HRP20050451A2 - 4-oxo-1-(3-substituted phenyl-1,4-dihydro-1,8-naphthyridine-3-carboxamide phosphodiesterase-4 inhibitors - Google Patents

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Publication number

HRP20050451A2

HRP20050451A2 HR20050451A HRP20050451A HRP20050451A2 HR P20050451 A2 HRP20050451 A2 HR P20050451A2 HR 20050451 A HR20050451 A HR 20050451A HR P20050451 A HRP20050451 A HR P20050451A HR P20050451 A2 HRP20050451 A2 HR P20050451A2

Authority

HR

Croatia

Prior art keywords

6alkyl

oxo

naphthyridin

carbonyl

biphenyl

Prior art date

2002-11-22

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• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 17
• 150000001875 compounds Chemical class 0.000 claims abstract description 168
• 150000003839 salts Chemical class 0.000 claims abstract description 72
• 208000006673 asthma Diseases 0.000 claims abstract description 6
• 239000003112 inhibitor Substances 0.000 claims abstract description 4
• 238000000034 method Methods 0.000 claims description 65
• 150000002367 halogens Chemical group 0.000 claims description 48
• -1 hydroxy, amino Chemical group 0.000 claims description 47
• 229910052736 halogen Inorganic materials 0.000 claims description 46
• 125000000217 alkyl group Chemical group 0.000 claims description 37
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
• 229910052739 hydrogen Inorganic materials 0.000 claims description 23
• 239000001257 hydrogen Substances 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 125000001072 heteroaryl group Chemical group 0.000 claims description 21
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 125000001424 substituent group Chemical group 0.000 claims description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 16
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 15
• 241000282414 Homo sapiens Species 0.000 claims description 15
• 206010040070 Septic Shock Diseases 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 230000003930 cognitive ability Effects 0.000 claims description 13
• 125000005843 halogen group Chemical group 0.000 claims description 13
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 12
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 12
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
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• 230000001684 chronic effect Effects 0.000 claims description 10
• 150000002825 nitriles Chemical group 0.000 claims description 10
• 230000036303 septic shock Effects 0.000 claims description 10
• 210000001519 tissue Anatomy 0.000 claims description 10
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 241001465754 Metazoa Species 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 8
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
• 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 7
• 239000003937 drug carrier Substances 0.000 claims description 7
• 230000002757 inflammatory effect Effects 0.000 claims description 7
• 125000004076 pyridyl group Chemical group 0.000 claims description 7
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
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• 229940124639 Selective inhibitor Drugs 0.000 claims description 5
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• 230000001154 acute effect Effects 0.000 claims description 5
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• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
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• 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 5
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
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• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
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• QSSUFFIQEMZNMT-UHFFFAOYSA-N 1-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=CC=1C1(C(=O)O)CC1 QSSUFFIQEMZNMT-UHFFFAOYSA-N 0.000 claims description 4
• NRJGMLZSMBAMDU-UHFFFAOYSA-N 1-cyano-3-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-2,2-dimethylcyclopropane-1-carboxylic acid Chemical compound N#CC1(C(O)=O)C(C)(C)C1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1 NRJGMLZSMBAMDU-UHFFFAOYSA-N 0.000 claims description 4
• MPZBCGCVHYPZKF-UHFFFAOYSA-N 2-[3-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 MPZBCGCVHYPZKF-UHFFFAOYSA-N 0.000 claims description 4
• IBMPVTKUXLINEX-UHFFFAOYSA-N 4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=CC(N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 IBMPVTKUXLINEX-UHFFFAOYSA-N 0.000 claims description 4
• XYUCHDNQNMEHJV-UHFFFAOYSA-N 5-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid Chemical compound O1C(C)(C)OC(C(O)=O)C1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1 XYUCHDNQNMEHJV-UHFFFAOYSA-N 0.000 claims description 4
• 206010006895 Cachexia Diseases 0.000 claims description 4
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• 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
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• 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 4
• 125000005494 pyridonyl group Chemical group 0.000 claims description 4
• 230000003612 virological effect Effects 0.000 claims description 4
• PSYPBAHXIIVDCJ-FCHUYYIVSA-N (1r,2r)-2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]-2-fluorophenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1F PSYPBAHXIIVDCJ-FCHUYYIVSA-N 0.000 claims description 3
• SFPJVJIEXHMQRQ-XZOQPEGZSA-N (1r,2r)-2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1 SFPJVJIEXHMQRQ-XZOQPEGZSA-N 0.000 claims description 3
• JJOFHTMQOOJCKZ-BJKOFHAPSA-N (1r,2r)-2-[4-[3-[3-(cyclopropylmethylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NCC3CC3)=C2)C=C1 JJOFHTMQOOJCKZ-BJKOFHAPSA-N 0.000 claims description 3
• MESVEPTYRCXMJY-DHIUTWEWSA-N (1r,2s)-2-[3-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@@H]1C1=CC=CC(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 MESVEPTYRCXMJY-DHIUTWEWSA-N 0.000 claims description 3
• PSYPBAHXIIVDCJ-FGZHOGPDSA-N (1r,2s)-2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]-2-fluorophenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1F PSYPBAHXIIVDCJ-FGZHOGPDSA-N 0.000 claims description 3
• SFPJVJIEXHMQRQ-DHIUTWEWSA-N (1r,2s)-2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=C1 SFPJVJIEXHMQRQ-DHIUTWEWSA-N 0.000 claims description 3
• DJFGUPNWNRNTTF-UHFFFAOYSA-N 1-[3-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=CC(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=CC=1C1(C(=O)O)CC1 DJFGUPNWNRNTTF-UHFFFAOYSA-N 0.000 claims description 3
• WAKPDAFHEHAAKT-UHFFFAOYSA-N 1-[[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]methyl]cyclobutane-1-carboxylic acid Chemical compound C=1C=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)C=CC=1CC1(C(=O)O)CCC1 WAKPDAFHEHAAKT-UHFFFAOYSA-N 0.000 claims description 3
• RQUMVCBQWQXWRT-UHFFFAOYSA-N 2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-2-hydroxyacetic acid Chemical compound C1=CC(C(C(O)=O)O)=CC=C1C1=CC=CC(N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 RQUMVCBQWQXWRT-UHFFFAOYSA-N 0.000 claims description 3
• FJGBSZXAHMUSMT-UHFFFAOYSA-N 2-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-2-methylpropanoic acid Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C1=CC=CC(N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 FJGBSZXAHMUSMT-UHFFFAOYSA-N 0.000 claims description 3
• DLEKOQWTRJCXHT-UHFFFAOYSA-N 3-[4-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]-3-methylbutanoic acid Chemical compound C1=CC(C(C)(CC(O)=O)C)=CC=C1C1=CC=CC(N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 DLEKOQWTRJCXHT-UHFFFAOYSA-N 0.000 claims description 3
• KUSDBQMOIWMGIY-UHFFFAOYSA-N 3-methyl-3-[4-[3-[4-oxo-3-(propan-2-ylcarbamoyl)-1,8-naphthyridin-1-yl]phenyl]phenyl]butanoic acid Chemical compound C12=NC=CC=C2C(=O)C(C(=O)NC(C)C)=CN1C(C=1)=CC=CC=1C1=CC=C(C(C)(C)CC(O)=O)C=C1 KUSDBQMOIWMGIY-UHFFFAOYSA-N 0.000 claims description 3
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• ATXMNZYFWUTKMU-VQTJNVASSA-N (1r,2r)-2-[2-fluoro-4-[3-[4-oxo-3-(2,2,2-trifluoroethylcarbamoyl)-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)NCC(F)(F)F)=C2)C=C1F ATXMNZYFWUTKMU-VQTJNVASSA-N 0.000 claims description 2
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• AYBLQENTZBLEKJ-XZOQPEGZSA-N (1r,2r)-2-[4-[3-[3-(2-methylsulfonylethylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C12=NC=CC=C2C(=O)C(C(=O)NCCS(=O)(=O)C)=CN1C(C=1)=CC=CC=1C(C=C1)=CC=C1[C@@H]1C[C@H]1C(O)=O AYBLQENTZBLEKJ-XZOQPEGZSA-N 0.000 claims description 2
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• AYEYUQJGEKTWIU-BJKOFHAPSA-N (1r,2r)-2-[4-[3-[3-(morpholine-4-carbonyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=C(C=2C=C(C=CC=2)N2C3=NC=CC=C3C(=O)C(C(=O)N3CCOCC3)=C2)C=C1 AYEYUQJGEKTWIU-BJKOFHAPSA-N 0.000 claims description 2
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• 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
• DDVHCGNQPCSRQB-XZOQPEGZSA-N (1r,2r)-2-[2-[3-[3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1-yl]phenyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC=C1C1=CC=CC(N2C3=NC=CC=C3C(=O)C(C(=O)NC3CC3)=C2)=C1 DDVHCGNQPCSRQB-XZOQPEGZSA-N 0.000 claims 1
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