JP2019521092A - ヒストン脱アセチル化酵素6阻害剤およびその使用 - Google Patents
ヒストン脱アセチル化酵素6阻害剤およびその使用 Download PDFInfo
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- JP2019521092A JP2019521092A JP2018560157A JP2018560157A JP2019521092A JP 2019521092 A JP2019521092 A JP 2019521092A JP 2018560157 A JP2018560157 A JP 2018560157A JP 2018560157 A JP2018560157 A JP 2018560157A JP 2019521092 A JP2019521092 A JP 2019521092A
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- arh
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- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BOZPGPXECPAKQL-UHFFFAOYSA-N methyl 3-[(quinolin-8-ylamino)methyl]benzoate Chemical compound N1=CC=CC2=CC=CC(=C12)NCC=1C=C(C(=O)OC)C=CC=1 BOZPGPXECPAKQL-UHFFFAOYSA-N 0.000 description 1
- UVSBCUAQEZINCQ-UHFFFAOYSA-N methyl 3-formylbenzoate Chemical compound COC(=O)C1=CC=CC(C=O)=C1 UVSBCUAQEZINCQ-UHFFFAOYSA-N 0.000 description 1
- GIZCKBSSWNIUMZ-UHFFFAOYSA-N methyl 4-(aminomethyl)benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=C(CN)C=C1 GIZCKBSSWNIUMZ-UHFFFAOYSA-N 0.000 description 1
- GBYPFEOGOLJZBL-UHFFFAOYSA-N methyl 4-(quinolin-3-ylcarbamoyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(=O)NC1=CN=C(C=CC=C2)C2=C1 GBYPFEOGOLJZBL-UHFFFAOYSA-N 0.000 description 1
- BRSNXZRBZYJPKB-UHFFFAOYSA-N methyl 4-(quinolin-5-ylcarbamoyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(=O)NC1=CC=CC2=NC=CC=C12 BRSNXZRBZYJPKB-UHFFFAOYSA-N 0.000 description 1
- AOPIYLQCOFKTPQ-UHFFFAOYSA-N methyl 4-(quinolin-6-ylcarbamoyl)benzoate Chemical compound COC(=O)c1ccc(cc1)C(=O)Nc1ccc2ncccc2c1 AOPIYLQCOFKTPQ-UHFFFAOYSA-N 0.000 description 1
- RXANEQSAGMIYDZ-UHFFFAOYSA-N methyl 4-(quinolin-8-ylamino)benzoate Chemical compound N1=CC=CC2=CC=CC(=C12)NC1=CC=C(C(=O)OC)C=C1 RXANEQSAGMIYDZ-UHFFFAOYSA-N 0.000 description 1
- RHYNCTKKCZTBFT-UHFFFAOYSA-N methyl 4-[(isoquinolin-1-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2nccc3ccccc23)cc1 RHYNCTKKCZTBFT-UHFFFAOYSA-N 0.000 description 1
- XQZJMEGYTKHRIY-UHFFFAOYSA-N methyl 4-[(isoquinolin-4-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2cncc3ccccc23)cc1 XQZJMEGYTKHRIY-UHFFFAOYSA-N 0.000 description 1
- WIZSSHOKRGUZPE-UHFFFAOYSA-N methyl 4-[(isoquinolin-5-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2cccc3cnccc23)cc1 WIZSSHOKRGUZPE-UHFFFAOYSA-N 0.000 description 1
- FDYSDFRQSOHMBO-UHFFFAOYSA-N methyl 4-[(isoquinolin-8-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2cccc3ccncc23)cc1 FDYSDFRQSOHMBO-UHFFFAOYSA-N 0.000 description 1
- GIDBLHHFOOYGTL-UHFFFAOYSA-N methyl 4-[(quinolin-3-ylamino)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC1=CN=C(C=CC=C2)C2=C1 GIDBLHHFOOYGTL-UHFFFAOYSA-N 0.000 description 1
- CWYUQWRPTNKSJZ-UHFFFAOYSA-N methyl 4-[(quinolin-4-ylamino)methyl]benzoate Chemical compound N1=CC=C(C2=CC=CC=C12)NCC1=CC=C(C(=O)OC)C=C1 CWYUQWRPTNKSJZ-UHFFFAOYSA-N 0.000 description 1
- RLIOUNJQABDDRH-UHFFFAOYSA-N methyl 4-[(quinolin-5-ylamino)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC1=CC=CC2=NC=CC=C12 RLIOUNJQABDDRH-UHFFFAOYSA-N 0.000 description 1
- KIDMOBCPFJLXGI-UHFFFAOYSA-N methyl 4-[(quinolin-6-ylamino)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CNC1=CC=C(N=CC=C2)C2=C1 KIDMOBCPFJLXGI-UHFFFAOYSA-N 0.000 description 1
- FPZRMJZKWFRAGN-UHFFFAOYSA-N methyl 4-[(quinolin-7-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2ccc3cccnc3c2)cc1 FPZRMJZKWFRAGN-UHFFFAOYSA-N 0.000 description 1
- JYUQSJJQONNPEC-UHFFFAOYSA-N methyl 4-[(quinoxalin-5-ylamino)methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2cccc3nccnc23)cc1 JYUQSJJQONNPEC-UHFFFAOYSA-N 0.000 description 1
- ORHWVKKSHLLNMV-UHFFFAOYSA-N methyl 4-[[(2-methylquinolin-8-yl)amino]methyl]benzoate Chemical compound COC(=O)c1ccc(CNc2cccc3ccc(C)nc23)cc1 ORHWVKKSHLLNMV-UHFFFAOYSA-N 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005564 oxazolylene group Chemical group 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 238000012342 propidium iodide staining Methods 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- OPCQDOJDTZBLEJ-UHFFFAOYSA-N quinolin-8-ylmethanamine Chemical compound C1=CN=C2C(CN)=CC=CC2=C1 OPCQDOJDTZBLEJ-UHFFFAOYSA-N 0.000 description 1
- 235000012752 quinoline yellow Nutrition 0.000 description 1
- 229940051201 quinoline yellow Drugs 0.000 description 1
- FZUOVNMHEAPVBW-UHFFFAOYSA-L quinoline yellow ws Chemical compound [Na+].[Na+].O=C1C2=CC=CC=C2C(=O)C1C1=NC2=C(S([O-])(=O)=O)C=C(S(=O)(=O)[O-])C=C2C=C1 FZUOVNMHEAPVBW-UHFFFAOYSA-L 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Description
さらに好ましくは、
CとともにC=Oを形成するR3およびR4を有する。
酢酸(1M)にアミノキノリン(1当量)、および、メチル4−ホルミルベンゾエート、または、(E)−メチル3−(4−ホルミルフェニル)アクリレート(1.05当量)を溶解したものを、室温にて30分撹拌した。酢酸(1M)にトリアセトキシホウ化水素ナトリウム(2当量)を溶解したものを前の溶液に滴下した。結果として生じた溶液を室温にて1時間撹拌した。その溶液に氷水を注ぎ、溶液のpH値を水酸化ナトリウム溶液で10に調整した。このようにして生成された混合物を酢酸エチルで抽出し、最上層である有機層を収集した。有機層の濃縮残渣を酢酸エチルおよびヘキサンで溶出するクロマトグラフィーで精製し、固体を得た。
メタノールに混合したメチル4−(アミノメチル)ベンゾエート塩酸塩(1.5当量)に水酸化ナトリウム(1.5当量)粉末を0℃にて添加した。結果として生じた混合物を0℃にて一時間撹拌し、その後ろ過した。ろ液を真空で濃縮することにより、溶媒を除去した。このようにして得た遊離アミンを酢酸エチルで抽出し、水で洗浄した。その後、最上層の有機層を収集し、トルエン(0.5M)に溶解してアミン溶液を生成した。このようにして生成されたアミン溶液を、ブロモキノリン(1当量)、Pd(OAc)2(0.06当量)、ビス[2−(ジフェニルホスフィノ)フェニル]エーテル(0.12当量)、および、K3PO4(3当量)の撹拌混合物に、室温にてアルゴン保護下で添加した。結果として得た混合物を12時間100℃まで加熱し、室温まで冷却した後、ろ過し、酢酸エチルで洗浄した。最上層の有機層を収集し、濃縮し、酢酸エチルおよびヘキサンで溶出するクロマトグラフィーで精製し、所望の生成物を得た。
ジクロロメタン(DCM、0.5M)にアミノキノリン(1.3当量)およびトリエチルアミン(2当量)を溶解したものに、メチル4−(クロロカルボニル)ベンゾエート(1当量)を0℃にて分割して添加した。このようにして生成した溶液を室温にて12時間撹拌した。結果として生じた溶液を酢酸エチルで希釈し、2N塩酸で洗浄した。最上層の有機層を収集し、真空で濃縮することにより、所望の生産物を得た。
ジクロロメタン(DCM:0.1M)に、アミノキノリン(1当量)、4−ジメチルアミノピリジン、および、モノメチルテレフタレート、または、(E)−メチル3−(4−ホルミルフェニル)アクリレート(1.2当量)を溶解したものを室温にて12時間撹拌した。溶液に水を加え、未精製反応混合物をDCMで抽出した。収集した有機層を濃縮し、酢酸エチルおよびヘキサンで溶出するクロマトグラフィーで精製することにより、所望の生成物を得た。
(E)−メチル3−(4−((キノリン−8−イルアミノ)メチル)フェニル)アクリレート
メチル3−(キノリン−8−イルカルバモイル)ベンゾエート
メチル4−((キノリン−2−イルアミノ)メチル)ベンゾエート
メチル4−((キノリン−7−イルアミノ)メチル)ベンゾエート
HDAC6を阻害する際の式(I)の化合物の阻害活性、ガン細胞の成長を抑制する際のテスト化合物の増殖抑制作用、および、他のHDACアイソフォームと比較したHDAC6の阻害選択性を評価すべく、検査を行った。
式(I)の化合物の活性により、ヒト多発性骨髄腫細胞株(RPMI8226、U266、および、NCI−H929)におけるアセチル−α−チューブリン発現が増加するか評価すべく検査を行った。
式(I)の化合物の活性により、ポリユビキチン化タンパク質の蓄積を誘導するHDAC6とダイニンとの結合が阻害されるか評価すべく検査を行った。
ボルテゾミブを組み合わせた式(I)の化合物が多発性骨髄腫細胞におけるアポトーシスの誘導に効果を発揮するか評価すべく検査を行った。
ボルテゾミブを組み合わせた式(I)の化合物が多発性骨髄腫細胞におけるカスパーゼ−3、カスパーゼ−8、および、カスパーゼ−9開裂の増加に効果を発揮するか評価すべく検査を行った。
式(I)の化合物がアミロイド前駆体タンパク(APP)レベル、および、Aβ42の生成に効果を発揮するか評価すべく検査を行った。
式(I)の化合物が複数の型のヒトガンにおける腫瘍成長の阻止に効果を発揮するか評価すべく検査を行った。
式(I)の化合物がアルツハイマー病に関連する記憶障害の改善に効果を発揮するか評価すべく、インビボ検査を行った。
本願明細書に開示されるすべての特徴は、いかなるように組み合わせてもよい。本願明細書に開示される特徴のそれぞれは、同じ、等価な、または、同様の目的を果たす代替的な特徴と置き換えられてよい。したがって、明記しないかぎり、開示された各特徴は、等価なまたは同様の特徴の一般的な例に過ぎない。
Claims (25)
- 以下に示された式(I)の化合物、または、薬学的に許容されるその塩であって、
Wは、二環式アリール、または、二環式ヘテロアリールであり;
Xは、CR5R6、O、S、または、NR7であり、R5、R6、および、R7は、それぞれ独立して、H、−COR、−COOR、−CONR’R”、C1−5アルキル、C2−5アルケニル、C2−5アルキニル、C2−5アルコキシ、シクロアルキル、ヘテロシクロアルキル、アリール、または、ヘテロアリールであり;
Yは、アリーレン、または、ヘテロアリーレンであり;
Zは、結合、メチレン、または、エチレンであり、
mおよびnは、それぞれ0または1であり、
C1−5アルキル、C2−5アルケニル、C2−5アルキニル、C2−5アルコキシ、C1−8アルキル、C2−8アルケニル、C2−8アルキニル、C1−8アルコキシ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリーレン、および、ヘテロアリーレンのそれぞれは、ハロゲン、シアノ、アミノ、ヒドロキシル、ニトロ、スルフヒドリル、C1−5アルキル、C2−5アルコキシ、シクロアルキル、ヘテロシクロアルキル、アリール、または、ヘテロアリールと置換されないか置換される、
化合物、または、薬学的に許容されるその塩。 - Wは、二環式ヘテロアリール、Yは、アリーレン、mは0、nは1である、請求項1に記載の化合物、または、薬学的に許容されるその塩。
- Xは、CH2、O、S、または、NHである、請求項2に記載の化合物、または、薬学的に許容されるその塩。
- Yはフェニレンであり、Zは結合である、請求項3に記載の化合物、または、薬学的に許容されるその塩。
- Wは、キノリン、イソキノリン、キノキサリン、または、ベンゾピリミジンである、請求項2に記載の化合物、または、薬学的に許容されるその塩。
- Xは、CH2、または、NHである、請求項5に記載の化合物、または、薬学的に許容されるその塩。
- Yはフェニレンであり、Zは結合である、請求項6に記載の化合物、または、薬学的に許容されるその塩。
- Xは、NHである、請求項8に記載の化合物、または、薬学的に許容されるその塩。
- Yはフェニレンであり、Zは結合である、請求項9に記載の化合物、または、薬学的に許容されるその塩。
- Yは、パラフェニレン、または、メタフェニレンである、請求項10に記載の化合物、または、薬学的に許容されるその塩。
- Wは、キノリン、イソキノリン、キノキサリン、または、ベンゾピリミジンであり、mは0、nは1である、請求項1に記載の化合物、または、薬学的に許容されるその塩。
- Yは、パラフェニレン、または、メタフェニレンである、請求項13に記載の化合物、または、薬学的に許容されるその塩。
- Xは、NHである、請求項13に記載の化合物、または、薬学的に許容されるその塩。
- Yは、パラフェニレン、または、メタフェニレンである、請求項15に記載の化合物、または、薬学的に許容されるその塩。
- Yは、パラフェニレンであり、Zは、結合である、請求項16に記載の化合物、または、薬学的に許容されるその塩。
- 化合物4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、47、50、52、54、56、59、61、63、66、68、71、73、もしくは、75、または、化合物28−メシレートである請求項1に記載の化合物、または、薬学的に許容されるその塩。
- 医薬的に許容される担体、および、請求項1に記載の化合物または薬学的に許容されるその塩を含む医薬組成物。
- 前記化合物または薬学的に許容されるその塩は、化合物12、化合物28、または、化合物28−メシレートである、請求項19に記載の医薬組成物。
- ヒストン脱アセチル化酵素6関連症状を治療する方法であって、請求項1に記載の化合物または薬学的に許容されるその塩を必要とする被検者に有効量で投与することを含む、方法。
- 前記化合物または薬学的に許容されるその塩は、化合物12、化合物28、または、化合物28−メシレートである、請求項21に記載の方法。
- 前記症状は、ガン、または、神経変性疾患である、請求項21に記載の方法。
- 前記化合物または薬学的に許容されるその塩は、経口投与される、請求項23に記載の方法。
- 前記化合物または薬学的に許容されるその塩は、化合物12、化合物28、または、化合物28−メシレートである、請求項24に記載の方法。
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