NZ580313A - Smac mimetic dimers and trimers useful as anti-cancer agents - Google Patents

Info

Publication number

NZ580313A

NZ580313A NZ580313A NZ58031308A NZ580313A NZ 580313 A NZ580313 A NZ 580313A NZ 580313 A NZ580313 A NZ 580313A NZ 58031308 A NZ58031308 A NZ 58031308A NZ 580313 A NZ580313 A NZ 580313A

Authority

NZ

New Zealand

Prior art keywords

optionally substituted

ring

alkyl

independently

group

Prior art date

2007-04-12

Links

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• 229940075439 smac mimetic Drugs 0.000 title claims description 32
• 239000000539 dimer Substances 0.000 title description 38
• 239000013638 trimer Substances 0.000 title description 15
• 239000002246 antineoplastic agent Substances 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 500
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 22
• 201000011510 cancer Diseases 0.000 claims abstract description 17
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 15
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 293
• 125000003118 aryl group Chemical group 0.000 claims description 256
• 229920006395 saturated elastomer Polymers 0.000 claims description 159
• 125000005842 heteroatom Chemical group 0.000 claims description 158
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 157
• 229910052717 sulfur Inorganic materials 0.000 claims description 148
• 125000004122 cyclic group Chemical group 0.000 claims description 143
• 229910052760 oxygen Inorganic materials 0.000 claims description 141
• 239000000178 monomer Substances 0.000 claims description 123
• 125000001072 heteroaryl group Chemical group 0.000 claims description 104
• 125000005647 linker group Chemical group 0.000 claims description 103
• 125000004429 atom Chemical group 0.000 claims description 100
• 229910052757 nitrogen Inorganic materials 0.000 claims description 96
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 78
• 229910052727 yttrium Inorganic materials 0.000 claims description 76
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 75
• 229910052721 tungsten Inorganic materials 0.000 claims description 75
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 74
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 73
• 125000002947 alkylene group Chemical group 0.000 claims description 73
• 239000000203 mixture Substances 0.000 claims description 71
• 238000000034 method Methods 0.000 claims description 69
• 150000003839 salts Chemical class 0.000 claims description 59
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 53
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 52
• 125000004474 heteroalkylene group Chemical group 0.000 claims description 52
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• 125000004450 alkenylene group Chemical group 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 38
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• 229910052705 radium Inorganic materials 0.000 claims description 32
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 31
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• 125000002619 bicyclic group Chemical group 0.000 claims description 23
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• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 20
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• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 17
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• VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 14
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• 206010061218 Inflammation Diseases 0.000 claims description 13
• 125000000623 heterocyclic group Chemical group 0.000 claims description 13
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• 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 claims description 10
• 125000002837 carbocyclic group Chemical group 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
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• 230000006907 apoptotic process Effects 0.000 abstract description 28
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• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
• 125000000217 alkyl group Chemical group 0.000 description 89
• -1 small molecule compounds Chemical class 0.000 description 77
• 230000002829 reductive effect Effects 0.000 description 73
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 72
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
• 125000001424 substituent group Chemical group 0.000 description 67
• 235000019439 ethyl acetate Nutrition 0.000 description 61
• 239000012074 organic phase Substances 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 52
• 239000012267 brine Substances 0.000 description 46
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 46
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 43
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 43
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 42
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 41
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• 125000000304 alkynyl group Chemical group 0.000 description 31
• 239000007858 starting material Substances 0.000 description 31
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