AU2004275770A1 - Small molecule compositions and methods for increasing drug efficiency using compositions thereof - Google Patents

Info

Publication number

AU2004275770A1

AU2004275770A1 AU2004275770A AU2004275770A AU2004275770A1 AU 2004275770 A1 AU2004275770 A1 AU 2004275770A1 AU 2004275770 A AU2004275770 A AU 2004275770A AU 2004275770 A AU2004275770 A AU 2004275770A AU 2004275770 A1 AU2004275770 A1 AU 2004275770A1

Authority

AU

Australia

Prior art keywords

conjugate

alkyl

aryl

arylureido

drug

Prior art date

2003-09-22

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
• Discuss

• 239000003814 drug Substances 0.000 title claims description 297
• 229940079593 drug Drugs 0.000 title claims description 293
• 238000000034 method Methods 0.000 title claims description 96
• 239000000203 mixture Substances 0.000 title claims description 67
• 150000003384 small molecules Chemical class 0.000 title description 5
• -1 nitro, formyl Chemical group 0.000 claims description 299
• 125000005647 linker group Chemical group 0.000 claims description 217
• 239000000758 substrate Substances 0.000 claims description 181
• 239000002777 nucleoside Substances 0.000 claims description 133
• 125000000217 alkyl group Chemical group 0.000 claims description 117
• 229910052739 hydrogen Inorganic materials 0.000 claims description 108
• 229910052757 nitrogen Inorganic materials 0.000 claims description 102
• 125000003118 aryl group Chemical group 0.000 claims description 88
• 150000003833 nucleoside derivatives Chemical class 0.000 claims description 75
• 125000001072 heteroaryl group Chemical group 0.000 claims description 74
• 229910052727 yttrium Inorganic materials 0.000 claims description 67
• 125000004429 atom Chemical group 0.000 claims description 63
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 61
• 125000000623 heterocyclic group Chemical group 0.000 claims description 61
• IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 59
• 150000001875 compounds Chemical class 0.000 claims description 59
• 108091000080 Phosphotransferase Proteins 0.000 claims description 58
• 102000020233 phosphotransferase Human genes 0.000 claims description 58
• 210000004027 cell Anatomy 0.000 claims description 56
• 206010028980 Neoplasm Diseases 0.000 claims description 55
• 125000005842 heteroatom Chemical group 0.000 claims description 54
• 125000001424 substituent group Chemical group 0.000 claims description 53
• 229940104230 thymidine Drugs 0.000 claims description 52
• 125000002947 alkylene group Chemical group 0.000 claims description 48
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 46
• 230000000694 effects Effects 0.000 claims description 46
• 102000006601 Thymidine Kinase Human genes 0.000 claims description 45
• 108020004440 Thymidine kinase Proteins 0.000 claims description 45
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 42
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 42
• 201000011510 cancer Diseases 0.000 claims description 41
• 229920001223 polyethylene glycol Polymers 0.000 claims description 37
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 36
• 108010033174 Deoxycytidine kinase Proteins 0.000 claims description 36
• 102100029588 Deoxycytidine kinase Human genes 0.000 claims description 36
• 125000000304 alkynyl group Chemical group 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 35
• 229960001592 paclitaxel Drugs 0.000 claims description 35
• 229910052799 carbon Inorganic materials 0.000 claims description 33
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 32
• DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 31
• 125000003545 alkoxy group Chemical group 0.000 claims description 31
• IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 31
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 29
• 239000003795 chemical substances by application Substances 0.000 claims description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 28
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 27
• 238000011282 treatment Methods 0.000 claims description 27
• 229930012538 Paclitaxel Natural products 0.000 claims description 26
• RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 25
• 239000002202 Polyethylene glycol Substances 0.000 claims description 24
• 125000004432 carbon atom Chemical group C* 0.000 claims description 24
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 23
• 125000003342 alkenyl group Chemical group 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
• 125000003835 nucleoside group Chemical group 0.000 claims description 22
• 230000004071 biological effect Effects 0.000 claims description 21
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
• AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 20
• 235000000346 sugar Nutrition 0.000 claims description 20
• 230000003612 virological effect Effects 0.000 claims description 19
• 230000009471 action Effects 0.000 claims description 18
• 125000001188 haloalkyl group Chemical group 0.000 claims description 18
• 125000001118 alkylidene group Chemical group 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 17
• 150000002632 lipids Chemical class 0.000 claims description 17
• 125000002577 pseudohalo group Chemical group 0.000 claims description 17
• 102000001253 Protein Kinase Human genes 0.000 claims description 16
• JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 16
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
• 108060006633 protein kinase Proteins 0.000 claims description 16
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 15
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 15
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 15
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 15
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 15
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 15
• 125000005110 aryl thio group Chemical group 0.000 claims description 15
• 125000004104 aryloxy group Chemical group 0.000 claims description 15
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 15
• 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 15
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
• 102000005548 Hexokinase Human genes 0.000 claims description 14
• 108700040460 Hexokinases Proteins 0.000 claims description 14
• 229920001774 Perfluoroether Polymers 0.000 claims description 14
• 241000534944 Thia Species 0.000 claims description 14
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 14
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 14
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 14
• 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 14
• 125000005138 alkoxysulfonyl group Chemical group 0.000 claims description 14
• 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 14
• 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 14
• 125000003282 alkyl amino group Chemical group 0.000 claims description 14
• 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 claims description 14
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 14
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 14
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 14
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 14
• 125000005107 alkyl diaryl silyl group Chemical group 0.000 claims description 14
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 14
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 14
• 125000005281 alkyl ureido group Chemical group 0.000 claims description 14
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 14
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 14
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 14
• 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 claims description 14
• 239000002246 antineoplastic agent Substances 0.000 claims description 14
• 125000005128 aryl amino alkyl group Chemical group 0.000 claims description 14
• 125000001769 aryl amino group Chemical group 0.000 claims description 14
• 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims description 14
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 14
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 14
• 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 14
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 14
• 125000005200 aryloxy carbonyloxy group Chemical group 0.000 claims description 14
• 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 14
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
• 231100000433 cytotoxic Toxicity 0.000 claims description 14
• 230000001472 cytotoxic effect Effects 0.000 claims description 14
• 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 14
• 125000005202 dialkylaminocarbonyloxy group Chemical group 0.000 claims description 14
• 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 14
• 125000005105 dialkylarylsilyl group Chemical group 0.000 claims description 14
• 125000004986 diarylamino group Chemical group 0.000 claims description 14
• 125000004992 haloalkylamino group Chemical group 0.000 claims description 14
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 14
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 14
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 14
• 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 14
• 125000005368 heteroarylthio group Chemical group 0.000 claims description 14
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 14
• 150000002825 nitriles Chemical class 0.000 claims description 14
• 125000004043 oxo group Chemical group O=* 0.000 claims description 14
• 125000006684 polyhaloalkyl group Polymers 0.000 claims description 14
• 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims description 14
• 125000004665 trialkylsilyl group Chemical group 0.000 claims description 14
• 125000005106 triarylsilyl group Chemical group 0.000 claims description 14
• 229960003048 vinblastine Drugs 0.000 claims description 14
• JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 14
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 13
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 13
• 230000000340 anti-metabolite Effects 0.000 claims description 13
• 229940100197 antimetabolite Drugs 0.000 claims description 13
• 239000002256 antimetabolite Substances 0.000 claims description 13
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 13
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 13
• 229940127089 cytotoxic agent Drugs 0.000 claims description 13
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
• 239000003937 drug carrier Substances 0.000 claims description 13
• 230000004913 activation Effects 0.000 claims description 12
• 208000024891 symptom Diseases 0.000 claims description 12
• DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 230000001588 bifunctional effect Effects 0.000 claims description 10
• 229960004679 doxorubicin Drugs 0.000 claims description 10
• 210000004881 tumor cell Anatomy 0.000 claims description 10
• 108010058222 Deoxyguanosine kinase Proteins 0.000 claims description 9
• NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims description 8
• 229910003827 NRaRb Inorganic materials 0.000 claims description 8
• 208000001132 Osteoporosis Diseases 0.000 claims description 8
• 108090000704 Tubulin Proteins 0.000 claims description 8
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• OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 8
• 239000002254 cytotoxic agent Substances 0.000 claims description 8
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
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• ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 claims description 7
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• HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
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• 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 6
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• OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 6
• 239000002168 alkylating agent Substances 0.000 claims description 6
• 229940100198 alkylating agent Drugs 0.000 claims description 6
• HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 6
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• 229910052705 radium Inorganic materials 0.000 claims description 6
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• NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 5
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 5
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• LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 claims description 4
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• MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims description 4
• CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 4
• UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 4
• NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims description 4
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• NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
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