JP2022078094A - Olig2活性の阻害 - Google Patents
Olig2活性の阻害 Download PDFInfo
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- JP2022078094A JP2022078094A JP2022021420A JP2022021420A JP2022078094A JP 2022078094 A JP2022078094 A JP 2022078094A JP 2022021420 A JP2022021420 A JP 2022021420A JP 2022021420 A JP2022021420 A JP 2022021420A JP 2022078094 A JP2022078094 A JP 2022078094A
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- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 235000010956 sodium stearoyl-2-lactylate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- KNYAZNABVSEZDS-UHFFFAOYSA-M sodium;2-octadecanoyloxypropanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC(C)C([O-])=O KNYAZNABVSEZDS-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007886 soft shell capsule Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 150000003398 sorbic acids Chemical class 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000011584 spitz nevus Diseases 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000008833 sun damage Effects 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- WPWXYQIMXTUMJB-UHFFFAOYSA-N tert-butyl 3-(aminomethyl)piperidine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCCC(CN)C1 WPWXYQIMXTUMJB-UHFFFAOYSA-N 0.000 description 1
- PNQYAMWGTGWJDW-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)-n-methylcarbamate Chemical compound NCCCN(C)C(=O)OC(C)(C)C PNQYAMWGTGWJDW-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 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
- 239000003440 toxic substance Substances 0.000 description 1
- 108091006107 transcriptional repressors Proteins 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 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
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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
- 229940117958 vinyl acetate Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/12—Nitrogen atoms not forming part of a nitro radical
- C07D239/18—Nitrogen atoms not forming part of a nitro radical with hetero atoms attached to said nitrogen atoms, except nitro radicals, e.g. hydrazine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- 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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
本出願は、2016年8月26日に出願された米国仮特許出願第62/380,281号の利益を主張するものであり、これはその全体において参照により本明細書に組み込まれる。
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4とR5は独立して、H、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R6は、H、非置換のC1-C6アルキル、C1-C6ハロアルキル、-(C(R14)(R15))mR17、-(C(R14)(R15))mN(R11)(R12)、-(C(R14)(R15))mOR13、-(C(R14)(R15))nR16、または-OR22であり、
R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して置換または非置換のC1-C6アルキルであり、
R10はH、または非置換のC1-C4アルキルであり、
R11はH、置換または非置換のC1-C6アルキル、-C(=O)R19、あるいは-S(=O)2R19であり、
R12はH、あるいは置換または非置換のC1-C6アルキルであり、
R13はH、あるいは置換または非置換のC1-C6アルキルであり、
R14とR15はそれぞれ独立して、H、ハロゲン、あるいは置換または非置換のC1-C6アルキルであり、
R16は置換または非置換のC2-C7ヘテロシクロアルキル、あるいは-C(=O)N(R18)2であり、
R17は-C(=O)R20、-CO2R21、-C(=O)N(R21)2、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R18はそれぞれ独立して、H、置換または非置換のC1-C6アルキル、置換または非置換のC2-C7ヘテロシクロアルキル、あるいは、置換または非置換のC3-C8シクロアルキルであり、あるいは、2つのR18は一体となってヘテロシクロアルキル環を形成し、
R19は置換または非置換のC1-C6アルキルであり、
R20は置換または非置換のC1-C6アルキルであり、
R21はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、あるいは、2つのR21は一体となってヘテロシクロアルキル環を形成し、
R22は、H、あるいは置換または非置換のC1-C6アルキルであり,
mは2-6であり、および、
nは1-5である。
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のフェノキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、あるいは、2つのR1は一体となって、置換または非置換の複素環、あるいは置換または非置換の炭素環を形成し、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4はH、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、
R6は-OR7であり、
R7はHあるいは置換または非置換のC1-C6アルキルであり、
R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して、置換または非置換のC1-C6アルキル、あるいは、置換または非置換のC6-C10アリールであり、および、
nは0-5である。
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4とR5は独立して、H、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R6は、H、非置換のC1-C6アルキル、C1-C6ハロアルキル、-(C(R14)(R15))mR17、-(C(R14)(R15))mN(R11)(R12)、-(C(R14)(R15))mOR13、-(C(R14)(R15))nR16、または-OR22であり、
R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して置換または非置換のC1-C6アルキルであり、
R10はH、または非置換のC1-C4アルキルであり、
R11はH、置換または非置換のC1-C6アルキル、-C(=O)R19、あるいは-S(=O)2R19であり、
R12はH、あるいは置換または非置換のC1-C6アルキルであり、
R13はH、あるいは置換または非置換のC1-C6アルキルであり、
R14とR15はそれぞれ独立して、H、ハロゲン、あるいは置換または非置換のC1-C6アルキルであり、
R16は置換または非置換のC2-C7ヘテロシクロアルキル、あるいは-C(=O)N(R18)2であり、
R17は-C(=O)R20、-CO2R21、-C(=O)N(R21)2、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R18はそれぞれ独立して、H、置換または非置換のC1-C6アルキル、置換または非置換のC2-C7ヘテロシクロアルキル、あるいは、置換または非置換のC3-C8シクロアルキルであり、あるいは、2つのR18は一体となってヘテロシクロアルキル環を形成し、
R19は置換または非置換のC1-C6アルキルであり、
R20は置換または非置換のC1-C6アルキルであり、
R21はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、あるいは、2つのR21は一体となってヘテロシクロアルキル環を形成し、
R22は、H、あるいは置換または非置換のC1-C6アルキルであり、
mは2-6であり、および、
nは1-5である。
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のフェノキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、あるいは、2つのR1は一体となって、置換または非置換の複素環、あるいは置換または非置換の炭素環を形成し、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4はH、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、
R6は-OR7であり、
R7はHあるいは置換または非置換のC1-C6アルキルであり、R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して、置換または非置換のC1-C6アルキル、あるいは、置換または非置換のC6-C10アリールであり、および、
nは0-5である。
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4とR5は独立して、H、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R6はH、非置換のC1-C6アルキル、-(C(R14)(R15))mR17、-(C(R14)(R15))mN(R11)(R12)、-(C(R14)(R15))mOR13、-(C(R14)(R15))nR16、または-OR22であり、
R7は置換または非置換のフェノキシまたは-C(=O)R23であり、
R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して置換または非置換のC1-C6アルキルであり、
R10はH、または非置換のC1-C4アルキルであり、
R11はH、置換または非置換のC1-C6アルキル、-C(=O)R19、あるいは-S(=O)2R19であり、
R12はH、あるいは置換または非置換のC1-C6アルキルであり、
R13はH、あるいは置換または非置換のC1-C6アルキルであり、
R14とR15はそれぞれ独立して、H、ハロゲン、あるいは置換または非置換のC1-C6アルキルであり、
R16は置換または非置換のC2-C7ヘテロシクロアルキル、あるいは-C(=O)N(R18)2であり、
R17は-C(=O)R20、-CO2R21、-C(=O)N(R21)2、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R18はそれぞれ独立して、H、置換または非置換のC1-C6アルキル、置換または非置換のC2-C7ヘテロシクロアルキル、あるいは、置換または非置換のC3-C8シクロアルキルであり、あるいは、2つのR18は一体となってヘテロシクロアルキル環を形成し、
R19は置換または非置換のC1-C6アルキルであり、
R20は置換または非置換のC1-C6アルキルであり、
R21はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、あるいは、2つのR21は一体となってヘテロシクロアルキル環を形成し、
R22は、H、あるいは置換または非置換のC1-C6アルキルであり、
R23は置換または非置換のC6-C10アリールであり、
mは2-6であり、
nは1-5であり、および、
pは0-4である。
R1はそれぞれ独立して、ハロゲン、-OCF3、-OCH2F、-OCF2H、-CF3、非置換のC1-C6アルキル、非置換のC1-C6アルコキシ、非置換のフェニル、あるいは非置換のC2-C9ヘテロアリールであり、
R6はH、非置換のC1-C6アルキル、-(CH2)mN(R11)(R12)、あるいは-(CH2)mOR13であり、
R9は非置換のC1-C6アルキルであり、
R10はH、または非置換のC1-C4アルキルであり、
R11はH、非置換のC1-C6アルキル、-C(=O)R9、あるいは-S(=O)2R9であり、
R12はHまたは非置換のC1-C6アルキルであり、
R13はHまたは非置換のC1-C6アルキルであり、
mは2-4であり、および、
pは1-3である。
本明細書に記載される化合物は、場合によっては、ジアステレオマー、エナンチオマー、あるいは他の立体異性の形態として存在することがある。本明細書で提示される化合物は、すべてのジアステレオマー形態、エナンチオマー形態、およびエピマー形態と、その適切な混合物とを含む。立体異性体の分離は、クロマトグラフィー、またはジアステレオマー形成、および再結晶化による分離、またはクロマトグラフィー、またはその任意の組み合わせによって実行可能である(Jean Jacques, Andre Collet, Samuel H. Wilen, ”Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981、本開示のために参照により組み込まれる)。立体異性体は立体選択的な合成によっても得られることがある。
いくつかの実施形態において、本明細書に記載される化合物の合成は、化学の文献に記載される手段を用いて、本明細書に記載される方法を用いて、あるいはこれらの組み合わせによって達成される。さらに、本明細書に示される溶媒、温度、および他の反応条件は変動することもある
別段の定めのない限り、本明細書で使用される技術用語と科学用語は、本願の主題が属するものと一般に理解されるのと同じ意味を持っている。本明細書の用語に複数の定義がある場合、この項の定義が優先される。特許、特許出願、公開、および本明細書で引用される公開されたヌクレオチドとアミノ酸配列(例えばGenBankまたは他のデータベースで入手可能な配列)はすべて、参照により組み込まれる。URLまたは他のそのような識別子あるいはアドレスについて言及される場合、こうした識別子を変更することができ、かつインターネット上の特定の情報は現れたり消えたりし得るが、同等な情報をインターネット検索により発見できることを理解されたい。こうしたことに対する言及は、そのような情報の利用可能性や公的な普及を証拠づけるものである。
別の態様では、医薬組成物は、式(I)、(II)、(III)、または(IV)の化合物、あるいはその薬学的に許容可能な塩、溶媒和物、またはプロドラッグ、および少なくとも1つの薬学的に許容可能な賦形剤を含む。
医薬組成物は、薬学的に使用可能な調製物への活性化合物の処理を促す賦形剤と助剤を含む、1つ以上の生理学的に許容可能な担体を使用して、従来のやり方で処方されてもよい。適切な製剤は、選択される投与の経路に依存する。本明細書に記載される医薬組成物に適切な賦形剤に関するさらなる詳細は、例えば、Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995);Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;およびPharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins1999)(Lippincott Williams & Wilkins1999)で見ることができ、これらの文献は、開示のために引用することで本明細書に組み込まれる。
本明細書に記載される化合物は、癌の処置のための、または、Olig2阻害から少なくとも部分的に利益を得ることになる疾患または疾病の処置のための、薬物の調製において使用され得る。加えて、上記処置を必要としている患者における本明細書に記載の疾患または疾病のいずれかを処置するための方法は、本明細書に記載の少なくとも1つの化合物を含有する医薬組成物、または、それらの薬学的に許容可能な塩、薬学的に許容可能なプロドラッグ、または、薬学的に許容可能な溶媒化合物の上記被験体に治療上効果的な量での投与を含む。
式(I)、(II)、(III)、または(IV)の化合物、およびその組成物も、処置される疾病の治療価値のために選択される他の治療剤と組み合わせて使用されてもよい。一般に、本明細書に記載される組成物と、併用療法が用いられる実施形態においては、他の薬剤とは、同じ医薬組成物で投与される必要はなく、様々な物理的および化学的な特性ゆえに様々な経路によって投与されなければならないこともある。投与のモードと投与の妥当性の判定は、可能な場合には、同じ医薬組成物において、十分に臨床医の知識の範囲内である。最初の投与は当該技術分野で認識されている確立されたプロトコルにしたがって行うことができ、その後、観察された効果、投与量、投与モード、および投与の回数に基づいて、臨床医によって修正可能である。
本明細書に記載される治療用途で使用するために、キットと製品も本明細書に記載されている。このようなキットは、例えば、バイアル、チューブなどの1以上の容器を受けるために仕切られた、運搬装置、パッケージ、または容器を含み、こうした容器の各々は、本明細書中に記載される方法で使用される別個の要素の1つを含んでいる。適切な容器は、例えば、ボトル、バイアル、シリンジ、および試験管を含む。容器は、ガラスまたはプラスチックのような様々な材料から形成され得る。
TGD(%)=T-C/Cx100
T=処置群の中央値のTTE
C=対照群の中央値のTTE。
*X線写真で証明された再発性の、頭蓋内の多形神経膠芽腫、あるいは神経膠肉腫の患者は、このプロトコルに適格である。患者は、Rb陽性の疾患の証拠書類を持っていなければならない。
*すべての患者は、この試験の調査の性質を承知していることを示すインフォームドコンセントに署名しなければならない。患者は、保護された健康情報の公開の認定書に署名していなければならない。患者は治験薬を用いる処置の前に登録されなければならない。処置は登録の7日以内に行わなければならない。処置が7日よりも遅れる場合には、適格性と病歴のための検体検査と健康診断を繰り返さなければならない。
*患者は先に外部ビーム放射とテモゾロミド化学療法を受けていなければならない。使用される先の化学療法の数には制限はない。患者は1回目、2回目、または3回目の再発で処置を受けることもある。
*患者は>18歳を超え、かつ、そして平均寿命>8週間でなければならない。
*患者は、>60のカルノフスキー・パフォーマンス・ステータスを持っていなければならない。
*登録の時点で:患者は先の治療の中毒作用から回復していなければならない。任意の治験薬から>28日[注:FDAで承認された薬剤の適用外使用は、このプロトコルの目的のための調査とはみなさない]、先の細胞毒性治療から>28日、ニトロソ尿素から>42日、ベバシズマブから>28日、および、非細胞毒性薬、例えば、インターフェロン、タモキシフェン、サリドマイド、シス-レチン酸、および、エルロチニブなどから>7日。非細胞毒性薬の定義に関係するいかなる質問も、主任研究者に委ねられなければならない。
*患者は治療を始める前に、適切な骨髄機能(WBC>3,000/μl、ANC>1,500/mm3、>100,000/mm3の血小板数、およびヘモグロビン>10gm/dl)、適切な肝機能(SGOTおよびビリルビン<ULNの2倍)、および適切な腎機能(クレアチニン<1.5mg/dL)を有していなければならない。試験前EKGはすべての患者に要求され、患者は正常なQT間隔を持っていなければならない。これらの試験は登録前14日間以内に行なわれなければならない。ヘモグロビンの適格性レベルに輸血によって到達してもよい。
*患者は、MRI走査によって腫瘍進行の明白なX線証拠写真を示していなければならない。走査は、登録前の14日以内に、かつ、少なくとも7日間は安定しているステロイド投与量で行われなければならない。ステロイド投与が画像処理日と登録日の間で増加した場合、新しいベースラインMRIが必要となる。同じタイプの走査、つまり、MRIは、腫瘍測定のためのプロトコル処置の期間にわたって使用されなければならない。MR画像処理を受けることができない患者は適格ではない。
*以下の条件のすべてが適用される限り、再発性または進行性の腫瘍の最近の切除を経験した患者は適格となる:
○ 患者は手術の影響から回復している。
○ 再発性の頭蓋内の多形神経膠芽腫あるいは神経膠肉腫の切除後の残存疾患は、試験への適格性のために強制されるものではない。手術後に残存病変の範囲を最良に評価するために、MRIは、登録前の14日間以内で、手術直後の96時間以内に、あるいは術後少なくとも4週間に行わなければならない。96時間の走査が登録前の14日間を超える場合、走査は反復する必要がある。ステロイド投与が画像処理日と登録日との間で増加した場合、新しいベースラインMRIは少なくとも7日間、安定したステロイド投与量で必要である。
*患者は先の放射線治療およびテモゾロミドに失敗していなければならず、放射線治療の完了から試験エントリーまで42日以上の間隔を空けていなければならない。
*間質放射線治療、定位手術的照射、あるいはGliadelウエハーを含む先の治療を受けた患者は、PET走査法に基づく放射線壊死、MR分光法、あるいは疾患の手術証拠書類よりもむしろ、真の進行性疾患の確認を行わなければならない。
*15人の患者の一部は計画された指示された外科的切除の前に登録される。患者は、手術候補であり、急性頭蓋内出血の証拠がなく、かつ、手術の7日前にプロトコル処置を始めることができる場合にのみ、手術前に登録することができる。
*生殖能力のある男女の患者は、試験処置の停止中および停止後の3ヶ月間に、適切な場合に、承認されている避妊の方法(例えば、子宮内器具[IUD]、避妊薬、あるいはバリア装置)を使用しなければならない。出産に可能性のある女性は、登録前の14日間以内に陰性のβ-HCG妊娠テストを文書化しなければならない。
*以前の手術の腫瘍組織のブロックあるいはスライドは、IHC Rb染色を行うのに利用可能でなければならない。陰性の腫瘍(Rb陰性)の患者は試験から除外される。
除外基準:
*患者は、調査者の見解が適切な治療では適切に制御できないか、あるいは、この治療に耐える患者の能力を損なうことになる重大な医学的疾患を抱えていてはならない。
*任意の他の癌(頚部の非黒色腫性の皮膚癌あるいは上皮内癌以外)の病歴がある患者は、完全寛解ではなく、最低3年間のその疾患のすべての治療から離れていない限り、不適格である。
*患者は活性な感染あるいは深刻な介入性の医学的疾患を抱えてはならない。急性頭蓋内出血の病歴のある患者も除外される。
*患者は妊娠していてはならず/母乳による育児を行っていてはならず、適切な避妊を行うことに同意しなければならない。
*患者は、毒性を隠すか、または薬物代謝を危険なほどに変える疾患を抱えてはならない。
*薬理相互作用の可能性があることから、酵素誘導抗痙攣薬あるいはCYP3A酵素誘導あるいは阻害を引き起こす他の薬物を摂取している患者は、少なくとも14日間治療から離れていない限り、適格ではない。
*EKGのQT間隔の延長について先天的あるいはそれ以外の理由のある患者は除外される。
*無進行生存によって決定されるような有効性[時間枠:1-2年][安全性の問題として指定される:なし]
*6ヶ月目の無進行生存によって測定されるように、Rb陽性の再発性の多形神経膠芽腫あるいは神経膠肉腫の患者における式(I)、(II)、(III)、または(IV)の化合物の有効性を判定する。合計30人の患者が処置される;計画された意図された外科的切除を受ける15人が、手術の前に7日間、薬物を受け入れ、その後、手術から回復後に薬物を受ける。15人の患者は計画された外科手術を受けずに薬物を受け入れる。
*安全性と耐性の尺度としての有害事象を有する参加者の数[時間枠:1-2年][安全性問題として指定された:はい]
*再発性、進行性、または、標準的な治療に対して耐性があり、かつ、既知の治癒的な治療がない、髄芽腫(後頭蓋窩PNETを含む)の診断が組織学的に確認された患者は適格である。段落に記載されるような試験前MRIでは、残存する測定可能な疾患あるいは病変の証拠がなければならない。測定可能な脊椎脊髄疾患を患う患者は適格となる。
*診断は処置機関で確認されなければならず、(診断または再発から、あるいは、好ましくは両時点からの)組織は生体試験に利用可能でなければならない。
*神経障害を抱える患者は、登録前に最低1週間安定している障害を抱えていなければならない。これはデータベースに記録される。
*米国東海岸癌臨床試験グループ(ECOG)パフォーマンスステータス0-2
*試験エントリーの4週間(事前にニトロソ尿素の場合は6週間)以内にいかなる他の骨髄抑制化学療法あるいは免疫療法もない。
*デカドロン投与は、治療開始の少なくとも1週間(7日)前には安定しているか、あるいは減少していなければならない。
*放射線治療(XRT)≧頭蓋脊髄照射への試験エントリーの3ヶ月前(≧23Gy);≧原発性腫瘍への局部照射に8週間;≧徴候的な転移部への焦点照射について試験エントリーの前に2週間
*試験エントリー(GCSF、GM CSF、エリスロポエチン)の≧1週間前のすべてのコロニー刺激因子から
*絶対好中球数(ANC)≧1000/μL
*血小板数≧50,000/uL(独立した輸血)
*ヘモグロビン≧8.0gm/dL(RBC輸液剤を受け入れてもよい)
*クレアチニンクリアランスあるいはラジオアイソトープGFR≧70ml/min/1.73m2、または
*血清中クレアチニン≦2.0mg/dL
*総ビリルビン≦年齢の正常上限(ULN)の1.5x
*血清グルタミン酸ピルビン酸トランスアミナーゼ(SGPT)(アラニンアミノトランスフェラーゼ[ALT])≦2.5x制度上のULN
*血清グルタミン酸オキサロ酢酸トランスアミナーゼ(SGOT)(アスパラギン酸アミノトランスフェラーゼ[AST])≦制度上のULNの2.5倍
*血清アルブミン≧2.5g/dL
*患者はこの試験に入る前にすべての以前の治療の有意な急性毒性から回復していなければならず、他のすべての適格基準を満たさなければならない。
*妊娠は、出産の可能性の女性への最後の投与後12ヶ月間は回避されなければならない。出産の可能性の女性の患者は妊娠していてはならず、授乳していてもならない。出産の可能性の女性の患者は処置を始める前に24時間以内に負の血清または尿妊娠テストを持っていなければならない。
*出産の可能性のある女性は、試験への参加中および最後の投与後の12ヶ月間の1つの障害式避妊法を含む許容可能な避妊の2つの形態を使用することを要求される;医学的な理由または個人的な理由で、禁断に対する100%の関与は産児制限の許容可能な形態と考えられる。すべての患者は、調査者による、あるいはOB/婦人科医による、あるいはこの専門領域で資格のある他の医師による避妊のカウンセリングを受け入れなければならない。
*制度上のガイドラインに従って署名したインフォームドコンセントが得られなければならない。
除外基準:
*プロトコル治療に耐える患者の能力を損なうことになるか、試験の手順または結果に干渉することになる可能性が高い、任意の臨床的に有意な無関係な全身疾患(深刻な感染症あるいは重大な心機能不全、肺機能不全、肝機能不全、他の臓器機能不全)を抱える患者
*任意の他の抗癌治療または治験薬治療を受ける患者
*フォローアップ訪問のために戻ったり、あるいは治療に対する毒性を評価するのに必要なフォローアップ試験を受けたりすることができない患者
*執刀医によって決定されるように平均寿命<12週間
*カプセル剤を呑み込むことができないこと
*腸管内吸収に干渉することになる吸収不良症候群あるいは他の疾病
*うっ血性心不全の病歴
*薬物を必要とする心室性不整脈の病歴
*適切な電解液の追加にもかかわらず機関の正常下限未満として定義された制御されない低カルシウム血症、低マグネシウム血症、低ナトリウム血症、あるいは低カリウム血症
*先天性QT延長症候群。
*RECIST基準を使用する段階的な奏効率(PRとCR)[時間枠:最大で12か月][安全性の問題として指定されたもの:なし]
*真の未知の奏効率の95パーセントの信頼区間推定値は3つの層の各々について構築される。確認された完全寛解、部分寛解、および安定した疾患が確認された患者の割合は3つの層の各々について記述的に報告される。時間対客観的応答の累積発生率の関数も提供される。
*保持された客観的応答の持続時間[時間枠:その後確認された完全寛解または部分寛解を記録する最初の走査から、記録された進行または研究中の死亡の早い方まで。最大で12ヶ月評価した][安全性の問題として指定されたもの:なし]
*無進行生存[時間枠:式(I)、(II)、(III)、または(IV)の化合物を用いる当初の処置の日付から、試験中の進行あるいは死亡の中で最も早いときまで。最大で12ヶ月評価した][安全性の問題として指定されたもの:なし]
*移植後の最初の6ヶ月間の医療費
*患者および移植片生着
*試験の性質について知らされており、書面によるインフォームドコンセントをうけている。
*少なくとも18歳
*0、1、あるいは2のECOGパフォーマンス、あるいはKPS(カルノフスキー・パフォーマンス・ステータス)≧60。
*WHOグレード4星細胞腫(神経膠芽腫または神経膠肉腫)、またはWHOグレード3未分化星状細胞腫、退形成乏突起神経膠腫、未分化の乏突起星細胞腫、あるいは未分化の上衣腫の病理学的な検証。
*化学療法と放射線の少なくとも1つの処置に失敗した後の記録された再発性の神経膠芽腫、神経膠肉腫、未分化星状細胞腫、退形成乏突起神経膠腫、未分化の乏突起星細胞腫、あるいは未分化の上衣腫。
*少なくとも3ヶ月の予想生存期間
*実施された場合、腫瘍細胞減少手術から少なくとも2週間、ベバシズマブあるいは他の化学療法から4週間(以前の化学療法がニトロソ尿素だった場合、6週間)、および、放射線療法の完了から12週間。
*プロトコルで定義されるように周期的に画像処理色素を用いないまたは用いるMRI走査を受けることができる能力
*少なくとも7日間の薬物の投薬中断は、式(I)、(II)、(III)、または(IV)の化合物の最初の投与量の投与前にCYP2C9とCYP3A4を誘発する
*保存された主要な臓器機能、すなわち:血液白血球数≧3.0×109/L血液絶対好中球数≧1.5×109/L血小板数≧100x109/L血液ヘモグロビン≧100g/l(輸液剤が許可される)血漿総ビリルビンレベル≦l正常l(つまり基準)範囲の制度上の上限(ULN)の1.5倍血漿AST(アスパラギン酸アミノトランスフェラーゼ)あるいはALT≦l正常l範囲の制度上の上限(ULN)の2.5倍血漿クレアチニン≦l正常l範囲の制度上の上限(ULN)の1.5倍12-リードECG正常なトレーシングを用いる;あるいは、臨床的に有意でなく、医療的介入を必要としない変化は、およびQTc<500ms最初の試験処置日前にCYP2C9あるいはCYP3A4を阻害または誘導する少なくとも7日間の投薬中断。
除外基準:
*調査者に従って患者に許容しがたいリスクをもたらす進行中の感染あるいは他の主要な最近のまたは進行中の疾患
*過去28日以内のグレード3以上の便秘あるいは無作為化前14日間以内のグレード2の便秘。(便秘が便秘の最適な管理でグレード1まで低下した場合、過去14日以内のグレード2の便秘を抱える患者を再度選別することができる)
*限定されないが、活性な心疾患と重大な痴呆を含む共存する制御されない病状
*抗レトロウイルス療法を必要とする、B型肝炎またはC型肝炎、あるいは、HIV感染症
*基底細胞皮膚癌以外の活性な悪性病変
*過去3年の他の活性な悪性病変
*4週間以内の主要な外科手術
*機能的なニューロイメージング(PET、ダイナミックMRI、MRS、SPECT)によって、あるいは再発の記録された組織学的な確認での再操作によって明白な進行がない限り、従来の定位放射線照射またはガンマナイフ放射線照射あるいは陽子放射線
*以下のような以前の抗腫瘍治療:放射線治療から少なくとも12週間;少なくともテモゾロミドまたはベバシズマブを用いる以前の処置から4週間、BCNUあるいはCCNUの6週間。
*産児制限(経口避妊薬、IUD)の許容可能な方法の使用に同意しない出産の可能性のある女性(WOCBP)。この試験の目的のために、WOCBPは、初経を経験し、卵管結紮術を経験しておらず、および、閉経後ではないあらゆる女性を含む。閉経後は以下のように定義される:無月経≧別の原因のなく連続して12か月。
*医学的に制御されない1型または2型糖尿病
*妊娠あるいは授乳
*4週間以内の他の治験に現在参加していること。
*薬物の最適化後の米国東海岸癌臨床試験グループ(ECOG)パフォーマンスステータス>2(付録4を参照)、あるいはKPS<60
*3ヶ月未満の予想される平均寿命
*治験薬への禁忌あるいは既知のまたは疑いのある過敏症
*CYP2C9を誘導し、またはCYP2C9の有力な阻害剤であり、あるいは治療域が狭いCYP3A4の敏感な基質である併用薬を摂取しなければならない患者は参加しないこともある。
*任意の理由により調査者によって判断される試験への参加の適切性が欠けていること
*第I相-推奨される第II相の投与量を決定する。[時間枠:8か月][安全性の問題として指定されたもの:はい]
*第II相-抗腫瘍効果を決定する[時間枠:4か月][安全性の問題として指定されたもの:はい]
*第I相-安全性と耐性の尺度としての有害事象を抱える参加者の数[時間枠:6か月][安全性の問題として指定されたもの:はい]
*物理的な/神経学的検査(病理学的所見および質と量)。
*有害事象(1投与レベル当たりの質および量)
*バイタルサイン、ECG、検査パラメータ(検査パラメータ、記述統計学のための質と量としての病理学的所見)
*腎臓の第I相-最大耐量(MTD)[時間枠:8か月][安全性の問題として指定されたもの:はい]式(I)、(II)、(III)、または(IV)の化合物のMTDを同定すること。
*第I相-最適応答の分子マーカー[時間枠:8か月][安全性の問題として指定されたもの:はい]最適応答のサブ集団群を予測することがある潜在的な分子マーカーの評価
*第I相-IGF(インシュリン様増殖因子)-1R経路の分子マーカー[時間枠:8か月][安全性の問題として指定されたもの:はい]悪性の星細胞腫を抱える患者における式(I)、(II)、(III)、または(IV)の化合物による処置の後にIGF-1R経路活性化/阻害の代替分子マーカーを評価すること。
*第II相-無増悪期間(TTP)および全生存期間(OS)[時間枠:4か月][安全性の問題として指定されたもの:はい]式(I)、(II)、(III)、または(IV)の化合物を用いて処置された患者の無増悪期間(TTP)と全生存期間(OS)を判定すること。
*第II相-全奏効率[時間枠:4か月][安全性の問題として指定されたもの:はい]式(I)、(II)、(III)、または(IV)の化合物を用いる処置の後に再発性の悪性星細胞腫の全奏効率(ORR)を評価すること。
*第II相-応答の画像化の証拠。[時間枠:4か月][安全性の問題として指定されたもの:はい]RANO基準(T2-FLAIR、DWI(拡散強調画像法)、潅流MRIおよびマルチボクセルMRS(磁気共鳴分光法)配列にさらなる特別な注意を払って)MRI(磁気共鳴撮像)配列上の応答の代替的な画像処理の証拠を同定すること。
実施例149A:非経口組成物
経口送達のための医薬組成物を調製するために、100mgの式(I)、(II)、(III)、または(IV)の化合物を750mgのスターチと混合する。経口投与に適した硬ゼラチンカプセルなどの経口投与ユニットに混合物を入れる。
硬ドロップ剤などの口腔送達用の医薬組成物を調製するために、式(I)、(II)、(III)、または(IV)の化合物100mgを、1.6mLのライトコーンシロップ、2.4mLの蒸留水、および、0.42mLのミント抽出物と混ぜ合わせた420mgの粉砂糖と混合する。混合物を穏やかに混ぜ合わせ、型に注ぐことで、口腔投与に適した錠剤を形成する。
吸入送達用の医薬組成物を調製するために、式(I)、(II)、(III)、または(IV)の化合物20mgを、50mgの無水クエン酸、および、100mLの0.9%塩化ナトリウム溶液と混合する。吸入投与に適した、例えば噴霧器のような吸入送達ユニットに混合物を組み込む。
直腸送達に適した医薬組成物を調製するために、式(I)、(II)、(III)、または(IV)の化合物100mgを、2.5gのメチルセルロース(1500mPa)、100mgのメチルパラペン、5gのグリセリン、および、100mLの精製水と混合する。結果として生じたゲル混合物を、その後、直腸投与に適した、例えばシリンジのような直腸送達ユニットに組み込む。
総重量2.5gの座薬は、式(I)、(II)、(III)、または(IV)の化合物100mgを、Witepsol(商標)H-15(飽和植物脂肪酸のトリグリセリド;Riches-Nelson,Inc.,New York)と混合することによって生成され、以下の組成物を有する:
医薬的な局所ゲル組成物を調製するために、式(I)、(II)、(III)、または(IV)の化合物100mgを、1.75gのヒドロキシプロピルセルロース、10mLのプロピレングリコール、10mLのミリスチン酸イソプロピル、および、100mLの精製アルコールUSPと混合する。結果として生じたゲル混合物を、その後、局所投与に適した、例えばチューブなどの容器に組み込む。
医薬的な点眼液組成物を調製するために、式(I)、(II)、(III)、または(IV)の化合物100mgを、100mLの精製水中の0.9gのNaClと混合させ、0.2.ミクロンのフィルタを用いてろ過する。結果として生じた点眼溶液をその後、点眼投与に適した点眼容器のような点眼送達ユニットに組み込む。
Claims (82)
- 式(I)の構造を有する化合物、あるいは、その薬学的に許容可能な塩、溶媒和物またはプロドラッグであって、
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4とR5は独立して、H、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R6は、H、非置換のC1-C6アルキル、C1-C6ハロアルキル、-(C(R14)(R15))mR17、-(C(R14)(R15))mN(R11)(R12)、-(C(R14)(R15))mOR13、-(C(R14)(R15))nR16、または-OR22であり、
R8はそれぞれ独立して、Hあるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して、置換または非置換のC1-C6アルキルであり、
R10はH、または非置換のC1-C4アルキルであり、
R11はH、置換または非置換のC1-C6アルキル、-C(=O)R19、あるいは-S(=O)2R19であり、
R12はH、あるいは置換または非置換のC1-C6アルキルであり、
R13はH、あるいは置換または非置換のC1-C6アルキルであり、
R14とR15はそれぞれ独立して、H、ハロゲン、あるいは置換または非置換のC1-C6アルキルであり、
R16は置換または非置換のC2-C7ヘテロシクロアルキル、あるいは-C(=O)N(R18)2であり、
R17は-C(=O)R20、-CO2R21、-C(=O)N(R21)2、あるいは置換または非置換のC2-C9ヘテロアリールであり、
R18はそれぞれ独立して、H、置換または非置換のC1-C6アルキル、置換または非置換のC2-C7ヘテロシクロアルキル、あるいは、置換または非置換のC3-C8シクロアルキルであり、あるいは、2つのR18は一体となってヘテロシクロアルキル環を形成し、
R19は置換または非置換のC1-C6アルキルであり、
R20は置換または非置換のC1-C6アルキルであり、
R21はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、あるいは、2つのR21は一体となってヘテロシクロアルキル環を形成し、
R22は、H、あるいは置換または非置換のC1-C6アルキルであり、
mは2-6であり、
および、nは1-5である、化合物、あるいは、その薬学的に許容可能な塩、溶媒和物またはプロドラッグ。 - R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルである、請求項1に記載の化合物。
- R2とR3はそれぞれHである、請求項2に記載の化合物。
- R6は-(C(R14)(R15))mN(R11)(R12)である、請求項1-3のいずれか1つに記載の化合物。
- R12がHである、請求項1-4のいずれか1つに記載の化合物。
- R12が非置換のC1-C6アルキルである、請求項1-4のいずれか1つに記載の化合物。
- R12が-CH3である、請求項6に記載の化合物。
- R11が-C(=O)R19である、請求項1-7のいずれか1つに記載の化合物。
- R11が-S(=O)2R19である、請求項1-7のいずれか1つに記載の化合物。
- R19が非置換のC1-C6アルキルである、請求項1-9のいずれか1つに記載の化合物。
- R19が-CH3である、請求項10に記載の化合物。
- R11が非置換のC1-C6アルキルである、請求項1-7のいずれか1つに記載の化合物。
- R11が-CH3である、請求項12に記載の化合物。
- R11が置換されたC1-C6アルキルである、請求項1-7のいずれか1つに記載の化合物。
- R11が-OHで置換されたC1-C6アルキルである、請求項14に記載の化合物。
- R11がHである、請求項1-7のいずれか1つに記載の化合物。
- R6が-(C(R14)(R15))mOR13である、請求項1-3のいずれか1つに記載の化合物。
- R13がHである、請求項17に記載の化合物。
- R13が置換または非置換のC1-C6アルキルである、請求項17に記載の化合物。
- R6が-(C(R14)(R15))mR17である、請求項1-3のいずれか1つに記載の化合物。
- R17が-C(=O)R20である、請求項20に記載の化合物。
- R20が非置換のC1-C6アルキルである、請求項21に記載の化合物。
- R17が-CO2R21である、請求項20に記載の化合物。
- R17が-C(=O)N(R21)2である、請求項20に記載の化合物。
- R21がそれぞれ独立して、Hまたは非置換のC1-C6アルキルである、請求項24に記載の化合物。
- R17が置換または非置換のC2-C9ヘテロアリールである、請求項20に記載の化合物。
- mが2である、請求項1-26のいずれか1つに記載の化合物。
- mが3である、請求項1-26のいずれか1つに記載の化合物。
- mが4である、請求項1-26のいずれか1つに記載の化合物。
- R6が-(C(R14)(R15))nR16である、請求項1-3のいずれか1つに記載の化合物。
- nが1である、請求項30に記載の化合物。
- R16が置換または非置換のC2-C7ヘテロシクロアルキルである、請求項31に記載の化合物。
- R16が-C(=O)N(R18)2である、請求項31に記載の化合物。
- R18がそれぞれ独立して、Hまたは非置換のC1-C6アルキルである、請求項33に記載の化合物。
- R14とR15がそれぞれ独立して、H、ハロゲン、あるいは非置換のC1-C6アルキルである、請求項1-34のいずれか1つに記載の化合物。
- R14およびR15がそれぞれHである、請求項1-34のいずれか1つに記載の化合物。
- R6が-OR22である、請求項1-3のいずれか1つに記載の化合物。
- R22がHである、請求項37に記載の化合物。
- R22が非置換のC1-C6アルキルである、請求項37に記載の化合物。
- R6がHである、請求項1-3のいずれか1つに記載の化合物。
- R6が非置換のC1-C6アルキルである、請求項1-3のいずれか1つに記載の化合物。
- R4がHである、請求項1-41のいずれか1つに記載の化合物。
- R4が非置換のC1-C6アルキルである、請求項1-41のいずれか1つに記載の化合物。
- R4が-CH3である、請求項43に記載の化合物。
- R4が非置換のC3-C8シクロアルキルである、請求項1-41のいずれか1つに記載の化合物。
- R5がHである、請求項1-45のいずれか1つに記載の化合物。
- R10がHである、請求項1-46のいずれか1つに記載の化合物。
- 式(II)の構造を有する化合物、あるいは、その薬学的に許容可能な塩、溶媒和物またはプロドラッグであって、
R1はそれぞれ独立して、ハロゲン、-CN、-NO2、-OH、-OCF3、-OCH2F、-OCF2H、-CF3、-SR8、-N(R8)S(=O)2R9、S(=O)2N(R8)2、-S(=O)R9、-S(=O)2R9、-C(=O)R9、-CO2R8、-N(R8)2、-C(=O)N(R8)2、-N(R8)C(=O)R9、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のフェノキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、あるいは、2つのR1は一体となって、置換または非置換の複素環、あるいは置換または非置換の炭素環を形成し、
R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルであり、あるいは、R2とR3は一体となって、5または6員の複素環を形成し、
R4はH、ハロゲン、-CN、-OH、-CF3、置換または非置換のC1-C6アルキル、置換または非置換のC1-C6アルコキシ、置換または非置換のC1-C6ヘテロアルキル、置換または非置換のC2-C7ヘテロシクロアルキル、置換または非置換のC3-C8シクロアルキル、置換または非置換のC6-C10アリール、あるいは置換または非置換のC2-C7ヘテロアリールであり、
R6は-OR7であり、
R7はHあるいは置換または非置換のC1-C6アルキルであり、
R8はそれぞれ独立してH、あるいは置換または非置換のC1-C6アルキルであり、
R9はそれぞれ独立して、置換または非置換のC1-C6アルキル、あるいは、置換または非置換のC6-C10アリールであり、および、
nは0-5である、化合物、あるいは、その薬学的に許容可能な塩、溶媒和物またはプロドラッグ。 - R2とR3はそれぞれ独立して、H、-CN、C1-C4アルキル、C3-C6シクロアルキル、またはC2-C7ヘテロシクロアルキルである、請求項57に記載の化合物。
- R2とR3がそれぞれHである、請求項58に記載の化合物。
- R7がHである、請求項57-59のいずれか1つに記載の化合物。
- R7が非置換のC1-C6アルキルである、請求項57-59のいずれか1つに記載の化合物。
- R7が-CH3である、請求項61に記載の化合物。
- R4がHである、請求項57-62のいずれか1つに記載の化合物。
- R4が非置換のC1-C6アルキルである、請求項57-62のいずれか1つに記載の化合物。
- R4が-CH3である、請求項64に記載の化合物。
- R1がそれぞれ独立して、ハロゲン、-OCF3、-CF3、-C(=O)R9、非置換のフェノキシ、あるいは非置換のC6-C10アリールである、請求項57-65のいずれか1つに記載の化合物。
- R1がそれぞれ独立して、-OCF3、-CF3、-C(=O)R9、非置換のフェノキシ、あるいは非置換のC6-C10アリールである、請求項57-65のいずれか1つに記載の化合物。
- nが2である、請求項57-67のいずれか1つに記載の化合物。
- nが1である、請求項57-67のいずれか1つに記載の化合物。
- nが0である、請求項57-65のいずれか1つに記載の化合物。
- 請求項1-76のいずれか1つの化合物、あるいはその薬学的に許容可能な塩、溶媒和物、またはプロドラッグ、および、少なくとも1つの薬学的に許容可能な賦形剤を含む、医薬組成物。
- 請求項1-76のいずれか1つの化合物、あるいはその薬学的に許容可能な塩、溶媒和物、あるいはプロドラッグを含む組成物を、それを必要としている被験体に投与する工程を含む、被験体の疾患を処置するための方法であって、
疾患は癌またはダウン症候群である、方法。 - 疾患が癌である、請求項78に記載の方法。
- 癌が、脳癌、多形性神経膠芽腫、髄芽細胞腫、星状細胞腫、脳幹神経膠腫、髄膜腫、乏突起神経膠腫、黒色腫、肺癌、乳癌、または白血病である、請求項79に記載の方法。
- 疾患がダウン症候群である、請求項78に記載の方法。
- 細胞中のOlig2の活性を阻害する方法であって、請求項1-76のいずれか1つの化合物、あるいはその薬学的に許容可能な塩、溶媒和物、またはプロドラッグに、細胞を接触させる工程を含む、方法。
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US20210253535A1 (en) | 2021-08-19 |
JP7028860B2 (ja) | 2022-03-02 |
CN115215807A (zh) | 2022-10-21 |
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AU2017314842A1 (en) | 2019-03-21 |
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JP2019526568A (ja) | 2019-09-19 |
ZA201901367B (en) | 2023-09-27 |
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