JP5124443B2 - 新規なイソインドール誘導体、これを含有する組成物、これらの調製及び特にシャペロンタンパク質hsp90活性の阻害薬としてのこれらの医薬的使用 - Google Patents
新規なイソインドール誘導体、これを含有する組成物、これらの調製及び特にシャペロンタンパク質hsp90活性の阻害薬としてのこれらの医薬的使用 Download PDFInfo
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- JP5124443B2 JP5124443B2 JP2008504804A JP2008504804A JP5124443B2 JP 5124443 B2 JP5124443 B2 JP 5124443B2 JP 2008504804 A JP2008504804 A JP 2008504804A JP 2008504804 A JP2008504804 A JP 2008504804A JP 5124443 B2 JP5124443 B2 JP 5124443B2
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- 238000007142 ring opening reaction Methods 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 239000004758 synthetic textile Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- MBMQEIFVQACCCH-UHFFFAOYSA-N trans-Zearalenon Natural products O=C1OC(C)CCCC(=O)CCCC=CC2=CC(O)=CC(O)=C21 MBMQEIFVQACCCH-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical class C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
これらの分子質量に従って分類される、「熱ショックタンパク質」ファミリー(HSP)の分子シャペロン(Hsp27、Hsp70、Hsp90など)は、タンパク質の正しいフォールディングに応答性である細胞タンパク質の合成と分解との間のバランスに於ける重要な要素である。これらは、細胞ショックに対する応答で極めて重要な役割を演じる。HSP、特にHsp90は、また、細胞増殖又はアポプトーシス中に含まれる種々のクライアントタンパク質とのこれらの会合により、細胞の種々の主要機能の調節に含まれる(Jolly C.and Morimoto R.I.,J.N.Cancer Inst.(2000),92,1564−72;Smith D.F.et al,Pharmacological Rev.(1998),50,493−513;Smith D.F.,Molecular Chaperones in the Cell、165−178,Oxford University Pres 2001)。
細胞のタンパク質含有量の1から2%を表すHsp90シャペロンは、最近、抗癌治療に於いて特に有望な標的として示された(総説について、Moloney A.and Workman P.,Expert Opin.Biol.Ther.(2002),2(1),3−24;Choisis et al,Drug Discovery Today(2004),9,881−888参照)。この利点は、特に、Hsp90とHsp90の主クライアントタンパク質との細胞質相互作用からもたらされ、これらのタンパク質は、Hanahan D.及びWeinberg R.A.(Cell(2002),100,57−70)によって定義されているような、腫瘍進行の6個の機構、即ち、
増殖因子の不存在下で増殖する能力:EGFR−R/HER2、Src、Akt、Raf、MEK、Bcr−Abl、Flt−3など、
アポプトーシスを免れる能力:p53、Akt、スルビビン(Survivin)などの突然変異形、
増殖停止シグナルに対する非感受性:Cdk4、Plk、Wee1など、
血管形成を活性化する能力:VEGF−R、FAK、HIF−1、Aktなど、
複製限界無しで増殖する能力:hTertなど、
新規な組織を冒し、転移する能力:c−Met
内に含まれる。
Hsp90の最初の公知の阻害薬は、アンサマイシンファミリーの化合物、特に、ゲルダナマイシン(1)及びハービマイシンAである。X線研究によって、ゲルダナマイシンが、Hsp90のN−末端ドメインのATPサイトに結合し、そこでこれは、シャペロンのATPアーゼ活性を阻害することが示された(Prodromou C.et al,Cell(1997),90,65−75)。
nは、整数1又は2であり、
R1は、酸素若しくは硫黄原子又は基NRbであり、
R2は、独立して、H、ハロゲン、CF3、ニトロ、シアノ、メチル、エチル、ヒドロキシル、メルカプト、アミノ、メトキシ、チオメトキシ、メチルアミノ、ジメチルアミノ、アセチルアミノ、カルボキシル及びカルボキサミドからなる群から選択され、
Raは、H、ハロゲン、CF3、ヒドロキシル、メルカプト、ニトロ、アミノ、OR3、SR3、NR3R4、NH−OH、NH−CO−H、NH−CO−OH、NH−CO−NH2、カルボキシル、シアノ、カルボキサミド、Y−(CH2)p−アルキル、Y−(CH2)p−シクロアルキル、Y−(CH2)p−ヘテロシクロアルキル、Y−(CH2)p−アリール又はY−(CH2)p−ヘテロアリールからなる群から選択され、ここで、Y=O、S、NH、O−C(O)、C(O)−NH、NH−C(O)、NH−S(O)又はNH−S(O)2であり、p=1、2又は3であり、アリール基は6から10個の環員を含有し、シクロアルキル基は3から10個の環員を含有し並びにヘテロアリール又はヘテロシクロアルキル基は、O、N又はSから選択された1から3個のヘテロ原子を含む4から10個の環員を含有し、全てのこれらの基は場合により置換されており、
R3及びR4は、独立して、水素原子又はアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル若しくはヘテロアラルキル基から選択され、上記の全てのアルキル、アルケニル、アルキニル、アリール、ヘテロアリール、アラルキル若しくはヘテロアラルキル基は、場合により置換されており、
Rbは、H、(CH2)m−シクロアルキル、(CH2)m−ヘテロシクロアルキル、(CH2)m−アリール又は(CH2)m−ヘテロアリールからなる群から選択され、ここで、m=0、1又は2であり、全てのこれらの基は場合により置換されている]
の生成物であり、該式(I)の生成物は、全ての可能性のあるラセミ、エナンチオマー及びジアステレオ異性異性体形並びにまた、式(I)の該生成物の、無機酸及び有機酸との又は無機塩基及び有機塩基との付加塩である。
塩化化合物の中で、無機塩基、例えば、当量のナトリウム、カリウム、リチウム、カルシウム、マグネシウム若しくはアンモニウム又は有機塩基、例えば、メチルアミン、プロピルアミン、トリメチルアミン、ジエチルアミン、トリエチルアミン、N,N−ジメチルエタノールアミン、トリス(ヒドロキシメチル)アミノメタン、エタノールアミン、ピリジン、ピコリン、ジシクロヘキシルアミン、モルホリン、ベンジルアミン、プロカイン、リジン、アルギニン、ヒスチジン若しくはN−メチルグルカミンを、
エステル化化合物の中で、アルコキシカルボニル基、例えば、メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル又はベンジルオキシカルボニルを形成するためのアルキル基(これらのアルキル基について、例えば、ハロゲン原子、ヒドロキシル基、アルコキシ基、アシル基、アシルオキシ基、アルキルチオ基、アミノ基又はアリール基から選択された基によって置換されて、例えば、クロロメチル、ヒドロキシプロピル、メトキシメチル、プロピオニルオキシメチル、メチルチオメチル、ジメチルアミノエチル、ベンジル又はフェネチル基にされることが可能である)を挙げることができる。
(式中、A1、A2及びA4はCHであり、A3はN、CH又はCOHであり、
nは整数2であり、
R1は酸素原子であり、
R2はHである)
の生成物に関し、式(I)の該生成物は、全ての可能なラセミ、エナンチオマー及びジアステレオ異性異性体形並びにまた、式(I)の該生成物の、無機酸及び有機酸との又は無機塩基及び有機塩基との付加塩である。
1−{3−H−イミダゾ[4,5−c]ピリジン−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン、
1−{1−H−6−ヒドロキシベンゾイミダゾール−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン
を有する、前記定義されたような式(I)の生成物に関し、式(I)の該生成物は、全ての可能なラセミ、エナンチオマー及びジアステレオ異性異性体形並びにまた、式(I)の該生成物の、無機酸及び有機酸との又は無機塩基及び有機塩基との付加塩である。
上記研究に基づいた、一般的スキーム1に記載された、最初の独創的な一般的方法が開発され、本発明に関連して、特に6−オキソ−2,3,4,6−テトラヒドロピリド[2,1−a]イソインドール型の誘導体の合成のために、特に有利であることが証明された。
D.Barton et al著、Comprehensive Organic Chemistry(Pergamon Press);
J.Marsh著、Advanced Organic Chemistry(Wiley Interscience)
中に記載されているものに従って実施することができる。
1−{3−H−イミダゾ[4,5−c]ピリジン−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン、
1−{1−H−6−ヒドロキシベンゾイミダゾール−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン
を有する生成物及びこのプロドラッグ[式(I)の該生成物は、全ての可能なラセミ、エナンチオマー及びジアステレオ異性異性体形並びにまた、式(I)の該生成物の、無機酸及び有機酸との又は無機塩基及び有機塩基との医薬的に許容される付加塩である]の、医薬製品としての使用である。
EGF−R又はHER2を過発現する、「非小細胞」肺癌、乳癌、卵巣癌及び膠芽腫;
Bcr−Ablを過発現する、慢性骨髄性白血病;
Flt−3を過発現する、急性リンパ芽球性白血病;
Aktを過発現する、乳癌、前立腺癌、肺癌、膵臓癌、結腸癌又は卵巣癌;
B−Rafタンパク質の突然変異した形を過発現する、転移性黒色腫及び甲状腺腫瘍;
アンドロゲン依存性及びアンドロゲン独立性前立腺癌;
エストロゲン依存性及びエストロゲン独立性乳癌;
HIF−1a又は突然変異したc−metタンパク質を発現する、腎臓癌などを挙げることができる。
ピリジン−3,4−ジアミン4g及び5−(1,3−ジオキソ−1,3−ジヒドロイソインドール−2−イル)ペンタン酸9.5gを、250mLの丸底フラスコの中に導入し、続いてポリリン酸(PPA)45gを導入する。この固体混合物を油浴中で210℃まで加熱する。反応の間に、2−{4−(3H−イミダゾ[4,5−c]ピリジン−2−イル)ブチル}イソインドール−1,3−ジオンの過渡生成が認められる。16時間加熱した後、反応は完結する。冷却した後、反応混合物を水中に溶解する。酢酸エチルによる抽出によって、不純物を除去する。水性相を2N水酸化ナトリウムで中和する(pH7)。酢酸エチル及びメタノールの混合物(9/1体積基準)による6回の連続的抽出の後、生成物を回収する。溶離を、ジクロロメタン及びメタノールの混合物(95/5体積基準)で実施する、フラッシュクロマトグラフィーシリカによって精製した後、1−{3−H−イミダゾ[4,5−c]ピリジン−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン1.46gが、白色固体の形で得られ、この特性は、下記の通りである。
1H NMR スペクトル(400 MHz DMSO−d6):2.08(m,2H);2.88(t,J=6.0Hz,2H);3.81(t,J=6.0Hz,2H),7.54(m,2H)7.60(d,J=5.5Hz,1H);7.78(m,1H);7.95(ブロード m,1H)8.34(d,J=5.5Hz,1H);8.97(s,1H);12.95(非常にブロード m,1H)。質量スペクトル(E/I):m/z=302(M+)
工程1:Eur.J.Org.Chem.1999,3489に従って得ることができる、3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン−1−カルボン酸メチルエステル942mgを、25mLの三つ口フラスコ内で、ジオキサン10mL中に溶解させ、水酸化リチウム一水和物168mgを添加する。環境温度で6時間撹拌した後、ジオキサンを蒸発除去し、生成物を水20mLに溶解し、次いで、1Mの塩酸水溶液の添加によって、溶液をpH=2にする。生成した沈殿をフィルター乾燥し、水で洗浄し、次いでオーブン内で真空下で50℃で乾燥する。このようにして3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン−1−カルボン酸820mgが、白色粉末の形で得られ、これをこのまま次の工程で使用する。
工程4:酢酸2mL及び48%臭化水素酸水溶液3mL中の、1−{1−H−6−メトキシベンゾイミダゾール−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン61mgの溶液を、25mLの三つ口フラスコ内で、環境温度で20時間攪拌する。この反応混合物を、水100mLの中に注ぎ、ジクロロメタン25mLの存在下で、飽和炭酸水素ナトリウム溶液によって中和する。水性相をジクロロメタン25mLによって2回再抽出する。一緒にした有機相を、硫酸マグネシウムで乾燥し、減圧下で濃縮する。粗製生成物が、溶離をジクロロメタン及びメタノールの混合物(95/5次いで90/10体積基準)で実施する、シリカゲル上のクロマトグラフィーによって得る。このようにして、1−{1−H−6−ヒドロキシベンゾイミダゾール−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン49mgが、白色フォームの形で得られ、この特性は、下記の通りである。
1H NMR スペクトル(400 MHz DMSO−d6):2.04(m,2H);2.83(t,J=6.0Hz,2H);3.80(t,J=6.0Hz,2H),6.74(ブロード d,J=8.5Hz,1H);6.90(ブロード m,1H);7.42(ブロード m,1H);7.53(m,2H);7.75(m,1H);8.02(ブロード m,1H);9.22(ブロード m,1H);12,4(非常にブロード m,1H)。
下記の配合に対応する錠剤を製剤した。
1gの最終質量を有する錠剤のための賦形剤
(賦形剤の詳細:ラクトース、タルク、デンプン、ステアリン酸マグネシウム)。
Hsp82のATPアーゼ活性によるATPの加水分解の間に放出される有機ホスファートを、マラカイトグリーン法によって定量する。この試薬の存在下で、無機ホスファート−モリブダート−マラカイトグリーン錯体の形成が起こり、この錯体は620nmの波長で吸収する。
B:1μM<IC50<10μM
C:10μM<IC50<100μM
Claims (16)
- 下記の名称:
1−{3−H−イミダゾ[4,5−c]ピリジン−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン、
1−{1−H−6−ヒドロキシベンゾイミダゾール−2−イル}−3,4−ジヒドロ−2H−ピリド[2,1−a]イソインドール−6−オン
を有する、請求項1に記載の式(I)の化合物。 - 医薬製品としての、請求項1に記載の式(I)の化合物。
- 医薬製品としての、請求項2に記載の式(I)の化合物。
- 活性成分として、請求項3及び4に記載の化合物の少なくとも1つを含有する医薬組成物。
- 医薬製品として使用されることを特徴とする、請求項5に記載の医薬組成物。
- 癌化学療法のための他の医薬製品の活性成分も含有する、請求項5又は6に記載の医薬組成物。
- Hsp90タンパク質の活性の妨害によって特徴付けられる、疾患を予防又は治療する際に使用するための請求項1又は2に記載の式(I)の化合物又はその医薬的に許容される塩から製造された医薬。
- Hsp90タンパク質の活性を阻害する際に使用するための請求項1又は2に記載の式(I)の化合物又はその医薬的に許容される塩から製造された医薬。
- 癌を治療する際に使用するための請求項1又は2に記載の式(I)の化合物又はその医薬的に許容される塩から製造された医薬。
- 治療すべき疾患が、固体腫瘍又は液体腫瘍からなる癌である、請求項10に記載の医薬。
- 治療すべき疾患が、細胞毒性剤に対して耐性である癌である、請求項11に記載の医薬。
- 肺癌、乳癌及び卵巣癌、膠芽腫、慢性骨髄性白血病、急性リンパ芽球性白血病、前立腺癌、膵臓癌及び結腸癌、転移性黒色腫、甲状腺腫瘍及び腎臓癌からなる群から選択される癌を治療する際に使用するための請求項1又は2に記載された式(I)の化合物又はその医薬的に許容される塩から製造された医薬。
- 単独で又は化学療法若しくは放射線療法と組み合わせて又はその代わりに他の治療薬と組み合わせて使用するための請求項1又は2に記載の式(I)の化合物又はその医薬的に許容される塩から製造された医薬。
- 治療薬が、抗腫瘍薬である、請求項14に記載の医薬。
- Hsp90阻害薬としての請求項1又は2に記載の式(I)の化合物。
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FR0503511A FR2884252B1 (fr) | 2005-04-08 | 2005-04-08 | Nouveaux derives d'isoindoles, compositions les contenant, leur preparation et leurs utilisations pharmaceutiques notamment en tant qu'inhibiteurs d'activites de la proteine chaperone hsp90 |
PCT/FR2006/000750 WO2006108948A2 (fr) | 2005-04-08 | 2006-04-05 | Nouveaux derives d'isoindoles, compositions les contenant, leur preparation et leurs utilisations pharmaceutiques notamment en tant qu'inhibiteurs d'activites de la proteine chaperone hsp90 |
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FR2885904B1 (fr) * | 2005-05-19 | 2007-07-06 | Aventis Pharma Sa | Nouveaux derives du fluorene, compositions les contenant et utilisation |
WO2008045529A1 (en) * | 2006-10-12 | 2008-04-17 | Serenex, Inc. | Purine and pyrimidine derivatives for treatment of cancer and inflammatory diseases |
FR2932484B1 (fr) * | 2008-06-16 | 2010-06-18 | Sanofi Aventis | Nouveaux derives de pyrroloindole inhibiteurs d'hsp90, compositions les contenant et utilisation |
AR077405A1 (es) | 2009-07-10 | 2011-08-24 | Sanofi Aventis | Derivados del indol inhibidores de hsp90, composiciones que los contienen y utilizacion de los mismos para el tratamiento del cancer |
FR2949467B1 (fr) | 2009-09-03 | 2011-11-25 | Sanofi Aventis | Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation |
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KR101925395B1 (ko) | 2016-01-29 | 2019-02-27 | 계명대학교 산학협력단 | Hsp90 억제 활성을 갖는 신규 디히드록시페닐계 화합물 또는 이의 약제학적으로 허용가능한 염 및 이의 의학적 용도 |
CN109843888B (zh) | 2016-10-24 | 2022-03-01 | 阿斯利康(瑞典)有限公司 | 可用于治疗癌症的6,7,8,9-四氢-3H-吡唑并[4,3-f]异喹啉衍生物 |
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KR20190014474A (ko) | 2017-08-02 | 2019-02-12 | 계명대학교 산학협력단 | Hsp90 억제 활성을 갖는 디히드록시페닐계 입체이성질체 및 이의 의학적 용도 |
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WO2006108948A2 (fr) | 2006-10-19 |
EP1869042B1 (fr) | 2011-02-02 |
DE602006019953D1 (de) | 2011-03-17 |
JP2008534660A (ja) | 2008-08-28 |
AR053206A1 (es) | 2007-04-25 |
RU2007141398A (ru) | 2009-05-20 |
US20080119507A1 (en) | 2008-05-22 |
US8034939B2 (en) | 2011-10-11 |
WO2006108948A3 (fr) | 2007-10-11 |
EP1869042A2 (fr) | 2007-12-26 |
FR2884252A1 (fr) | 2006-10-13 |
TW200718700A (en) | 2007-05-16 |
ATE497501T1 (de) | 2011-02-15 |
KR20080002809A (ko) | 2008-01-04 |
CN101287733A (zh) | 2008-10-15 |
AU2006234396A1 (en) | 2006-10-19 |
UY29468A1 (es) | 2006-11-30 |
RU2375361C2 (ru) | 2009-12-10 |
CA2603634A1 (fr) | 2006-10-19 |
FR2884252B1 (fr) | 2007-05-18 |
IL186050A0 (en) | 2008-06-05 |
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