EA027147B1 - Ингибиторы c-концевого домена hsp90 - Google Patents

Info

Publication number

EA027147B1

EA027147B1 EA201491496A EA201491496A EA027147B1 EA 027147 B1 EA027147 B1 EA 027147B1 EA 201491496 A EA201491496 A EA 201491496A EA 201491496 A EA201491496 A EA 201491496A EA 027147 B1 EA027147 B1 EA 027147B1

Authority

EA

Eurasian Patent Office

Prior art keywords

acetamide

biphenyl

oxy

methoxy

ethyl

Prior art date

2012-02-09

Links

• Espacenet
• Global Dossier
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• 239000003481 heat shock protein 90 inhibitor Substances 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 131
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 23
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 12
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 305
• 229910052739 hydrogen Inorganic materials 0.000 claims description 114
• 239000001257 hydrogen Substances 0.000 claims description 106
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 86
• 150000002431 hydrogen Chemical class 0.000 claims description 80
• -1 C 1 -C 6 atoms Chemical compound 0.000 claims description 79
• 125000000217 alkyl group Chemical group 0.000 claims description 71
• 229910052736 halogen Inorganic materials 0.000 claims description 57
• 150000002367 halogens Chemical class 0.000 claims description 57
• 125000002837 carbocyclic group Chemical group 0.000 claims description 56
• 125000000623 heterocyclic group Chemical group 0.000 claims description 43
• 150000003839 salts Chemical class 0.000 claims description 43
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 37
• 239000008103 glucose Substances 0.000 claims description 37
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
• 125000003545 alkoxy group Chemical group 0.000 claims description 28
• 125000004429 atom Chemical group 0.000 claims description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• 230000000324 neuroprotective effect Effects 0.000 claims description 19
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 18
• 238000000034 method Methods 0.000 claims description 18
• 239000001301 oxygen Substances 0.000 claims description 18
• 231100000419 toxicity Toxicity 0.000 claims description 18
• 230000001988 toxicity Effects 0.000 claims description 18
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 17
• 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 17
• 125000004432 carbon atom Chemical group C* 0.000 claims description 16
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
• 208000024891 symptom Diseases 0.000 claims description 10
• 125000002947 alkylene group Chemical group 0.000 claims description 8
• 125000005605 benzo group Chemical group 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 5
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 125000004104 aryloxy group Chemical group 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 239000011593 sulfur Substances 0.000 claims description 5
• 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 4
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
• VBMJHAAMTRDGAN-UHFFFAOYSA-N n-[2-[2-(3-fluorophenyl)-4-(4-phenylmethoxycyclohexyl)oxyphenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC(CC1)CCC1OCC1=CC=CC=C1 VBMJHAAMTRDGAN-UHFFFAOYSA-N 0.000 claims description 4
• LOGWBHYAVRGPRK-UHFFFAOYSA-N n-[2-[4-(4-tert-butylcyclohexyl)oxy-2-(3-fluorophenyl)phenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC1CCC(C(C)(C)C)CC1 LOGWBHYAVRGPRK-UHFFFAOYSA-N 0.000 claims description 4
• 230000001537 neural effect Effects 0.000 claims description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
• 239000004305 biphenyl Substances 0.000 claims description 2
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
• XAWGNQVOGSWZJO-UHFFFAOYSA-N n-[2-[2-(3-fluorophenyl)-4-(4-piperidin-4-ylcyclohexyl)oxyphenyl]ethyl]acetamide Chemical compound C1=C(C=2C=C(F)C=CC=2)C(CCNC(=O)C)=CC=C1OC(CC1)CCC1C1CCNCC1 XAWGNQVOGSWZJO-UHFFFAOYSA-N 0.000 claims 2
• JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 claims 1
• 150000002829 nitrogen Chemical class 0.000 claims 1
• 210000004899 c-terminal region Anatomy 0.000 abstract description 9
• 239000003112 inhibitor Substances 0.000 abstract description 9
• 230000002265 prevention Effects 0.000 abstract description 6
• 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 abstract 1
• 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 abstract 1
• 239000000203 mixture Substances 0.000 description 46
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
• 102100030817 Liver carboxylesterase 1 Human genes 0.000 description 37
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 37
• 239000000243 solution Substances 0.000 description 36
• 101710169844 Sesquipedalian-1 Proteins 0.000 description 35
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 35
• 238000006243 chemical reaction Methods 0.000 description 29
• 125000003118 aryl group Chemical group 0.000 description 28
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 239000007787 solid Substances 0.000 description 27
• 101150116038 AEP2 gene Proteins 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 26
• 238000004440 column chromatography Methods 0.000 description 25
• 125000003342 alkenyl group Chemical group 0.000 description 23
• 201000010099 disease Diseases 0.000 description 23
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 22
• 125000000304 alkynyl group Chemical group 0.000 description 22
• 125000003710 aryl alkyl group Chemical group 0.000 description 22
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
• 230000015572 biosynthetic process Effects 0.000 description 21
• 238000003786 synthesis reaction Methods 0.000 description 21
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
• 229920006395 saturated elastomer Polymers 0.000 description 19
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
• 239000000126 substance Substances 0.000 description 17
• 210000002569 neuron Anatomy 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 125000003396 thiol group Chemical group [H]S* 0.000 description 15
• 208000035475 disorder Diseases 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• 239000011734 sodium Chemical class 0.000 description 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
• 125000001424 substituent group Chemical group 0.000 description 12
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
• PIAOLBVUVDXHHL-UHFFFAOYSA-N 2-nitroethenylbenzene Chemical class [O-][N+](=O)C=CC1=CC=CC=C1 PIAOLBVUVDXHHL-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 238000004458 analytical method Methods 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• 230000003833 cell viability Effects 0.000 description 10
• 230000000875 corresponding effect Effects 0.000 description 10
• 230000001120 cytoprotective effect Effects 0.000 description 10
• 229910052700 potassium Inorganic materials 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• 108090000623 proteins and genes Proteins 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• 101150072179 ATP1 gene Proteins 0.000 description 9
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• 101100003366 Arabidopsis thaliana ATPA gene Proteins 0.000 description 9
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
• 102100021649 Elongator complex protein 6 Human genes 0.000 description 9
• 101100065219 Homo sapiens ELP6 gene Proteins 0.000 description 9
• 239000007864 aqueous solution Substances 0.000 description 9
• 101150105046 atpI gene Proteins 0.000 description 9
• 230000003993 interaction Effects 0.000 description 9
• YJQPYGGHQPGBLI-KGSXXDOSSA-M novobiocin(1-) Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C([O-])=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-M 0.000 description 9
• 102000004169 proteins and genes Human genes 0.000 description 9
• 206010012289 Dementia Diseases 0.000 description 8
• 125000002252 acyl group Chemical group 0.000 description 8
• 239000012300 argon atmosphere Substances 0.000 description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
• 150000002148 esters Chemical class 0.000 description 8
• 201000001421 hyperglycemia Diseases 0.000 description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
• 230000004112 neuroprotection Effects 0.000 description 7
• 239000003921 oil Substances 0.000 description 7
• 235000019198 oils Nutrition 0.000 description 7
• 238000010992 reflux Methods 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 6
• 241001465754 Metazoa Species 0.000 description 6
• YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 description 6
• 125000003277 amino group Chemical group 0.000 description 6
• 125000000753 cycloalkyl group Chemical group 0.000 description 6
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
• 239000012153 distilled water Substances 0.000 description 6
• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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• 239000000651 prodrug Substances 0.000 description 6
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• 210000001044 sensory neuron Anatomy 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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• 108010006519 Molecular Chaperones Proteins 0.000 description 5
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• MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 5
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• 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 5
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
• IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 4
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
• 208000024827 Alzheimer disease Diseases 0.000 description 4
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• KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
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• KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 4
• LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
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• 239000011780 sodium chloride Substances 0.000 description 4
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• 230000035882 stress Effects 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
• STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
• ZWPJRCPOAARPNR-JLHYYAGUSA-N 4-[2-[(e)-2-nitroethenyl]-5-phenylmethoxyphenyl]pyridine Chemical compound C1=C(C=2C=CN=CC=2)C(/C=C/[N+](=O)[O-])=CC=C1OCC1=CC=CC=C1 ZWPJRCPOAARPNR-JLHYYAGUSA-N 0.000 description 3
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