90- 6.81 (m, 2H), 5.68 (d, J = 5.1 Hz, 1H), 5.00 (t, J = 5.5 Hz,1H), 4.85 (dt, J = 51.4, 4.9 Hz, 1H), 4.49 (dd, J = 16.1, 4.5 Hz,1H), 4.20 (m, 1H), 3.92 (t, J = 6.5 Hz, 2H), 3.91 - 3.75 (m, 2H), 3.68(m, 1H), 3.40 - 3.28 (m, 1H), 3.09 (dddd, J = 7.6, 6.1, 4.7, 0.9 Hz,1H), 1.68 (m, 2H), 1.46 - 1.33 (m, 2H), 1.28 (m, 8H), 0.90 - 0.82 (m, 3H).
13C NMR (101 MHz, DMSO-d6) δ 158.15, 131.59, 130.42,129.75, 128.59, 127.86, 114.79, 99.37, 97.49, 75.29, 75.06, 67.81, 64.27,64.25, 53.22, 53.19, 50.32, 50.13, 36.00, 35.97, 31.67, 29.18, 29.13, 29.10,25.97, 22.51, 14.38.
19F-NMR (400 MHz, DMSO-d6) δ -186.62 (dddd, 1F)
(3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イルアセテート(10)
1H NMR (400 MHz, Chloroform-d) δ 6.02 - 5.88 (m, 1H), 5.09 (dd, J= 7.1, 4.5 Hz, 0.2H), 5.00 - 4.92 (m, 0.5H), 4.83 (dd, J = 9.3, 4.7 Hz,0.3H), 4.50 (ddd, J = 12.1, 9.3, 8.0 Hz, 0.5H), 4.33 (dt, J =14.7, 7.5 Hz, 0.5H), 3.87 - 3.68 (m, 2H), 3.54 (dtd, J = 7.9, 5.1, 1.3Hz, 0.5H), 3.24 (ddd, J = 7.9, 5.3, 4.5 Hz, 0.5H), 2.88 (s, 1H), 2.11(m, 3H).
19F NMR (376 MHz, Chloroform-d) δ -188.81 (dt, J = 51.3,15.2 Hz), -193.39 (dd, J = 50.9, 12.2 Hz).
(3S,4S,5R)-4-((tert-ブチルジフェニルシリル)オキシ)-5-(((tert-ブチルジフェニルシリル)オキシ)メチル)-3-フルオロテトラヒドロチオフェン-2-イルアセテート(11)
1H NMR (400 MHz, Chloroform-d) δ 7.78 - 7.68 (m, 4H), 7.65 - 7.46(m, 4H), 7.46 - 7.20 (m, 12H), 6.07 - 5.87 (m, 1H), 5.15 - 4.86 (m, 1H), 4.37 -4.19 (m, 1H), 3.81 (qd, J = 6.1, 3.1 Hz, 0.4H), 3.64 (m, 1H), 3.41 (m,1H), 3.25 (ddd, J = 24.0, 10.3, 8.5 Hz, 1H), 2.17 (s, 2H), 1.88 (s, 1H),1.07 (s, 9H), 0.94 (s, 9H). 19F NMR (376 MHz, Chloroform-d) δ-184.98 (dt, J = 49.3, 14.2 Hz), -190.33 - -190.64 (m).
4-アミノ-1-((2R,3S,4S,5R)-4-((tert-ブチルジフェニルシリル)オキシ)-5-(((tert-ブチルジフェニルシリル)オキシ)メチル)-3-フルオロテトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オン(12)
プロトン、C-1アルファアノマー:1H NMR (400 MHz, Chloroform-d) δ 8.85 (s,1H), 7.53 (ddd, J = 14.6, 8.0, 4.2 Hz, 6H), 7.48 - 7.25 (m, 14H), 6.75 (s, 1H),6.10 (dd, J = 14.0, 1.8 Hz, 1H), 5.72 (s, 1H), 5.09 (dt, J = 46.7, 2.0 Hz, 1H),4.30 (m, 1H), 3.97 - 3.88 (m, 1H), 3.47 (dd, J = 10.2, 6.6 Hz, 1H), 3.43 - 3.33(m, 1H), 0.96 (m,18H).
フッ素、C-1アルファアノマー:19F NMR (376 MHz, Chloroform-d) δ-177.38 (dt, J = 46.8, 12.5 Hz).
プロトン、C-1ベータアノマー:1H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J= 2.6 Hz, 1H), 7.68 - 7.52 (m, 6H), 7.57 - 7.42 (m, 4H), 7.47 - 7.28 (m, 10H),7.04 - 6.99 (m, 1H), 6.80 (dd, J = 24.5, 3.6 Hz, 1H), 5.69 (s, 1H), 4.81 (dt, J= 50.8, 2.8 Hz, 1H), 4.47 (m, 1H), 3.70 - 3.65 (m, 1H), 3.60 - 3.44 (m, 2H),1.10 (s, 9H), 0.89 (s, 9H).
フッ素、C-1ベータアノマー:19F NMR (376 MHz, Chloroform-d) δ-194.16 (ddd, J = 50.5, 24.6, 7.4 Hz).
4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オン(1)
1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 1.3 Hz, 1H), 7.68 - 7.60 (m,2H), 6.29 (dd, J = 11.6, 5.4 Hz, 1H), 5.92 (d, J = 5.2 Hz, 1H), 5.34 (t, J =5.2 Hz, 1H), 5.00 (dt, J = 50.7, 5.8 Hz, 1H), 4.27 (m, 1H), 3.68 (m, 2H), 3.23(q, J = 5.5 Hz, 1H) ppm. 13C NMR (101 MHz, dmso) δ 165.87, 158.07,158.04, 153.63, 96.79, 94.87, 73.44, 73.21, 61.28, 61.26, 57.44, 57.27, 51.97,51.93. 19F NMR (376 MHz, DMSO-d6) δ -192.78 (dt, J = 50.6, 11.7 Hz).融点:208~209℃、d.燃焼解析:計算値:C,36.64;H,4.23;F,7.24;N,21.36;S,12.22,実測値:C,36.66;H,4.14;F,7.04;N,21.08;S,12.27。
1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 1.3Hz, 1H), 7.64 - 7.57 (m, 2H), 6.23 (dd, J = 11.5, 5.4 Hz, 1H), 5.89 (d, J= 5.2 Hz, 1H), 5.31 (t, J = 5.2 Hz, 1H), 4.96 (dt, J = 50.7, 5.9Hz, 1H), 4.22 (dq, J = 11.5, 5.7 Hz, 1H), 3.71 - 3.55 (m, 2H), 3.17 (q, J= 5.5 Hz, 1H).
13C NMR (101 MHz, DMSO-d6) δ 165.88, 158.08, 158.05,153.65, 96.78, 94.86, 73.42, 73.19, 61.26, 57.43, 57.26, 51.94, 51.90 ppm.
19F NMR (376 MHz, DMSO-d6) δ -192.77 (dt, J =50.8, 11.7 Hz).
LC/MS:[M+H]=263.1、98.2%純度。
実施例2
NCI60ヒト腫瘍細胞株抗がん薬スクリーニング
サンプル調製のための標準的な操作手順:
可溶化の標準的な操作手順
NCI60スクリーニング方法
NCI60細胞の1用量スクリーニング:
NCI60細胞5用量スクリーニング:
Ti>/=Tzである濃度の場合、[(Ti-Tz)/(C-Tz)]×100
Ti<Tzである濃度の場合、[(Ti-Tz)/Tz]×100
実施例3
異種移植研究
実施例4
ハロゲン化5-アザ-T-dCydアナログによる処置
本発明は、例えば、以下の項目を提供する。
(項目1)
式Iaに記載の化合物またはその立体異性体、互変異性体もしくは薬学的に許容され得る塩であって、
式中、Xは、ハロであり;
Yは、水素、ハロまたはジュウテリウムであり;
各Rは、独立して、水素またはジュウテリウムであり;
R a は、水素、ジュウテリウム、アルキル、アルコキシ、アミノまたはハロである、
化合物またはその立体異性体、互変異性体もしくは薬学的に許容され得る塩。
(項目2)
(i)Xが、Fである;または
(ii)Yが、水素またはFである;または
(iii)各Rが、水素である;または
(iv)R a が、水素である;または
(v)(i)、(ii)、(iii)および(iv)の任意の組み合わせである、
項目1に記載の化合物。
(項目3)
式IIa~Vaのいずれか1つに記載の立体化学、またはそれらの任意の組み合わせを有する、項目1または項目2に記載の化合物。
(項目4)
前記化合物が、
またはそれらの任意の組み合わせである、項目1に記載の化合物。
(項目5)
前記化合物が、
またはそれらの任意の組み合わせである、項目1に記載の化合物。
(項目6)
前記化合物が、4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オン:
である、項目1に記載の化合物。
(項目7)
項目1~6のいずれか1項に記載の化合物および薬学的に許容され得るキャリアを含む薬学的組成物。
(項目8)
前記薬学的組成物が、静脈内、経口、腹腔内、皮下、直腸または頬側投与のために製剤化されている、項目7に記載の薬学的組成物。
(項目9)
新形成を阻害する方法であって、前記方法は、
新生物性細胞を有効量の項目1~6のいずれか1項に記載の化合物と接触させる工程
を含む、方法。
(項目10)
前記新生物性細胞を前記有効量の前記化合物と接触させる工程が、前記新生物性細胞の増殖を低減する、項目9に記載の方法。
(項目11)
前記化合物が、4-アミノ-1-((2R,3S,4S,5R)-3-フルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロチオフェン-2-イル)-1,3,5-トリアジン-2(1H)-オン:
である、項目9または項目10に記載の方法。
(項目12)
前記新生物性細胞を前記有効量の前記化合物と接触させる工程が、新生物性細胞の存在を少なくとも部分的に特徴とする疾患を有するかまたは有すると疑われる被験体に治療有効量の前記化合物を投与する工程を含む、項目9~11のいずれか1項に記載の方法。
(項目13)
前記疾患が、がんである、項目12に記載の方法。
(項目14)
前記がんが、腎臓、膀胱、乳房、結腸、子宮内膜、皮膚、血液、膵臓、前立腺、骨、肝臓、肺、食道または中枢神経系のがんである、項目13に記載の方法。
(項目15)
前記治療有効量の前記化合物を前記被験体に投与する工程が、前記疾患の徴候または症候を低減する、項目12~14のいずれか1項に記載の方法。
(項目16)
前記疾患の前記徴候または症候が、固形腫瘍であり、前記治療有効量の前記化合物を前記被験体に投与する工程が、前記固形腫瘍の成長を低減するか、前記固形腫瘍の体積を小さくするか、前記固形腫瘍の転移を減少させるか、またはそれらの任意の組み合わせである;または
前記疾患の前記徴候または症候が、異常な全血球数であり、前記治療有効量の前記化合物を前記被験体に投与する工程が、前記全血球数を少なくとも部分的に正常化する、
項目15に記載の方法。
(項目17)
前記治療有効量の前記化合物を投与する工程が、前記治療有効量の前記化合物を含む薬学的組成物を前記被験体に投与する工程を含む、項目12~16のいずれか1項に記載の方法。
(項目18)
投与する工程が、静脈内、経口、腹腔内、皮下、直腸または頬側投与を含む、項目12~17のいずれか1項に記載の方法。
(項目19)
第2の活性な作用物質を前記被験体に投与する工程をさらに含む、項目12~18のいずれか1項に記載の方法。
(項目20)
前記第2の活性な作用物質が、抗がん剤、抗炎症剤、抗菌剤、抗ウイルス剤、麻酔剤またはそれらの任意の組み合わせである、項目19に記載の方法。
Claims (13)
- 請求項1に記載の化合物および薬学的に許容され得るキャリアを含む薬学的組成物。
- 前記薬学的組成物が、静脈内、経口、腹腔内、皮下、直腸または頬側投与のために製剤化されている、請求項2に記載の薬学的組成物。
- 前記新生物性細胞を前記化合物と接触させる工程が、前記新生物性細胞の増殖を低減する、請求項4に記載の組成物。
- 前記新生物性細胞を前記化合物と接触させる工程が、新生物性細胞の存在を少なくとも部分的に特徴とする疾患を有するかまたは有すると疑われる被験体に前記組成物を投与する工程を含む、請求項4~5のいずれか1項に記載の組成物。
- 前記疾患が、がんである、請求項6に記載の組成物。
- 前記がんが、腎臓、膀胱、乳房、結腸、子宮内膜、皮膚、血液、膵臓、前立腺、骨、肝臓、肺、食道または中枢神経系のがんである、請求項7に記載の組成物。
- 前記組成物を前記被験体に投与する工程が、前記疾患の徴候または症候を低減する、請求項6~8のいずれか1項に記載の組成物。
- 前記疾患の前記徴候または症候が、固形腫瘍であり、前記組成物を前記被験体に投与する工程が、前記固形腫瘍の成長を低減するか、前記固形腫瘍の体積を小さくするか、前記固形腫瘍の転移を減少させるか、またはそれらの任意の組み合わせである;または
前記疾患の前記徴候または症候が、異常な全血球数であり、前記組成物を前記被験体に投与する工程が、前記全血球数を少なくとも部分的に正常化する、
請求項9に記載の組成物。 - 投与する工程が、静脈内、経口、腹腔内、皮下、直腸または頬側投与を含む、請求項6~10のいずれか1項に記載の組成物。
- 前記組成物が、第2の活性な作用物質と組み合わせて前記被験体に投与される、請求項6~11のいずれか1項に記載の組成物。
- 前記第2の活性な作用物質が、抗がん剤、抗炎症剤、抗菌剤、抗ウイルス剤、麻酔剤またはそれらの任意の組み合わせである、請求項12に記載の組成物。
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