CA2294548A1

CA2294548A1 - Pyridazinones as prostaglandin endoperoxide h synthase biosynthesis inhibitors

Pyridazinones as prostaglandin endoperoxide h synthase biosynthesis inhibitors Download PDF

Info

Publication number: CA2294548A1
Authority: CA; Canada
Prior art keywords: alkyl; group; heterocyclic; aryl; cycloalkyl
Prior art date: 1997-08-22
Legal status : Abandoned

Application number

CA002294548A

Other languages

English (en)

French (fr)

Inventor

Lawrence A. Black

Current Assignee

Abbott Laboratories

Original Assignee

Individual

Priority date

1997-08-22

Filing date

1998-08-20

Publication date

1999-03-04

1998-08-20 Application filed by Individual filed Critical Individual

1999-03-04 Publication of CA2294548A1 publication Critical patent/CA2294548A1/en

Status Abandoned legal-status Critical Current

Links

150000003180 prostaglandins Chemical class 0.000 title claims description 35
230000015572 biosynthetic process Effects 0.000 title claims description 29
AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title abstract description 9
239000003112 inhibitor Substances 0.000 title abstract description 6
150000001875 compounds Chemical class 0.000 claims abstract description 153
125000000217 alkyl group Chemical group 0.000 claims description 370
125000000623 heterocyclic group Chemical group 0.000 claims description 315
125000003118 aryl group Chemical group 0.000 claims description 216
-1 cycloalkenylalkyl Chemical group 0.000 claims description 215
125000000753 cycloalkyl group Chemical group 0.000 claims description 191
125000003342 alkenyl group Chemical group 0.000 claims description 173
125000000392 cycloalkenyl group Chemical group 0.000 claims description 155
125000003710 aryl alkyl group Chemical group 0.000 claims description 144
229910052739 hydrogen Inorganic materials 0.000 claims description 135
239000001257 hydrogen Substances 0.000 claims description 133
125000000304 alkynyl group Chemical group 0.000 claims description 117
125000001188 haloalkyl group Chemical group 0.000 claims description 83
150000002367 halogens Chemical group 0.000 claims description 80
229910052736 halogen Inorganic materials 0.000 claims description 76
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 72
125000004093 cyano group Chemical group *C#N 0.000 claims description 68
125000003545 alkoxy group Chemical group 0.000 claims description 63
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 63
239000000651 prodrug Substances 0.000 claims description 54
229940002612 prodrug Drugs 0.000 claims description 54
150000003839 salts Chemical class 0.000 claims description 54
150000002148 esters Chemical class 0.000 claims description 53
125000003282 alkyl amino group Chemical group 0.000 claims description 51
125000004663 dialkyl amino group Chemical group 0.000 claims description 51
238000000034 method Methods 0.000 claims description 46
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 37
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 24
229910052760 oxygen Inorganic materials 0.000 claims description 21
229910052717 sulfur Inorganic materials 0.000 claims description 21
125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 20
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 19
125000004181 carboxyalkyl group Chemical group 0.000 claims description 19
241000124008 Mammalia Species 0.000 claims description 18
125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 18
125000004966 cyanoalkyl group Chemical group 0.000 claims description 18
125000005015 aryl alkynyl group Chemical group 0.000 claims description 17
230000002401 inhibitory effect Effects 0.000 claims description 17
125000001424 substituent group Chemical group 0.000 claims description 16
101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 14
125000005018 aryl alkenyl group Chemical group 0.000 claims description 14
125000001769 aryl amino group Chemical group 0.000 claims description 14
125000004986 diarylamino group Chemical group 0.000 claims description 14
125000003107 substituted aryl group Chemical group 0.000 claims description 14
125000001691 aryl alkyl amino group Chemical group 0.000 claims description 13
239000008194 pharmaceutical composition Substances 0.000 claims description 13
125000002947 alkylene group Chemical group 0.000 claims description 12
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
206010028980 Neoplasm Diseases 0.000 claims description 10
208000002193 Pain Diseases 0.000 claims description 10
206010037660 Pyrexia Diseases 0.000 claims description 10
239000000460 chlorine Chemical group 0.000 claims description 10
229910052801 chlorine Chemical group 0.000 claims description 10
229910052731 fluorine Inorganic materials 0.000 claims description 10
239000011737 fluorine Chemical group 0.000 claims description 10
125000000232 haloalkynyl group Chemical group 0.000 claims description 10
125000001072 heteroaryl group Chemical group 0.000 claims description 10
201000008482 osteoarthritis Diseases 0.000 claims description 10
206010039073 rheumatoid arthritis Diseases 0.000 claims description 10
201000011510 cancer Diseases 0.000 claims description 9
125000000262 haloalkenyl group Chemical group 0.000 claims description 9
125000002102 aryl alkyloxo group Chemical group 0.000 claims description 8
125000006239 protecting group Chemical group 0.000 claims description 8
125000004104 aryloxy group Chemical group 0.000 claims description 7
229910052757 nitrogen Inorganic materials 0.000 claims description 7
125000004450 alkenylene group Chemical group 0.000 claims description 6
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
125000003368 amide group Chemical group 0.000 claims description 4
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
150000003573 thiols Chemical group 0.000 claims description 4
IHEMNNMLSUVEEZ-UHFFFAOYSA-N 3-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-1h-pyridazin-6-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(=O)NN=C1C1=CC=C(F)C=C1 IHEMNNMLSUVEEZ-UHFFFAOYSA-N 0.000 claims description 3
150000001356 alkyl thiols Chemical group 0.000 claims description 3
125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 3
125000004429 atom Chemical group 0.000 claims description 3
WYIGWUYDVCXJNM-UHFFFAOYSA-N 2-(cyclobutylmethyl)-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=N1)C=2C=CC(F)=CC=2)=CC(=O)N1CC1CCC1 WYIGWUYDVCXJNM-UHFFFAOYSA-N 0.000 claims description 2
AKFGBYFBZJUESI-UHFFFAOYSA-N 2-benzyl-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=N1)C=2C=CC(F)=CC=2)=CC(=O)N1CC1=CC=CC=C1 AKFGBYFBZJUESI-UHFFFAOYSA-N 0.000 claims description 2
UWUSIPXSLCHMCZ-UHFFFAOYSA-N 2-but-2-ynyl-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(CC#CC)N=C1C1=CC=C(F)C=C1 UWUSIPXSLCHMCZ-UHFFFAOYSA-N 0.000 claims description 2
CEKBVUHYFPRNPF-UHFFFAOYSA-N 2-butyl-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(CCCC)N=C1C1=CC=C(F)C=C1 CEKBVUHYFPRNPF-UHFFFAOYSA-N 0.000 claims description 2
HBWPTXKYUGBWEE-UHFFFAOYSA-N 2-cyclohexyl-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(=O)N(C2CCCCC2)N=C1C1=CC=C(F)C=C1 HBWPTXKYUGBWEE-UHFFFAOYSA-N 0.000 claims description 2
FCBYDHKSDHFPCS-UHFFFAOYSA-N 2-ethyl-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(CC)N=C1C1=CC=C(F)C=C1 FCBYDHKSDHFPCS-UHFFFAOYSA-N 0.000 claims description 2
WLOWNVVSWSJFNO-UHFFFAOYSA-N 6-(4-fluorophenyl)-2-(3-methylbut-1-en-2-yl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(C(=C)C(C)C)N=C1C1=CC=C(F)C=C1 WLOWNVVSWSJFNO-UHFFFAOYSA-N 0.000 claims description 2
CBXPTSMLKPJUSL-UHFFFAOYSA-N 6-(4-fluorophenyl)-2-[(4-fluorophenyl)methyl]-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=N1)C=2C=CC(F)=CC=2)=CC(=O)N1CC1=CC=C(F)C=C1 CBXPTSMLKPJUSL-UHFFFAOYSA-N 0.000 claims description 2
YNAUYLOVCGOAES-UHFFFAOYSA-N 6-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(C)N=C1C1=CC=C(F)C=C1 YNAUYLOVCGOAES-UHFFFAOYSA-N 0.000 claims description 2
LNXUHMWVSSMKKP-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-pentylpyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(CCCCC)N=C1C1=CC=C(F)C=C1 LNXUHMWVSSMKKP-UHFFFAOYSA-N 0.000 claims description 2
JXSSGODIOZBYOE-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-phenacylpyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=N1)C=2C=CC(F)=CC=2)=CC(=O)N1CC(=O)C1=CC=CC=C1 JXSSGODIOZBYOE-UHFFFAOYSA-N 0.000 claims description 2
KNMZTBNKEGWGEZ-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-prop-2-ynylpyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(=O)N(CC#C)N=C1C1=CC=C(F)C=C1 KNMZTBNKEGWGEZ-UHFFFAOYSA-N 0.000 claims description 2
SDSFHMREKJLQOD-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-propylpyridazin-3-one Chemical compound C=1C=C(S(C)(=O)=O)C=CC=1C1=CC(=O)N(CCC)N=C1C1=CC=C(F)C=C1 SDSFHMREKJLQOD-UHFFFAOYSA-N 0.000 claims description 2
PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 38
QQYDLKGNJHDUMF-UHFFFAOYSA-N 2-(cyclohexylmethyl)-6-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=N1)C=2C=CC(F)=CC=2)=CC(=O)N1CC1CCCCC1 QQYDLKGNJHDUMF-UHFFFAOYSA-N 0.000 claims 1
102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 abstract description 20
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230000000694 effects Effects 0.000 abstract description 8
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229940124639 Selective inhibitor Drugs 0.000 abstract description 5
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108010029485 Protein Isoforms Proteins 0.000 abstract description 4
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108010037464 Cyclooxygenase 1 Proteins 0.000 abstract description 3
102000004190 Enzymes Human genes 0.000 abstract description 3
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230000002496 gastric effect Effects 0.000 abstract description 3
230000001939 inductive effect Effects 0.000 abstract description 3
210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
210000003734 kidney Anatomy 0.000 abstract description 2
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 64
229910000069 nitrogen hydride Inorganic materials 0.000 description 24
238000005481 NMR spectroscopy Methods 0.000 description 23
239000000243 solution Substances 0.000 description 23
238000000921 elemental analysis Methods 0.000 description 20
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UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 7
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HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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