JP2018502841A - Hdac1/2阻害剤としてのピペリジン誘導体 - Google Patents
Hdac1/2阻害剤としてのピペリジン誘導体 Download PDFInfo
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- JP2018502841A JP2018502841A JP2017531260A JP2017531260A JP2018502841A JP 2018502841 A JP2018502841 A JP 2018502841A JP 2017531260 A JP2017531260 A JP 2017531260A JP 2017531260 A JP2017531260 A JP 2017531260A JP 2018502841 A JP2018502841 A JP 2018502841A
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- WICNYNXYKZNNSN-UHFFFAOYSA-N hydron;4-methylpiperazine-1-carbonyl chloride;chloride Chemical compound Cl.CN1CCN(C(Cl)=O)CC1 WICNYNXYKZNNSN-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- 229960003793 midazolam Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- RYGUCYSSMOFTSH-UHFFFAOYSA-N oxane-4-carbonyl chloride Chemical compound ClC(=O)C1CCOCC1 RYGUCYSSMOFTSH-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- AKGSNUOZGBDODP-UHFFFAOYSA-N piperazine-1-carbonyl chloride Chemical compound ClC(=O)N1CCNCC1 AKGSNUOZGBDODP-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- JHLNSXAYRYQYFG-UHFFFAOYSA-N tert-butyl n-(2-amino-4-phenylphenyl)carbamate Chemical compound C1=C(N)C(NC(=O)OC(C)(C)C)=CC=C1C1=CC=CC=C1 JHLNSXAYRYQYFG-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 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
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 239000012443 tonicity enhancing agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 108091008023 transcriptional regulators Proteins 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 101150005573 uvrA gene Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Hydrogenated Pyridines (AREA)
Abstract
Description
本出願は、参照によりその全体が本明細書に組み込まれる2014年12月12日に出願された米国仮特許出願第62/091,221号、及び2015年10月8日に出願された米国仮特許出願第62/238,931号の優先権を主張する。
以下に記載されているのは、本発明を説明するために使用される様々な用語の定義である。これらの定義は、他の特定の場合に限定されない限り、個別に若しくはより大きなグループの一部として、本明細書及び請求項の全体で使用される用語に適用される。
一つの態様では、本明細書において、式I:
X1は、CR7又はNであり、
X2は、CH又はNであり、
Yは、
Zは、H、C1〜C6-アルキル、C6-アリール、C(O)NR4R5、C(O)OR6、C(O)C1〜C6-アルキル、C(O)C0〜C6-アルキル-C6-アリール、C(O)-C3〜C6-シクロアルキル、C(O)-C2〜C6-ヘテロシクリル、及びC(O)C0〜6-アルキル-ヘテロアリールからなる群から選択され、ここでアリール、ヘテロアリール、シクロアルキル、及びヘテロシクリル基は、C1〜C6-アルキル、ハロ、C1〜C6-ハロアルキル、ヒドロキシ、又はC1〜C6-アルコキシのうちの1つ又は2つによって任意選択で置換され、
Ra及びRbは、Hであるか、又はRa及びRbは一緒に縮合C6-アリールを形成し、
R1は、H及びC1〜C6-アルキルからなる群から選択され、
R2は、H、C1〜C6-アルキル、及びC6-アリールからなる群から選択され、
R3は、H、C1〜C6-アルキル、及びC6-アリールからなる群から選択されるか、
又はR2及びR3は一緒にC3〜C6-ヘテロシクリルを形成し、
R4は、H、C1〜C6-アルキル、C1〜C6-アルキル-OH、及びC1〜C6-NH2からなる群から選択され、
R5は、C1〜C6-アルキルであるか、
又はR4及びR5は一緒にC2〜C6-ヘテロシクリルを形成し、ここでヘテロシクリルは、C1〜C6-アルキル、ハロ、C1〜C6-ハロアルキル、ヒドロキシ、又はC1〜C6-アルキルのうちの1つ又は2つによって任意選択で置換され、
R6は、C1〜C6-アルキル及びC0〜C6-アルキル-C6-アリールからなる群から選択され、ここでアリールは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換され、
R7は、H、C1〜C6-アルキル、及びC3〜C6-シクロアルキルからなる群から選択される)
の化合物又はその薬学的に許容される塩を提供する。式Iの化合物の一つの実施形態では、Ra及びRbは、Hであり、R3は、H及びC6-アリールからなる群から選択される。
R6はC6-アリールである。
R6は、C6-アリールである。
R1は、Hであり、
R2は、Hであり、
R3は、H又はC1〜C4-アルキルであり、
R4及びR5は一緒に、モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルからなる群から選択されるヘテロシクリルを形成し、ここでモルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換される。
R1は、Hであり、
R2は、Hであり、
R3は、Hであり、
R4及びR5は一緒に、モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルからなる群から選択されるヘテロシクリルを形成し、ここでモルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換される。
R1は、Hであり、
R2は、Hであり、
R3は、Hである。
R1は、Hであり、
R2は、Hであり、
R3は、Hであり、
R4及びR5は一緒に、モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルからなる群から選択されるヘテロシクリルを形成し、ここでモルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換される。
また、本明細書において、薬学的に許容される担体と一緒に、本発明の化合物、又はその薬学的に許容される塩を含む医薬組成物も提供する。
本明細書において、所望の結果を達成するのに必要であるような量及び時間で、治療有効量の本発明の化合物を対象に投与することによって、ヒト又は他の動物等の対象における障害を治療又は予防する方法を提供する。本発明の化合物の「治療有効量」という用語は、対象における障害の症状を減少させるのに十分な量の化合物を意味する。医学分野において十分に理解されているように、治療有効量の本発明の化合物は任意の医療的処置に適用可能な妥当な利益/リスク比である。
化合物001の合成
化合物002の合成
化合物003の合成
化合物004の合成
化合物005の合成
化合物006の合成
化合物007の合成
化合物008の合成
化合物009の合成
化合物010の合成
化合物011の合成
化合物012の合成
化合物013の合成
化合物014の合成
化合物015の合成
化合物016の合成
化合物017の合成
化合物018の合成
化合物019の合成
化合物020の合成
化合物021の合成
化合物022の合成
化合物023の合成
化合物024の合成
化合物025の合成
化合物026の合成
化合物027の合成
化合物028の合成
化合物029の合成
化合物030の合成
化合物031の合成
化合物032の合成
化合物033の合成
化合物034の合成
化合物035の合成
化合物036の合成
化合物037の合成
化合物038の合成
化合物039の合成
化合物040の合成
化合物041の合成
化合物042の合成
HDAC酵素アッセイ
試験するための化合物をDMSO中で50倍の最終濃度に希釈し、10点の3倍希釈系列を作製した。化合物をアッセイ緩衝液(50mM HEPES、pH7.4、100mM KCl、0.001% Tween-20、0.05% BSA、20μm トリス(2-カルボキシエチル)ホスフィン)中で6倍のそれらの最終濃度に希釈した。HDAC酵素(BPS Biosciences社から購入した)をアッセイ緩衝液中で1.5倍のそれらの最終濃度に希釈し、基質の添加前に24時間にわたって化合物とプレインキュベートした。
薬物動態
オスのSDラットを一晩絶食させた。本発明の化合物を10倍の最終濃度にてジメチルアセトアミド中に溶解し、次いでSolutol HS 15(BASF社)を10%の最終濃度に加えた。最後に80%の生理食塩水を加え、ボルテックスして、透明な溶液にした。IV投薬について、1mg/kgの化合物を、足背静脈を介して3匹の動物に注射した。PO投薬について、5mg/kgの化合物を強制経口投与によって送達した。投薬後、5分、15分、30分、1時間、2時間、4時間、8時間及び24時間にてK2EDTA管内に尾静脈を介して血液を採取した。血液を4℃にて5分間、2000gで遠心分離して、血漿を得た。血漿をアセトニトリルで抽出し、化合物のレベルをLC/MS/MSによって分析した。血漿中の化合物のレベルはラット血漿における標準曲線から算出した。IVクリアランス及び曲線下面積は、WinNonLinソフトウェアを使用して算出した。IV及び経口投薬のために用量を調整した曲線下面積を使用して、経口バイオアベイラビリティを算出した。
胎児グロビン誘導
ヒト骨髄から単離したCD34+細胞は、赤血球系統への細胞分化を補助する培地中での7日の増殖段階、その後、赤血球細胞発生が継続する3日間の分化段階からなる、Bradner JE(Proc Natl Acad Sci USA.2010年7月13日;107(28):12617-22頁)に記載されている方法を使用してインビトロで培養した。分化期の終わりに、これらの細胞は主に後期赤芽球である。成体型メジャーβ-グロビン(adult major β-globin)(β)、成体型マイナーβ-グロビン(adult minor β-globin)(δ)、胎児型β様グロビン(HbG、γ)、及び胚型β様グロビン(ε)に対して設計したプライマー/プローブセットを使用した定量的リアルタイムPCRによってmRNAレベルを決定した。胎児型ヘモグロビン(HbF)又は成体型ヘモグロビン(HbA)に対する蛍光抗体を使用したフローサイトメトリーによってタンパク質レベルを決定した。
更なる研究
化合物003が、hERG、CYP阻害、及び遺伝毒性を欠いていることを示す更なる実験を実施した。
様々なHDAC1/2阻害剤での赤血球前駆細胞の処理はGata2 mRNAの誘導を導く
ヒト骨髄由来CD34+細胞を、Sankaranら、Science、vol.322(5909)、1839-42頁(2008年)に記載されているように7日間増殖させた。次いで、赤血球生成を補助する培地中で3日間、示した濃度の化合物005、化合物A(別の公知のHDAC1/2阻害剤)、又はビヒクル対照(DMSO)の存在下で細胞を分化した(Huら、「Isolation and functional characterization of human erythroblasts at distinct stages:implications for understanding of normal and disordered erythropoiesis in vivo」、Blood、vol.121(16)、3246-53頁(2005年))。定量的リアルタイムPCRを使用してGata2 mRNAを決定し、一定のベータ-アクチンmRNA対照と比較して表した。初代赤血球前駆細胞の化合物005又は化合物A処理の結果、%HbG(図6)及びGata2 mRNA(図7)の等価の用量及び時間依存的誘導を生じる。
本出願全体を通して引用した全ての参照(参考文献、発行された特許、公開された特許出願、及び同時係属特許出願を含む)の内容は、完全に本明細書に明確に組み込まれる。他に定義しない限り、本明細書で使用した全ての技術的及び科学的用語は、当業者に一般的に知られている意味と一致する。
当業者は、慣例の実験のみを使用して、本明細書に記載される本発明の特定の実施形態の多くの等価物を認識するか、又は確認できる。そのような等価物は以下の請求項に包含されることを意図する。
Claims (34)
- 式I:
X1は、CR7又はNであり、
X2は、CH又はNであり、
Yは、
Zは、H、C1〜C6-アルキル、C6-アリール、C(O)NR4R5、C(O)OR6、C(O)C1〜C6-アルキル、C(O)C0〜C6-アルキル-C6-アリール、C(O)-C3〜C6-シクロアルキル、C(O)-C2〜C6-ヘテロシクリル、及びC(O)C0〜6-アルキル-ヘテロアリールからなる群から選択され、ここで前記アリール、ヘテロアリール、シクロアルキル、及びヘテロシクリル基は、C1〜C6-アルキル、ハロ、C1〜C6-ハロアルキル、ヒドロキシ、又はC1〜C6-アルコキシのうちの1つ又は2つによって任意選択で置換され、
Ra及びRbはHであるか、又はRa及びRbは一緒に縮合C6-アリールを形成し、
R1は、H及びC1〜C6-アルキルからなる群から選択され、
R2は、H、C1〜C6-アルキル、及びC6-アリールからなる群から選択され、
R3は、H、C1〜C6-アルキル、及びC6-アリールからなる群から選択されるか、
又はR2及びR3は一緒にC2〜C6-ヘテロシクリルを形成し、
R4は、H、C1〜C6-アルキル、C1〜C6-アルキル-OH、及びC1〜C6-NH2からなる群から選択され、
R5は、C1〜C6-アルキルであるか、
又はR4及びR5は一緒にC2〜C6-ヘテロシクリルを形成し、ここでヘテロシクリルは、C1〜C6-アルキル、ハロ、C1〜C6-ハロアルキル、ヒドロキシ、又はC1〜C6-アルコキシのうちの1つ又は2つによって任意選択で置換され、
R6は、C1〜C6-アルキル及びC0〜C6-アルキル-C6-アリールからなる群から選択され、ここでアリールは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換され、
R7は、H、C1〜C6-アルキル、及びC3〜C6-シクロアルキルからなる群から選択される)
の化合物又はその薬学的に許容される塩。 - 式IIの構造:
- X1及びX2が、各々Nであるか、又はX1及びX2が、各々CHである、請求項1又は2に記載の化合物。
- Yが、
- Zが、C(O)NR4R5、C(O)OR6、C(O)-C3〜C6-シクロアルキル、C(O)-C2〜C6-ヘテロシクリル、及びC(O)C0〜6-アルキル-ヘテロアリールからなる群から選択され、ここでヘテロアリール、シクロアルキル、又はヘテロシクリルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換され、
R6が、C6-アリールである、請求項1から4のいずれか一項に記載の化合物。 - Zが、H、C1〜C6-アルキル、及びC6-アリールからなる群から選択される、請求項1から4のいずれか一項に記載の化合物。
- R1が、Hである、請求項1から6のいずれか一項に記載の化合物。
- R2が、Hである、請求項1から7のいずれか一項に記載の化合物。
- R3が、H、メチル、エチル、イソプロピル、又はフェニルである、請求項1から8のいずれか一項に記載の化合物。
- 式IIIの構造:
- X1及びX2が、各々Nであるか、又はX1及びX2が、各々CHである、請求項10に記載の化合物。
- R2が、Hである、請求項10又は11に記載の化合物。
- R3が、H、メチル、又はイソプロピルである、請求項10から12のいずれか一項に記載の化合物。
- R4が、Hであり、R5が、C1〜C6-アルキルである、請求項10から13のいずれか一項に記載の化合物。
- R4及びR5が一緒に、モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルからなる群から選択されるヘテロシクリルを形成し、ここで前記モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換される、請求項10から13のいずれか一項に記載の化合物。
- X1及びX2が、Nであり、
R1が、Hであり、
R2が、Hであり、
R3が、H又はC1〜C4-アルキルであり、
R4及びR5が一緒に、モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルからなる群から選択されるヘテロシクリルを形成し、ここで前記モルホリニル、ピペリジニル、ピペラジニル、及びピロリジニルは、C1〜C6-アルキル、ハロ、又はヒドロキシのうちの1つ又は2つによって任意選択で置換される、請求項10から15のいずれか一項に記載の化合物。 -
-
- 請求項1から18のいずれか一項に記載の化合物と、薬学的に許容される担体とを含む医薬組成物。
- 請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩を投与することを含む、対象におけるHDAC1及び/又はHDAC2の活性を阻害する方法。
- 請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩を対象に投与することを含む、対象におけるHDAC1及び/又はHDAC2によって媒介される疾患を治療する方法。
- 疾患が、骨髄異形成症候群である、請求項21に記載の方法。
- 疾患が、異常ヘモグロビン症である、請求項21に記載の方法。
- 異常ヘモグロビン症が、鎌状細胞疾患又はベータ-サラセミアである、請求項23に記載の方法。
- 疾患が、肺がん、結腸がん、乳がん、神経芽細胞腫、白血病、又はリンパ腫である、請求項21に記載の方法。
- 疾患が、急性骨髄性白血病又は急性巨核球性白血病である、請求項21に記載の方法。
- 疾患が、神経芽細胞腫である、請求項21に記載の方法。
- 治療有効量の請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩を対象に投与することを含む、それを必要とする対象における鎌状細胞疾患、ベータサラセミア、骨髄異形成症候群、急性骨髄性白血病、神経芽細胞腫、又は急性巨核球性白血病を治療する方法。
- 対象が、ヒトである、請求項20から28のいずれか一項に記載の方法。
- 治療有効量の請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩を、それを必要とする対象に投与することを含む、GATA結合タンパク質2(Gata2)欠乏症を伴う疾患又は障害を治療する方法。
- 細胞を、請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩と接触させることを含む、細胞におけるGATA結合タンパク質2(Gata2)発現を増加させる方法。
- Gata2過剰発現が、HbG(ガンマグロビン)を誘導する、請求項31に記載の方法。
- 請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩を対象に投与することを含む、対象におけるHbG(ガンマグロビン)発現を誘導する方法。
- 請求項1から18のいずれか一項に記載の化合物、又はそれらの薬学的に許容される塩が、対象におけるHbGの約2倍〜約20倍の増加を生じる投薬量で投与される、請求項33に記載の方法。
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