EA032357B1 - Конденсированные [1,4]диазепиновые соединения в качестве ингибиторов продукции аутотаксина (atx) и лизофосфатидиловой кислоты (lpa) - Google Patents

Info

Publication number

EA032357B1

EA032357B1 EA201691794A EA201691794A EA032357B1 EA 032357 B1 EA032357 B1 EA 032357B1 EA 201691794 A EA201691794 A EA 201691794A EA 201691794 A EA201691794 A EA 201691794A EA 032357 B1 EA032357 B1 EA 032357B1

Authority

EA

Eurasian Patent Office

Prior art keywords

pyridin

carbonyl

carboxylate

diazepin

triazolo

Prior art date

2014-03-26

Links

• Espacenet
• Global Dossier
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• 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 title claims description 32
• 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 title claims description 31
• 239000003112 inhibitor Substances 0.000 title claims description 7
• 238000004519 manufacturing process Methods 0.000 title description 11
• POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical class N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 title description 3
• WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 title 1
• AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 149
• -1 alkyl substituted Chemical class 0.000 claims description 438
• 125000000217 alkyl group Chemical group 0.000 claims description 78
• UFRRUTVPIWRYKT-UHFFFAOYSA-N 5H-1,4-diazepine-6-carboxylic acid Chemical compound C1C(=CN=CC=N1)C(=O)O UFRRUTVPIWRYKT-UHFFFAOYSA-N 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 40
• 125000003545 alkoxy group Chemical group 0.000 claims description 39
• PLDLWHLVVCDBFP-UHFFFAOYSA-N 1h-1,4-diazepine-7-carboxylic acid Chemical compound OC(=O)C1=CC=NC=CN1 PLDLWHLVVCDBFP-UHFFFAOYSA-N 0.000 claims description 35
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 33
• KFKGPHPBBMBSTB-UHFFFAOYSA-N 1h-1,4-diazepine-6-carboxylic acid Chemical compound OC(=O)C1=CNC=CN=C1 KFKGPHPBBMBSTB-UHFFFAOYSA-N 0.000 claims description 21
• 229910052736 halogen Inorganic materials 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• 125000004076 pyridyl group Chemical group 0.000 claims description 16
• 125000003342 alkenyl group Chemical group 0.000 claims description 15
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 125000004122 cyclic group Chemical group 0.000 claims description 10
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 9
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 8
• 125000001424 substituent group Chemical group 0.000 claims description 6
• HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 5
• 125000005842 heteroatom Chemical group 0.000 claims description 4
• 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 4
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 3
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
• 239000008194 pharmaceutical composition Substances 0.000 claims description 3
• HCDJQBTVYWELRZ-UHFFFAOYSA-N 1h-diazepine-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC=NN1 HCDJQBTVYWELRZ-UHFFFAOYSA-N 0.000 claims description 2
• 230000002401 inhibitory effect Effects 0.000 claims description 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 5
• 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims 4
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
• OTLNTAZCEJJZBD-UHFFFAOYSA-N 2,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbaldehyde Chemical compound C1N(C=O)CCC2=NNN=C21 OTLNTAZCEJJZBD-UHFFFAOYSA-N 0.000 claims 2
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• YUOJULDAKIAAMA-UHFFFAOYSA-N CCC1=C(OCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=CC(=C1)C#N Chemical compound CCC1=C(OCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=CC(=C1)C#N YUOJULDAKIAAMA-UHFFFAOYSA-N 0.000 claims 1
• VRACARYEVTZMOE-UHFFFAOYSA-N COC1=CC=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound COC1=CC=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 VRACARYEVTZMOE-UHFFFAOYSA-N 0.000 claims 1
• JGLOZZNBXVELFE-UHFFFAOYSA-N FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 JGLOZZNBXVELFE-UHFFFAOYSA-N 0.000 claims 1
• OSDIQCRELWDETA-UHFFFAOYSA-N FC(F)OC1=C(F)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)OC1=C(F)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 OSDIQCRELWDETA-UHFFFAOYSA-N 0.000 claims 1
• PRWLPVCFKAAQDK-UHFFFAOYSA-N FC(F)OC1=C(F)C=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)OC1=C(F)C=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 PRWLPVCFKAAQDK-UHFFFAOYSA-N 0.000 claims 1
• YDCAZIJEAPBGIW-UHFFFAOYSA-N FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 Chemical compound FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 YDCAZIJEAPBGIW-UHFFFAOYSA-N 0.000 claims 1
• TTWYWZFETSEMJI-UHFFFAOYSA-N O=C(COC1=C(C=C(C=C1)C#N)C1CC1)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 Chemical compound O=C(COC1=C(C=C(C=C1)C#N)C1CC1)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 TTWYWZFETSEMJI-UHFFFAOYSA-N 0.000 claims 1
• BJMFVUKWCFELMG-UHFFFAOYSA-N O=C(OCC1=CC=C(C=C1)C1CC1)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 Chemical compound O=C(OCC1=CC=C(C=C1)C1CC1)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 BJMFVUKWCFELMG-UHFFFAOYSA-N 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 46
• 238000000034 method Methods 0.000 abstract description 17
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
• 239000000543 intermediate Substances 0.000 description 90
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 89
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 86
• 239000000243 solution Substances 0.000 description 52
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 45
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 31
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
• 125000000753 cycloalkyl group Chemical group 0.000 description 24
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• 230000003176 fibrotic effect Effects 0.000 description 19
• 208000017169 kidney disease Diseases 0.000 description 19
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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 18
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
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