DK2547677T3 - SEMICARBAZID SENSITIVE AMINOXIDASE INHIBITORS - Google Patents

Info

Publication number

DK2547677T3

DK2547677T3 DK11707689.3T DK11707689T DK2547677T3 DK 2547677 T3 DK2547677 T3 DK 2547677T3 DK 11707689 T DK11707689 T DK 11707689T DK 2547677 T3 DK2547677 T3 DK 2547677T3

Authority

DK

Denmark

Prior art keywords

alkyl

pyrrolo

mmol

chlorophenyl

pyridin

Prior art date

2010-03-15

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• 239000003112 inhibitor Substances 0.000 title description 12
• 150000001875 compounds Chemical class 0.000 claims description 210
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 190
• -1 cyano, amino, hydroxyl Chemical group 0.000 claims description 126
• 125000000217 alkyl group Chemical group 0.000 claims description 83
• 229910052739 hydrogen Inorganic materials 0.000 claims description 24
• 239000001257 hydrogen Substances 0.000 claims description 23
• 238000011282 treatment Methods 0.000 claims description 23
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 19
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 18
• 125000001072 heteroaryl group Chemical group 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 15
• 230000005764 inhibitory process Effects 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 125000001153 fluoro group Chemical group F* 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 150000002367 halogens Chemical class 0.000 claims description 12
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 208000027866 inflammatory disease Diseases 0.000 claims description 11
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
• 125000003277 amino group Chemical group 0.000 claims description 10
• 230000004054 inflammatory process Effects 0.000 claims description 10
• 206010061218 Inflammation Diseases 0.000 claims description 9
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 9
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 208000026278 immune system disease Diseases 0.000 claims description 6
• 125000002757 morpholinyl group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000003386 piperidinyl group Chemical group 0.000 claims description 6
• 150000001204 N-oxides Chemical class 0.000 claims description 5
• 208000035475 disorder Diseases 0.000 claims description 5
• 230000002757 inflammatory effect Effects 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 5
• 229920006395 saturated elastomer Polymers 0.000 claims description 5
• 230000004614 tumor growth Effects 0.000 claims description 5
• AHTLZZSSNIMDDX-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,3-c]pyridine Chemical compound C1CN(C)CCN1CC(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 AHTLZZSSNIMDDX-UHFFFAOYSA-N 0.000 claims description 4
• UXBOPANQZQDGFP-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[1-(1h-pyrazol-5-ylmethyl)piperidin-4-yl]pyrrolo[2,3-c]pyridine Chemical compound C1=CC(Cl)=CC=C1N1C2=CN=CC=C2C(C2CCN(CC3=NNC=C3)CC2)=C1 UXBOPANQZQDGFP-UHFFFAOYSA-N 0.000 claims description 4
• ICTHLQAYBCVJAA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-[1-[(1-methylpyrazol-4-yl)methyl]piperidin-4-yl]pyrrolo[2,3-c]pyridine Chemical compound C1=NN(C)C=C1CN1CCC(C=2C3=CC=NC=C3N(C=3C=CC(Cl)=CC=3)C=2)CC1 ICTHLQAYBCVJAA-UHFFFAOYSA-N 0.000 claims description 4
• GIYVZZSXUQYABS-UHFFFAOYSA-N 3-(3,6-dihydro-2h-pyran-4-yl)-2-methyl-1-(4-methylphenyl)pyrrolo[2,3-c]pyridine Chemical compound C12=CC=NC=C2N(C=2C=CC(C)=CC=2)C(C)=C1C1=CCOCC1 GIYVZZSXUQYABS-UHFFFAOYSA-N 0.000 claims description 4
• FGYKHVGONVOUOE-UHFFFAOYSA-N 4-[[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]methyl]morpholine Chemical compound C1=CC(Cl)=CC=C1N1C2=CN=CC=C2C(CN2CCOCC2)=C1 FGYKHVGONVOUOE-UHFFFAOYSA-N 0.000 claims description 4
• 208000024827 Alzheimer disease Diseases 0.000 claims description 4
• 208000023275 Autoimmune disease Diseases 0.000 claims description 4
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
• 239000005977 Ethylene Substances 0.000 claims description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• 206010047115 Vasculitis Diseases 0.000 claims description 4
• 125000004122 cyclic group Chemical group 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical group C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 3
• BCTZJRGISGITFZ-UHFFFAOYSA-N 1-[4-[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]piperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound C1CN(C(=O)CN(C)C)CCC1C(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 BCTZJRGISGITFZ-UHFFFAOYSA-N 0.000 claims description 3
• PVKFTMXILNTSOY-UHFFFAOYSA-N 1-[[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]methyl]piperidin-4-ol Chemical compound C1CC(O)CCN1CC(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 PVKFTMXILNTSOY-UHFFFAOYSA-N 0.000 claims description 3
• ZZPKYLOQWXZCBX-UHFFFAOYSA-N 2-[[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]methylamino]ethanol Chemical compound C12=CN=CC=C2C(CNCCO)=CN1C1=CC=C(Cl)C=C1 ZZPKYLOQWXZCBX-UHFFFAOYSA-N 0.000 claims description 3
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
• 206010019280 Heart failures Diseases 0.000 claims description 3
• 206010003246 arthritis Diseases 0.000 claims description 3
• 201000008937 atopic dermatitis Diseases 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
• 125000002950 monocyclic group Chemical group 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• 201000006417 multiple sclerosis Diseases 0.000 claims description 3
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
• FZFSUNWMWPGDQM-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,3-c]pyridine Chemical compound C1=CC(Cl)=CC=C1N1C2=CN=CC=C2C(C=2CCNCC=2)=C1 FZFSUNWMWPGDQM-UHFFFAOYSA-N 0.000 claims description 2
• KUKHQQQVBFTSPF-UHFFFAOYSA-N 1-(5-chloropyridin-2-yl)-3-(oxan-4-yl)pyrrolo[2,3-c]pyridine Chemical compound N1=CC(Cl)=CC=C1N1C2=CN=CC=C2C(C2CCOCC2)=C1 KUKHQQQVBFTSPF-UHFFFAOYSA-N 0.000 claims description 2
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• AGOLRJPOKXWUNE-UHFFFAOYSA-N 2-[1-[[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]methyl]piperidin-4-yl]ethanol Chemical compound C1CC(CCO)CCN1CC(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 AGOLRJPOKXWUNE-UHFFFAOYSA-N 0.000 claims description 2
• SXONDVGUWVLMQZ-UHFFFAOYSA-N 3-amino-1-[4-[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]piperidin-1-yl]propan-1-one Chemical compound C1CN(C(=O)CCN)CCC1C(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 SXONDVGUWVLMQZ-UHFFFAOYSA-N 0.000 claims description 2
• ZSMAHLWYKQUKJJ-UHFFFAOYSA-N 4-[1-(4-chloro-2-methylphenyl)pyrrolo[2,3-c]pyridin-3-yl]cyclohexan-1-amine Chemical compound CC1=CC(Cl)=CC=C1N1C2=CN=CC=C2C(C2CCC(N)CC2)=C1 ZSMAHLWYKQUKJJ-UHFFFAOYSA-N 0.000 claims description 2
• 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
• 208000022309 Alcoholic Liver disease Diseases 0.000 claims description 2
• 201000001320 Atherosclerosis Diseases 0.000 claims description 2
• 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 2
• 206010007558 Cardiac failure chronic Diseases 0.000 claims description 2
• 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 2
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
• 208000011231 Crohn disease Diseases 0.000 claims description 2
• 206010012442 Dermatitis contact Diseases 0.000 claims description 2
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
• 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
• 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 2
• 201000004681 Psoriasis Diseases 0.000 claims description 2
• 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
• 206010063837 Reperfusion injury Diseases 0.000 claims description 2
• 206010040047 Sepsis Diseases 0.000 claims description 2
• 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 2
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
• 201000004810 Vascular dementia Diseases 0.000 claims description 2
• ACDAWIRIJKZIBF-UHFFFAOYSA-N [1-[[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]methyl]piperidin-4-yl]methanol Chemical compound C1CC(CO)CCN1CC(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 ACDAWIRIJKZIBF-UHFFFAOYSA-N 0.000 claims description 2
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
• 208000006673 asthma Diseases 0.000 claims description 2
• 230000001363 autoimmune Effects 0.000 claims description 2
• 208000018093 autoimmune cholangitis Diseases 0.000 claims description 2
• 208000019069 chronic childhood arthritis Diseases 0.000 claims description 2
• 208000010247 contact dermatitis Diseases 0.000 claims description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
• 230000003176 fibrotic effect Effects 0.000 claims description 2
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
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• 210000004185 liver Anatomy 0.000 claims description 2
• 208000010125 myocardial infarction Diseases 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 2
• 230000002685 pulmonary effect Effects 0.000 claims description 2
• 208000010157 sclerosing cholangitis Diseases 0.000 claims description 2
• 201000004595 synovitis Diseases 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims 8
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 7
• 125000003545 alkoxy group Chemical group 0.000 claims 6
• 150000002431 hydrogen Chemical class 0.000 claims 5
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
• 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims 2
• VIUQFKJKEZNIOV-UHFFFAOYSA-N 1-[4-[1-(4-chlorophenyl)pyrrolo[2,3-c]pyridin-3-yl]piperidin-1-yl]-2-hydroxyethanone Chemical compound C1CN(C(=O)CO)CCC1C(C1=CC=NC=C11)=CN1C1=CC=C(Cl)C=C1 VIUQFKJKEZNIOV-UHFFFAOYSA-N 0.000 claims 1
• 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
• 206010016654 Fibrosis Diseases 0.000 claims 1
• 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 claims 1
• 208000034189 Sclerosis Diseases 0.000 claims 1
• 230000001154 acute effect Effects 0.000 claims 1
• 125000003282 alkyl amino group Chemical group 0.000 claims 1
• 125000002947 alkylene group Chemical group 0.000 claims 1
• PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 claims 1
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
• 230000007882 cirrhosis Effects 0.000 claims 1
• 208000019425 cirrhosis of liver Diseases 0.000 claims 1
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims 1
• 230000000302 ischemic effect Effects 0.000 claims 1
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 33
• 239000000243 solution Substances 0.000 description 33
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 18
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 18
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
• 239000012071 phase Substances 0.000 description 17
• 239000002904 solvent Substances 0.000 description 17
• WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 16
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