JP5176063B2 - 環状ニトロ化合物、その医薬組成物および用途 - Google Patents
環状ニトロ化合物、その医薬組成物および用途 Download PDFInfo
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- JP5176063B2 JP5176063B2 JP2008526299A JP2008526299A JP5176063B2 JP 5176063 B2 JP5176063 B2 JP 5176063B2 JP 2008526299 A JP2008526299 A JP 2008526299A JP 2008526299 A JP2008526299 A JP 2008526299A JP 5176063 B2 JP5176063 B2 JP 5176063B2
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- alkyl
- substituted
- compound
- nitro
- pharmaceutical composition
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- -1 Cyclic nitro compounds Chemical class 0.000 title claims description 181
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 85
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 46
- 239000001257 hydrogen Substances 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
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- 239000012453 solvate Substances 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000003834 intracellular effect Effects 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000001959 radiotherapy Methods 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
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- 150000002431 hydrogen Chemical class 0.000 claims 9
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- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
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- 201000010982 kidney cancer Diseases 0.000 claims 1
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 35
- JODKFOVZURLVTG-UHFFFAOYSA-N 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone Chemical compound [O-][N+](=O)C1([N+]([O-])=O)CN(C(=O)CBr)C1 JODKFOVZURLVTG-UHFFFAOYSA-N 0.000 description 31
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- 238000013270 controlled release Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
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- 239000002585 base Substances 0.000 description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 6
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Description
本発明は、環状ニトロ化合物、環状ニトロ化合物の医薬組成物、および異常細胞の増殖に関連する疾患を治療または予防するために環状ニトロ化合物またはその医薬組成物を使用する方法を提供することによって、本要求および他の要求を満足する。
R1、R2、R3、およびR4は各々独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ハロ、ヒドロキシ、またはニトロであり;
R5およびR6は各々独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ハロ、ヒドロキシ、またはニトロであり;
oは、0、1、2、3、または4であり;
R7は、置換アルキル、置換アリールアルキル、置換ヘテロアルキル、置換ヘテロアリール、置換ヘテロアリールアルキル、置換アシル、置換アルコキシカルボニル、置換ホスホニル、または置換スルホニルであり;
但し、R1、R2、R3、R4、R5、およびR6の少なくとも1つはニトロである]
で示される化合物、またはその塩、溶媒和物もしくは水和物、を提供する。
定義
「アルキル」はそれ自身または別の置換基の一部として、親のアルカン、アルケンまたはアルキンの1個の炭素原子からの1個の水素原子の除去によって派生する、飽和または不飽和の分枝、直鎖または環状の一価の炭化水素基を意味する。典型的なアルキル基は、メチル;エチル類、例えばエタニル、エテニル、エチニル;プロピル類、例えばプロパン−1−イル、プロパン−2−イル、シクロプロパン−1−イル、プロパ−1−エン−1−イル、プロパ−1−エン−2−イル、プロパ−2−エン−1−イル(アリル)、シクロプロパ−1−エン−1−イル、シクロプロパ−2−エン−1−イル、プロパ−1−イン−1−イル、プロパ−2−イン−1−イルなど;ブチル類、例えばブタン−1−イル、ブタン−2−イル、2−メチル−プロパン−1−イル、2−メチル−プロパン−2−イル、シクロブタン−1−イル、ブタ−1−エン−1−イル、ブタ−1−エン−2−イル、2−メチル−プロパ−1−エン−1−イル、ブタ−2−エン−1−イル、ブタ−2−エン−2−イル、ブタ−1,3−ジエン−1−イル、ブタ−1,3−ジエン−2−イル、シクロブタ−1−エン−1−イル、シクロブタ−1−エン−3−イル、シクロブタ−1,3−ジエン−1−イル、ブタ−1−イン−1−イル、ブタ−1−イン−3−イル、ブタ−3−エン−1−イルなど;などを含むが、これらに限定されない。
本発明は、環状ニトロ化合物、環状ニトロ化合物の医薬組成物、および異常細胞の増殖に関連する疾患を治療または予防するための環状ニトロ化合物またはその医薬組成物を使用する方法を提供する。
R1、R2、R3、およびR4は各々独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ハロ、ヒドロキシ、またはニトロであり;
R5およびR6は各々独立して、水素、アルキル、置換アルキル、アリール、置換アリール、アリールアルキル、置換アリールアルキル、ヘテロアルキル、置換ヘテロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロアリールアルキル、置換ヘテロアリールアルキル、ハロ、ヒドロキシ、またはニトロであり;
oは、0、1、2、3、または4であり;
R7は、置換アルキル、置換アリールアルキル、置換ヘテロアルキル、置換ヘテロアリール、置換ヘテロアリールアルキル、置換アシル、置換アルコキシカルボニル、置換ホスホニル、または置換スルホニルであり;
但し、R1、R2、R3、R4、R5、およびR6の少なくとも1つはニトロである]
で示される化合物、またはその塩、溶媒和物もしくは水和物、
を提供する。
各Xは独立して、−F、−Cl、−Br、−I、または−OS(O)2R8(ここで、R8は、メチル、CF3、フェニル、またはトリルであり、そして各pは独立して1、2、3、または4である)である]
を有する。
各Xは独立して、−F、−Cl、−Br、−I、または−OS(O)2R8(ここで、R8は、メチル、−CF3、フェニル、またはトリルである)である]
を有する。ある具体的な実施態様において、該環状ニトロ化合物は、構造式:
環状ニトロ化合物および/またはその医薬組成物は、ヒト医学において有利に使用し得る。上記の5.2項目において上記する通り、環状ニトロ化合物および/またはその医薬組成物は、様々な疾患または障害(例えば、上記するもの)の治療または予防に有用である。
本発明の医薬組成物は典型的に、患者にとって適当な投与のための形態を供するため、治療学的に有効な量の1個以上の環状ニトロ化合物(純粋な形態が好ましい)を、適当な量の医薬的に許容し得るビヒクルと合わせて含む。患者に投与する場合には、該環状ニトロ化合物および医薬的に許容し得るビヒクルは滅菌することが好ましい。該環状ニトロ化合物を静脈内投与する場合には、水は好ましいビヒクルである。生理食塩水溶液、およびデキストロース水溶液およびグリセロール水溶液はまた、特に注射液剤のための液体ビヒクルとして使用し得る。適当な医薬的なビヒクルはまた賦形剤を含み、これは例えば、澱粉、グルコース、ラクトース、スクロース、セラチン、麦芽、米、小麦粉、粉乳、シリカゲル、ステアリン酸ナトリウム、グリセロールモノステアリン酸、タルク、塩化ナトリウム、乾燥脱脂乳、グリセロール、プロピレン、グリコール、水、エタノールなどを挙げられる。所望するならば、本発明の医薬組成物はまた、微量の湿潤剤もしくは乳化剤、またはpH緩衝化剤を含み得る。加えて、補助剤、安定化剤、増粘剤、滑沢剤、および、着色剤を使用し得る。
環状ニトロ化合物および/またはその医薬組成物は通常、意図する目的を達成するのに有効な量で使用する。上記の疾患または障害を治療または予防するための用途において、該環状ニトロ化合物および/またはその医薬組成物は、治療学的に有効な量で投与しまたは適用する。
本発明のある実施態様において、環状ニトロ化合物および/またはその医薬組成物は、少なくとも1つの他の治療薬との併用療法で使用し得る。該環状ニトロ化合物および/またはその医薬組成物、並びに該治療薬は、相加的またはより好ましくは相乗的に作用し得る。1実施態様において、環状ニトロ化合物および/またはその医薬組成物は、別の治療薬の投与と同時に投与する。別の実施態様において、環状ニトロ化合物および/またはその医薬組成物は、別の治療薬の投与の前または後に投与する。
本発明はまた、環状ニトロ化合物および/またはその医薬組成物を含有する治療キットを提供する。該治療キットはまた、他の化合物(例えば、化学療法薬、天然物、アポトーシス−誘発剤など)またはその医薬組成物を含み得る。
ABDNAZおよび放射線照射による腫瘍細胞中でのROSの産生
ヒト結腸癌セルラインHT29細胞およびマウス扁平上皮癌腫セルラインSCC VII細胞を96ウェルプレート中、37℃で終夜増殖させ、次いで、蛍光プローブ2',7'−ジクロロフルオレセイン二酢酸(DCFH−DA)を20μMの濃度で1時間かけて加え、次いでこのものを洗い流した。ABDNAZを、該増殖培地中に濃度が1μM、10μM、または100μMで加えた。緑色蛍光を、蛍光顕微鏡下で測定し、そしてマイクロプレート蛍光光度計(励起光488nmおよび発光525nm)を使用して測定した。ABDNAZおよび放射線照射の両方を用いて処理した細胞の場合には、該プレートは、137Cs供給源を用いてABDNAZの添加の直後に照射した。
ABDNAZによるHL60細胞の増殖の抑制
急性前骨髄球性白血病セルラインであるHL60セルラインを、bcl−2癌遺伝子を用いて安定にトランスフェクトした(HL60 bcl−2細胞)。該HL60ネオ細胞をコントロール(HL60ネオ)として使用した。細胞を、1μM、2μMまたは5μMの濃度のABDNAZの存在下でRPMI1640培地中で増殖させた。生存細胞の数を、10日間毎日カウントした。細胞増殖曲線を図4に示し、これは、ABDNAZが用量依存性の様式で細胞増殖を抑制することを実証する。用量5μMのABDNAZは細胞増殖を>95%抑制し、そしてHL60 bcl−2細胞はABDNAZに対して、ネオ細胞と同程度に感受性であった。
ABDNAZによるHL60細胞のアポトーシスの誘発
上記実施例2中に記載する通りに調製および増殖させた細胞を、ABDNAZの添加の24、48および72時間後に収集し、そしてFACSを用いて分析した。図5は、ABDNAZの存在下での、時間に対するアポトーシスのパーセントを示す。図5、6および7において知り得る通り、ABDNAZは、HL60ネオ細胞およびbcl−2細胞の両方中で用量依存の様式で、非常に高レベルのアポトーシス細胞死を誘発した。5μMのABDNAZは、ネオ細胞およびbcl−2細胞について48時間で、それぞれ95%および78%のアポトーシスを誘発した。2μMの場合には、ABDNAZは、アポトーシス細胞死を生じ、これは、HL60ネオ細胞およびbcl−2細胞中で非常に同程度であり、8時間で〜40%のピークを有した。図6および7は、HL60ネオ細胞およびHL60 bcl−2細胞のそれぞれについてのFACS分析の詳細なヒストグラムを示す。
ABDNAZによるbcl−2癌遺伝子発現の抑制
HL60細胞を、上記実施例2に記載する通りに処理した。細胞を、ウェスタンブロット分析について6および24時間に収集した。図8に示す通り、ABDNAZ(2および5μM)は、ネオ細胞およびbcl−2細胞の両方中で用量依存様式で、bcl−2タンパク質発現を抑制した。HL60 bcl−2トランスフェクト細胞中での該bcl−2タンパク質は、2μM ABDNAZの存在下で切断され得て、このことは、6および24時間後の両方での低分子量バンドの存在によって示される。
ABDNAZの製造
25mLの三ツ口丸底フラスコを、塩化メチレン(7mL)およびt−BuDNAZ(これは、Archibaldらによる, Journal of Organic Chemistry, 1990, 2920中に記載する通り製造する)(2.50g、12.3mmol)で満たした。窒素下、三フッ化ホウ素エーテラート(0.16mL、1.23mmol)を加えた。周囲温度で5分間撹拌後に、ブロモアセチルブロミド(0.54mL、6.15mol)を加えた。該溶液を50〜60℃の間で2時間加熱した。該暗くなった反応混合物を周囲温度まで冷却し、塩化メチレン(50mL)を用いて希釈し、そしてろ過した。該固体は、t−BuDNAZのHBr塩として同定した。該塩化メチレンのろ液を、水(2×20mL部)を用いて洗浄し、硫酸ナトリウムを用いて乾燥し、ろ過し、そして減圧下で蒸発させた。得られた固体をエチルエーテル(3×20mL部)を用いて洗浄し、そして真空下で乾燥して白色固体のBrADNAZ(1.24g(ブロモアセチルブロミド基準で75.2%))を得た。1H NMR (CDCl3): δ 3.76 (s, 2H), 4.88 (br s, 2H), 5.14 (br s, 2H); 13C NMR (CDCl3): δ 165.2, 105.0, 59.72, 57.79, 23.90。元素分析(C5H6BrN3O5として計算)計算値:%C 22.41、%H 2.26、%N 15.68;実測値:%C 22.61、%H 2.36、%N 15.58。HPLC/MS C−8逆相カラム(アセトニトリル/水の移動相を使用)。m/e 266.95 (100%), 268.95 (98.3%)。FT-IR 3014.24 (弱い), 1677.66, 1586.30, 1567.65, 1445.55 (NO2), 1367.80, 1338.00, 1251.27 cm−1。
N−(クロロアセチル)−3,3−ジニトロアゼチジン(ClADNAZ)の製造
25mLの三ツ口丸底フラスコを、塩化メチレン(7mL)およびt−BuDNAZ(2.50g(12.3mmol))で満たした。窒素下、三フッ化ホウ素エーテラート(0.16mL(1.23mmol))を加えた。周囲温度で5分間撹拌後に、クロロアセチルクロリド(0.54mL(6.15mmol))を加えた。該溶液を50〜60℃の間で2時間加熱した。該暗くなった反応混合物を周囲温度まで冷却し、塩化メチレン(50mL)を用いて希釈し、そしてろ過した。該固体を、t−BuDNAZのHBr塩として同定した。該塩化メチレンろ液を、水(2×20mL部)を用いて洗浄し、硫酸ナトリウムを用いて乾燥し、ろ過し、そして減圧下で蒸発させた。得られた固体をエチルエーテル(3×20mL部)を用いて洗浄し、そして真空下で乾燥して白色固体(mp:130〜132℃)(60%収率)で得た。元素分析(C5H6ClN3O5として計算)実測値:C: 26.94%, H: 2.53%, N:17.77%; 計算値:C: 26.86%, H: 2.71% N: 18.79%。FTIR: 2979(弱い), 1690.01, 1577.57, 1438.91(NO2), 1368.21, 1338.99, 1286.21 cm−1。1H NMR: (DMSO-d6), δ 5.09(2H), 4.81(2H), 3.77(2H)。13C NMR: (DMSO-d6), δ 168.58, 106.98, 60.39, 50.38。HPLC:>98%純度。安全性データ: ABL衝撃耐性(Impact): 80 cm; ABL摩擦耐性(Friction): 800@ 8 ft/秒;50%での非拘束TC ESD: 1.10ジュール(バルク試験での物体燃焼)。DSC開始: 259.56℃。
N−ヨードアセチル−3,3−ジニトロアゼチジン(IADNAZ)の製造
100mLの三ツ口丸底フラスコを、窒素下で無水アセトン(40mL)およびBrADNAZ(2.01g)で満たした。K2CO3(1.4g)を加え、続いてヨウ化ナトリウム(1.2g)を加えた。該反応混合物を終夜還流し、そしてプロトンNMRによって追跡した。該暗くなった溶液を塩化メチレンを用いて希釈し、該固体をろ過し、そして該ろ液をジクロロメタン(2×30mL部)および水を用いて抽出した。該有機層を硫酸ナトリウムを用いて乾燥し、そして真空下で濃縮した。該固体をフラッシュカラムクロマトグラフィー(10%酢酸エチル/ヘキサンを使用)によって精製して、白色固体(mp 97〜100℃)(80%収率)で得た。元素分析(C5H6IN3O5として計算):実測値:C: 19.67%, H: 1.80%, N: 12.70%;計算値:C: 19.06%, H: 1.92%, N: 13.24%。FTIR: 2980 (弱い), 1667.44, 1568.49, 1439.74 (NO2), 1373.69, 1335.60, 1305.35 cm−1。1H NMR: (DMSO-d6), δ 5.09(2H), 4.81(2H), 3.77(2H)。13C NMR: (DMSO-d6), δ 168.58, 106.98, 60.39, 50.38。HPLC:>98%純度。安全性データ: ABL衝撃耐性: 80 cm; ABL摩擦耐性: 800@ 8 ft/秒; 50%での非拘束TC ESD 7.30ジュール(バルク試験での物体燃焼); SBAT開始: 286 oF。DSC開始: 253.52℃。
N−アジドアセチル−3,3−ジニトロアゼチジン(AzADNAZ)の製造
100mLの三ツ口丸底フラスコを、窒素下で無水アセトン(40mL)およびBrADNAZ(2.01g)で満たした。K2CO3(1.05g)を加え、続いてアジ化ナトリウム(0.4g)を加えた。該反応混合物を終夜還流し、そしてプロトンNMRによって追跡した。該暗くなった溶液を塩化メチレンを用いて希釈し、該固体をろ過した。該ろ液をジクロロメタン(2×30mL部)および水を用いて抽出した。該有機層を硫酸ナトリウムを用いて乾燥し、そして真空下で濃縮した。該固体をフラッシュカラムクロマトグラフィー(10%酢酸エチル/ヘキサンを使用)によって精製して、白色固体(mp 103〜104℃)(80%収率)で得た。元素分析(C5H6N6O5として計算)実測値:C: 26.84%, H: 2.70%, N: 35.49%;計算値:C: 26.09%, H: 2.63%, N: 34.76%。FTIR: 2981.60 (弱い), 2109.15 (強い), 1678.88, 1598.80, 1571.47, 1463.18 (NO2), 1446.89, 1332.20, 1275.28 cm−1。1H NMR: (DMSO-d6), δ 5.08(2H), 4.83(2H), 4.02(2H)。13C NMR: (DMSO-d6), δ 169.098, 107.74, 59.84, 58.16。HPLC:>99.7%純度。安全性データ: ABL衝撃耐性: 64 cm; ABL摩擦耐性: 800@ 8 ft/秒; 50%での非拘束TC ESD <0.5ジュール(バルク試験での物体燃焼); SBAT開始: 314oF。
N−スクシニル−3,3−ジニトロアゼチジンの製造
100mLの三ツ口丸底フラスコを、窒素下で無水ジクロロメタン(30mL)およびtert−ブチル−3,3−ジニトロアゼチジン(t−BDNAZ)(5.0g)で満たした。塩化スクシニル(4.5g)を加え、続いて三フッ化ホウ素エーテラート(0.5mL)を加えた。該反応混合物を50℃まで加熱し、そしてプロトンNMRによって追跡した。該反応混合物を氷中にゆっくりと注ぎ、次いでこれをろ過した。該褐色固体をジクロロメタン(3×20mL部)を用いて洗浄し、硫酸ナトリウムを用いて乾燥し、そして真空下で濃縮した。該固体をフラッシュカラムクロマトグラフィー(10%酢酸エチル/ヘキサンを使用)によって精製して、淡白色固体(mp 190〜192℃)(20%収率)で得た。元素分析(C7H9N3O7として計算)実測値:C: 33.93%, H: 3.63%, N: 19%;計算値:C: 34.02%; H: 3.67%; N: 17.00%。FTIR: 3004.44(弱い), 1644.78(強い), 1558.45, 1472.60, 1450.06, 1423.01, 1369.90, 1338.05, 1310.05, 1260.99 cm−1。1H NMR: (DMSO-d6), δ 5.27(2H), 4.85(2H), 2.03(4H)。HPLC:>97%。安全性データ: ABL衝撃耐性: 64 cm; ABL摩擦耐性: 800@ 8 ft/秒; 50%での非拘束TC ESD<0.26ジュール(8ジュールでの物体燃焼なし)。DSC開始: 253.86℃。
N−フマリル−3,3−ジニトロアゼチジンの製造
100mLの三ツ口丸底フラスコを、窒素下でtert−ブチル−3,3−ジニトロアゼチジン(t−BDNAZ)(8.69g)で満たし、そして塩化フマリル(5mL)を加え、続いて三フッ化ホウ素エーテラート(0.5mL)を0℃で2時間かけて加えた。該反応混合物をNMRによって追跡した。該濃厚なペーストをメタノールを用いて洗浄し、次いでこのものを氷水中にそそいだ。該固体をろ過し、水洗(200mL)し、そして真空下で乾燥して、淡黄色固体(20%収率(mp: 240℃))を得た。元素分析(C7H7N3O7として計算)実測値:C: 34.9%, H: 3.2%, N: 19.6%;計算値:C: 34.3%; H: 2.9%; N: 17.1%。FTIR: 3082.73(弱い), 1664.79(強い), 1577.69, 1430.19 (NO2), 1366.92, 1274.30, 1231.24, 1213.45 cm−1。1H NMR: (DMSO-d6), δ 5.88(2H), 5.29(2H), 4.90(2H)。HPLC:>96%。安全性データ: ABL摩擦耐性: 800@ 8 ft/秒, 50%での非拘束TC ESD: 1.05ジュール(バルク試験での物体燃焼)。
N−トリフルオロアセチル−3,3−ジニトロアゼチジンの製造
100mLの三ツ口丸底フラスコを、窒素下でtert−ブチル−3,3−ジニトロアゼチジン(t−BDNAZ)(2.28g)で満たした。無水トリフルオロ酢酸(10mL)を加え、続いて三フッ化ホウ素エーテラート(0.3mL)を加えた。該反応混合物を50℃まで加熱し、そしてNMRによって追跡した。該反応液を真空下で濃縮した。該残留油状物を水洗した。該残留油状物を熱ヘキサンに加えて、白色針状晶(mp:70〜71℃)(460mg)を得た。元素分析(C5H4F3N3O5として計算)実測値:C: H:, N;計算値:C: 24.70%, H: 1.66%, N: 17.29%。FTIR: 2991 (弱い), 1716, 1683.96, 1591.37, 1576.43 (NO2), 1165.92, 1134.12 cm−1。1H NMR: (DMSO-d6), δ 5.39(2H), 5.04(2H)。HPLC:>96%純度。安全性データ: ABL摩擦耐性: 800@ 8ft/秒; 50%での非拘束TC ESD: >8ジュール。DSC開始: 240.75℃。
Claims (28)
- 構造式(I):
R1、R2、R3、およびR4は各々独立して、水素、アルキル、アリール、アリールアルキル、またはニトロであり;
R5およびR6は各々独立して、水素、アルキル、アリール、アリールアルキル、またはニトロであり;
oは、0、1、または2であり;
R7は、−C(O)−アルキル、−C(O)−シクロアルキル、または−C(O)−アリールアルキルであって、これらの各々はハロゲン、−OR 60 、−SR 60 、−CF 3 及び−OS(O) 2 R 60 からなる群から独立して選ばれる1個以上の置換基で置換され;そして、
R 60 は、アルキル、置換アルキル、シクロアルキル、置換シクロアルキル、アリール、または置換アリールであり;
但し、R1、R2、R3、R4、R5、およびR6の少なくとも1つはニトロである]
で示される化合物、またはその塩、溶媒和物もしくは水和物。 - R1、R2、R3、R4、R5、およびR6の少なくとも2つがニトロである、請求項1記載の化合物。
- R1、R2、R3、およびR4が各々独立して、水素、アルキル、またはニトロであり、そしてR5およびR6が各々独立して、水素、アルキル、またはニトロである、請求項1記載の化合物。
- R7が、ハロゲン、−OR 60 、−SR 60 、−CF 3 及び−OS(O) 2 R 60 からなる群から独立して選ばれる1個以上の置換基で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- R7が、ハロゲン、−CF 3 または−OS(O) 2 R 8 (ここで、R8が、アルキル、置換アルキル、アリール、または置換アリールである)の1個以上で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- R3およびR4がニトロである、請求項1記載の化合物。
- R1、R2、R3、およびR4が各々独立して、水素、アルキル、またはニトロであり、R5およびR6が各々独立して、水素、アルキル、またはニトロであり、そしてR7が、ハロゲン及び−OS(O) 2 R 60 からなる群から独立して選ばれる1個以上の置換基で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- R1、R2、R3、およびR4が各々独立して、水素、アルキル、またはニトロであり、R5およびR6が各々独立して、水素、アルキル、またはニトロであり、そしてR7が、1個以上のハロゲン、−CF3、または−OS(O)2R8(ここで、R8が、アルキル、置換アルキル、アリール、または置換アリールである)で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- R1およびR2が各々独立して、水素またはアルキルであり、R3およびR4がニトロであり、R5およびR6が各々独立して、水素またはアルキルであり、そしてR7が、ハロゲン及び−OS(O) 2 R 60 からなる群から独立して選ばれる1個以上の置換基で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- R1およびR2が各々独立して、水素またはアルキルであり、R3およびR4がニトロであり、R5およびR6が各々独立して、水素またはアルキルであり、そしてR7が、1個以上のハロゲン、−CF3、または−OS(O)2R8(ここで、R8が、アルキル、置換アルキル、アリール、または置換アリールである)で置換された、−C(O)−アルキルである、請求項1記載の化合物。
- oが1である、請求項1〜10のいずれか1つに記載の化合物。
- R 7 が1個以上のハロゲンで置換された−C(O)CH 3 である、請求項1〜3、6または9のいずれか1つに記載の化合物。
- R1およびR2が各々独立して、水素またはアルキルであり、R3およびR4がニトロであり、R5およびR6が各々独立して、水素またはアルキルであり、R7が1個以上のハロゲンで置換された−C(O)CH 3 であり、そしてoが1である、請求項1記載の化合物。
- R1およびR2が水素であり、R3およびR4がニトロであり、R5およびR6が水素であり、R7が1個以上のハロゲンで置換された−C(O)−アルキルであり、そしてoが1である、請求項1記載の化合物。
- 請求項1〜18のいずれか1つに記載の化合物および医薬的に許容し得るビヒクルを含有する、医薬組成物。
- 化合物が請求項9記載の化合物である、請求項19記載の医薬組成物。
- 癌を治療または予防するための、請求項19記載の医薬組成物。
- 癌が、乳癌、腎臓癌、脳腫瘍、結腸癌、結腸直腸癌、前立腺癌、または肺癌である、請求項22記載の医薬組成物。
- 還元性の細胞内環境を用いて腫瘍細胞を処置するための、請求項19記載の医薬組成物。
- 固形腫瘍を治療または予防するための、請求項19記載の医薬組成物。
- 白血病およびリンパ腫を治療または予防するための、請求項19記載の医薬組成物。
- 結腸癌、扁平上皮癌、または白血病を処置するための、請求項19記載の医薬組成物。
- 医薬組成物を放射線療法と組み合わせて使用する、請求項19〜27のいずれか1つに記載の医薬組成物。
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