OA12865A - Benzofused heteroaryl aminde derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use. - Google Patents
Benzofused heteroaryl aminde derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use. Download PDFInfo
- Publication number
- OA12865A OA12865A OA1200400325A OA1200400325A OA12865A OA 12865 A OA12865 A OA 12865A OA 1200400325 A OA1200400325 A OA 1200400325A OA 1200400325 A OA1200400325 A OA 1200400325A OA 12865 A OA12865 A OA 12865A
- Authority
- OA
- OAPI
- Prior art keywords
- mmole
- alkyl
- nmr
- aryl
- methyl
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 12
- 238000000034 method Methods 0.000 title abstract description 42
- 239000003814 drug Substances 0.000 title description 10
- 229940125670 thienopyridine Drugs 0.000 title description 4
- 239000002175 thienopyridine Substances 0.000 title description 4
- 229940124597 therapeutic agent Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 241000124008 Mammalia Species 0.000 claims abstract description 30
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims description 67
- 125000000623 heterocyclic group Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- -1 methylureido group Chemical group 0.000 claims description 54
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 14
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 208000035475 disorder Diseases 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 12
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 claims description 11
- 230000033115 angiogenesis Effects 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000004069 aziridinyl group Chemical group 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
- 210000000481 breast Anatomy 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 230000002611 ovarian Effects 0.000 claims description 9
- 210000002307 prostate Anatomy 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 210000004072 lung Anatomy 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000005189 alkyl hydroxy group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 230000004862 vasculogenesis Effects 0.000 claims description 7
- 210000001072 colon Anatomy 0.000 claims description 6
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 208000032612 Glial tumor Diseases 0.000 claims description 5
- 206010018338 Glioma Diseases 0.000 claims description 5
- 208000002780 macular degeneration Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
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- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 4
- 229940030600 antihypertensive agent Drugs 0.000 claims description 4
- 239000002220 antihypertensive agent Substances 0.000 claims description 4
- 208000037976 chronic inflammation Diseases 0.000 claims description 4
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 4
- 201000011066 hemangioma Diseases 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 208000017520 skin disease Diseases 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 230000005747 tumor angiogenesis Effects 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 8
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 2
- 229940002612 prodrug Drugs 0.000 abstract description 66
- 239000000651 prodrug Substances 0.000 abstract description 66
- 239000002207 metabolite Substances 0.000 abstract 2
- 239000012453 solvate Substances 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 262
- 239000000463 material Substances 0.000 description 210
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 192
- 239000007787 solid Substances 0.000 description 188
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 140
- 238000006243 chemical reaction Methods 0.000 description 136
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 115
- 239000000243 solution Substances 0.000 description 112
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 106
- 229910000024 caesium carbonate Inorganic materials 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 88
- 239000000203 mixture Substances 0.000 description 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 82
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 50
- 239000003795 chemical substances by application Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- 229910015845 BBr3 Inorganic materials 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 238000012360 testing method Methods 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 25
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 239000007832 Na2SO4 Substances 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000003112 inhibitor Substances 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 19
- 238000003818 flash chromatography Methods 0.000 description 18
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- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 16
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- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
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- LJYQFQKUXOCPNI-UHFFFAOYSA-N 7-chloro-2-(1-methylimidazol-2-yl)thieno[3,2-b]pyridine Chemical compound CN1C=CN=C1C1=CC2=NC=CC(Cl)=C2S1 LJYQFQKUXOCPNI-UHFFFAOYSA-N 0.000 description 12
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 11
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- RXKGVJSYESLRAK-MRVPVSSYSA-N (7-chlorothieno[3,2-b]pyridin-2-yl)-[(3r)-3-methoxypyrrolidin-1-yl]methanone Chemical compound C1[C@H](OC)CCN1C(=O)C1=CC2=NC=CC(Cl)=C2S1 RXKGVJSYESLRAK-MRVPVSSYSA-N 0.000 description 9
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- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
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| US38911002P | 2002-06-14 | 2002-06-14 |
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| OA1200400325A OA12865A (en) | 2002-06-14 | 2003-06-04 | Benzofused heteroaryl aminde derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use. |
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