CA2228050A1 - Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation - Google Patents
Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation Download PDFInfo
- Publication number
- CA2228050A1 CA2228050A1 CA002228050A CA2228050A CA2228050A1 CA 2228050 A1 CA2228050 A1 CA 2228050A1 CA 002228050 A CA002228050 A CA 002228050A CA 2228050 A CA2228050 A CA 2228050A CA 2228050 A1 CA2228050 A1 CA 2228050A1
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- alkyl
- pyridyl
- group
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 121
- 238000000034 method Methods 0.000 title claims abstract description 45
- 239000000203 mixture Substances 0.000 title abstract description 41
- 102000004127 Cytokines Human genes 0.000 claims abstract description 35
- 108090000695 Cytokines Proteins 0.000 claims abstract description 35
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 230000001404 mediated effect Effects 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 108090001005 Interleukin-6 Proteins 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- 108090001007 Interleukin-8 Proteins 0.000 claims abstract description 4
- -1 4-fluorothiophen-2-yl Chemical group 0.000 claims description 326
- 125000000217 alkyl group Chemical group 0.000 claims description 100
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 88
- 125000003118 aryl group Chemical group 0.000 claims description 66
- 125000001072 heteroaryl group Chemical group 0.000 claims description 63
- 125000000623 heterocyclic group Chemical group 0.000 claims description 53
- 125000000304 alkynyl group Chemical group 0.000 claims description 47
- 125000003342 alkenyl group Chemical group 0.000 claims description 46
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 39
- 229910020008 S(O) Inorganic materials 0.000 claims description 37
- 125000005843 halogen group Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000004429 atom Chemical group 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000002883 imidazolyl group Chemical group 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 13
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 11
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 10
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 10
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 10
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 9
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 9
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 8
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 8
- 206010040070 Septic Shock Diseases 0.000 claims description 8
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
- 101100240526 Caenorhabditis elegans nhr-20 gene Proteins 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 6
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 101100240527 Caenorhabditis elegans nhr-22 gene Proteins 0.000 claims description 6
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 101100173726 Arabidopsis thaliana OR23 gene Proteins 0.000 claims description 5
- 206010006895 Cachexia Diseases 0.000 claims description 5
- 201000005569 Gout Diseases 0.000 claims description 5
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 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 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010014824 Endotoxic shock Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 230000000747 cardiac effect Effects 0.000 claims description 3
- 230000002452 interceptive effect Effects 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 3
- 230000009385 viral infection Effects 0.000 claims description 3
- WCOFTYDKNNNTJJ-UHFFFAOYSA-N 4-[2-(3-chlorophenyl)-5-(4-methylsulfonylphenyl)-1h-pyrrol-3-yl]pyridine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C=2C=CN=CC=2)=C(C=2C=C(Cl)C=CC=2)N1 WCOFTYDKNNNTJJ-UHFFFAOYSA-N 0.000 claims description 2
- IADKHNLYTDEPGD-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)-5-(4-methylsulfinylphenyl)-1h-pyrrol-3-yl]pyridine Chemical compound C1=CC(S(=O)C)=CC=C1C1=CC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 IADKHNLYTDEPGD-UHFFFAOYSA-N 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 2
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims 4
- 125000005945 imidazopyridyl group Chemical group 0.000 claims 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims 2
- GFYZFDVAKCDQST-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-1h-pyrrol-3-yl]pyridine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CC(C=2C=CN=CC=2)=C(C=2C=CC(F)=CC=2)N1 GFYZFDVAKCDQST-UHFFFAOYSA-N 0.000 claims 1
- YQRNUALOCZZODT-UHFFFAOYSA-N 4-[2-(4-methylsulfinylphenyl)-5-phenyl-1h-pyrrol-3-yl]pyridine Chemical compound C1=CC(S(=O)C)=CC=C1C1=C(C=2C=CN=CC=2)C=C(C=2C=CC=CC=2)N1 YQRNUALOCZZODT-UHFFFAOYSA-N 0.000 claims 1
- 125000004864 4-thiomethylphenyl group Chemical group 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010053879 Sepsis syndrome Diseases 0.000 claims 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims 1
- 208000019664 bone resorption disease Diseases 0.000 claims 1
- DGBLAQLVJBSWLW-UHFFFAOYSA-N chembl91196 Chemical compound C1=CC(O)=CC=C1C1=C(C=2C=CN=CC=2)C=C(C=2C=CC=CC=2)N1 DGBLAQLVJBSWLW-UHFFFAOYSA-N 0.000 claims 1
- 208000024908 graft versus host disease Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 claims 1
- 102000004889 Interleukin-6 Human genes 0.000 abstract description 14
- 229940100601 interleukin-6 Drugs 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 102000000589 Interleukin-1 Human genes 0.000 abstract description 7
- 108010002352 Interleukin-1 Proteins 0.000 abstract description 7
- 102000004890 Interleukin-8 Human genes 0.000 abstract description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 abstract description 3
- 230000007365 immunoregulation Effects 0.000 abstract description 2
- 229940096397 interleukin-8 Drugs 0.000 abstract 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 abstract 2
- 102000003390 tumor necrosis factor Human genes 0.000 abstract 2
- 102000051325 Glucagon Human genes 0.000 abstract 1
- 108060003199 Glucagon Proteins 0.000 abstract 1
- 239000005557 antagonist Substances 0.000 abstract 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 abstract 1
- 229960004666 glucagon Drugs 0.000 abstract 1
- 230000004962 physiological condition Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 47
- 239000000243 solution Substances 0.000 description 41
- 239000000047 product Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 229920000136 polysorbate Polymers 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000008878 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- HVSLQABINWNLGZ-UHFFFAOYSA-N 2-(4-fluoropyridin-2-yl)-1-phenylethanone Chemical compound FC1=CC=NC(CC(=O)C=2C=CC=CC=2)=C1 HVSLQABINWNLGZ-UHFFFAOYSA-N 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 238000002965 ELISA Methods 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000002158 endotoxin Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 150000003233 pyrroles Chemical class 0.000 description 7
- 125000000168 pyrrolyl group Chemical group 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 238000010790 dilution Methods 0.000 description 6
- 239000012895 dilution Substances 0.000 description 6
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
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- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
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- IGELFKKMDLGCJO-UHFFFAOYSA-N xenon difluoride Chemical compound F[Xe]F IGELFKKMDLGCJO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US209495P | 1995-08-10 | 1995-08-10 | |
US60/002,094 | 1995-08-10 | ||
US1418296P | 1996-03-26 | 1996-03-26 | |
US60/014,182 | 1996-03-26 | ||
GBGB9607253.3A GB9607253D0 (en) | 1996-04-04 | 1996-04-04 | 2,5-Substituted aryl pyrroles, compositions containing such compounds of use |
GB9607253.3 | 1996-04-04 | ||
GB9608472.8 | 1996-04-25 | ||
GBGB9608472.8A GB9608472D0 (en) | 1996-04-25 | 1996-04-25 | 2,5-Substituted aryl pyrroles,compositions containing such compounds and methods of use |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2228050A1 true CA2228050A1 (fr) | 1997-02-20 |
Family
ID=27451430
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002228050A Abandoned CA2228050A1 (fr) | 1995-08-10 | 1996-08-06 | Pyrroles d'aryle substitues en position 2 et 5, compositions contenant de tels composes et leurs modes d'utilisation |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0871444A4 (fr) |
JP (1) | JPH11510511A (fr) |
AU (1) | AU699148B2 (fr) |
CA (1) | CA2228050A1 (fr) |
WO (1) | WO1997005878A1 (fr) |
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IL134723A0 (en) | 1997-09-23 | 2001-04-30 | Zeneca Ltd | Amide derivatives for the treatment of diseases mediated by cytokines |
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AR017219A1 (es) | 1997-12-19 | 2001-08-22 | Smithkline Beecham Corp | Derivados de imidazol 1,4,5 sustituidos, composiciones que los comprenden, procedimiento para la preparacion de dichos derivados, uso de los derivados parala manufactura de un medicamento |
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AU749293B2 (en) | 1998-05-15 | 2002-06-20 | Astrazeneca Ab | Benzamide derivatives for the treatment of diseases mediated by cytokines |
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TR200100300T2 (tr) | 1998-08-04 | 2001-07-23 | Astrazeneca Ab | Sitokinlerin üretiminde engelleyici olarak kullanışlı amid türevleri |
PL346854A1 (en) | 1998-09-25 | 2002-03-11 | Astrazeneca Ab | Benzamide derivatives and their use as cytokine inhibitors |
CN1158266C (zh) | 1998-10-01 | 2004-07-21 | 阿斯特拉曾尼卡有限公司 | 化合物 |
US6649617B1 (en) | 1998-10-07 | 2003-11-18 | Smithkline Beecham Corporation | Treatment for stroke management |
ATE258055T1 (de) | 1998-11-04 | 2004-02-15 | Smithkline Beecham Corp | Pyridin-4-yl oder pyrimidin-4-yl substituierte pyrazine |
JP2000247959A (ja) | 1999-02-26 | 2000-09-12 | Kowa Co | ピリダジン−3−オン誘導体及びこれを含有する医薬 |
ES2219319T3 (es) | 1999-03-17 | 2004-12-01 | Astrazeneca Ab | Derivados de amida. |
AU4315100A (en) * | 1999-04-28 | 2000-11-17 | Sankyo Company Limited | Preventive or inhibitory agents for hepatopathy |
IL146465A0 (en) * | 1999-05-14 | 2002-07-25 | Ortho Mcneil Pharm Inc | Substituted 3-pyridyl-4-arylpyrroles and related therapeutic and prophylactic methods |
US7122666B2 (en) | 1999-07-21 | 2006-10-17 | Sankyo Company, Limited | Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses |
WO2001030778A1 (fr) * | 1999-10-27 | 2001-05-03 | Novartis Ag | Composes thiazole et imidazo [4,5-b] pyridine et leur utilisation pharmaceutique |
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MXPA03006468A (es) * | 2001-01-18 | 2003-09-22 | Sankyo Co | Composiciones para la prevencion o tratamiento de hepatopatia. |
WO2002057255A1 (fr) * | 2001-01-22 | 2002-07-25 | Sankyo Company, Limited | Derives du pyrrole substitues en 4 ou 5 |
EG23054A (en) * | 2001-01-22 | 2004-02-29 | Sankyo Co | Pyrrole derivatives their preparation and their therapeutic uses |
MY130778A (en) * | 2001-02-09 | 2007-07-31 | Vertex Pharma | Heterocyclic inhibitiors of erk2 and uses thereof |
GB0112348D0 (en) | 2001-05-19 | 2001-07-11 | Smithkline Beecham Plc | Compounds |
JP2005505562A (ja) * | 2001-09-05 | 2005-02-24 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Rafキナーゼ阻害剤としてのピリジルフランおよびピロール |
US20050043331A1 (en) * | 2002-09-27 | 2005-02-24 | Bullington James L. | Substituted 3-(2,5-disubstituted)pyridyl-4-aryl pyrroles for treating inflammatory diseases |
MXPA05009972A (es) | 2003-03-18 | 2005-11-04 | Kowa Co | Derivado de fenilpiridazina soluble en agua y medicina que contiene el mismo. |
GB0324790D0 (en) | 2003-10-24 | 2003-11-26 | Astrazeneca Ab | Amide derivatives |
EP2152269B1 (fr) | 2007-06-08 | 2014-04-23 | Janssen Pharmaceutica, N.V. | Dérivés de piperidine/piperazine |
US8981094B2 (en) | 2007-06-08 | 2015-03-17 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
US8835437B2 (en) | 2007-06-08 | 2014-09-16 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
PE20140572A1 (es) | 2008-06-05 | 2014-05-16 | Janssen Pharmaceutica Nv | Combinaciones de drogas que comprenden un inhibidor de dgat y un agonista de ppar |
EP2319831A4 (fr) * | 2008-08-25 | 2012-10-24 | Santen Pharmaceutical Co Ltd | Nouveau dérivé de pyrrole ayant, en tant que substituants, un groupe uréide, un groupe aminocarbonyle et un groupe bicyclique qui peut avoir un substituant |
JP5936683B2 (ja) * | 2011-05-17 | 2016-06-22 | ジョイント ストック カンパニー ”ファーマシンテズ” | 癒着の治療及び予防のための化合物、医薬組成物及び方法 |
CN102863371B (zh) * | 2011-07-06 | 2016-04-13 | 中国科学院上海有机化学研究所 | 氟代二氢吡咯或氟代吡咯 |
CN111662239B (zh) * | 2019-03-06 | 2023-07-28 | 中国医学科学院药物研究所 | 1,2,4-三唑类化合物及其制法和药物用途 |
CN113354616B (zh) * | 2020-03-05 | 2024-03-26 | 中国医学科学院药物研究所 | 二芳基-1,2,4-三唑类化合物及其制法和药物用途 |
CN114394934B (zh) * | 2022-01-06 | 2023-06-13 | 苏州大学 | 吡唑苯甲酰胺类化合物及其制备方法和应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997016441A1 (fr) * | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Pyrroles aryliques de substitution, compositions renfermant de telles composes et methodes d'utilisation de ces substances |
-
1996
- 1996-08-06 EP EP96928099A patent/EP0871444A4/fr not_active Withdrawn
- 1996-08-06 WO PCT/US1996/012922 patent/WO1997005878A1/fr not_active Application Discontinuation
- 1996-08-06 JP JP9508661A patent/JPH11510511A/ja active Pending
- 1996-08-06 CA CA002228050A patent/CA2228050A1/fr not_active Abandoned
- 1996-08-06 AU AU67691/96A patent/AU699148B2/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
WO1997005878A1 (fr) | 1997-02-20 |
AU699148B2 (en) | 1998-11-26 |
EP0871444A1 (fr) | 1998-10-21 |
EP0871444A4 (fr) | 1999-01-13 |
AU6769196A (en) | 1997-03-05 |
JPH11510511A (ja) | 1999-09-14 |
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