JP5975581B2 - ミグラスタチンおよびその使用 - Google Patents
ミグラスタチンおよびその使用 Download PDFInfo
- Publication number
- JP5975581B2 JP5975581B2 JP2014504053A JP2014504053A JP5975581B2 JP 5975581 B2 JP5975581 B2 JP 5975581B2 JP 2014504053 A JP2014504053 A JP 2014504053A JP 2014504053 A JP2014504053 A JP 2014504053A JP 5975581 B2 JP5975581 B2 JP 5975581B2
- Authority
- JP
- Japan
- Prior art keywords
- aliphatic
- pharmaceutically acceptable
- methyl
- compound
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HAMAGKWXRRTWCJ-UHFFFAOYSA-N pyrido[2,3-b][1,4]oxazin-3-one Chemical compound C1=CN=C2OC(=O)C=NC2=C1 HAMAGKWXRRTWCJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N pyrocatechol monomethyl ether Natural products COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- FLCPORVHXQFBHT-UHFFFAOYSA-N quinolin-8-yl carbamate Chemical compound C1=CN=C2C(OC(=O)N)=CC=CC2=C1 FLCPORVHXQFBHT-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
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- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
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- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
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- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000012760 regulation of cell migration Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
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- 102000007268 rho GTP-Binding Proteins Human genes 0.000 description 1
- 108010033674 rho GTP-Binding Proteins Proteins 0.000 description 1
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- YBKWIGSMABMNJZ-UHFFFAOYSA-N s-(2,3,4,5,6-pentachlorophenyl)thiohydroxylamine Chemical compound NSC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl YBKWIGSMABMNJZ-UHFFFAOYSA-N 0.000 description 1
- RTKRAORYZUBVGQ-UHFFFAOYSA-N s-(2,4-dinitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O RTKRAORYZUBVGQ-UHFFFAOYSA-N 0.000 description 1
- LOVVSIULYJABJF-UHFFFAOYSA-N s-(2-nitrophenyl)thiohydroxylamine Chemical compound NSC1=CC=CC=C1[N+]([O-])=O LOVVSIULYJABJF-UHFFFAOYSA-N 0.000 description 1
- BDEZGPKAMAVGBE-UHFFFAOYSA-N s-(3-nitropyridin-2-yl)thiohydroxylamine Chemical compound NSC1=NC=CC=C1[N+]([O-])=O BDEZGPKAMAVGBE-UHFFFAOYSA-N 0.000 description 1
- DAXSYWBYJZACTA-UHFFFAOYSA-N s-(4-methoxy-2-nitrophenyl)thiohydroxylamine Chemical compound COC1=CC=C(SN)C([N+]([O-])=O)=C1 DAXSYWBYJZACTA-UHFFFAOYSA-N 0.000 description 1
- LOFZYSZWOLKUGE-UHFFFAOYSA-N s-benzyl carbamothioate Chemical compound NC(=O)SCC1=CC=CC=C1 LOFZYSZWOLKUGE-UHFFFAOYSA-N 0.000 description 1
- MAGSSGQAJNNDLU-UHFFFAOYSA-N s-phenylthiohydroxylamine Chemical compound NSC1=CC=CC=C1 MAGSSGQAJNNDLU-UHFFFAOYSA-N 0.000 description 1
- PIDYQAYNSQSDQY-UHFFFAOYSA-N s-tritylthiohydroxylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SN)C1=CC=CC=C1 PIDYQAYNSQSDQY-UHFFFAOYSA-N 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
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- BPELEZSCHIEMAE-UHFFFAOYSA-N salicylaldehyde imine Chemical compound OC1=CC=CC=C1C=N BPELEZSCHIEMAE-UHFFFAOYSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 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
- 150000003333 secondary alcohols Chemical class 0.000 description 1
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- 238000007493 shaping process Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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- 239000001509 sodium citrate Substances 0.000 description 1
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000009331 sowing Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 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
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 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
- 229960004528 vincristine Drugs 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
- 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
- 229960002066 vinorelbine Drugs 0.000 description 1
- LVLANIHJQRZTPY-UHFFFAOYSA-N vinyl carbamate Chemical compound NC(=O)OC=C LVLANIHJQRZTPY-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- 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
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Description
本出願は、2011年4月7日に出願された米国仮特許出願第61/473,131号、および2011年7月15日に出願された米国仮特許出願第61/508,275号の優先権を主張する。これらの各米国仮特許出願の全内容が、参考として本明細書に援用される。
多くのがんによる死亡が、原発性腫瘍からではなく、転移性疾患の結果として生じることは、周知である。この事実を認めて、がんを処置する手段として、転移を妨げるかもしくは停止させることに強い臨床的利益がある。
本発明は、国立衛生研究所によって授与された助成金CA103823の下で、合衆国政府による支援を受けて行われた。本発明はまた、Terri Brodeur Breast Cancer Foundationからの研究支援金によって支援されている。合衆国政府は、本発明において一定の権利を有する。
本開示の特定の化合物、および具体的官能基の定義は、以下に、より詳細に記載される。本開示の目的で、化学元素は、元素周期表(CASバージョン, Handbook of Chemistry and Physics, 75th Ed.,内表紙)に従って同定され、具体的官能基は、そこに記載されるとおりに一般的に定義される。さらに、有機化学の一般原理、ならびに具体的官能部分および反応性は、「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito: 1999(その内容全体が、本明細書に参考として援用される)に記載されている。
本発明は、がんの処置において有用であり、そして/またはがん転移を阻害するときに有効である化学療法用化合物の必要性が未だにあるという認識を包含する。
ここで、
R1は、水素もしくは必要に応じて置換されたC1−6脂肪族であり;
R2は、酸素保護基、水素もしくは必要に応じて置換されたC1−6脂肪族であり;
R3およびR5は、各々独立して、必要に応じて置換されたC1−6脂肪族であり;そして
R4は、水素もしくは−T−Yであって、
−T−は、必要に応じて置換されたC1−8二価飽和もしくは不飽和の、直鎖状もしくは分枝状の炭化水素鎖であり、ここで1個以上のメチレン単位は、−NR−、−N(R)C(O)−、−C(O)N(R)−、−N(R)SO2−、−SO2N(R)−、−O−、−C(O)−、−OC(O)−、−OC(O)O−、−C(O)O−、−OC(O)N(R)−、−S−、−SO−、もしくは−SO2−によって必要に応じてかつ独立して置き換えられ;
各Rは、独立して、−H、またはC1−20脂肪族、C1−20ヘテロ脂肪族、6〜10員のアリール、5〜12員のヘテロアリール、3〜14員の炭素環、3〜12員の複素環式からなる群より選択される必要に応じて置換された基であり;そして
−Yは、水素もしくはアシルである。
本明細書で記載される場合、本発明は、新規治療剤の開発において有用な、特に、がん治療剤に有用である化合物および合成方法論を提供する。一般に、本明細書で開示されるように調製される化合物は、がんに罹患している被験体におけるがんの処置および/もしくは予防(好ましくは、転移の予防)に有用であり得る。
例えば、本発明の創意工夫のある抗がん剤と組み合わせて使用され得る他の治療もしくは抗がん剤としては、いくつか挙げると、以下が挙げられる:外科手術、放射線療法(いくつか挙げると、γ線照射、中性子線照射療法、電子線照射療法、陽子線療法、小線源療法、および全身放射活性同位体(systemic radioactive isotopes))、内分泌療法、生物学的応答改変因子(biologic response modifiers)(いくつか挙げると、インターフェロン、インターロイキン、および腫瘍壊死因子(TNF))、温熱療法および寒冷療法、任意の有害効果を減少させる薬剤(例えば、制吐剤)、ならびに他の承認された化学療法薬(アルキル化薬物(メクロレタミン、クロラムブシル、シクロホスファミド、メルファラン、イホスファミド)、代謝拮抗物質(メトトレキサート)、プリンアンタゴニストおよびピリミジンアンタゴニスト(6−メルカプトプリン、5−フルオロウラシル、シタラビン(Cytarabile)、ゲムシタビン)が挙げられるが、これらに限定されない)、紡錘体毒素(spindle poisons)(ビンブラスチン、ビンクリスチン、ビノレルビン、パクリタキセル)、ポドフィロトキシン(エトポシド、イリノテカン、トポテカン)、抗生物質(ドキソルビシン、ブレオマイシン、マイトマイシン)、ニトロソウレア(カルムスチン、ロムスチン)、無機イオン(シスプラチン、カルボプラチン)、酵素(アスパラギナーゼ)、ならびにホルモン(タモキシフェン、ロイプロリド、フルタミド、およびメゲストロール)。特定の実施形態において、抗がん剤は、エポチロン、タキソール、ラディシコールもしくはTMC−95A/Bである。特定の実施形態において、上記エポチロンは、12,13−デスオキシエポチロンB、(E)−9,10−デヒドロ−12,13−デスオキシEpoBおよび26−CF3−(E)−9,10−デヒドロ−12,13−デスオキシEpoBである。さらに、本発明はまた、現在臨床試験中であり、最終的にはFDAによって承認され得る特定の細胞傷害性薬剤もしくは抗がん剤(エポチロンおよびそのアナログならびにゲルダナマイシンおよびそのアナログが挙げられるが、これらに限定されない)の使用を包含する。
分析装置: 旋光度を、室温において、JASCO P−2000デジタル偏光計で測定した。g/100ml単位の濃度(c)および溶媒を括弧に入れて示される。1H−および13C−NMRスペクトルを、CDCl3中で、Bruker AMX−400もしくはBruker DRX−500分光計で記録した。ケミカルシフト(δ値)を、内部標準として残余の重水素化していないCDCl3を用いてppm単位で報告する(1H−NMRについては7.26ppmおよび13C−NMRについては77.0ppmとして引用される)。カップリング定数(J)(H,H)は、Hz単位で示され、スペクトル分割パターン(spectral splitting patterns)を、一重線(s)、二重線(d)、三重線(t)、四重線(q)、多重線もしくはより重なるシグナル(m)、見かけ(app)、ブロードシグナル(br)として示す。低分解能マススペクトル(イオンスプレー、エレクトロスプレーのバリエーション)を、Perkin−Elmer Sciex API 100分光計で取得した。サンプルを直接注入によって導入した。高分解能マススペクトル(高速原子衝撃,FAB)を、分光光度計で取得した。フラッシュクロマトグラフィー(FC)を、E.Merckシリカゲル(60,粒度0.040〜0.063mm)で行った。
方法1: アリル型アルコール(allylic alcohol)11(6.2g,30.97mmol)および2,6−ルチジン(4.3mL,37.08mmol)を、無水CH3CN(350mL)中で合わせた。四臭化炭素(16.2g,49.44mmol)を添加し、この溶液を0℃へと冷却した。Ph3P(10.53g,40.17mmol)を、少しずつ添加し、この混合物を室温へと加温した。30分間にわたって撹拌した後、飽和NH4Cl(200mL)の中に注ぐことによってこの反応をクエンチした。その水相をEt2Oで抽出し(2×200mL)、合わせた有機抽出物を乾燥させ(MgSO4)、濾過し、濃縮した。その残渣を、シリカゲル(EtOAc−ヘキサン,1:19)のプラグを通して濾過し、濃縮した。得られた残渣を、フラッシュクロマトグラフィー(EtOAc−ヘキサン,1:9)によって精製して、臭化アリル(allylic bromide)12(6.9g,85%)を無色油状物として得た。[α]20D −7.01 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 5.75 (m, 1H), 5.36−5.27 (m, 3H), 4.04 (d, 1 H, J = 9.6 Hz), 3.96 (d, 1 H, J = 9.7 Hz), 3.48 (dd, 1 H, J = 5.1, 8.0 Hz), 3.29 (m+s, 4H), 2.67 (m, 1H), 2.59 (d, 1 H, J = 5.2 Hz), 1.85 (s, 3H), 1.04 (d, 3 H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3): δ 135.7, 134.7, 131.5, 119.9, 83.9, 77.3, 56.7, 35.6, 32.6, 22.4, 15.8; HRMS (ESI) 計算値[C11H19O2Br+ Na]+: 285.0466, 実測値: 285.0475。
酸24(8mg,55%), [α]20D + 108.79 (c 0.35, 1:4 MeOH/CHCl3); 1H NMR (CDCl3, 500 MHz): δ 13C NMR (CDCl3, 125 MHz): δ HRMS (ESI) 計算値 [C18H28O5+ Na]+: 347.1834, 実測値: 347.1826。
酸32(14mg,45%), [α]20D 75.38 (c 0.6, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 11.98 (br, OH), 13C NMR (CDCl3, 125 MHz): δ 19F NMR (CDCl3, MHz): δ HRMS (ESI) 計算値 [C19H27O5F3+ Na]+: 415.1708, 実測値: 415.1691。
酸36(10mg,25 %), [α]20D 99.67 (c 0.4, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 13C NMR (CDCl3, 125 MHz): δ 19F NMR (CDCl3, MHz): δ HRMS (ESI) 計算値 [C19H27O5F3+ Na]+: 415.1708, 実測値: 415.1691。
1. Aubert, C.; Begue, J. P.; Charpentier−Morize, M.; Nee, G.; Langlois, B.. General method of preparation of trifluoromethyl ketones. Part I. Direct alkylation of ethyl trifluoroacetylacetate. Journal of Fluorine Chemistry (1989), 44(3), 361−76.
2. Aubert, C.; Begue, J. P.; Charpentier−Morize, M.; Nee, G.; Langlois, B. General method of preparation of trifluoromethyl ketones. Part II. Indirect alkylation of ethyl trifluoroacetylacetate. Journal of Fluorine Chemistry (1989), 44(3), 377−94.
(実施例12)
MDA231BrM2aは、脳に転移するヒト乳がん細胞系である(Bosら、2009年)。これら細胞は、生体発光によって、および抗GFP抗体での免疫蛍光によって、検出を可能にする三重融合タンパク質(チミジンキナーゼ−GFP−ルシフェラーゼ)を安定して発現する。細胞(5×105細胞)を、心内注射によって免疫不全マウスの血流に接種した。カルボキシメチル−ミグラエーテル(cME)を、注射後0日目、3日目および5日目に投与した(20mg/kg,腹腔内)。接種後7日間で、マウスを屠殺した。これらマウスの脳を連続切片にした(80μm切片)。抗GFP免疫蛍光を行い、脳あたりのGFP(+)細胞(事象)の数を定量した(図1)。結果は、血液脳関門(BBB)を横切るこれらがん細胞の管外遊出が、接種後最初の7日間の間に生じることを立証する。従って、図1の実験において、cMEは、管外遊出工程の間に細胞を標的とする。脳あたりの事象の数における2倍の低下は、cME処置動物に観察された(図1)。結果は、cMEの細胞標的が、上記BBBを横断するがん細胞移動を媒介することを示す。
この実施例は、創傷治癒アッセイにおけるインビトロがん細胞移動を阻害する能力、およびトランスウェル移動アッセイにおける化学走性を評価することによって、新たなミグラスタチンアナログの抗転移特性を評価する。図3に示されるように、100μMのミグラスタチンエーテル(ME)およびカルボキシ−メチルミグラスタチンエーテル(CME)は、ひっかき傷に応じたヒト非小細胞肺がん(NSCLC)A549細胞の移動をほぼ完全にブロックした。μM未満の濃度において、CME化合物はなお、かなり有効であった(32%の移動阻害)。類似の結果が、ヒト肺がん細胞系の一団(H1975、H647、H522、H1703(データは示さず))で得られた。
この実施例は、NSCLC系の一団を評価するために、改変Boydenチャンバ系において血清勾配に応じた化学走性を示す。このアッセイは、用量応答研究が最大半値阻害濃度(IC50)を決定するために行われることを可能にする、再現可能な強いデータを提供した。図4および表1に示されるように、ミグラスタチンコアエーテルアナログは、上記血清勾配に応じた8μm孔挿入物を貫通するヒト肺がん細胞の移動を効率的にブロックした。比較的に、CME化合物は、A549、H1975、およびH299がん細胞に対して、それぞれ、ME化合物(1.5〜8.2μM)より低いIC50値(0.5〜5μM)を示す。なぜなら、本発明者らは、軽度の毒性およびμM濃度範囲において細胞増殖に対する効果に気づいたので、1mM以上でのCMEおよびMEでの実験を、このIC50計算について含めなかった。まとめると、これら結果は、インビトロ移動阻害に関して、細胞傷害性を生じる濃度から2桁低い濃度より低い、非常に感度の高い応答を示した。
この実施例は、上記MEアナログがヒト小細胞肺がん(SCLC)初代異種移植片モデルにおいて腫瘍転移に影響を与えるどうかを研究した。NOD−SCIDマウスにおいて初代のおよびその後のインビボ継代におけるこれら細胞は、肝臓転移を形成した。この腫瘍細胞を、三重融合タンパク質レポーター構築物(AC3−TGL)で安定して形質転換し、NOD/SCID IL2Rγヌル(NSG)マウスへとマトリゲルとともに皮下注射によって移植した。腫瘍細胞の接種の1日前に開始して、ME処置を、5匹のマウスの群において1週間に3回、40mg/kg(ME40)もしくは200mg/kg(ME200)において腹腔内注射によって開始した。コントロールマウスをDMSOビヒクルで処置した。腫瘍負荷および転移性拡散を、連続非侵襲性生体発光画像化によって5日ごとにモニターした。図5aに示されるように、薬物処置は、最初の注射部位において腫瘍増殖動力学に、有意に干渉しなかった。コントロールおよびME40処置群とは対照的に、毒性が最高の投与量(ME200群)で認められ、3匹のマウスは、エンドポイント前に死亡した。しかし、ME処置の45日後に2匹の生き残ったマウスに関しては、体重減少はなく、致死的なもしくは他の明らかな副作用は認められなかった。上記エンドポイントにおいて、潜在的転移部位(肝臓、肺、脾臓、心臓および腎臓、胃腸管)を外科手術により切除し、ルシフェラーゼ活性をエキソビボ生体発光画像化によって定量した(図5b)。コントロールと比較すると、低用量ME(40mg/kg)での処置群は、全体的な転移に関して有意な減少を示す(93%,p値=0.008)(図5c)。さらにより大きな程度の転移阻害(99%)は、高用量ME(200mg/kg)で処置した上記2匹の生き残っているマウスにおいて認められた。種々の器官の除去後のマウスのバイオイメージングは、他の転移部位を示さなかった。これら結果は、MEが、小細胞肺がんの転移の強力なインビボインヒビターであることを示し、類似のアナログ(例えば、式Iの化合物)が類似の活性を有することが予測される。
トランスウェル細胞移動アッセイ
MDA231−LM2肺転移性乳がん細胞を、示された濃度のMEもしくはカルボキシメチル−MEで、24時間にわたって予備処理した。予備処理の後に、3μm孔サイズフィルタを備えたBoydenチャンバを使用して、移動を決定した。細胞を、5時間にわたってこのチャンバを通って移動させた(MEもしくはカルボキシメチル−MEの存在下で)。多孔性膜を横断した細胞を分析し、蛍光顕微鏡下でスコア付けした。CM−MEは、乳がん細胞の限定的移動を阻害するときに、MEより約20倍強力である。結果を、光学視野1つあたりの移動細胞として表す。データは、三連の平均±S.D.である(図6を参照のこと)。
ヒトSCLC異種移植片モデルにおけるME(19)およびCME(25)の抗転移活性の評価。 NOD/SCIDマウスにおける初代およびその後のインビボ継代でのこれら細胞は、肝臓転移を形成する傾向にある。この腫瘍細胞を、三重融合タンパク質レポーター構築物(AC3−TGL)で安定して形質導入し、次いで、NOD/SCID IL2Rγヌル(NSG)マウスへとマトリゲルと一緒に皮下注射によって移植した。
移動アッセイ
多発性骨髄腫細胞化学走性を、96ウェルプレート(HTS Transwell−96 System, Corning)の各ウェルに設置した細胞培養挿入物(4.26mm直径、8μm孔ポリエステル膜)からなる改変Boydenチャンバにおいて、SDF−1αに対して行った。簡潔には、多発性骨髄腫細胞をコンフルエント未満の培養物として増殖させ、次いで、無血清IMDM培地中で24時間にわたって飢餓状態にした。単一細胞懸濁物を、機械的解離によって調製し、次いで、この細胞を計数し、無血清IMDM培地中に懸濁させた合計5.104個の細胞を、上側のチャンバに播種し、次いで、SDF−1α(200ng/mLで)ありもしくはなしの培地を含む96ウェルプレートに置いた。ミグラスタチンアナログによる移動の阻害をアッセイするために、24時間長の飢餓状態にしたMM細胞を、薬物(5μMおよび250μM)もしくはDMSO(ビヒクル)で8時間にわたって予備処理し、次いで、この挿入物に播種した。ミグラスタチンアナログもしくはDMSO(ビヒクル)を、両方のチャンバ中0.5%で上記培地へと添加した。移動アッセイを、37℃、5%CO2の加湿チャンバ中で6時間にわたって行った。アッセイエンドポイントにおいて、上記挿入物を取り出し、移動しつつある細胞を、ウェル中で計数した。上記試験条件に応じた移動を、上記DMSOビヒクルコントロールに対して計算した。
多発性骨髄腫および肺がん細胞系に対する化合物42〜45の毒性の決定
化合物42〜45の毒性およびそれらのIC50を、多発性骨髄腫のヒト腫瘍細胞系起源の一団(RPMI8226、MM1S、MM1R、ARP−GL、CAG−GL、OPM2−GL、SKO−007−GL、U266−GL)および肺がん細胞系起源の一団(H299−GL、H522−GL、H647−GL、A549−GL、A549−GL、HI993、H1075−GL、HI373、H17030)に対して決定した。腫瘍細胞を、トリプシン/コラゲナーゼIV処理によって単一細胞懸濁物へと解離し、500個の細胞/ウェルを、10%FCSを含むRPMI培地50μlの中で384マイクロウェルプレートの各ウェルへとアリコートに分けた。化合物42〜45をDMSOに溶解し、RPMI培地+10%FCS中で連続希釈し、腫瘍細胞を含む四連のウェルに添加した(1mM〜1nM)。化合物なしのDMSOの希釈物を、コントロールとして使用した。18時間もしくは2日後に、この培養物に、6μlのalamarBlue(登録商標)(Invitrogen Inc. Grand Island, NY)を添加し、一晩インキュベートした。上記alamarBlue(登録商標)は、代謝活性に基づいて細胞増殖インジケーターを提供する。上記アッセイシステムは、細胞増殖の結果として生じる増殖培地の化学的還元に応じて蛍光を発しかつ色を変化させる酸化−還元インジケーターを組み込む。蛍光強度を、Synergy H1 Microplate Reader(Biotek Inc, Winooski, VT)を使用して測定し、用量−応答曲線を、IC50決定のために確立した。データを表4に示し、これは、化合物42〜45が最小限にしか毒性でなく、非常に高濃度においてのみ毒性である(IC50 300〜795μM)ことを示す。
薬物動態研究
混合性別マウス(B6D2F1)の群を使用した。薬物動態(PK)を、代表的には、CMEのボーラス静脈内注射もしくは腹腔内注射の後、0時間、0.17時間、0.5時間、0.75時間、1時間、2時間、4時間、8時間、16時間および24時間において得られたヘパリン処理マウス血漿サンプルで行った。サンプルを、HPLC−MS/MS法を使用して分析した。CMEのレベルを決定するために、上記薬物を、サンプル予備処理とともに血漿から最初に単離した。アセトニトリルを使用して、サンプル中のタンパク質を除去した。次いで、均一濃度HPLC−MS/MS法を使用して、いかなる潜在的な干渉からも薬物を分離した。化合物レベルを、複数反応モニタリング(MRM)モードでのMS検出によって測定した。PKデータを、分析のWinNonlinプログラム(ver. 5.3, Pharsight)区画モデルを使用して分析した。
一実施形態において、たとえば、以下の項目が提供される。
(項目1)
式Iの化合物
もしくはその薬学的に受容可能な塩であって、ここで、
R 1 は、水素もしくは必要に応じて置換されたC 1−6 脂肪族であり;
R 2 は、酸素保護基、水素、もしくは必要に応じて置換されたC 1−6 脂肪族であり;
R 3 およびR 5 は、各々独立して、必要に応じて置換されたC 1−6 脂肪族であり;そして
R 4 は、水素もしくは−T−Yであり;
−T−は、必要に応じて置換されたC 1−8 二価飽和もしくは不飽和の、直鎖状もしくは分枝状の炭化水素鎖であり、ここで1個以上のメチレン単位は、−NR−、−N(R)C(O)−、−C(O)N(R)−、−N(R)SO 2 −、−SO 2 N(R)−、−O−、−C(O)−、−OC(O)−、−OC(O)O−、−C(O)O−、−OC(O)N(R)−、−S−、−SO−、もしくは−SO 2 −によって必要に応じてかつ独立して置き換えられ;
各Rは、独立して、−H、またはC 1−20 脂肪族、C 1−20 ヘテロ脂肪族、6〜10員のアリール、5〜12員のヘテロアリール、3〜14員の炭素環、3〜12員の複素環式からなる群より選択される必要に応じて置換された基であり;そして
−Yは、水素もしくはアシルである、
化合物もしくはその薬学的に受容可能な塩。
(項目2)
R 1 は、1個以上のハロゲンで置換されたC 1−3 脂肪族であるか、またはR 4 は、−T−Yであって、ここで−T−はCH 2 であり、−Yはアシルである、上記項目1に記載の化合物。
(項目3)
R 1 は、−CF 3 であるか、またはR 4 は、−T−Yであって、ここで−T−はCH 2 であり、−Yは−CO 2 Hである、上記項目2に記載の化合物。
(項目4)
前記化合物は、式II、式III、もしくは式IVの化合物
である、上記項目1に記載の化合物もしくはその薬学的に受容可能な塩。
(項目5)
前記化合物は、式II−a、式III−a、もしくは式IV−aの化合物
である、上記項目1に記載の化合物もしくはその薬学的に受容可能な塩。
(項目6)
R 1 は、水素もしくは1個以上のハロゲンで置換されたC 1−3 脂肪族であり、R 2 は、C 1−3 脂肪族であり、R 3 は、C 1−3 脂肪族であり、R 4 は、水素もしくは−T−Yであって、ここで−T−は共有結合もしくは−CH 2 −であり、Yは、−CO 2 Rおよび−C(O)N(R) 2 からなる群より選択され、ここでRは、水素もしくはC 1−3 脂肪族であり、R 5 は、C 1−3 脂肪族であり、そして
は、単結合である、上記項目1または4に記載の化合物。
(項目7)
R 1 は、水素もしくは1個以上のハロゲンで置換されたC 1−3 脂肪族であり、R 2 は、C 1−3 脂肪族であり、R 3 は、C 1−3 脂肪族であり、R 4 は、水素もしくは−T−Yであって、ここで−T−は、共有結合もしくは−CH 2 −であり、Yは、−CO 2 Rおよび−C(O)N(R) 2 からなる群から選択され、ここでRは、水素もしくはC 1−3 脂肪族であり、R 5 は、C 1−3 脂肪族であり、そして
は、(Z)−二重結合である、上記項目1または4に記載の化合物。
(項目8)
R 1 は、水素もしくは1個以上のハロゲンで置換されたC 1−3 脂肪族であり、R 2 は、C 1−3 脂肪族であり、R 3 は、C 1−3 脂肪族であり、R 4 は、水素もしくは−T−Yであって、ここで−T−は共有結合もしくは−CH 2 −であり、Yは、−CO 2 Rおよび−C(O)N(R) 2 からなる群より選択され、ここでRは、水素もしくはC 1−3 脂肪族であり、R 5 は、C 1−3 脂肪族であり、そして
は、(E)−二重結合である、上記項目1または4に記載の化合物。
(項目9)
R 1 は、水素であり、R 2 は、メチルであり、R 3 は、メチルであり、R 4 は、−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Rおよび−C(O)N(R) 2 からなる群より選択され、ここでRは、メチルであり、R 5 は、メチルであり、そして
は、単結合である、上記項目1または4に記載の化合物。
(項目10)
R 1 は、水素であり、R 2 は、メチルであり、R 3 は、メチルであり、R 4 は、−T−Yであって、ここで−T−は、−CH 2 CH 2 O−であり、Yは、水素であり、ここでRは、メチルであり、R 5 は、メチルであり、そして
は、単結合である、上記項目1または4に記載の化合物。
(項目11)
R 1 は、水素であり、R 2 は、メチルであり、R 3 は、メチルであり、R 4 は、−T−Yであって、ここで−T−は、共有結合であり、Yは、−C(O)NHRであり、ここでRは、エチルであり、R 5 は、メチルであり、そして
は、単結合である、上記項目1または4に記載の化合物。
(項目12)
は、二重結合であり、R 1 は、−CF 3 であり、R 2 、R 3 およびR 5 は、メチルであり、そしてR 4 は、水素もしくは−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Hである、上記項目1または4に記載の化合物。
(項目13)
は、単結合もしくは二重結合であり、R 1 は、水素もしくはメチルであり、R 2 、R 3 およびR 5 は、メチルであり、そしてR 4 は、水素もしくは−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Hである、上記項目1または4に記載の化合物。
(項目14)
は、二重結合であり、R 1 は、水素もしくはメチルであり、R 2 、R 3 およびR 5 は、メチルであり、R 4 は、水素もしくは−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Hである、上記項目13に記載の化合物。
(項目15)
は、(E)−二重結合であり、R 1 は、水素もしくはメチルであり、そしてR 2 、R 3 およびR 5 は、メチルであり、R 4 は、水素である、上記項目14に記載の化合物。
(項目16)
は、単結合であり、R 1 は、水素であり、R 2 、R 3 およびR 5 は、メチルであり、R 4 は、−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Hである、上記項目13に記載の化合物。
(項目17)
は、(E)−二重結合であり、R 1 は、水素もしくは−CF 3 であり、R 2 、R 3 およびR 5 は、メチルであり、そしてR 4 は、水素である、上記項目1または4に記載の化合物。
(項目18)
は、(Z)−二重結合であり、R 1 は、メチルであり、R 2 、R 3 およびR 5 は、メチルであり、そしてR 4 は、−T−Yであって、ここで−T−は、−CH 2 −であり、Yは、−CO 2 Hである、上記項目1または4に記載の化合物。
(項目19)
前記化合物は、以下の
から選択される、上記項目1に記載の化合物もしくはその薬学的に受容可能な塩。
(項目20)
上記項目1〜5または19のいずれか1項に記載の化合物および薬学的に受容可能なキャリアを含む、薬学的組成物。
(項目21)
ある疾患、障害、もしくは状態を処置する方法であって、該方法は、ある疾患、障害、もしくは状態に罹患しているか、またはこれらに罹りやすい被験体に、治療上有効な量の上記項目1〜5または19のいずれかに記載の化合物またはその薬学的組成物を投与する工程を包含する、方法。
(項目22)
前記疾患、障害、もしくは状態は、がんであるかもしくはがんを含む、上記項目21に記載の方法。
(項目23)
前記治療上有効な量は、がんの転移性拡散を阻害するかもしくは減少させるのに有効な量を含む、上記項目22に記載の方法。
(項目24)
前記がんは、乳がんもしくは肺がんである、上記項目23に記載の方法。
(項目25)
がんを処置する方法であって、該方法は、がんに罹患しているかもしくはがんに罹りやすい被験体に、治療上有効な量の以下の式の化合物
を投与する工程を包含する、方法。
(項目26)
前記治療上有効な量は、がんの転移性拡散を阻害するかもしくは減少させるのに有効な量を含む、上記項目25に記載の方法。
(項目27)
前記がんは、乳がんもしくは肺がんである、上記項目26に記載の方法。
(項目28)
前記がんは、多発性骨髄腫である、上記項目23または26のいずれか1項に記載の方法。
Claims (26)
- 式Iの化合物
R1は、水素もしくは1個以上のハロゲンで置換されていてもよいC1−6脂肪族であり;
R2は、C1−6脂肪族であり;
R3およびR5は、各々独立して、C1−6脂肪族であり;そして
R4は、−T−Yであり;
−T−は、C1−8二価飽和もしくは不飽和の、直鎖状もしくは分枝状の炭化水素鎖であり;そして
−Yは、−CO2Rもしくは−C(O)N(R)2であり、ここで各Rは独立して−HまたはC1−20脂肪族である、
化合物もしくはその薬学的に受容可能な塩。 - R1は、1個以上のハロゲンで置換されたC1−3脂肪族であるか、またはR4は、−T−Yであって、ここで−T−はCH2であり、−Yは−CO2Rもしくは−C(O)N(R)2である、請求項1に記載の化合物もしくはその薬学的に受容可能な塩。
- R1は、−CF3であるか、またはR4は、−T−Yであって、ここで−T−はCH2であり、−Yは−CO2Hである、請求項2に記載の化合物もしくはその薬学的に受容可能な塩。
- 前記化合物は、式II、式III、もしくは式IVの化合物
である、請求項1に記載の化合物もしくはその薬学的に受容可能な塩。 - 前記化合物は、式II−a、式III−a、もしくは式IV−aの化合物
である、請求項1に記載の化合物もしくはその薬学的に受容可能な塩。 - R1は、水素もしくは1個以上のハロゲンで置換されたC1−3脂肪族であり、R2は、C1−3脂肪族であり、R3は、C1−3脂肪族であり、R4は、−T−Yであって、ここで−T−は−CH2−であり、Yは、−CO2Rおよび−C(O)N(R)2からなる群より選択され、ここでRは、水素もしくはC1−3脂肪族であり、R5は、C1−3脂肪族であり、そして式I中の
- R1は、水素もしくは1個以上のハロゲンで置換されたC1−3脂肪族であり、R2は、C1−3脂肪族であり、R3は、C1−3脂肪族であり、R4は、−T−Yであって、ここで−T−は、−CH2−であり、Yは、−CO2Rおよび−C(O)N(R)2からなる群から選択され、ここでRは、水素もしくはC1−3脂肪族であり、R5は、C1−3脂肪族であり、そして式I中の
- R1は、水素もしくは1個以上のハロゲンで置換されたC1−3脂肪族であり、R2は、C1−3脂肪族であり、R3は、C1−3脂肪族であり、R4は、−T−Yであって、ここで−T−は−CH2−であり、Yは、−CO2Rおよび−C(O)N(R)2からなる群より選択され、ここでRは、水素もしくはC1−3脂肪族であり、R5は、C1−3脂肪族であり、そして式I中の
- R1は、水素であり、R2は、メチルであり、R3は、メチルであり、R4は、−T−Yであって、ここで−T−は、−CH2−であり、Yは、−CO2Rおよび−C(O)N(R)2からなる群より選択され、ここでRは、メチルであり、R5は、メチルであり、そして式I中の
- R1は、水素であり、R2は、メチルであり、R3は、メチルであり、R4は、−T−Yであって、ここで−T−は、−CH2−であり、Yは、−C(O)NHRであり、ここでRは、エチルであり、R5は、メチルであり、そして式I中の
- 式I中の
- 式I中の
- 式I中の
- 式I中の
- 式I中の
- 式I中の
- 式I中の
- 前記化合物は、以下の
から選択される、請求項1に記載の化合物もしくはその薬学的に受容可能な塩。 - 以下
から選択される化合物もしくはその薬学的に受容可能な塩。 - 請求項1〜5、18または19のいずれか1項に記載の化合物もしくはその薬学的に受容可能な塩および薬学的に受容可能なキャリアを含む、薬学的組成物。
- ある疾患、障害、もしくは状態に罹患しているか、またはこれらに罹りやすい被験体において、ある疾患、障害、もしくは状態を処置するための、請求項1〜5、18もしくは19のいずれか1項に記載の化合物もしくはその薬学的に受容可能な塩またはその薬学的組成物の治療上有効な量を含む組成物。
- 前記疾患、障害、もしくは状態は、がんであるかもしくはがんを含む、請求項21に記載の組成物。
- 前記治療上有効な量は、がんの転移性拡散を阻害するかもしくは減少させるのに有効な量を含む、請求項22に記載の組成物。
- 前記がんは、乳がんもしくは肺がんである、請求項23に記載の組成物。
- 前記がんは、多発性骨髄腫である、請求項23に記載の組成物。
- 前記組成物は、1種以上の他の所望の治療剤もしくは医療手順と同時に、その前に、もしくはその後に、投与される、請求項23に記載の組成物。
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