JP5137849B2 - ヒストンデアセチラーゼのインヒビターとしての置換インドリル−アルキル−アミノ−誘導体 - Google Patents
ヒストンデアセチラーゼのインヒビターとしての置換インドリル−アルキル−アミノ−誘導体 Download PDFInfo
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- JP5137849B2 JP5137849B2 JP2008550744A JP2008550744A JP5137849B2 JP 5137849 B2 JP5137849 B2 JP 5137849B2 JP 2008550744 A JP2008550744 A JP 2008550744A JP 2008550744 A JP2008550744 A JP 2008550744A JP 5137849 B2 JP5137849 B2 JP 5137849B2
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- GGHDAUPFEBTORZ-UHFFFAOYSA-N propane-1,1-diamine Chemical compound CCC(N)N GGHDAUPFEBTORZ-UHFFFAOYSA-N 0.000 description 1
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- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
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- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
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- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
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- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
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- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
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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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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
fferentiation)を誘発し、そして腫瘍の形成を抑制することが報告された(非特許文献1参照)。
ン酸(2−アミノ−フェニル)−アミド誘導体を開示している(特許文献16参照)。
nは0又は1であり、そしてnが0である時は直接結合が意図されており、
mは0、1又は2であり、そしてnが0である時は直接結合が意図されており、
pは0又は1であり、そしてnが0である時は直接結合が意図されており、
Xはそれぞれ独立してN又はCHであり、
Yはそれぞれ独立してO、NH、N−C1−6アルキル、CH又はCH2であり、そしてYがCHである時は、置換基は環式構造物のY原子に結合されており、
R1はヒドロキシ又は式(a−1)
R9はヒドロキシ又は−NH2であり、
R10は水素、チエニル、フラニル又はフェニルであり、そしてチエニル、フラニル又はフェニルはそれぞれ、場合によりハロ、アミノ、ニトロ、シアノ、ヒドロキシ、フェニル、C1−6アルキル、(ジC1−6アルキル)アミノ、C1−6アルキルオキシ、フェニルC1−6アルキルオキシ、ヒドロキシC1−6アルキル、C1−6アルキルオキシカルボニル、ヒドロキシカルボニル、C1−6アルキルカルボニル、ポリハロC1−6アルキルオキシ、ポリハロC1−6アルキル、C1−6アルキルスルホニル、ヒドロキシカルボニルC1−6アルキル、C1−6アルキルカルボニルアミノ、アミノスルホニル、アミノスルホニルC1−6アルキル、イソオキサゾリル、アミノカルボニル、フェニルC2−6アルケニル、フェニルC3−6アルキニル又はピリジニルC3−6アルキニルで置換されていてもよく、
R6、R7及びR8はそれぞれ独立して水素、−NH2、ニトロ、フラニル、ハロ、C1−6アルキル、C1−6アルキルオキシ、トリフルオロメチル、チエニル、フェニル、C1−6アルキルカルボニルアミノ、アミノカルボニルC1−6アルキル又は−C≡C−CH2−R11であり、ここで
R11は水素、C1−6アルキル、ヒドロキシ、アミノ又はC1−6アルキルオキシであり、
R2はC1−6アルキル、C3−7シクロアルキル、C1−6アルキルアミノカルボニル又はC1−6アルキルオキシカルボニルであり、
R3は水素、C1−6アルキル、C3−7シクロアルキル、ヒドロキシC1−6アルキル、C1−6アルキルオキシC1−6アルキル、C1−6アルキルオキシカルボニル又はC1−6アルキルアミノカルボニルであるか、あるいは
R2及びR3がメチレン、エチレン又はプロピレン橋により架橋されていてもよく(すなわち環式環系を形成する)、
R4は水素、C1−6アルキル、−C(=O)−CHR12R13又は−S(=O)2−N(CH3)2であり、ここで
R12及びR13はそれぞれ独立して水素、アミノ、C1−6アルキル又はアミノC1−6アルキルであり、そして
R5は水素、ヒドロキシ、アミノ、ハロ、C1−6アルキル,ポリハロC1−6アルキル、C1−6アルキルオキシカルボニル、ヒドロキシカルボニル、C1−6アルキルカルボニルアミノ、C1−6アルキルオキシ又はモノ−もしくはジ(C1−6アルキル)アミノである]
の化合物、それらのN−オキシド、製薬学的に許容できる付加塩及び立体化学的異性体を対象とする。
a)nが1であり、
b)pが0であり、
c)XがそれぞれNであり、
d)YがそれぞれCHであり、
e)R1がヒドロキシであり、
f)R2がC1−6アルキルであり、
g)R2及びR3がメチレン、エチレン又はプロピレン橋で架橋されていてもよく、
h)R3が水素であり、
i)R4がC1−6アルキルであり、そして
j)R5が水素である。
a)nが1であり、
b)pが0であり、
c)YがそれぞれCHであり、
d)R10が水素であり、
e)R6、R7及びR8がそれぞれ独立して水素であり、
f)R2がC1−6アルキルであり、
g)R2及びR3がメチレン、エチレン又はプロピレン橋で架橋されていてもよく、
h)R3が水素であり、
i)R4がC1−6アルキルであり、そして
j)R5が水素である。
a)nが0であり、
b)Yがそれぞれ独立してO、CH又はCH2であり、
c)R1がヒドロキシであり、そして
d)R3がC3−7シクロアルキル、C1−6アルキルオキシカルボニル又はC1−6アルキルアミノカルボニルである。
a)nが1であり、
b)mが1又は2であり、
c)pが0であり、
d)XがそれぞれNであり、
e)YがそれぞれCHであり、
f)R2及びR3がメチレン、エチレン又はプロピレン橋で架橋されており、
g)R4がC1−6アルキルであり、
h)R5が水素である。
R5が水素である、式(I)の化合物よりなる。
はテトラヒドロピラニルオキシアミノカルボニルであり、そしてn、m、p、X、Y、Z、R2、R3、R4及びR5が式(I)に対して定義されたとおりである、集合的に式(A)の化合物と呼ばれる、式(II)、(III)、(X)、(X−a)及び(X−b)の中間体並びにそれらのN−オキシド、製薬学的に許容できる付加塩及び立体化学的異性体を対象とする。
ば結腸腺癌及び結腸腺腫のような、例えば結腸直腸癌)、進行疾患を包含する前立腺癌、リンパ系の造血器官腫瘍(例えば急性リンパ性白血病、B−細胞リンパ腫、ブルキットリンパ腫)、骨髄性白血病(例えば、急性骨髄性白血病(AML))、甲状腺濾胞腺癌、骨髄異形成症候群(MDS)、間葉細胞源の腫瘍(例えば繊維肉腫及び横紋筋肉腫)、メラノーマ、奇形癌、神経芽細胞腫、神経膠腫、皮膚の良性腫瘍(例えば、角化棘細胞腫)、乳癌(例えば進行乳癌)、腎臓癌、卵巣癌、膀胱癌及び表皮癌である。
a)癌を処置するための腫瘍の放射線照射前、その間又はその後に本発明に従う化合物を投与することにより放射線治療に対して腫瘍を感受性化させる、
b)関節リューマチ、変形性関節炎、若年性関節炎、痛風、多発性関節炎、乾癬性関節炎、強直性脊椎炎及び全身性エリテマドーデスのような関節症及び骨病理状態を処置する、c)血管増殖障害、アテローム性動脈硬化症及び再狭窄を包含する平滑筋細胞増殖を抑制する、
d)潰瘍性大腸炎、クローン病、アレルギー性鼻炎、移植片対宿主病、結膜炎、喘息、ARDS、ベーチェット病、移植拒絶、蕁麻疹、アレルギー性皮膚炎、円形脱毛症、強皮症、発疹、湿疹、皮膚筋炎、ニキビ、糖尿病、全身性エリテマドーデス、川崎病、多発性硬化症、気腫、嚢胞性繊維症及び慢性気管支炎のような炎症状態及び皮膚状態を処置する、e)子宮内膜症、子宮筋腫、不正子宮出血及び子宮内膜増殖症を処置する、
f)網膜及び脈絡膜血管に影響する血管疾患を包含する眼科血管形成を処置する、
g)心機能不全を処置する、
h)HIV感染症の処置のような免疫抑制状態を抑制する、
i)腎機能不全を処置する、
j)内分泌障害を抑制する、
k)糖新生の機能不全を抑制する、
l)神経病理、例えばパーキンソン病あるいは、認識障害、例えばアルツハイマー病又はポリグルタミン関連神経疾患をもたらす神経病理を処置する、
m)精神障害、例えば精神***病、双極性障害、鬱病、心配症及び精神病を処置する、
n)神経筋肉病理、例えば筋萎縮性側索硬化症を抑制する、
o)脊髄筋萎縮症を処置する、
p)遺伝子の発現を強化することにより、処置に敏感な他の病理学的状態を処置する、
q)遺伝子治療を高める、
r)脂質生成を抑制する、
s)マラリアのような寄生虫症を処置する、
のために、使用することができる。
ロゲナーゼ、好ましくはホースラディッシュのペルオキシダーゼを包含する。発光物質は例えばルミノール、ルミノール誘導体、ルシフェリン、エクオリン及びルシフェラーゼを包含する。
合わせ物が想定される。
−白金配位化合物、例えばシスプラチン、カルボプラチン又はオキサリプラチン、
−タキサン化合物、例えばパクリタキセル又はドセタキセル、
−カンプトテシン化合物のようなトポイソメラーゼIインヒビター、例えばイリノテカン又はトポテカン、
−抗癌性ポドフィロトキシン誘導体のようなトポイソメラーゼIIインヒビター、例えばエトポシド又はテニポシド、
−抗腫瘍ビンカアルカロイド、例えばビンブラスチン、ビンクリスチン又はビノレルビン−抗腫瘍ヌクレオシド誘導体、例えば5−フルオロウラシル、ゲンシタビン又はカペシタビン、
−ナイトロジェンマスタード又はニトロソ尿素のようなアルキル化剤、例えばシクロホスホアミド、クロランブシル、カルムスチン又はロムスチン、
−抗腫瘍、アントラサイクリン誘導体、例えばダウノルビシン、ドキソルビシン、イダルビシン又はミトキサントロン、
−HER2抗体、例えばトラストズマブ、
−エストロゲン受容体アンタゴニスト又は選択的エストロゲン受容体モジュレーター、例えばタモキシフェン、トレミレン、ドロルオキシフェン、ファスロデックス又はラルオキシフェン、
−エキセメスタン、アナストロゾール、レトラゾール及びボロゾールのようなアロマターゼインヒビター、
−レチノイド、ビタミンD及びレチノイン酸代謝阻害剤(RAMBA)のような分化剤、例えばアキュタン、
−DNAメチルトランスフェラーゼインヒビター、例えばアザシチジン、
−キナーゼインヒビター、例えばフラボペリドール、イマチニブメシレート又はゲフィチニブ、
−ファルネシルトランスフェラーゼインヒビター、
−他のHDACインヒビター、
−ユビキチン−プロテアソム経路のインヒビター、例えばVelcade、あるいは
−Yondelis、
である。
odytes foetida)に由来する非水溶性アルカロイドである親カンプトテシン化合物に関連した、又はそれから誘導される化合物を表すために使用される。
−カルボキシレート、例えばブチレート、桂皮酸、4−フェニルブチレート又はバルプロ酸、
−ヒドロキサム酸、例えばスベロイルアニリドヒドロキサム酸(SAHA)、ピペラジン含有SAHA類似体、二アリールヒドロキサメートA−161906及びそのカルボゾリルエーテル−、テトラヒドロピリジン−及びテトラロン−類似体、二環式アリール−N−ヒドロキシカルボキシアミド、ピロキシアミド、CG−1521、PXD−101、スルホンアミドヒドロキサム酸、LAQ−824、LBH−589、トリコスタチンA(TSA)、オキサムフラチン、スクリプタイド、スクリプタイド関連三環式分子、m−カルボキシ桂皮酸ビスヒドロキサム酸(CBHA)、CBHA−様ヒドロキサム酸、トラポキシン−ヒドロキサム酸類似体、CRA−024781、R306465及び関連ベンゾイル−及びヘテロアリール−ヒドロキサム酸、アミノスベレート及びマロニルジアミド、
−環式テトラペプチド、例えばトラポキシン、アピジシン、デプシペプチド、スピルコスタチン−関連化合物、RedFK−228、スルフヒドリル−含有環式テトラペプチド(SCOP)、ヒドロキサム酸含有環式テトラペプチド(CHAP)、TAN−174及びアズムアミド、
−ベンズアミド、例えばMS−275又はCI−994、あるいは
−デプデシン
を含んでなる。
る。
えば120〜200mg/m2、特にシクロホスホアミドに対しては約100〜500mg/m2、クロランブシルに対しては約0.1〜0.2mg/kg、カルムスチンに対しては約150〜200mg/m2、そしてロムスチンに対しては約100〜150mg/m2の用量で投与される。
以下の実施例は本発明を具体的に示す。
−プロパンジアミン、一塩酸、「DCM」はジクロロメタン、「DMSO」はジメチルスルホキシド、「EtOAc」は酢酸エチル、「EtOH」はエタノール、「HOBt」は1−ヒドロキシ−1H−ベンゾトリアゾール、「MeOH」はメタノール、「TFA」はトリフルオロ酢酸、そして「THF」はテトラヒドロフランとして定義される。
〈実施例A1〉
a)中間体1の製造
b)中間体2の製造
c)中間体3の製造
a)中間体4の製造
b)中間体5の製造
c)中間体6の製造
a)中間体7の製造
b)中間体8の製造
c)中間体9の製造
d)中間体10の製造
e)中間体11の製造
a)中間体12の製造
b)中間体13の製造
c)中間体14の製造
〈実施例B1〉化合物1の製造
ヒストンデアセチラーゼの阻害のインビトロアッセイ(実施例C.1参照)は、式(I)の化合物により得られるHDAC酵素活性の阻害を測定する。
Immunological Methods 65:55−63,1983)(実施例C.2参照)。
要素を含有しないp21の1300bpプロモーターフラグメントを含有する発現ベクトルで安定にトランスフェクションすることができ、そこで対照レベルに比較して、リポーター遺伝子発現の増加が化合物をp21誘発能をもつものと特定する。リポーター遺伝子は蛍光タンパク質であり、リポーター遺伝子の発現は発光される蛍光の量として測定される(実施例C.6.a参照)。
BiomolのHDAC蛍光活性アッセイ/薬剤発見キット(カタログ番号:AK−500−0001)を使用した。HDAC蛍光活性アッセイはFluor de Lys(Fluorogenic Histone deAcetylase Lysyl(蛍光発生ヒストンデアセチラーゼリシル))基質及び発色剤の組み合わせ物に基づく。Fluor de Lys基質はアセチル化リシン側鎖を含んでなる。その基質の脱アセチル化は、第2工程において、Fluor de Lys発色剤による処理が発蛍光団を生成するように基質を感受性にさせる。
IC50−値のマイナス対数値)として表される(表F−2参照)。
試験されるすべての化合物をDMSOに溶解し、更に培養培地中に希釈した。細胞増殖アッセイにおける最終DMSO濃度は0.1%(v/v)を決して超えなかった。対照は化合物を含まずにA2780細胞及びDMSOを含有し、そしてブランクはDMSOを含有したが、細胞を含まなかった。MTTをPBS中5mg/mlに溶解した。NaOH(1N)でpH10.5にバッファーされた、0.1Mのグリシン及び0.1MのNaClよりなるグリシンバッファーを調製した(すべての試薬はMerckから購入した)。
C.3.a.水性媒質中の動力学的溶解度
5000−9.8μM(1/2希釈物)からのDMSO−ストック溶液を96ウェルストック溶液プレート中でDMSO中に調製する(200μl/ウェル)。各希釈後、サンプルを混合する。次にこれらのDMSO溶液のアリコート(2μl)を、200μl/ウェルの水性バッファーを含有する2個の他の96ウェルバッファープレートに移す。各バッファープレートは水性バッファー(pH7.4)又は水性バッファー(pH4.0)のいずれかを含有する。最後の希釈後、バッファープレートを混合し、サンプルを1/2時間室温で安定化する。偶発的誤差を排除するために各化合物に対して希釈を二重に実施する。次に混合物を沈殿の発生に対してBD Gentest Solubility Scannerにおいてスキャンする。混合物中の沈殿物の不在/存在に基づき、動力学的溶解度を外挿により計算する。3クラスへの評価を実施する。
異なるpHにおける化合物の溶解度はまた、化学発光窒素検出計の使用により測定することができる(表F−2を参照)。
ストックサンプル(100%DMSO中5mMのストック溶液の10μlのアリコート)をpH4又はpH7.4の水性バッファー系の2ml含有ディープウェルプレート又はプレミックスプレート中に希釈した(PSR4 System Solution Concentrate(pION))。
細胞以下の組織調製物をGorrod等(Xenobiotica 5:453−462.1975)に従って、組織の機械的ホモジネート化後の遠心分離により調製した。肝組織を氷冷した0.1MのTris−HCl(pH7.4)バッファー中ですすいで、過剰な血液を洗浄した。次に組織をブロット乾燥し、秤量し、外科用はさみを使用して粗く刻んだ。組織片を、Teflon乳棒の付いたPotter−S(Braun,Italy)又はSorvall Omni−Mixホモジナイザーのいずれかを使用して、7×10秒間、3容量の氷冷0.1Mのリン酸バッファー(pH7.4)中にホモジナイズした。双方の場合に、容器はホモジナイズ工程中氷中/上に維持された。
〈実施例C.6.a.〉細胞法
A2780細胞(ATCC)を37℃の、5%CO2を含む湿潤化インキュベーター内の、10%FCS、2mMのL−グルタミン及びゲンタマイシンを添加されたRPMI 1640培地中で培養した。すべての細胞培養液はGibco−BRL(Gaithersburg,MD)により提供される。他の材料はNuncにより提供される。
トランスフェクション細胞はG418(Gibco−BRL,Gaithersburg,MD)により10日間選択し、単一の細胞懸濁物を増殖させた。3週後、単一のクローンを得た。
選択されたクローンをヌードマウスの脇腹に皮下注射し(107細胞/200μl)、12日後に、カリパー測定可能な腫瘍を得た。12日から、動物に溶媒及び20〜40mpkの化合物(各4〜10匹の動物)を6日間毎日経口又は静脈内投与した。腫瘍を、社内で開発されたAutomated Whole Body Imaging System(自動化全身撮影システム)(GFPフィルターを備え、National Instruments(R)からのIMAQ Vision Softwareに基づくソフトウエアパッケージにより制御されるCCDカメラタイプのJAI(R)CV−M90に接続された蛍光立体顕微鏡タイプのOlympus(R)SZX12)により蛍光を評価した。
試験されたすべての化合物をDMSO(5mM)に溶解し、アセトニトリル中に5 10−4Mに更に希釈した。アッセイバッファー(0.1MのNaKリン酸バッファー、pH7.4)中に更に希釈し、最終溶媒濃度は2%を決して超えなかった。
ー+1.15%のKCl中)、NADPH生成系(アッセイバッファー中、0.41mMのグルコース−6−リン酸、0.4U/mlのグルコース−6−リン酸デヒドロゲナーゼ、0.0082mMのNADP及び0.41mMのMgCl2.6H2O)及び化合物を含んでなる。37℃で5分間のプレインキュベート後に、アッセイバッファー中に3μMの蛍光プローブ基質AMMCの添加により酵素反応を開始した。室温で45分間のインキュベート後、2容量のアセトニトリルの添加後に反応を終結した。405nmの励起波長及び460nmの発光波長で蛍光の測定を実施した。本実験の対照化合物としてキニジン(IC50−値<5×10−8M)を包含した。
錠剤コアの調製
100gの式(I)の化合物、570gのラクトース及び200gのデンプンの混合物を十分混合し、その後、5gのナトリウムドデシルスルフェート及び10gのポリビニル−ピロリドンの溶液(約200mlの水中)で湿潤化する。湿った粉末混合物をふるい、乾燥し、再度ふるう。次いで100gの微細結晶セルロース及び15gの水素化植物油を添加する。全体を十分に混合し、打錠すると、各10mgの式(I)の化合物を含んでなる10.000錠を与える。
10gのメチルセルロースの溶液(75mlの変性エタノール中)に5gのエチルセルロースの溶液(150mlのジクロロメタン中)を添加する。次いで75mlのジクロロメタン及び2.5mlの1,2,3−プロパントリオールを添加する。10gのポリエチレングリコールを融解し、75mlのジクロロメタン中に溶解する。後者の溶液を前者に添加し、次に2.5gのマグネシウムオクタデカノエート、5gのポリビニルピロリドン及び30mlの濃厚色素懸濁液を添加し、全体をホモジネート化する。コーティング装置内で、錠剤のコアをこのように得た混合物でコートする。
Claims (18)
- 式(I)
nは0又は1であり、そしてnが0である時は直接結合が意図されており、
mは0、1又は2であり、そしてnが0である時は直接結合が意図されており、
pは0又は1であり、そしてnが0である時は直接結合が意図されており、
Xはそれぞれ独立してN又はCHであり、
Yはそれぞれ独立してO、NH、N−C1-6アルキル、CH又はCH2であり、そしてYがCHである時は、置換基は環式構造物のY原子に結合されており、
R1はヒドロキシ又は式(a−1)
R9はヒドロキシ又は−NH2であり、
R10は水素、チエニル、フラニル又はフェニルであり、そしてチエニル、フラニル又はフェニルはそれぞれ、場合によりハロ、アミノ、ニトロ、シアノ、ヒドロキシ、フェニル、C1-6アルキル、ジ(C1-6アルキル)アミノ、C1-6アルキルオキシ、フェニルC1-6アルキルオキシ、ヒドロキシC1-6アルキル、C1-6アルキルオキシカルボニル、ヒドロキシカルボニル、C1-6アルキルカルボニル、ポリハロC1-6アルキルオキシ、ポリハロC1-6アルキル、C1-6アルキルスルホニル、ヒドロキシカルボニルC1-6アルキル、C1-6アルキルカルボニルアミノ、アミノスルホニル、アミノスルホニルC1-6アルキル、イソオキサゾリル、アミノカルボニル、フェニルC2-6アルケニル、フェニルC3-6アルキニル又はピリジニルC3-6アルキニルで置換されていてもよく、
R6、R7及びR8はそれぞれ独立して水素、−NH2、ニトロ、フラニル、ハロ、C1-6アルキル、C1-6アルキルオキシ、トリフルオロメチル、チエニル、フェニル、C1-6アルキルカルボニルアミノ、アミノカルボニルC1-6アルキル又は−C≡C−CH2−R11であり、ここで
R11は水素、C1-6アルキル、ヒドロキシ、アミノ又はC1-6アルキルオキシであり、
R2はC1-6アルキル、C3-7シクロアルキル、C1-6アルキルアミノカルボニル又はC1-6アルキルオキシカルボニルであり、
R3は水素、C1-6アルキル、C3-7シクロアルキル、ヒドロキシC1-6アルキル、C1-6アルキルオキシC1-6アルキル、C1-6アルキルオキシカルボニル又はC1-6アルキルアミノカルボニルであるか、あるいは
R2及びR3がメチレン、エチレン又はプロピレン橋により架橋されていてもよく(すなわち環式環系を形成する)、
R4は水素、C1-6アルキル、−C(=O)−CHR12R13又は−S(=O)2−N(CH3)2であり、ここで
R12及びR13はそれぞれ独立して水素、アミノ、C1-6アルキル又はアミノC1-6アルキルであり、そして
R5は水素、ヒドロキシ、アミノ、ハロ、C1-6アルキル,ポリハロC1-6アルキル、C1-6アルキルオキシカルボニル、ヒドロキシカルボニル、C1-6アルキルカルボニルアミノ、C1-6アルキルオキシ又はモノ−もしくはジ(C1-6アルキル)アミノである]
の化合物、又は該化合物のN−オキシド、製薬学的に許容できる付加塩若しくは立体異性体。 - nが1であり、pが0であり、YがそれぞれCHであり、R10が水素であり、R6、R7及びR8がそれぞれ独立して水素であり、R2がC1-6アルキルでありそしてR3が水素であるかあるいは、R2及びR3がメチレン、エチレン又はプロピレ橋で架橋されていてもよく、R4がC1-6アルキルであり、そしてR5が水素である、請求項1記載の化合物。
- nが1であり、mが1又は2であり、pが0であり、XがそれぞれNであり、YがそれぞれCHであり、R2及びR3がメチレン、エチレン又はプロピレ橋で架橋されており、R4がC1-6アルキルであり、そしてR5が水素である、請求項1又は2記載の化合物。
- 製薬学的に許容できる担体及び、有効成分として、治療的有効量の、請求項1〜4のいずれかに記載の化合物を含んでなる製薬学的組成物。
- 製薬学的に許容できる担体及び請求項1〜4のいずれかに記載の化合物が密接に混合される、請求項5に記載の製薬学的組成物の調製方法。
- 医薬としての使用のための請求項1〜4のいずれかに記載の化合物。
- 増殖性疾患の処置のための医薬の製造のための、請求項1〜4のいずれかに記載の化合物の使用。
- 抗癌剤及び請求項1〜4のいずれかに記載の化合物を活性成分として含んでなる、増殖性疾患の処置のための併用剤。
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