CA2594726C - Heteroaryl sulfonamides and ccr2 - Google Patents
Heteroaryl sulfonamides and ccr2 Download PDFInfo
- Publication number
- CA2594726C CA2594726C CA2594726A CA2594726A CA2594726C CA 2594726 C CA2594726 C CA 2594726C CA 2594726 A CA2594726 A CA 2594726A CA 2594726 A CA2594726 A CA 2594726A CA 2594726 C CA2594726 C CA 2594726C
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- Canada
- Prior art keywords
- substituted
- unsubstituted
- group
- alkyl
- chloro
- 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.)
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- -1 Heteroaryl sulfonamides Chemical class 0.000 title description 88
- 229940124530 sulfonamide Drugs 0.000 title description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 162
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 claims abstract description 101
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 claims abstract description 101
- 238000000034 method Methods 0.000 claims abstract description 92
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 69
- 201000010099 disease Diseases 0.000 claims abstract description 62
- 230000001404 mediated effect Effects 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims description 170
- 229910052739 hydrogen Inorganic materials 0.000 claims description 170
- 239000000203 mixture Substances 0.000 claims description 159
- 125000000623 heterocyclic group Chemical group 0.000 claims description 155
- 201000006417 multiple sclerosis Diseases 0.000 claims description 143
- 125000000217 alkyl group Chemical group 0.000 claims description 137
- 150000002431 hydrogen Chemical group 0.000 claims description 102
- 229910052736 halogen Inorganic materials 0.000 claims description 97
- 150000002367 halogens Chemical class 0.000 claims description 77
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 75
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 70
- 125000001072 heteroaryl group Chemical group 0.000 claims description 69
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 61
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 55
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 41
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 31
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
- 125000004429 atom Chemical group 0.000 claims description 20
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 229910052717 sulfur Chemical group 0.000 claims description 11
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 8
- 206010063725 Idiopathic pneumonia syndrome Diseases 0.000 claims description 8
- 208000008589 Obesity Diseases 0.000 claims description 8
- 208000007915 ichthyosis prematurity syndrome Diseases 0.000 claims description 8
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 6
- 201000002793 renal fibrosis Diseases 0.000 claims description 6
- 208000037803 restenosis Diseases 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 238000002054 transplantation Methods 0.000 claims description 6
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 claims description 5
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000024908 graft versus host disease Diseases 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 4
- 208000021722 neuropathic pain Diseases 0.000 claims description 4
- 208000015943 Coeliac disease Diseases 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 23
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims 23
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 claims 4
- 238000000338 in vitro Methods 0.000 claims 2
- 206010058019 Cancer Pain Diseases 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 12
- 239000005557 antagonist Substances 0.000 abstract description 10
- 206010061218 Inflammation Diseases 0.000 abstract description 9
- 230000004054 inflammatory process Effects 0.000 abstract description 9
- 241001465754 Metazoa Species 0.000 abstract description 5
- 238000003556 assay Methods 0.000 abstract description 4
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 102000004497 CCR2 Receptors Human genes 0.000 abstract description 2
- 108010017312 CCR2 Receptors Proteins 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 abstract description 2
- 125000004421 aryl sulphonamide group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 284
- 239000000243 solution Substances 0.000 description 136
- 235000019439 ethyl acetate Nutrition 0.000 description 131
- 125000003118 aryl group Chemical group 0.000 description 100
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
- 229910001868 water Inorganic materials 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 82
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 80
- 230000002829 reductive effect Effects 0.000 description 77
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 76
- 239000000460 chlorine Substances 0.000 description 73
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 72
- 125000003342 alkenyl group Chemical group 0.000 description 69
- 125000000304 alkynyl group Chemical group 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 62
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 59
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 57
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 239000000047 product Substances 0.000 description 51
- 239000000741 silica gel Substances 0.000 description 49
- 229910002027 silica gel Inorganic materials 0.000 description 49
- 239000000284 extract Substances 0.000 description 48
- 239000012267 brine Substances 0.000 description 45
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 40
- 238000003818 flash chromatography Methods 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- 230000015572 biosynthetic process Effects 0.000 description 36
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 36
- 235000019341 magnesium sulphate Nutrition 0.000 description 36
- 235000017557 sodium bicarbonate Nutrition 0.000 description 36
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 239000002904 solvent Substances 0.000 description 30
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 29
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 102000009410 Chemokine receptor Human genes 0.000 description 22
- 108050000299 Chemokine receptor Proteins 0.000 description 22
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 22
- 125000005843 halogen group Chemical group 0.000 description 22
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 22
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 21
- 238000004587 chromatography analysis Methods 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 19
- NBHWWIRXQBCMQD-UHFFFAOYSA-N 5-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]sulfonylamino]pyridine-2-carboxamide Chemical class NC(=O)C1=NC=C(Cl)C=C1NS(=O)(=O)C1=CC=C(Cl)C(C(F)(F)F)=C1 NBHWWIRXQBCMQD-UHFFFAOYSA-N 0.000 description 19
- WOESZFOVOKHIPT-UHFFFAOYSA-N 5-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]sulfonylamino]pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=C(Cl)C=C1NS(=O)(=O)C1=CC=C(Cl)C(C(F)(F)F)=C1 WOESZFOVOKHIPT-UHFFFAOYSA-N 0.000 description 19
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 19
- 239000010410 layer Substances 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
- 229910052731 fluorine Inorganic materials 0.000 description 17
- 229910052801 chlorine Inorganic materials 0.000 description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 16
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 16
- 108010012236 Chemokines Proteins 0.000 description 15
- 102000019034 Chemokines Human genes 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- 239000011737 fluorine Substances 0.000 description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 description 15
- 150000003456 sulfonamides Chemical class 0.000 description 15
- 230000006870 function Effects 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 13
- 239000004480 active ingredient Substances 0.000 description 13
- 210000002540 macrophage Anatomy 0.000 description 13
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 12
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 11
- 210000001744 T-lymphocyte Anatomy 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- JTUXTQJWTCFIAF-UHFFFAOYSA-N n-(2-bromo-5-chloropyridin-3-yl)-4-chloro-n-(methoxymethyl)-3-(trifluoromethyl)benzenesulfonamide Chemical compound C=1C=C(Cl)C(C(F)(F)F)=CC=1S(=O)(=O)N(COC)C1=CC(Cl)=CN=C1Br JTUXTQJWTCFIAF-UHFFFAOYSA-N 0.000 description 11
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- 238000002360 preparation method Methods 0.000 description 11
- VFMIDVIAQMFGGP-UHFFFAOYSA-N 2-bromo-5-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC(Cl)=CN=C1Br VFMIDVIAQMFGGP-UHFFFAOYSA-N 0.000 description 10
- SSULGNXFUGLULI-UHFFFAOYSA-N 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC(S(Cl)(=O)=O)=CC=C1Cl SSULGNXFUGLULI-UHFFFAOYSA-N 0.000 description 10
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- 101150041968 CDC13 gene Proteins 0.000 description 9
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- 238000005755 formation reaction Methods 0.000 description 9
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 9
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- SDHUHRVYQKPZDF-UHFFFAOYSA-N 5-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl-(methoxymethyl)amino]pyridine-2-carboxylic acid Chemical compound C=1C=C(Cl)C(C(F)(F)F)=CC=1S(=O)(=O)N(COC)C1=CC(Cl)=CN=C1C(O)=O SDHUHRVYQKPZDF-UHFFFAOYSA-N 0.000 description 8
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- AZOXQBMBDRLSCQ-UHFFFAOYSA-N 2-bromo-5-chloropyridin-3-amine Chemical compound NC1=CC(Cl)=CN=C1Br AZOXQBMBDRLSCQ-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
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- UXJODOZORLBGIZ-UHFFFAOYSA-N 5-chloro-2-iodo-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC(Cl)=CN=C1I UXJODOZORLBGIZ-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- 238000013459 approach Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 5
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
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Classifications
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| EP1838674A4 (en) | 2010-01-06 |
| HK1109404A1 (en) | 2008-06-06 |
| IL184539A (en) | 2016-03-31 |
| WO2006076644A2 (en) | 2006-07-20 |
| ATE503741T1 (de) | 2011-04-15 |
| WO2006076644A3 (en) | 2007-02-15 |
| EP2354126B1 (en) | 2013-09-25 |
| MX2007008474A (es) | 2008-02-19 |
| JP2008526996A (ja) | 2008-07-24 |
| US20060173019A1 (en) | 2006-08-03 |
| AU2006204750C1 (en) | 2012-11-01 |
| CA2594726A1 (en) | 2006-07-20 |
| EP1838674A2 (en) | 2007-10-03 |
| JP5253815B2 (ja) | 2013-07-31 |
| EP1838674B9 (en) | 2011-11-02 |
| EP1838674B1 (en) | 2011-03-30 |
| EP2474532A1 (en) | 2012-07-11 |
| AU2006204750A1 (en) | 2006-07-20 |
| EP2354126A1 (en) | 2011-08-10 |
| PL1838674T3 (pl) | 2011-08-31 |
| PL2354126T3 (pl) | 2014-03-31 |
| DK2354126T3 (da) | 2014-01-13 |
| IL184539A0 (en) | 2007-10-31 |
| AU2006204750B2 (en) | 2011-09-22 |
| ES2440965T3 (es) | 2014-01-31 |
| HK1160856A1 (en) | 2012-08-17 |
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