CA2889717A1 - Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer - Google Patents

Info

Publication number

CA2889717A1

CA2889717A1 CA2889717A CA2889717A CA2889717A1 CA 2889717 A1 CA2889717 A1 CA 2889717A1 CA 2889717 A CA2889717 A CA 2889717A CA 2889717 A CA2889717 A CA 2889717A CA 2889717 A1 CA2889717 A1 CA 2889717A1

Authority

CA

Canada

Prior art keywords

alkyl

cycloalkyl

substituted

compound

aryl

Prior art date

2012-10-29

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 229940002612 prodrug Drugs 0.000 title claims abstract description 116
• 239000000651 prodrug Substances 0.000 title claims abstract description 116
• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 39
• 201000011510 cancer Diseases 0.000 title claims abstract description 31
• 238000011282 treatment Methods 0.000 title claims description 34
• 150000004712 monophosphates Chemical class 0.000 title abstract description 67
• 208000036142 Viral infection Diseases 0.000 title abstract description 8
• 230000009385 viral infection Effects 0.000 title abstract description 7
• 239000002719 pyrimidine nucleotide Substances 0.000 title 1
• 150000003230 pyrimidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 265
• 238000000034 method Methods 0.000 claims abstract description 79
• 241000713772 Human immunodeficiency virus 1 Species 0.000 claims abstract description 55
• 239000000203 mixture Substances 0.000 claims abstract description 55
• 241001263478 Norovirus Species 0.000 claims abstract description 49
• 208000031886 HIV Infections Diseases 0.000 claims abstract description 28
• 150000003839 salts Chemical class 0.000 claims abstract description 28
• 241000700588 Human alphaherpesvirus 1 Species 0.000 claims abstract description 23
• 241000725619 Dengue virus Species 0.000 claims abstract description 21
• 241000701074 Human alphaherpesvirus 2 Species 0.000 claims abstract description 21
• 208000003152 Yellow Fever Diseases 0.000 claims abstract description 19
• 241000713340 Human immunodeficiency virus 2 Species 0.000 claims abstract description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 232
• -1 C1-C6alkoxy Chemical group 0.000 claims description 160
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 113
• 125000003118 aryl group Chemical group 0.000 claims description 111
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 101
• 125000001072 heteroaryl group Chemical group 0.000 claims description 99
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 91
• 239000003814 drug Substances 0.000 claims description 85
• 125000001424 substituent group Chemical group 0.000 claims description 81
• 241000700605 Viruses Species 0.000 claims description 78
• 125000001153 fluoro group Chemical group F* 0.000 claims description 73
• 235000000346 sugar Nutrition 0.000 claims description 71
• 208000015181 infectious disease Diseases 0.000 claims description 69
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 60
• 239000003795 chemical substances by application Substances 0.000 claims description 60
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 53
• 125000003545 alkoxy group Chemical group 0.000 claims description 47
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 45
• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 41
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 41
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 38
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
• 125000003107 substituted aryl group Chemical group 0.000 claims description 37
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 34
• 229910052731 fluorine Inorganic materials 0.000 claims description 30
• 229910052801 chlorine Inorganic materials 0.000 claims description 29
• 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 28
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 27
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 27
• 229910052794 bromium Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 25
• 229910052740 iodine Inorganic materials 0.000 claims description 25
• 150000002191 fatty alcohols Chemical group 0.000 claims description 23
• 230000035772 mutation Effects 0.000 claims description 22
• 206010012310 Dengue fever Diseases 0.000 claims description 21
• 125000002252 acyl group Chemical group 0.000 claims description 21
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 229910052760 oxygen Inorganic materials 0.000 claims description 20
• 239000001226 triphosphate Substances 0.000 claims description 20
• 208000025729 dengue disease Diseases 0.000 claims description 19
• 208000001490 Dengue Diseases 0.000 claims description 18
• 229910052799 carbon Inorganic materials 0.000 claims description 18
• 235000011178 triphosphate Nutrition 0.000 claims description 18
• 235000011180 diphosphates Nutrition 0.000 claims description 17
• 125000004076 pyridyl group Chemical group 0.000 claims description 17
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
• 239000003937 drug carrier Substances 0.000 claims description 16
• 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 15
• 239000001177 diphosphate Substances 0.000 claims description 14
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
• 238000002360 preparation method Methods 0.000 claims description 14
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• 241000710886 West Nile virus Species 0.000 claims description 13
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• 125000003342 alkenyl group Chemical group 0.000 claims description 12
• 230000004071 biological effect Effects 0.000 claims description 12
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
• 229910052757 nitrogen Inorganic materials 0.000 claims description 11
• XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 10
• PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 10
• 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 10
• 241000710772 Yellow fever virus Species 0.000 claims description 10
• HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
• 150000002632 lipids Chemical class 0.000 claims description 10
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 9
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
• 229910052711 selenium Inorganic materials 0.000 claims description 9
• 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 8
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
• 229910052700 potassium Inorganic materials 0.000 claims description 8
• 229910052708 sodium Inorganic materials 0.000 claims description 8
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 7
• JLXCKKKWUBELSL-UHFFFAOYSA-N diphosphono hydrogen phosphate;pyrimidine Chemical class C1=CN=CN=C1.OP(O)(=O)OP(O)(=O)OP(O)(O)=O JLXCKKKWUBELSL-UHFFFAOYSA-N 0.000 claims description 7
• 150000002148 esters Chemical class 0.000 claims description 7
• 229910052744 lithium Inorganic materials 0.000 claims description 7
• WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 6
• IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims description 6
• 125000004442 acylamino group Chemical group 0.000 claims description 6
• 239000002246 antineoplastic agent Substances 0.000 claims description 6
• OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 claims description 6
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 235000012000 cholesterol Nutrition 0.000 claims description 4
• 239000001257 hydrogen Substances 0.000 claims description 4
• 150000003904 phospholipids Chemical class 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 3
• 150000008575 L-amino acids Chemical class 0.000 claims description 3
• 229910003870 O—Li Inorganic materials 0.000 claims description 3
• 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
• 229930195729 fatty acid Natural products 0.000 claims description 3
• 239000000194 fatty acid Substances 0.000 claims description 3
• 150000004665 fatty acids Chemical group 0.000 claims description 3
• BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 14
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 11
• 238000011321 prophylaxis Methods 0.000 claims 10
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 7
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• 125000006302 indol-3-yl methyl group Chemical group [H]N1C([H])=C(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])* 0.000 claims 3
• 125000006823 (C1-C6) acyl group Chemical group 0.000 claims 1
• 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims 1
• 230000000840 anti-viral effect Effects 0.000 abstract description 32
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