EA023441B1 - Бензодиазепиновый ингибитор бромодомена - Google Patents

Info

Publication number

EA023441B1

EA023441B1 EA201290184A EA201290184A EA023441B1 EA 023441 B1 EA023441 B1 EA 023441B1 EA 201290184 A EA201290184 A EA 201290184A EA 201290184 A EA201290184 A EA 201290184A EA 023441 B1 EA023441 B1 EA 023441B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

alkyl

chlorophenyl

methyloxy

triazolo

Prior art date

2009-11-05

Links

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• Global Dossier
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• 229940125763 bromodomain inhibitor Drugs 0.000 title description 20
• SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 title 1
• 229940049706 benzodiazepine Drugs 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 240
• 150000003839 salts Chemical class 0.000 claims abstract description 129
• 238000000034 method Methods 0.000 claims abstract description 50
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
• 201000011510 cancer Diseases 0.000 claims abstract description 18
• -1 -CO-carbocyclyl Chemical group 0.000 claims description 82
• 125000000217 alkyl group Chemical group 0.000 claims description 70
• 125000003545 alkoxy group Chemical group 0.000 claims description 37
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 28
• 238000011282 treatment Methods 0.000 claims description 27
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 229920006395 saturated elastomer Polymers 0.000 claims description 22
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 18
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 150000002367 halogens Chemical class 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims description 18
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 12
• 125000005842 heteroatom Chemical group 0.000 claims description 12
• 201000009030 Carcinoma Diseases 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 11
• 125000006413 ring segment Chemical group 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
• 125000004429 atom Chemical group 0.000 claims description 5
• 230000002440 hepatic effect Effects 0.000 claims description 5
• 150000002431 hydrogen Chemical class 0.000 claims description 5
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
• 125000003828 azulenyl group Chemical group 0.000 claims description 4
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
• 239000001301 oxygen Chemical group 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 125000005561 phenanthryl group Chemical group 0.000 claims description 4
• 229910052717 sulfur Chemical group 0.000 claims description 4
• 239000011593 sulfur Chemical group 0.000 claims description 4
• 210000000481 breast Anatomy 0.000 claims description 3
• 230000002489 hematologic effect Effects 0.000 claims description 3
• 210000004072 lung Anatomy 0.000 claims description 3
• 230000000926 neurological effect Effects 0.000 claims description 3
• 125000002837 carbocyclic group Chemical group 0.000 claims description 2
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
• 208000026310 Breast neoplasm Diseases 0.000 claims 1
• 206010009944 Colon cancer Diseases 0.000 claims 1
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
• 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims 1
• 201000005296 lung carcinoma Diseases 0.000 claims 1
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 4
• 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 abstract 1
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 181
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 170
• 235000002639 sodium chloride Nutrition 0.000 description 95
• 239000000203 mixture Substances 0.000 description 84
• 239000000543 intermediate Substances 0.000 description 81
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 77
• 239000000243 solution Substances 0.000 description 51
• 239000007787 solid Substances 0.000 description 49
• 239000011541 reaction mixture Substances 0.000 description 38
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• 102000001805 Bromodomains Human genes 0.000 description 35
• 239000002904 solvent Substances 0.000 description 35
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
• 108050009021 Bromodomains Proteins 0.000 description 33
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 32
• 229910052796 boron Inorganic materials 0.000 description 32
• YRBQVPLXZMRHLA-UHFFFAOYSA-N 2-[4-methyl-3-oxo-7-(1,3,4,9-tetrahydropyrido[3,4-b]indole-2-carbonyl)-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(C(=O)N3CC4=C(C5=CC=CC=C5N4)CC3)=CC=C21 YRBQVPLXZMRHLA-UHFFFAOYSA-N 0.000 description 29
• 230000002829 reductive effect Effects 0.000 description 29
• WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
• 239000008194 pharmaceutical composition Substances 0.000 description 23
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
• 239000000843 powder Substances 0.000 description 21
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
• 238000006243 chemical reaction Methods 0.000 description 19
• 201000010099 disease Diseases 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• 238000005481 NMR spectroscopy Methods 0.000 description 16
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 16
• 210000004027 cell Anatomy 0.000 description 16
• 238000003818 flash chromatography Methods 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 150000001412 amines Chemical class 0.000 description 15
• 239000010410 layer Substances 0.000 description 15
• 235000019198 oils Nutrition 0.000 description 15
• 239000000741 silica gel Substances 0.000 description 15
• 229910002027 silica gel Inorganic materials 0.000 description 15
• 150000001793 charged compounds Chemical class 0.000 description 14
• 239000007788 liquid Substances 0.000 description 14
• 239000012267 brine Substances 0.000 description 13
• 239000003112 inhibitor Substances 0.000 description 13
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• 239000003826 tablet Substances 0.000 description 13
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
• 108090000623 proteins and genes Proteins 0.000 description 12
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
• 238000002360 preparation method Methods 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
• 230000001154 acute effect Effects 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 230000001363 autoimmune Effects 0.000 description 9
• 238000001819 mass spectrum Methods 0.000 description 9
• HUPVBFQYJHFONM-UHFFFAOYSA-N 2-(4-fluorophenyl)acetamide Chemical compound NC(=O)CC1=CC=C(F)C=C1 HUPVBFQYJHFONM-UHFFFAOYSA-N 0.000 description 8
• 108010033040 Histones Proteins 0.000 description 8
• 235000011054 acetic acid Nutrition 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
• 230000001684 chronic effect Effects 0.000 description 8
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• 238000000132 electrospray ionisation Methods 0.000 description 7
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• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
• 230000002209 hydrophobic effect Effects 0.000 description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
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• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• 108010077544 Chromatin Proteins 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
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• 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 4
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