UA77532C2

UA77532C2 - Pyridazin-3(2h)-one derivatives as phosphodiesterase 4 inhibitors

Pyridazin-3(2h)-one derivatives as phosphodiesterase 4 inhibitors Download PDF

Info

Publication number: UA77532C2
Authority: UA; Ukraine
Prior art keywords: acetyl; amino; ethyl; phenylpyridazin; phenyl
Prior art date: 2002-05-16

Application number

UA20041210293A

Other languages

English (en)

Ukrainian (uk)

Priority date

2002-05-16

Filing date

2003-05-14

Publication date

2006-12-15

2003-05-14 Application filed filed Critical

2006-12-15 Publication of UA77532C2 publication Critical patent/UA77532C2/uk

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AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title claims abstract description 95
239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 2
238000000034 method Methods 0.000 claims abstract description 168
102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims abstract description 22
108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims abstract description 22
MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 claims abstract description 20
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
150000001875 compounds Chemical class 0.000 claims description 398
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 256
-1 cyano, difluoromethoxy Chemical group 0.000 claims description 88
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 76
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 73
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 57
125000001424 substituent group Chemical group 0.000 claims description 42
239000005711 Benzoic acid Substances 0.000 claims description 37
235000010233 benzoic acid Nutrition 0.000 claims description 36
125000003545 alkoxy group Chemical group 0.000 claims description 33
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
125000000217 alkyl group Chemical group 0.000 claims description 30
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
201000010099 disease Diseases 0.000 claims description 24
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 20
125000004414 alkyl thio group Chemical group 0.000 claims description 20
125000004663 dialkyl amino group Chemical group 0.000 claims description 20
150000003839 salts Chemical class 0.000 claims description 20
239000002253 acid Substances 0.000 claims description 18
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 17
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 17
125000003118 aryl group Chemical group 0.000 claims description 16
125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 15
VROMXVIODDASTK-UHFFFAOYSA-N 5-amino-1h-pyridazin-6-one Chemical compound NC1=CC=NNC1=O VROMXVIODDASTK-UHFFFAOYSA-N 0.000 claims description 14
125000002252 acyl group Chemical group 0.000 claims description 14
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 14
230000003993 interaction Effects 0.000 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 12
125000005843 halogen group Chemical group 0.000 claims description 12
150000002367 halogens Chemical class 0.000 claims description 12
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
229910052739 hydrogen Inorganic materials 0.000 claims description 10
125000004442 acylamino group Chemical group 0.000 claims description 9
125000005530 alkylenedioxy group Chemical group 0.000 claims description 9
150000001412 amines Chemical class 0.000 claims description 9
125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
125000000753 cycloalkyl group Chemical group 0.000 claims description 9
239000001257 hydrogen Substances 0.000 claims description 9
125000002947 alkylene group Chemical group 0.000 claims description 8
125000004104 aryloxy group Chemical group 0.000 claims description 8
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
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125000000623 heterocyclic group Chemical group 0.000 claims description 7
230000005764 inhibitory process Effects 0.000 claims description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
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229910052757 nitrogen Inorganic materials 0.000 claims description 6
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KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
238000004519 manufacturing process Methods 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
DAFCVMJHEGNTLP-UHFFFAOYSA-N 5-acetyl-2-ethyl-4-(naphthalen-1-ylamino)-6-(3-nitrophenyl)pyridazin-3-one Chemical compound CC(=O)C1=C(NC=2C3=CC=CC=C3C=CC=2)C(=O)N(CC)N=C1C1=CC=CC([N+]([O-])=O)=C1 DAFCVMJHEGNTLP-UHFFFAOYSA-N 0.000 claims description 4
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
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LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
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201000008937 atopic dermatitis Diseases 0.000 claims description 4
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
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239000003085 diluting agent Substances 0.000 claims description 4
150000004702 methyl esters Chemical class 0.000 claims description 4
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206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
125000003107 substituted aryl group Chemical group 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
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IDGKQVZCCDXRRF-UHFFFAOYSA-N 5-acetyl-2-methyl-4-(naphthalen-1-ylamino)-6-phenylpyridazin-3-one Chemical compound N=1N(C)C(=O)C(NC=2C3=CC=CC=C3C=CC=2)=C(C(=O)C)C=1C1=CC=CC=C1 IDGKQVZCCDXRRF-UHFFFAOYSA-N 0.000 claims description 3
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METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 3
125000002619 bicyclic group Chemical group 0.000 claims description 3
125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
229940126601 medicinal product Drugs 0.000 claims description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
125000002950 monocyclic group Chemical group 0.000 claims description 3
125000001624 naphthyl group Chemical group 0.000 claims description 3
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
229960004889 salicylic acid Drugs 0.000 claims description 3
125000004434 sulfur atom Chemical group 0.000 claims description 3
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
CETGNKMIBDNOPF-UHFFFAOYSA-N 5-acetyl-2-(cyclopropylmethyl)-4-(naphthalen-1-ylamino)-6-phenylpyridazin-3-one Chemical compound N1=C(C=2C=CC=CC=2)C(C(=O)C)=C(NC=2C3=CC=CC=C3C=CC=2)C(=O)N1CC1CC1 CETGNKMIBDNOPF-UHFFFAOYSA-N 0.000 claims description 2
OYBHIRQUMMJDIQ-UHFFFAOYSA-N 5-acetyl-2-ethyl-4-(naphthalen-1-ylamino)-6-phenylpyridazin-3-one Chemical compound CC(=O)C1=C(NC=2C3=CC=CC=C3C=CC=2)C(=O)N(CC)N=C1C1=CC=CC=C1 OYBHIRQUMMJDIQ-UHFFFAOYSA-N 0.000 claims description 2
206010022998 Irritability Diseases 0.000 claims description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
239000004202 carbamide Substances 0.000 claims description 2
125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
230000000968 intestinal effect Effects 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
OCYJXSUPZMNXEN-UHFFFAOYSA-N 2-amino-1-(4-nitrophenyl)propane-1,3-diol Chemical compound OCC(N)C(O)C1=CC=C([N+]([O-])=O)C=C1 OCYJXSUPZMNXEN-UHFFFAOYSA-N 0.000 claims 1
WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims 1
208000002551 irritable bowel syndrome Diseases 0.000 claims 1
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239000003279 phenylacetic acid Substances 0.000 claims 1
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238000002360 preparation method Methods 0.000 abstract description 9
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238000002560 therapeutic procedure Methods 0.000 abstract 1
239000007787 solid Substances 0.000 description 93
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
238000001819 mass spectrum Methods 0.000 description 51
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RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
238000002474 experimental method Methods 0.000 description 45
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230000014759 maintenance of location Effects 0.000 description 29
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
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XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
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PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
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WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
238000004949 mass spectrometry Methods 0.000 description 18
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
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KNXQDJCZSVHEIW-UHFFFAOYSA-N (3-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC(F)=C1 KNXQDJCZSVHEIW-UHFFFAOYSA-N 0.000 description 11
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HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 7
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DPIHHUHFMHCRRM-UHFFFAOYSA-N 2-chloro-2-hydroxyiminoacetic acid Chemical compound ON=C(Cl)C(O)=O DPIHHUHFMHCRRM-UHFFFAOYSA-N 0.000 description 5
PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 5
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