JP4791355B2 - 抗腫瘍活性を有するカンプトテシンの7−イミノ誘導体 - Google Patents
抗腫瘍活性を有するカンプトテシンの7−イミノ誘導体 Download PDFInfo
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- JP4791355B2 JP4791355B2 JP2006507637A JP2006507637A JP4791355B2 JP 4791355 B2 JP4791355 B2 JP 4791355B2 JP 2006507637 A JP2006507637 A JP 2006507637A JP 2006507637 A JP2006507637 A JP 2006507637A JP 4791355 B2 JP4791355 B2 JP 4791355B2
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- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 1
- 229950009073 gimatecan Drugs 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl 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])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000004967 organic peroxy acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 208000024719 uterine cervix neoplasm Diseases 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- A61P33/06—Antimalarials
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Hematology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
- カンプトテシン(CPT)、および多くのその活性誘導体は水溶性が低い;
-後続の誘導体は、胃腸および骨髄レベルで重篤な副作用を有する;
- いくつかの腫瘍系統ではトポイソメラーゼI阻害剤に対する抵抗性が発達している;
-より良好な治療係数についての研究が続いている。
このたび7位に芳香族エナミノ基を有するカンプトテシンが抗腫瘍活性を有することが驚くべきことに見いだされた。該化合物はよりよい治療係数を有する。
R1は、−C(R5)=N-R4 基、ここでR4はフェニル基であって、所望により以下からなる群から選択される1以上の基で置換されていてもよい: ハロゲン、ヒドロキシ、ケト、C1-C8 アルキル、C1-C8 アルコキシ、フェニル、シアノ、ニトロ、-NR6R7、ここでR6および R7は同一であっても異なっていてもよく、水素、(C1-C8) 直鎖状または分枝状アルキル; -S-S-(2-アミノフェニル)、-S-S-(4-アミノフェニル)、-S-(4-アミノフェニル)、-SCH3および-CH2ON=C(CH3)2;
R5は、水素、C1-C8 直鎖状または分枝状アルキル、C1-C8 直鎖状または分枝状アルケニル、C3-C10 シクロアルキル、(C3-C10) シクロアルキル - (C1-C8) 直鎖状または分枝状アルキル、C6-C14 アリール、(C6-C14) アリール - (C1-C8) 直鎖状または分枝状アルキル;
R2およびR3は同一であっても異なっていてもよく、水素、ヒドロキシ、C1-C8 直鎖状または分枝状アルコキシ];
その N1-オキシド、その単一の異性体、特にC(R5)=N-R4 基のsynおよびanti異性体、その可能性のあるエナンチオマー、ジアステレオ異性体および関連混合物、その医薬上許容される塩およびその活性代謝産物である。
本発明の範囲において、C1-C8 直鎖状または分枝状アルキル基の例として、メチル、エチル、プロピル、ブチル、ペンチル、オクチル、その可能性のある異性体、例えばイソプロピル、イソブチル、tert-ブチルが挙げられる。
7-(2-メチルフェニル)イミノメチルカンプトテシン (ST2212)
7-(2-クロロフェニル)イミノメチルカンプトテシン (ST2228)
7-(2,6-ジメチルフェニル)イミノメチルカンプトテシン (ST2317)
7-(2-ヨードフェニル)イミノメチルカンプトテシン (ST2316)
7-(2-メトキシフェニル)イミノメチルカンプトテシン (ST2343)
7-(4-メチルフェニル)イミノメチルカンプトテシン (ST2478)
7-(2-ヒドロキシフェニル)イミノメチルカンプトテシン (ST2389)
7-(4-クロロフェニル)イミノメチルカンプトテシン (ST2412)
7-(4-メトキシフェニル)イミノメチルカンプトテシン (ST2477)
7-[(4-イソプロピリデン-アミノ-オキシメチル)フェニル]イミノメチルカンプトテシン (ST2460)
7-(2-t-ブチルフェニル)イミノメチルカンプトテシン (ST2388)
7-フェニルイミノメチルカンプトテシン (ST1546)
7-(4-ニトロフェニル)イミノメチルカンプトテシン (ST1561)
7-2-(2-アミノフェニルジチオ)フェニルイミノメチルカンプトテシン (ST1737)
7-4-(4-アミノフェニルジチオ)フェニルイミノメチルカンプトテシン (ST2034)
7-4-(4-アミノフェニルチオ)フェニルイミノメチルカンプトテシン (ST2069)
7-(2-メチルチオフェニル)イミノメチルカンプトテシン (ST2138)
7-(4-tert-ブチルフェニルイミノメチル)-カンプトテシン (ST 2619)
7-(4-メチルチオフェニルイミノメチル)-カンプトテシン (ST 2667)
7-(4-ヒドロキシフェニルイミノメチル)-カンプトテシン (ST 2616)。
胸腺欠損 nu/nu Swiss マウス (Charles River、Calco、Italia)、10-12週齡を用いた。動物をUnited Kingdom Co-ordination Committee Cancer Researchのガイドラインにしたがって層流室中に維持した。実験プロトコールは、Istituto Nazionale per lo Studio e la Cura dei Tumoriの動物実験について倫理委員会の認可を受けた。
1対照腫瘍に対する治療腫瘍の最後の処置の11-12日後の腫瘍体積阻害 %
2薬剤処置によって誘導された体重減少%
3死/処置マウス。
一般方法: 4ÅMSを含む5 mlの無水 CH2Cl2中のYb(OTf)3 (16 mg、0.03 mmol)の懸濁液に20 mlの CH2Cl2中の7-ホルミルカンプトテシン (100 mg、0.26 mmol)の溶液を添加し、次いで0.5 mlのCH2Cl2 中のアミン(0.26 mmol)の溶液を添加する。その結果得られた混合物を反応が完了するまで室温で撹拌する。篩をろ過した後、20 mlの水を添加し、二相を分離する。水層を迅速にジクロロメタンで3回抽出する。混合有機相を乾燥させて蒸発させ、生成物をシリカゲルのフラッシュクロマトグラフィーで精製する。
IC50 (H-460、 μM): 0.10
M.P. 247-248 ℃ dec.、 1H NMR (DMSO-d6)δ : 0.87 (t、J = 7 Hz、H3-18)、 1.7-1.9 (m、H2-19)、2.5 (s、Ar-CH3)、5.4 (s、H2-17)、5.60 (s、H2-5)、6.55 (s、-OH)、7.25-7.50 (m、4H Ar、H-14)、7.75 (m、H-11)、7.95 (m、H-10)、8.25 (dd、H-12)、9.10 (dd、H-9)、9.65 (s、CH=N).
IC50 (H-460、 μM): 0.07
M.P. >240℃ dec.、1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.45 (s、H2-17)、5.60 (s、H2-5)、6.50 (s、-OH)、7.35-7.50 (m、H-14; 4H Arom.)、7.85 (m、H-11)、7.95 (m、H-10)、8.30 (dd、H-12)、9.10 (dd、H-9)、9.70 (s、CH=N).
IC50 (H-460、μM): 0.15
M.P. 250 ℃ dec.、 1H NMR (DMSO-d6)δ : 0.87(t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19 )、2.25 (s、2Ar-CH3)、5.4 (s、H2-17)、5.60 (s、H2-5)、6.55 (s、-OH)、7.0-7.30 (m、3H Ar)、7.40 (s、H-14)、7.8 (m、H-11)、7.9 (m、H-10)、8.25 (dd、H-12)、8.85 (dd、H-9)、9.5 (s、CH=N).
IC50 (H-460、μM): 0.06
M.P. 240 ℃ dec.、 1H NMR (DMSO-d6)δ : 0.87(t、J = 7 Hz、H3-18)、1.8-1.9 (m、H2-19)、5.45 (s、H2-17)、5.75 (s、H2-5)、6.55 (s、-OH)、7.1-7.6 (m、4H Ar、H-14)、7.8 (m、H-11)、7.9 (m、H-10)、8.30 (dd、H-12)、9.10 (dd、H-9)、9.65 (s、CH=N).
IC50 (H-460、μM): 0.06
M.P. 244-246℃ dec.、1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、3.95 (s、OCH3)、5.45 (s、H2-17)、5.55 (s、H2-5)、6.45 (s、-OH)、7.0-7.50 (m、H-14; 4H Arom.)、7.7 (m、H-11)、7.85 (m、H-10)、8.25 (dd、H-12)、8.9 (dd、H-9)、9.70 (s、CH=N).
IC50 (H-460、μM): 0.18
M.P. 159-160℃dec.、1H NMR(DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、2.35 (s、Ar-CH3)、5.37 (s、H2-17)、5.5 (s、H2-5)、6.45 (s、-OH)、7.25-7.35 (m、H-14; 2H Arom.)、7.4-7.5 (m、2H arom.)、7.7 (m、H-11)、7.85 (m、H-10)、8.16 (dd、H-12)、8.9 (dd、H-9)、9.55 (s、CH).
IC50 (H-460、μM): 0.06
M.P. 252-254 ℃ dec.、1H NMR (DMSO-d6)δ : 0.87 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.4 (s、H2-17)、5.60 (s、H2-5)、6.55 (s、-OH)、6.90-7.5 (m、4H Ar、H-14)、7.85-8.0 (m、H-11、H-10)、8.35 (dd、H-12)、8.90 (dd、H-9)、9.70 (s、CH=N).
IC50 (H-460、μM): 0.08
M.P. 246-247℃ dec.、1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.40 (s、H2-17)、5.55 (s、H2-5)、6.45 (s、-OH)、7.35 (s、H-14)、7.50-7.60 (m、4H arom.)、7.85 (m、H-11)、7.95 (m、H-10)、8.25 (dd、H-12)、8.95 (dd、H-9)、9.55 (s、CH=N).
IC50 (H-460、μM): 0.16
M.P. 252-255 ℃ dec.、 1H NMR (DMSO-d6)δ : 0.87(t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、3.8 (s、-OCH3)、5.4 (s、H2-17)、5.45 (s、H2-5)、6.55 (s、-OH)、7.05 (d、2H Ar)、7.35 (s、H-14)、7.60 (d、2H Ar)、7.85 (m、H-11)、7.9 (m、H-10)、8.25 (dd、H-12)、8.8 (dd、H-9)、9.5 (s、CH).
IC50 (H-460、μM): 0.01
M.P. 147℃ dec.、1H NMR (DMSO-d6)δ : 0.85 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19、C(CH3),2)、5.05 (s、CH2-O)、5.40-5.55 (m、H2-17、H2-5)、6.50 (s、-OH)、7.35 (s、H-14)、7.40-7.60 (m、4H arom.)、7.75-7.85 (m、H-11)、7.86-7.95 (m、H-10)、8.25 (dd、H-12)、8.95 (dd、H-9)、9.60 (s、CH=N).
IC50 (H-460、 μM): 0.07
M.P. 215℃ dec.、1H NMR (DMSO-d6)δ : 0.85 (t、J = 7 Hz、H3-18)、1.45 (s、9H、tBut)、1.7-1.9 (m、H2-19)、5.35-5.75 (m、H2-17、H2-5)、6.50 (s、-OH)、7.05-7.5 (m、H-14; 4H arom.)、7.75-7.85 (m、H-11)、7.88-7.95 (m、H-10)、8.25 (dd、H-12)、8.95 (dd、H-9)、9.45 (s、CH=N).
IC50 (H-460、μM): 0.13
1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.37 (s、H2-17)、5.5 (s、H2-5)、6.45 (s、-OH)、7.25-7.35 (m、H-14; H arom.)、7.4-7.5 (m、4H arom)、7.7 (m、H-11)、7.85 (m、H-10)、8.16 (dd、H-12)、8.9 (dd、H-9)、9.55 (s、CH=N)
IC50 (H-460、μM): 0.28
M.P. 260-265℃dec. 1H NMR (DMSO-d6)δ : 0.85 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.35 (s、H2-17)、5.48 (s、H2-5)、6.45 (s、-OH)、7.3 (s、H-14)、7.6-7.7 (m、2 Ar),7.8 (m、H-11)、7.9 (m、H-10)、8.25 (dd、H-12)、8.35-8.40 (m、2 Ar)、8.9 (dd、H-9)、9.67 (s、CH=N).
IC50 (H-460、μM): 0.017
1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18) 1.7-1.9 (m、H2-19) 5.35-5.75(6H、m、H2-5 + H-17 + NH2)、6.40 (1H、m、ArH)、6.5-6.6 (2H、m、1 ArH + OH)、6.90 (1H、m、ArH)、7.25-7.45 (4H、m、3 ArH + H-14)、7.15-8.0 (4H、m、4 ArH)、8.25 (1H、dd)、9.75 (1H、s、CH=N).
IC50 (H-460、μM): 0.39
M.P. 154-155℃ dec.、1H NMR (DMSO-d6)δ:0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.40 (s、H2-17)、5.55 (s、H2-5 + NH2)、6.50 (s、-OH)、6.55 (m、2H Ar)、7.25 (m、2H Ar),7.35 (s,H-14)、7.60 (m、4H Ar)、7.8 (m、H-11)、7.9(m、H-10)、8.25 (dd、H-12)、9.0 (dd、H-9)、9.70 (s、CH=N).
IC50 (H-460、μM): 0.24
M.P. 187-188℃ dec.、 1H NMR (DMSO-d6)δ : 0.87 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、5.4 (s、H2-17)、5.55 (s、H2-5 + NH2)、6.55 (s、-OH)、6.65 (m、2H Ar)、7.10-7.50 (m、6H Ar + H-14)、7.8 (m、H-11)、7.9 (m、H-10)、8.30 (dd、H-12)、9.0 (dd、H-9)、9.5 (s、CH=N).
IC50 (H-460、μM): 0.06
M.P. >250℃ dec.、1H NMR (DMSO-d6)δ:s0.83 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、2.50 (s、SCH3)、5.40 (s、H2-17)、5.70 (s、H2-5)、6.45 (s、-OH)、7.25-7.35 (m、H-14; 3H arom.)、7.6 (m、1H arom)、7.8 (m、H-11)、7.95 (m、H-10)、8.30 (dd、H-12)、9.10 (dd、H-9)、9.55 (s、CH=N).
7 mLの無水 CH2Cl2中の20S-カンプトテシン-7-アルデヒド (1) (100 mg、0.26 mmol)の懸濁液に適当なアミン (0.78 mmol)およびYb(OTf)3 (16 mg、0.03 mmol)を添加した。その結果得られた混合物を室温で反応が完了するまで撹拌した。篩をろ過した後、溶媒を蒸発させ、生成物をシリカゲルでのフラッシュクロマトグラフィーで精製した (Merck 230-400 メッシュ)。
溶液を1.5時間撹拌する。フラッシュクロマトグラフィー (溶出液: CH2Cl2:MeOH 99:1). 黄色粉末. 収率 50%、M.P. 250℃ dec.、1H NMR (DMSO-d6)δ:0.88 (t、J = 7 Hz、H3-18)、1.30 (s、tBut)、1.75-1.95 (m、H2-19)、5.45 (s、H2-17)、5.55 (s、H2-5)、6.55 (s、-OH)、7.35 (s、H-14)、7.45-7.60 (m、4H Ar)、7.80 (m、H-11)、7.95 (m、H-10)、8.25 (dd、H-12)、8.95 (dd、H-9)、9.7 (s、CH=N).
IC50 (H-460、μM): 0.09
溶液を22時間撹拌する。フラッシュクロマトグラフィー (溶出液: CH2Cl2:MeOH 98 : 2). 黄色粉末. 収率 36%、M.P. 160℃dec.、1H NMR (DMSO-d6)δ : 0.87 (t、J = 7 Hz、H3-18)、1.7-1.9 (m、H2-19)、2.55 (s、-SCH3)、5.45 (s、H2-17)、5.55 (s、H2-5)、6.50 (s、-OH)、7.35 (s、H-14)、7.40 (d、2H Ar)、7.55 (d、2H Ar)、7.80 (m、H-11)、7.9 (m、H-10)、8.20 (dd、H-12)、8.95 (dd、H-9)、9.7 (s、CH=N).
IC50 (H-460、μM): 0.074
溶液を3時間撹拌する。フラッシュクロマトグラフィー (溶出液: CH2Cl2:MeOH 96:4). 黄色粉末. 収率 79%、M.P. 250 ℃ dec.、1H NMR (DMSO-d6)δ: 0.90 (t、J = 7 Hz、H3-18)、1.75-2.0 (m、H2-19)、5.4 (s、H2-17)、5.55 (s、H2-5)、6.50 (s、-OH)、6.90 (d、2H Ar)、7.35 (s、H-14)、7.55 (d、2H Ar)、7.80 (m、H-11)、7.90 (m、H-10)、8.25 (dd、H-12)、9.0 (dd、H-9)、9.70 (s、CH=N).
IC50 (H-460、μM): 0.22
Claims (14)
- 式(I)の化合物:
[式中:
R1は、-C(R5)=N-R4 基、ここでR4はフェニル基であり、以下からなる群から選択される1以上の基で置換されている: -S-S-(2-アミノフェニル)、-S-S-(4-アミノフェニル)、-S-(4-アミノフェニル)、および -SCH3;
R5は、水素、C1-C8 直鎖状または分枝状アルキル、C 2 -C8 直鎖状または分枝状アルケニル、C3-C10 シクロアルキル、 (C3-C10) シクロアルキル - (C1-C8) 直鎖状または分枝状アルキル、C6-C14 アリール、 (C6-C14) アリール - (C1-C8) 直鎖状または分枝状アルキル;
R2およびR3は、同じであっても異なっていてもよく、水素、ヒドロキシ、C1-C8 直鎖状または分枝状アルコキシ];
そのN1-オキシド、その-C(R 5 )=N-R 4 基のsynまたはanti異性体、その可能性のあるエナンチオマー、ジアステレオ異性体、またはその医薬上許容される塩。 - フェニル基であるR 4 基がオルト位で置換されている請求項1の化合物。
- 以下からなる群から選択される請求項1の化合物:
7-2-(2-アミノフェニルジチオ)フェニルイミノメチルカンプトテシン (ST1737)
7-4-(4-アミノフェニルジチオ)フェニルイミノメチルカンプトテシン (ST2034)
7-4-(4-アミノフェニルチオ)フェニルイミノメチルカンプトテシン (ST2069)
7-(2-メチルチオフェニル)イミノメチルカンプトテシン (ST2138)、
そのN1-オキシド、またはその医薬上許容される塩。 - -C(R5)=N-R4基のsynまたは anti異性体である、請求項1〜3のいずれかに記載の化合物の異性体。
- 式 (Ia)の化合物と式 (IIa)の化合物のモル比が1:3〜3:1である請求項5に記載の方法。
- 医薬としての請求項1-4のいずれかの化合物。
- 治療上有効量の請求項1-4のいずれかの少なくとも1つの化合物を医薬上許容される媒体および賦形剤と混合して含む医薬組成物。
- 治療上有効量の請求項1-4のいずれかの少なくとも1つの化合物を医薬上許容される媒体および賦形剤と混合して含み、さらにその他の活性成分を含む医薬組成物。
- 該その他の活性成分が抗腫瘍性である請求項9の医薬組成物。
- 腫瘍の治療のための、請求項1-4のいずれかの化合物を含む医薬組成物。
- 該腫瘍が非小細胞肺腫瘍、結腸-直腸腫瘍、前立腺腫瘍および卵巣腫瘍、神経膠腫、肉腫ならびに白血病からなる群から選択される請求項11の医薬組成物。
- ウイルス感染の治療のための、請求項1-4のいずれかの化合物を含む医薬組成物。
- 抗熱帯熱マラリア原虫活性を有する、請求項1-4のいずれかの化合物を含む医薬組成物。
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PCT/IT2004/000118 WO2004083214A1 (en) | 2003-03-17 | 2004-03-10 | 7-imino derivatives of camptothecin having antitumor activity |
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ITRM20030344A1 (it) * | 2003-07-14 | 2005-01-15 | Ist Naz Stud Cura Dei Tumori | 7-n-poliamminoalchil(ossi)imminometilcamptotecine recanti gruppi protettivi. |
ITRM20040288A1 (it) * | 2004-06-11 | 2004-09-11 | Sigma Tau Ind Farmaceuti | Uso della 7-t-butossiimminometilcamptotecina per la preparazione di un medicamento per il trattamento delle neoplasie dell'utero. |
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US7291936B1 (en) * | 2006-05-03 | 2007-11-06 | Robson John H | Submersible electrical power generating plant |
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US4399276A (en) * | 1981-01-09 | 1983-08-16 | Kabushiki Kaisha Yakult Honsha | 7-Substituted camptothecin derivatives |
JPS58154582A (ja) | 1982-03-10 | 1983-09-14 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体およびその製造法 |
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US5614529A (en) | 1994-09-22 | 1997-03-25 | Research Triangle Institute | Inhibition of plasmodia parasites by camptothecin compounds |
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IT1282673B1 (it) | 1996-02-23 | 1998-03-31 | Ist Naz Stud Cura Dei Tumori | Derivati della camptotecina e loro uso come agenti antitumorali |
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KR101174112B1 (ko) | 2012-08-16 |
US20040018988A1 (en) | 2004-01-29 |
SI1603919T1 (sl) | 2009-04-30 |
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TW200504076A (en) | 2005-02-01 |
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CA2517450C (en) | 2011-06-14 |
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