EA022355B1 - Пирролопиримидины в качестве ингибиторов cdk4/6 - Google Patents

Info

Publication number

EA022355B1

EA022355B1 EA201201161A EA201201161A EA022355B1 EA 022355 B1 EA022355 B1 EA 022355B1 EA 201201161 A EA201201161 A EA 201201161A EA 201201161 A EA201201161 A EA 201201161A EA 022355 B1 EA022355 B1 EA 022355B1

Authority

EA

Eurasian Patent Office

Prior art keywords

pyrrolo

pyridin

ylamino

cyclopentyl

pyrimidine

Prior art date

2010-02-19

Links

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• 239000003112 inhibitor Substances 0.000 title abstract description 14
• 150000004944 pyrrolopyrimidines Chemical class 0.000 title description 5
• 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 title 1
• 238000000034 method Methods 0.000 claims abstract description 269
• 150000001875 compounds Chemical class 0.000 claims abstract description 157
• 150000003839 salts Chemical class 0.000 claims abstract description 80
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• 201000011510 cancer Diseases 0.000 claims abstract description 20
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• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 13
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 13
• 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 12
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 11
• 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims abstract description 10
• 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 10
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 10
• 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 10
• 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 10
• 206010006187 Breast cancer Diseases 0.000 claims abstract description 9
• 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 9
• 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
• 206010009944 Colon cancer Diseases 0.000 claims abstract description 6
• 239000003937 drug carrier Substances 0.000 claims abstract description 6
• -1 substituted Chemical class 0.000 claims description 1058
• YPOXGDJGKBXRFP-UHFFFAOYSA-N pyrimidine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=N1 YPOXGDJGKBXRFP-UHFFFAOYSA-N 0.000 claims description 206
• HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 claims description 205
• QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 163
• QLGFTMMDEPUTTK-UHFFFAOYSA-N n,n-dimethylpyrimidine-4-carboxamide Chemical compound CN(C)C(=O)C1=CC=NC=N1 QLGFTMMDEPUTTK-UHFFFAOYSA-N 0.000 claims description 89
• 229910052757 nitrogen Inorganic materials 0.000 claims description 39
• 229910052805 deuterium Inorganic materials 0.000 claims description 27
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 26
• 125000001424 substituent group Chemical group 0.000 claims description 26
• BQAWUZWNEZOTBB-UHFFFAOYSA-N CNC.N1=CN=CC=C1 Chemical compound CNC.N1=CN=CC=C1 BQAWUZWNEZOTBB-UHFFFAOYSA-N 0.000 claims description 25
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 20
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 229910052799 carbon Inorganic materials 0.000 claims description 13
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• 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 claims description 9
• 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 claims description 5
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
• CTFXSNFOZUKBMM-UHFFFAOYSA-N CNC.N1=CN=CC=C1C(=O)O Chemical compound CNC.N1=CN=CC=C1C(=O)O CTFXSNFOZUKBMM-UHFFFAOYSA-N 0.000 claims description 4
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
• 125000001188 haloalkyl group Chemical group 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 4
• 150000002367 halogens Chemical class 0.000 claims description 4
• 125000004043 oxo group Chemical group O=* 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
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• 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 abstract 1
• 206010030155 Oesophageal carcinoma Diseases 0.000 abstract 1
• 238000002360 preparation method Methods 0.000 description 298
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 145
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 67
• 239000011664 nicotinic acid Substances 0.000 description 62
• 125000006239 protecting group Chemical group 0.000 description 61
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• 229960003512 nicotinic acid Drugs 0.000 description 57
• 150000001408 amides Chemical class 0.000 description 56
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• 238000006243 chemical reaction Methods 0.000 description 43
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• FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 40
• 210000004027 cell Anatomy 0.000 description 38
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• 239000000725 suspension Substances 0.000 description 28
• 239000000460 chlorine Substances 0.000 description 27
• 239000012267 brine Substances 0.000 description 26
• GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 26
• 239000012071 phase Substances 0.000 description 26
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
• 229910052700 potassium Inorganic materials 0.000 description 25
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