ZA200405260B - N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. - Google Patents
N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. Download PDFInfo
- Publication number
- ZA200405260B ZA200405260B ZA200405260A ZA200405260A ZA200405260B ZA 200405260 B ZA200405260 B ZA 200405260B ZA 200405260 A ZA200405260 A ZA 200405260A ZA 200405260 A ZA200405260 A ZA 200405260A ZA 200405260 B ZA200405260 B ZA 200405260B
- Authority
- ZA
- South Africa
- Prior art keywords
- pyrazinyl
- pyrazine
- methylphenylsulfonylamino
- methoxy
- dichloro
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 25
- 201000010099 disease Diseases 0.000 title claims description 21
- 102000019034 Chemokines Human genes 0.000 title claims description 15
- 108010012236 Chemokines Proteins 0.000 title claims description 15
- 238000011282 treatment Methods 0.000 title claims description 12
- 230000001404 mediated effect Effects 0.000 title claims description 6
- KAPFAVLCJMCLFV-UHFFFAOYSA-N n-pyrazin-2-ylbenzenesulfonamide Chemical class C=1C=CC=CC=1S(=O)(=O)NC1=CN=CC=N1 KAPFAVLCJMCLFV-UHFFFAOYSA-N 0.000 title 1
- -1 C1. alkyl-OH Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 150000002367 halogens Chemical class 0.000 claims description 47
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 229920006395 saturated elastomer Polymers 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 23
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000012453 solvate Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000001246 bromo group Chemical group Br* 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 102000009410 Chemokine receptor Human genes 0.000 claims description 12
- 108050000299 Chemokine receptor Proteins 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Chemical group 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001301 oxygen Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 208000006673 asthma Diseases 0.000 claims description 11
- 125000000565 sulfonamide group Chemical group 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 7
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000002346 iodo group Chemical group I* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 102000004498 CCR4 Receptors Human genes 0.000 claims description 3
- 108010017317 CCR4 Receptors Proteins 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 235000019000 fluorine Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 128
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 64
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims 52
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims 40
- 239000000126 substance Substances 0.000 claims 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
- 229910052799 carbon Inorganic materials 0.000 claims 4
- 150000004702 methyl esters Chemical class 0.000 claims 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 3
- FNZJHAROBHVPRM-UHFFFAOYSA-N 4-methyl-n-[5-(2-methylpiperidine-1-carbonyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound CC1CCCCN1C(=O)C(N=C1OCC=2C=NC=CC=2)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 FNZJHAROBHVPRM-UHFFFAOYSA-N 0.000 claims 2
- ZFWOQGMFRGCASY-UHFFFAOYSA-N 5-[(4-methylphenyl)sulfonylamino]-n-propan-2-yl-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NC(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 ZFWOQGMFRGCASY-UHFFFAOYSA-N 0.000 claims 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- CJYOXPJUOZCVPQ-UHFFFAOYSA-N n-(2,2-dimethylpropyl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)NCC(C)(C)C)N=C1OCC1=CC=CN=C1 CJYOXPJUOZCVPQ-UHFFFAOYSA-N 0.000 claims 2
- KSUNMLGXEISDSY-UHFFFAOYSA-N n-(2-hydroxypropyl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCC(O)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 KSUNMLGXEISDSY-UHFFFAOYSA-N 0.000 claims 2
- FCHYDUMDMGRQNZ-UHFFFAOYSA-N n-butyl-n-ethyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N(CC)CCCC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 FCHYDUMDMGRQNZ-UHFFFAOYSA-N 0.000 claims 2
- IXHVLCDSWKUQOB-UHFFFAOYSA-N n-hexyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCCCCCC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 IXHVLCDSWKUQOB-UHFFFAOYSA-N 0.000 claims 2
- LGRUVALLOVYRGV-UHFFFAOYSA-N 2,3-dichloro-N-[5-chloro-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide 2,3-dichloro-N-[5-chloro-3-(pyrimidin-5-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound ClC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC=1C=NC=NC1.ClC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC=1C=NC=CC1 LGRUVALLOVYRGV-UHFFFAOYSA-N 0.000 claims 1
- WHMUBVTWRSLVOQ-UHFFFAOYSA-N 2,3-dichloro-n-(3-methoxy-5,6-dimethylpyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(C)=C(C)N=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl WHMUBVTWRSLVOQ-UHFFFAOYSA-N 0.000 claims 1
- LLWYTTSVRALNCB-UHFFFAOYSA-N 2,3-dichloro-n-(3-methoxy-5-methylpyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(C)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl LLWYTTSVRALNCB-UHFFFAOYSA-N 0.000 claims 1
- PLRNWFQJCWYACG-UHFFFAOYSA-N 2,3-dichloro-n-(3-methoxy-5-prop-2-enoxypyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(OCC=C)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl PLRNWFQJCWYACG-UHFFFAOYSA-N 0.000 claims 1
- TWNSSYPFTQHLQX-UHFFFAOYSA-N 2,3-dichloro-n-(3-prop-2-ynoxypyrazin-2-yl)benzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC=CN=2)OCC#C)=C1Cl TWNSSYPFTQHLQX-UHFFFAOYSA-N 0.000 claims 1
- LWAIURAHNVUOOS-UHFFFAOYSA-N 2,3-dichloro-n-(5-chloro-3-prop-2-enoxypyrazin-2-yl)benzenesulfonamide Chemical compound C=CCOC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl LWAIURAHNVUOOS-UHFFFAOYSA-N 0.000 claims 1
- HYFSICBVTXPGTM-UHFFFAOYSA-N 2,3-dichloro-n-(5-chloro-3-prop-2-ynoxypyrazin-2-yl)benzenesulfonamide Chemical compound C#CCOC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl HYFSICBVTXPGTM-UHFFFAOYSA-N 0.000 claims 1
- DWWLPLYNMAECSJ-UHFFFAOYSA-N 2,3-dichloro-n-(6-chloro-3-methoxy-5-morpholin-4-ylpyrazin-2-yl)benzenesulfonamide Chemical compound ClC=1N=C(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)C(OC)=NC=1N1CCOCC1 DWWLPLYNMAECSJ-UHFFFAOYSA-N 0.000 claims 1
- WFCNAAVTAPIYLR-UHFFFAOYSA-N 2,3-dichloro-n-[5,6-dichloro-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Cl)=C(Cl)N=2)OCC=2C=NC=CC=2)=C1Cl WFCNAAVTAPIYLR-UHFFFAOYSA-N 0.000 claims 1
- ZPSSRSCXEKXPNJ-UHFFFAOYSA-N 2,3-dichloro-n-[5-(3-hydroxyprop-1-ynyl)-3-methoxypyrazin-2-yl]benzenesulfonamide Chemical compound COC1=NC(C#CCO)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl ZPSSRSCXEKXPNJ-UHFFFAOYSA-N 0.000 claims 1
- YNPFQWJBJJYCHQ-UHFFFAOYSA-N 2,3-dichloro-n-[5-(hydroxymethyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C=1C=CN=CC=1COC1=NC(CO)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl YNPFQWJBJJYCHQ-UHFFFAOYSA-N 0.000 claims 1
- FWEXASLSCXAPON-UHFFFAOYSA-N 2,3-dichloro-n-[5-(hydroxymethyl)-3-methoxy-6-methylpyrazin-2-yl]benzenesulfonamide Chemical compound COC1=NC(CO)=C(C)N=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl FWEXASLSCXAPON-UHFFFAOYSA-N 0.000 claims 1
- CBNRVUVMLOCWER-UHFFFAOYSA-N 2,3-dichloro-n-[5-chloro-3-(1-cyclopropylethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C1CC1C(C)OC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl CBNRVUVMLOCWER-UHFFFAOYSA-N 0.000 claims 1
- JWQZJURFVIKNDK-UHFFFAOYSA-N 2,3-dichloro-n-[5-chloro-3-[[5-[(dimethylamino)methyl]furan-2-yl]methoxy]pyrazin-2-yl]benzenesulfonamide Chemical compound O1C(CN(C)C)=CC=C1COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl JWQZJURFVIKNDK-UHFFFAOYSA-N 0.000 claims 1
- QAQYPVLRKXSTEG-UHFFFAOYSA-N 2,3-dichloro-n-[6-chloro-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C=1C=CC(Cl)=C(Cl)C=1S(=O)(=O)NC1=NC(Cl)=CN=C1OCC1=CC=CN=C1 QAQYPVLRKXSTEG-UHFFFAOYSA-N 0.000 claims 1
- NGGNOHIEIHLJOF-UHFFFAOYSA-N 2,3-dichloro-n-[6-chloro-3-[[5-[(dimethylamino)methyl]furan-2-yl]methoxy]pyrazin-2-yl]benzenesulfonamide Chemical compound O1C(CN(C)C)=CC=C1COC1=NC=C(Cl)N=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl NGGNOHIEIHLJOF-UHFFFAOYSA-N 0.000 claims 1
- LVAYYCFLTAEZNF-UHFFFAOYSA-N 2,3-dichloro-n-[6-chloro-3-methoxy-5-(methoxymethyl)pyrazin-2-yl]benzenesulfonamide Chemical compound N1=C(Cl)C(COC)=NC(OC)=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl LVAYYCFLTAEZNF-UHFFFAOYSA-N 0.000 claims 1
- KFLGXFODSLRJDE-SBSPUUFOSA-N 2,3-dichloro-n-[6-chloro-3-methoxy-5-[[(2r)-pyrrolidin-2-yl]methoxy]pyrazin-2-yl]benzenesulfonamide;hydrochloride Chemical compound Cl.ClC=1N=C(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)C(OC)=NC=1OC[C@H]1CCCN1 KFLGXFODSLRJDE-SBSPUUFOSA-N 0.000 claims 1
- VENYJIJQEBQVRC-UHFFFAOYSA-N 2-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]oxy-n,n-diethylacetamide Chemical compound COC1=NC(OCC(=O)N(CC)CC)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl VENYJIJQEBQVRC-UHFFFAOYSA-N 0.000 claims 1
- VKUHEYSNOMZUJC-UHFFFAOYSA-N 2-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]sulfanylacetamide;2-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]sulfanyl-n-methylacetamide Chemical compound COC1=NC(SCC(N)=O)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl.COC1=NC(SCC(=O)NC)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl VKUHEYSNOMZUJC-UHFFFAOYSA-N 0.000 claims 1
- XZYYRNCAUGLUFA-UHFFFAOYSA-N 3,4-dichloro-n-(5,6-dichloro-3-methoxypyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(Cl)=C(Cl)N=C1NS(=O)(=O)C1=CC=C(Cl)C(Cl)=C1 XZYYRNCAUGLUFA-UHFFFAOYSA-N 0.000 claims 1
- VGZKJDWZVMCUBU-UHFFFAOYSA-N 3-[[6-chloro-3-[(2,3-dichlorophenyl)sulfonylamino]pyrazin-2-yl]oxymethyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(COC=2C(=NC=C(Cl)N=2)NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)=C1 VGZKJDWZVMCUBU-UHFFFAOYSA-N 0.000 claims 1
- LCBKYPGZLSAFPP-UHFFFAOYSA-N 3-chloro-n-(5-chloro-3-methoxypyrazin-2-yl)-2-fluorobenzenesulfonamide Chemical compound COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1F LCBKYPGZLSAFPP-UHFFFAOYSA-N 0.000 claims 1
- VBTIMGWSKZTTJH-UHFFFAOYSA-N 3-chloro-n-[5-chloro-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-2-fluorobenzenesulfonamide Chemical compound FC1=C(Cl)C=CC=C1S(=O)(=O)NC1=NC=C(Cl)N=C1OCC1=CC=CN=C1 VBTIMGWSKZTTJH-UHFFFAOYSA-N 0.000 claims 1
- ZPRWDRAGOKIYTD-UHFFFAOYSA-N 3-chloro-n-[5-chloro-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-2-methylbenzenesulfonamide Chemical compound CC1=C(Cl)C=CC=C1S(=O)(=O)NC1=NC=C(Cl)N=C1OCC1=CC=CN=C1 ZPRWDRAGOKIYTD-UHFFFAOYSA-N 0.000 claims 1
- NGTJHOCCPZVWNX-UHFFFAOYSA-N 4-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]oxybenzoic acid Chemical compound C=1N=C(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)C(OC)=NC=1OC1=CC=C(C(O)=O)C=C1 NGTJHOCCPZVWNX-UHFFFAOYSA-N 0.000 claims 1
- QNPDOOVUBQOACJ-UHFFFAOYSA-N 4-amino-2,3-dichloro-n-(5-chloro-3-methoxypyrazin-2-yl)benzenesulfonamide Chemical compound COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=C(N)C(Cl)=C1Cl QNPDOOVUBQOACJ-UHFFFAOYSA-N 0.000 claims 1
- ISGXBMNENPSNLR-UHFFFAOYSA-N 4-bromo-n-[3-(2-phenoxyethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(Br)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCCOC1=CC=CC=C1 ISGXBMNENPSNLR-UHFFFAOYSA-N 0.000 claims 1
- JAXOUQAEPRCVFF-UHFFFAOYSA-N 4-bromo-n-[3-[2-(n-methylanilino)ethoxy]pyrazin-2-yl]benzenesulfonamide Chemical compound C=1C=CC=CC=1N(C)CCOC1=NC=CN=C1NS(=O)(=O)C1=CC=C(Br)C=C1 JAXOUQAEPRCVFF-UHFFFAOYSA-N 0.000 claims 1
- NWMMZDHXNVLQNI-UHFFFAOYSA-N 4-ethyl-n-[3-[2-(n-methylanilino)ethoxy]pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(CC)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCCN(C)C1=CC=CC=C1 NWMMZDHXNVLQNI-UHFFFAOYSA-N 0.000 claims 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- SUTLDINQBBKTQX-UHFFFAOYSA-N 4-methyl-n-[3-(2-piperidin-1-ylethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCCN1CCCCC1 SUTLDINQBBKTQX-UHFFFAOYSA-N 0.000 claims 1
- VGUGLHSLWYCBJZ-UHFFFAOYSA-N 4-methyl-n-[3-(pyridin-3-ylmethoxy)-5-(pyrrolidine-1-carbonyl)pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2CCCC2)N=C1OCC1=CC=CN=C1 VGUGLHSLWYCBJZ-UHFFFAOYSA-N 0.000 claims 1
- IHKXXVLJJCBOAK-UHFFFAOYSA-N 4-methyl-n-[3-(pyridin-3-ylmethoxy)-5-(thiomorpholine-4-carbonyl)pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2CCSCC2)N=C1OCC1=CC=CN=C1 IHKXXVLJJCBOAK-UHFFFAOYSA-N 0.000 claims 1
- NDINEIOSXOKBDU-UHFFFAOYSA-N 4-methyl-n-[5-(4-methylpiperazine-1-carbonyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C1CN(C)CCN1C(=O)C(N=C1OCC=2C=NC=CC=2)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 NDINEIOSXOKBDU-UHFFFAOYSA-N 0.000 claims 1
- STYQJSOARWCTIV-UHFFFAOYSA-N 4-methyl-n-[5-(morpholine-4-carbonyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2CCOCC2)N=C1OCC1=CC=CN=C1 STYQJSOARWCTIV-UHFFFAOYSA-N 0.000 claims 1
- YZWYKWZNHHWJJP-UHFFFAOYSA-N 5-[(2,3-dichlorophenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl YZWYKWZNHHWJJP-UHFFFAOYSA-N 0.000 claims 1
- GJVNTOMYZOZPHV-UHFFFAOYSA-N 5-[(4-methylphenyl)sulfonylamino]-n,n-dipropyl-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N(CCC)CCC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 GJVNTOMYZOZPHV-UHFFFAOYSA-N 0.000 claims 1
- GYSWRFZJCIALAB-UHFFFAOYSA-N 5-[(4-methylphenyl)sulfonylamino]-n-(2-methylpropyl)-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCC(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 GYSWRFZJCIALAB-UHFFFAOYSA-N 0.000 claims 1
- KCEHCZYTPCWKCX-UHFFFAOYSA-N 5-[(4-methylphenyl)sulfonylamino]-n-pentan-2-yl-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NC(C)CCC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 KCEHCZYTPCWKCX-UHFFFAOYSA-N 0.000 claims 1
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 claims 1
- DGIXVGNCQYKKHX-UHFFFAOYSA-N BrC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC1=CN(C(C=C1)=O)C.BrC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC1=NC=CN=C1 Chemical compound BrC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC1=CN(C(C=C1)=O)C.BrC=1N=C(C(=NC1)NS(=O)(=O)C1=C(C(=CC=C1)Cl)Cl)OCC1=NC=CN=C1 DGIXVGNCQYKKHX-UHFFFAOYSA-N 0.000 claims 1
- KIYSOBYSRWQGBQ-UHFFFAOYSA-N COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1C#N.CNCc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1 Chemical compound COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1C#N.CNCc1ccc(COc2nccnc2NS(=O)(=O)c2cccc(Cl)c2Cl)o1 KIYSOBYSRWQGBQ-UHFFFAOYSA-N 0.000 claims 1
- PNPUVZWPNUXYPK-UHFFFAOYSA-N COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C.COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl Chemical compound COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C.COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl PNPUVZWPNUXYPK-UHFFFAOYSA-N 0.000 claims 1
- SDCCLGCPGYYUQA-UHFFFAOYSA-N ClC1=C(C=CC=C1OC)S(=O)(=O)NC1=NC=CN=C1OC.ClC1=C(C=CC=C1F)S(=O)(=O)NC1=NC=CN=C1OC.ClC1=C(C=CC=C1F)S(=O)(=O)NC1=NC=C(N=C1OC)Cl Chemical compound ClC1=C(C=CC=C1OC)S(=O)(=O)NC1=NC=CN=C1OC.ClC1=C(C=CC=C1F)S(=O)(=O)NC1=NC=CN=C1OC.ClC1=C(C=CC=C1F)S(=O)(=O)NC1=NC=C(N=C1OC)Cl SDCCLGCPGYYUQA-UHFFFAOYSA-N 0.000 claims 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims 1
- WQLOKXOWNBRRMS-UHFFFAOYSA-N N-(5-bromo-6-chloro-3-methoxypyrazin-2-yl)-2,3-dichlorobenzenesulfonamide 3-chloro-5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazine-2-carboxylic acid Chemical compound COc1nc(Br)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl.COc1nc(C(O)=O)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl WQLOKXOWNBRRMS-UHFFFAOYSA-N 0.000 claims 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- PARCGEBZYFCVQZ-UHFFFAOYSA-N methyl 2-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]sulfanylacetate Chemical compound COC1=NC(SCC(=O)OC)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl PARCGEBZYFCVQZ-UHFFFAOYSA-N 0.000 claims 1
- AXRXUGZSSSEQKO-UHFFFAOYSA-N methyl 3-[(2,3-dichlorophenyl)sulfonylamino]pyrazine-2-carboxylate Chemical compound COC(=O)C1=NC=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl AXRXUGZSSSEQKO-UHFFFAOYSA-N 0.000 claims 1
- HWDRBUSTZAMVJD-UHFFFAOYSA-N methyl 5-[(2,3-dichlorophenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxylate Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)OC)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl HWDRBUSTZAMVJD-UHFFFAOYSA-N 0.000 claims 1
- RVDZUYSXPQLFPV-UHFFFAOYSA-N methyl 5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxylate Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)OC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 RVDZUYSXPQLFPV-UHFFFAOYSA-N 0.000 claims 1
- XVTJKPNVWSMCAN-UHFFFAOYSA-N methyl 6-[(2,3-dichlorophenyl)sulfonylamino]-5-methoxypyrazine-2-carboxylate Chemical compound COC(=O)C1=CN=C(OC)C(NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)=N1 XVTJKPNVWSMCAN-UHFFFAOYSA-N 0.000 claims 1
- OCDUWRCGYVYLMV-UHFFFAOYSA-N n-(1-hydroxyethyl)-5-[(4-methylphenyl)sulfonylamino]-n-propan-2-yl-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N(C(C)O)C(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 OCDUWRCGYVYLMV-UHFFFAOYSA-N 0.000 claims 1
- WTQPZBYHIPNAIU-UHFFFAOYSA-N n-(2-hydroxyethyl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)NCCO)N=C1OCC1=CC=CN=C1 WTQPZBYHIPNAIU-UHFFFAOYSA-N 0.000 claims 1
- UJIBSHSXDIXCJL-UHFFFAOYSA-N n-(2-methylbutan-2-yl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NC(C)(C)CC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 UJIBSHSXDIXCJL-UHFFFAOYSA-N 0.000 claims 1
- CWOUGCRZMMDRDC-UHFFFAOYSA-N n-(2-methylbutyl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCC(C)CC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 CWOUGCRZMMDRDC-UHFFFAOYSA-N 0.000 claims 1
- DOBVQSOAXDKWQU-UHFFFAOYSA-N n-(3-butoxy-5-chloropyrazin-2-yl)-2,3-dichlorobenzenesulfonamide Chemical compound CCCCOC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl DOBVQSOAXDKWQU-UHFFFAOYSA-N 0.000 claims 1
- ZOWCXMLBGWNVFV-UHFFFAOYSA-N n-(3-methylbutan-2-yl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NC(C)C(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 ZOWCXMLBGWNVFV-UHFFFAOYSA-N 0.000 claims 1
- SXYYEPMWGVTQGV-UHFFFAOYSA-N n-(3-methylbutyl)-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCCC(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 SXYYEPMWGVTQGV-UHFFFAOYSA-N 0.000 claims 1
- OCZLUPURNBYDPZ-UHFFFAOYSA-N n-(5-bromo-3-methoxypyrazin-2-yl)-2,3-dichloro-4-fluorobenzenesulfonamide Chemical compound COC1=NC(Br)=CN=C1NS(=O)(=O)C1=CC=C(F)C(Cl)=C1Cl OCZLUPURNBYDPZ-UHFFFAOYSA-N 0.000 claims 1
- ACIIRRJZMDKZBV-UHFFFAOYSA-N n-(5-bromo-6-chloropyrazin-2-yl)-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2N=C(Cl)C(Br)=NC=2)=C1Cl ACIIRRJZMDKZBV-UHFFFAOYSA-N 0.000 claims 1
- HFNHXXDNSPMSEO-UHFFFAOYSA-N n-[2-(dimethylamino)ethyl]-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)NCCN(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 HFNHXXDNSPMSEO-UHFFFAOYSA-N 0.000 claims 1
- FPHMPVISWBZSHL-UHFFFAOYSA-N n-[3-(2-cyclopropylethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCCC1CC1 FPHMPVISWBZSHL-UHFFFAOYSA-N 0.000 claims 1
- IVJKLDKDDAJQBJ-UHFFFAOYSA-N n-[3-(2-phenoxyethoxy)pyrazin-2-yl]-4-propylbenzenesulfonamide Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCCOC1=CC=CC=C1 IVJKLDKDDAJQBJ-UHFFFAOYSA-N 0.000 claims 1
- CDJKXMXPEMDWDN-UHFFFAOYSA-N n-[3-(cyclopentylmethoxy)pyrazin-2-yl]-4-fluorobenzenesulfonamide Chemical compound C1=CC(F)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCC1CCCC1 CDJKXMXPEMDWDN-UHFFFAOYSA-N 0.000 claims 1
- VQHZRMRTECPHRN-UHFFFAOYSA-N n-[3-(cyclopentylmethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=CN=C1OCC1CCCC1 VQHZRMRTECPHRN-UHFFFAOYSA-N 0.000 claims 1
- LOTOAEQYZJAQAS-UHFFFAOYSA-N n-[3-[(2-amino-1,3-oxazol-4-yl)methoxy]-5-chloropyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound O1C(N)=NC(COC=2C(=NC=C(Cl)N=2)NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)=C1 LOTOAEQYZJAQAS-UHFFFAOYSA-N 0.000 claims 1
- BZGSICRNBXLQQL-UHFFFAOYSA-N n-[3-[(3-bromophenyl)methoxy]-5-chloropyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound C=1C=CC(Br)=CC=1COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl BZGSICRNBXLQQL-UHFFFAOYSA-N 0.000 claims 1
- BPKZMQDTAXKPRY-UHFFFAOYSA-N n-[3-[(5-bromopyridin-3-yl)methoxy]-5-chloropyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound C=1N=CC(Br)=CC=1COC1=NC(Cl)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl BPKZMQDTAXKPRY-UHFFFAOYSA-N 0.000 claims 1
- LOFZVNMTEQLWRJ-UHFFFAOYSA-N n-[5-(2-aminoethoxy)-3-methoxypyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound COC1=NC(OCCN)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl LOFZVNMTEQLWRJ-UHFFFAOYSA-N 0.000 claims 1
- XLWRRJQUFFSGGS-UHFFFAOYSA-N n-[5-(2-aminoethylsulfanyl)-3-(pyridin-2-ylmethoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound C=1C=CC=NC=1COC1=NC(SCCN)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl XLWRRJQUFFSGGS-UHFFFAOYSA-N 0.000 claims 1
- BUZWVYPPUNMIGZ-UHFFFAOYSA-N n-[5-(2-aminoethylsulfanyl)-3-methoxypyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound COC1=NC(SCCN)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl BUZWVYPPUNMIGZ-UHFFFAOYSA-N 0.000 claims 1
- BOQWWOMBLVDISM-UHFFFAOYSA-N n-[5-(3-hydroxypiperidine-1-carbonyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2CC(O)CCC2)N=C1OCC1=CC=CN=C1 BOQWWOMBLVDISM-UHFFFAOYSA-N 0.000 claims 1
- IRIBALYGNSJGLK-UHFFFAOYSA-N n-[5-(3-hydroxypyrrolidine-1-carbonyl)-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2CC(O)CC2)N=C1OCC1=CC=CN=C1 IRIBALYGNSJGLK-UHFFFAOYSA-N 0.000 claims 1
- KKKYOGFIGXCWDN-UHFFFAOYSA-N n-[5-[(2,3-dichlorophenyl)sulfonylamino]-6-methoxypyrazin-2-yl]-2-hydroxyacetamide Chemical compound COC1=NC(NC(=O)CO)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl KKKYOGFIGXCWDN-UHFFFAOYSA-N 0.000 claims 1
- OOXSFPWJDBJZCU-GOSISDBHSA-N n-[5-[(2r)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2[C@H](CCC2)CO)N=C1OCC1=CC=CN=C1 OOXSFPWJDBJZCU-GOSISDBHSA-N 0.000 claims 1
- OOXSFPWJDBJZCU-UHFFFAOYSA-N n-[5-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)N2C(CCC2)CO)N=C1OCC1=CC=CN=C1 OOXSFPWJDBJZCU-UHFFFAOYSA-N 0.000 claims 1
- QHXVWJBIGJSJCA-UHFFFAOYSA-N n-[5-bromo-3-(3-phenoxypropoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Br)=CN=2)OCCCOC=2C=CC=CC=2)=C1Cl QHXVWJBIGJSJCA-UHFFFAOYSA-N 0.000 claims 1
- SGTZGJSLXPPNSV-UHFFFAOYSA-N n-[5-bromo-3-(3-pyridin-3-ylpropoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Br)=CN=2)OCCCC=2C=NC=CC=2)=C1Cl SGTZGJSLXPPNSV-UHFFFAOYSA-N 0.000 claims 1
- KVLXPYVGRRKZQW-UHFFFAOYSA-N n-[5-bromo-3-(pyridin-3-ylmethoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Br)=CN=2)OCC=2C=NC=CC=2)=C1Cl KVLXPYVGRRKZQW-UHFFFAOYSA-N 0.000 claims 1
- DOCYGIZOHFMAOG-UHFFFAOYSA-N n-[5-bromo-3-(pyrimidin-5-ylmethoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Br)=CN=2)OCC=2C=NC=NC=2)=C1Cl DOCYGIZOHFMAOG-UHFFFAOYSA-N 0.000 claims 1
- MGMARBNJOADPBI-UHFFFAOYSA-N n-[5-bromo-3-(thiophen-3-ylmethoxy)pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound ClC1=CC=CC(S(=O)(=O)NC=2C(=NC(Br)=CN=2)OCC2=CSC=C2)=C1Cl MGMARBNJOADPBI-UHFFFAOYSA-N 0.000 claims 1
- ZHPPFHDYXXQSJJ-UHFFFAOYSA-N n-[5-bromo-3-[(3-fluorophenyl)methoxy]pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound FC1=CC=CC(COC=2C(=NC=C(Br)N=2)NS(=O)(=O)C=2C(=C(Cl)C=CC=2)Cl)=C1 ZHPPFHDYXXQSJJ-UHFFFAOYSA-N 0.000 claims 1
- CNZYJEOGKYBMJJ-UHFFFAOYSA-N n-[5-bromo-3-[[5-[(dimethylamino)methyl]furan-2-yl]methoxy]pyrazin-2-yl]-2,3-dichlorobenzenesulfonamide Chemical compound O1C(CN(C)C)=CC=C1COC1=NC(Br)=CN=C1NS(=O)(=O)C1=CC=CC(Cl)=C1Cl CNZYJEOGKYBMJJ-UHFFFAOYSA-N 0.000 claims 1
- AEZGLZPRELFUQG-UHFFFAOYSA-N n-cyclobutyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)NC2CCC2)N=C1OCC1=CC=CN=C1 AEZGLZPRELFUQG-UHFFFAOYSA-N 0.000 claims 1
- UYEZGYHJTYHHHN-UHFFFAOYSA-N n-cyclohexyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)NC2CCCCC2)N=C1OCC1=CC=CN=C1 UYEZGYHJTYHHHN-UHFFFAOYSA-N 0.000 claims 1
- XFNZHWPHGCCELN-UHFFFAOYSA-N n-ethyl-n-methyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N(C)CC)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 XFNZHWPHGCCELN-UHFFFAOYSA-N 0.000 claims 1
- BBUNXWXAMPTGTL-UHFFFAOYSA-N n-methyl-5-[(4-methylphenyl)sulfonylamino]-n-propan-2-yl-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C=1C=CN=CC=1COC1=NC(C(=O)N(C)C(C)C)=CN=C1NS(=O)(=O)C1=CC=C(C)C=C1 BBUNXWXAMPTGTL-UHFFFAOYSA-N 0.000 claims 1
- RAHWZDQXHDQMFI-UHFFFAOYSA-N n-tert-butyl-5-[(4-methylphenyl)sulfonylamino]-6-(pyridin-3-ylmethoxy)pyrazine-2-carboxamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1=NC=C(C(=O)NC(C)(C)C)N=C1OCC1=CC=CN=C1 RAHWZDQXHDQMFI-UHFFFAOYSA-N 0.000 claims 1
- 229920000728 polyester Polymers 0.000 claims 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 206010039083 rhinitis Diseases 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 5
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 108010004073 cysteinylcysteine Proteins 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102100023698 C-C motif chemokine 17 Human genes 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000002975 chemoattractant Substances 0.000 description 3
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 2
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 206010014950 Eosinophilia Diseases 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 2
- 101000978362 Homo sapiens C-C motif chemokine 17 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000721454 Pemphigus Species 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102100036154 Platelet basic protein Human genes 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 2
- 229960002023 chloroprocaine Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 108010035886 connective tissue-activating peptide Proteins 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 229940043237 diethanolamine Drugs 0.000 description 2
- 201000002491 encephalomyelitis Diseases 0.000 description 2
- 229940031098 ethanolamine Drugs 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 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 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 235000019371 penicillin G benzathine Nutrition 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- QUPFKBITVLIQNA-KPKJPENVSA-N (5e)-2-sulfanylidene-5-[[5-[3-(trifluoromethyl)phenyl]furan-2-yl]methylidene]-1,3-thiazolidin-4-one Chemical compound FC(F)(F)C1=CC=CC(C=2OC(\C=C\3C(NC(=S)S/3)=O)=CC=2)=C1 QUPFKBITVLIQNA-KPKJPENVSA-N 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 208000035939 Alveolitis allergic Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 201000008283 Atrophic Rhinitis Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 1
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- 101710155833 C-C motif chemokine 8 Proteins 0.000 description 1
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 1
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108091008927 CC chemokine receptors Proteins 0.000 description 1
- 102000005674 CCR Receptors Human genes 0.000 description 1
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 description 1
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 description 1
- 108050006947 CXC Chemokine Proteins 0.000 description 1
- 102000019388 CXC chemokine Human genes 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 108010082169 Chemokine CCL17 Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 108010078239 Chemokine CX3CL1 Proteins 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 206010057645 Chronic Inflammatory Demyelinating Polyradiculoneuropathy Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 102100031107 Disintegrin and metalloproteinase domain-containing protein 11 Human genes 0.000 description 1
- 101710121366 Disintegrin and metalloproteinase domain-containing protein 11 Proteins 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000027445 Farmer Lung Diseases 0.000 description 1
- 206010016228 Fasciitis Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 102000013818 Fractalkine Human genes 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000798902 Homo sapiens Atypical chemokine receptor 4 Proteins 0.000 description 1
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 description 1
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 description 1
- 101000716070 Homo sapiens C-C chemokine receptor type 9 Proteins 0.000 description 1
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 1
- 208000009388 Job Syndrome Diseases 0.000 description 1
- 206010024227 Lepromatous leprosy Diseases 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 201000002832 Lewy body dementia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 1
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000027771 Obstructive airways disease Diseases 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 206010060932 Postoperative adhesion Diseases 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010039088 Rhinitis atrophic Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 229920013632 Ryton Polymers 0.000 description 1
- 239000004736 Ryton® Substances 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044696 Tropical spastic paresis Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047112 Vasculitides Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000017760 chronic graft versus host disease Diseases 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 208000022195 farmer lung disease Diseases 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 206010051040 hyper-IgE syndrome Diseases 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 206010065579 multifocal motor neuropathy Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 208000020469 nerve plexus disease Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 208000018360 neuromuscular disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000012111 paraneoplastic syndrome Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 201000006380 plexopathy Diseases 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000017443 reproductive system disease Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 208000006961 tropical spastic paraparesis Diseases 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
®
N-PYRAZINYL-PHENYLSULPHONAMIDES AND THEIR USE IN THE TREATMENT } OF CHEMOKINE MEDIATED DISEASES - The present invention relates to a sulphonamide compound, processes and intermediates s used in their preparation, pharmaceutical compositions containing them and their use in therapy.
Certain sulphonamide compounds are known in the art, for example see
GB2295616, US patent 2002143024, WO 01/44239, EP 749964 and Esche, J; Wojahn, H. Arch. Pharm. (1966), 299(2), 147-153.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small-secreted 1s molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. At the present time, the chemokine superfamily comprises three groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C), Cys-Cys (C-C) and Cys-X3-Cys (C-X3-C) families. The C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The C-X;-C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the
NH-proximal pair of cysteine residues.
The C-X-C chemokines include several potent chemoattractants and activators of 2s neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils. Examples include human monocyte chemotactic proteins 1-3 (MCP-1,
MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and
Secreted), eotaxin and the macrophage inflammatory proteins 1a and 1 (MIP-1a and
MIP-18), Thymus and Activation Regulated Chemokine (TARC, CCL17) and Macrophage ’ Derived Chemokine (MDC, CCL22).
The C-X3-C chemokine (also known as fractalkine) is a potent chemoattractant and 35s activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
@ ) } Studies have demonstrated that the actions of chemokines are mediated by subfamilies of ’ G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, ‘ CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 ’ s (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCRS5 (for the C-X-C family) and CX3CR1 for the C-X;-C family. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
The present invention therefore provides a compound of formula (I) and pharmaceutically acceptable salts, solvates or N-oxides thereof:
R' 0
I oH 3 6 2
RY ONT OR
(D in which:
R!, R? and R? are independently hydrogen, halogen, cyano, CF3, OCF;, OC;.s alkyl or Cy. alkyl;
R*is halogen, COR",
Ci-6 alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group; 2s Cs. alkenyloxy or C;.¢ alkynyloxy where either may be optionally substituted with hydroxy or NR™R"?;
OC,.¢ alkyl-X-C.¢ alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OCigalkylR", or OC, alkyl-X-R'' where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'*R", SR'?, S(0).R", S(O)R" or COR";
® 3 ] OC, alkylR'S; * y R’ and R® are independently hydrogen, cyano, halogen, CO.R'?, CONRRY:
Ci.6 alkyl optionally substituted by hydroxy, NR"*R'>, or 1-3 fluorines;
Cis alkylR' or XCH(R')C)¢ alkyl or XCH(R'®)C,.¢ alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR*R"%;
NRYR"; NR'R'; X-(CH,)qNR “RY; (CH,)nNR “R'%; NHC(0)C, 6 alkyl optionally substituted by one or more hydroxy groups,
Cs.¢ alkynyl or Cs. alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O;
RY X-R'; X-R'%; X-CpealkylR'S; X-R'S; X-(CH,)nCO,R "2; X-(CH,)nCONRR';
X-(CHz)nR"'; X-(CHa)nCN; X-(CH,)qOR'% (CH,)nOR'%; (CHz)n-X-R''; X-(CH2)gNHC(O)NHR '?; X-(CH,)gNHC(O)R 2;
X-(CHz)qNHS(0)2R'?; X-(CH,)qNHS(O),R'}; X-Cs_galkenyl; X-C alkynyl; nis1,2,3,4o0rS5; qis 2,3,4,5 or 6;
X is NR", 0, 8, S(0), S(0)y;
R'! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR™R", C(O)OR'?, hydroxy, =O, =S, CN, NO,,
COR", NRMR", X(CH)qNR"R", (CH,)nNRR'®, (CH,)nOH, SR", S(O)R", S(O),R"
Ci. alkyl-X-Cy.¢ alkyl, C, alkyl or C, alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, ) halogen, NR'R"’, SR", S(O)R', S(O),R"3; :
® ‘
Rand R" are independently hydrogen or C;.¢ alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring; , “ R'" and R'® are independently hydrogen, C,.¢ alkyl, Cs.¢ cycloalkyl or (CH2)qOH,
S or R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.s alkyl, C,.¢ alkyl-OH, or hydroxy; and
R'®is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected trom hydroxy, cyano, halogen and =0, provided that: » when R” is halogen or C,4alkoxy and R® is hydrogen, halogen, C,4alkyl,
C).alkoxy, C;.oalkylthio, trifluoromethyl or ethynyl and when one of R!, R*orR? is Cy.¢alkyl or C,salkoxy and is meta to the sulphonarnide group then the group ortho to both the sulphonamide group and the C;.¢alkyl or C,.salkoxy group is not hydrogen, e when R* is halogen or C,.salkoxy and R® is hydrogen, halogen, C)alkyl,
Ci.palkoxy, Cyalkylthio, trifluoromethyl or ethynyl and when one of R’ s R? or R3 is Cygalkyl or C,salkoxy and is ortho to the sulphonamide group then the group ortho to the C,.4Alkyl or C,.salkoxy and also meta to the sulphonamide group is not hydrogen, e when two of R', R%, R® are hydrogen and the other is a methyl group para to the sulphonamide and R? is methoxy then R? is not hydrogen or bromo, and » when R® is methyl and RS is methoxy and one of R', R? or R’ is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group.
The term aryl includes phenyl and naphthyl. The term alkyl, whether alone or as part of another group, includes straight chain and branched chain alkyl groups. Examples of 5- to 7-membered heteroaromatic ring containing 1 to 4 heteroatoms include thienyl, furanyl, pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxazolyl, 3s thiazolyl, isoxazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl.
Examples of saturated 4- to 8-membered rings containing 1 to 3 heteroatoms include
® ; morpholine, piperidine and azetidine. Substituents on any rings can be present in any
E suitable ring position including suitable substituents on nitrogen atoms. “ Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will 5s be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Preferred halogen groups for R', R? and R? are chloro, bromo and fluoro. Preferably one of R!, R? and R*is hydrogen and the other is chloro, bromo or methyl. More preferably R! and R? are chloro at the 2- and 3-positions of the phenyl ring and R*is hydrogen (i.e. 2,3- dichlorophenyl), R' and R? are chloro at the 2- and 4-positions of the phenyl ring and Ris hydrogen (i.e. 2,4-dichlorophenyl) or R' is chloro at the 2-position and R? is methyl at the 3-position of the phenyl ring and R? is hydrogen (i.e 2-chloro-3-methylphenyl). Most 1s preferably R! and R” are chloro at the 2- and 3-positions of the phenyl ring and Ris hydrogen (i.e. 2,3-dichlorophenyl).
In a further aspect the invention provides a compound of formula (I) as defined above but without the provisos where R' and R? are chloro at the 2- and 3-positions of the phenyl ring and R?is hydrogen (i.e. 2,3-dichlorophenyl), R! and R? are chloro at the 2- and 4-positions of the phenyl ring and R?is hydrogen (i.e. 2,4-dichlorophenyl) or R' is chloro at the 2- position and R? is methyl at the 3-position of the phenyl ring and R* is hydrogen (i.e 2- chloro-3-methylphenyl). 2s For the group R* examples of Cs. alkenyloxy include OCH,CH=CH,, examples of
Cs.¢ alkynyloxy include OCH,CCH, examples of OC,.¢ alkyl-O-C, alkyl include
OCH,CH;0Me, examples of OC, alkylR"! include OCH,R", and examples of
OC, alkylR'® include OCH;pyrrolidine.
Preferred groups for R* include Cy alkoxy such as methoxy, 2-furanylmethoxy, bromo, } chloro, 2-methoxyethoxy, (5-methyl-3-isoxazolyl)methoxy, 2-, 3- or 4-pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(1-imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. More preferably R* is methoxy.
For R>and R® examples of NR"R" includes morpholine, pyrrolidine, NMe;,
NHCH,CH,0OMe, NHMe, and the groups below:
\ A
OO
OH and OH
Examples of X-(CH2)gNR'“R"* include SCH,CH,NH, and SCH,CH,NMe; , examples of (CHpnNR'R" include CHsmorpholine, examples of X-R'? includes SMe, OMe, OEt, OH,
SO,Me, examples of X-C,alkylR' includes OCH, pyrrolidine, examples of X- (CH2)nCO,R*? includes SCH,CO,H, SCH,CO,Me, SCH,CH,CO,;Me, examples of X- (CH2)nCONR"R" includes SCH,CONH, , SCH,CONHMe, OCH,;CONEt,, examples of X-(CH2)nR" includes the groups below:
N_
N= 0) Ze N.S
W — 07 P o> \ —/ -
Examples of X-(CH2),CN, includes SCH,CN, examples of X-(CH,)qOR includes
OCH,CH,OMe, examples of (CH2)nOR "2 includes CH,OH, CH,OMe, examples of 1s X-(CH»)QNHC(O)NHR'? includes SCH,CH,NHC(O)NHEY, and examples of
X-(CH,)qNHC(O)R ? includes NHCH,CH,NHC(O)Me. Examples of NHC(O)C,. alkyl optionally substituted by one or more hydroxy groups includes NHCOCH,OH.
Preferred groups for R® include hydrogen, halogen such as bromo and chloro, phenyl,
Cp alkyl such as methyl, CH,0OH, cyano and 2-aminothanethiol. More preferably Ris hydrogen, methyl, CH,OH or halogen such bromo or chloro.
Preferred groups for R® include hydrogen, C.s alkyl, CH,OH and halogen, more preferably hydrogen, methyl, CH,OH or chloro. : In a further aspect the invention provides a compound of formula (1A):
R! 0
No
Rr’ He N Y N bg R
RYTON ORE
(IA) in which sR’, R?’and R*are independently hydrogen, halogen, cyano, CFs, OCF;, C,¢ alkenyl! or
C 1-6 alkyl;
R*is halogen, C,.¢ alkoxy or OR’;
R® and R® are independently hydrogen, halogen, C,.¢ alkoxy, Ci. alkylthio, cyano, R’,
OR’, NR’R'’, SR’, S(CH2),CO,H, S(CH2),CO,R'%, S(CH2),CONR'?R", S(CH2),R" or a 5-to 7-membered heteroaromatic or saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur; nisl, 2or3;
R® and R'® are independently hydrogen, C,., alkyl optionally substituted by hydroxy, C). alkoxy or NHCOC,¢ alkyl, or R® and R' are optionally substituted aryl, C,.¢ alkyl-aryl or
Cig alkyl-R"” or R® and R" together with the nitrogen atom to which they are attached form a 4- to 8-membered saturated ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.¢ alkyl or C,.¢ alkyl-OH; and
R'is a 5- to 7-membered heteraromatic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C,.¢ alkyl; and
R7andR" are independently hydrogen or C,.¢ alkyl.
For compounds (IA) R', R? and R? are independently hydrogen, halogen, cyano, CF;,
OCF;, Cy alkenyl or C,.¢ alkyl, preferred halogen groups being chloro. Preferably one of
R!, R?and R*is methyl, ethenyl, cyano, chloro, fluoro, iodo or two are chloro or all three 2s are fluoro. More preferred are compounds where R' — R? together with the phenyl group to which they are attached form a 3-chloro-2-methylpheny! or a 2,3-dichlorophenyl group.
For compounds (IA) preferred groups for R* include halogen such as bromo and chloro,
C,.¢ alkoxy such as methoxy and ethoxy, C,_¢ alkyl or OR’ where R’ is CH,R'! where R"! isa 5- or 6-membered heteraromatic ring containing 1 or 2 heteroatoms.
g
More preferably R* is methoxy, halogen, such as chloro, or OR’ where R® is CH,R'! where . R'is furanyl, 5-methyl-3-isoxazolyl, pyridyl optionally substituted by methyl, pyridazinyl, pyrazinyl, 1-methyl-6-0xo-1,6-dihydro-3-pyridinyl. s For compounds (IA) preferably R’ is hydrogen, methyl, bromo, chloro, methoxy, morpholinyl, pyrrolinyl, dimethylamino, hydroxy, 2-methoxyethoxy, pyrazinyl, pyrimidinyl, O-Ph-CO,H, 2-hydroxyethylamino, 2-methoxyethylamino,
NHCH,CH,NHCOMe, cyano, 4-hydroxymethyl-1-piperidinyl, SMe, NHMe, or 2,4- difluorophenyl.
For compounds (IA) preferably Réis hydrogen or chloro.
Preferred compounds of formula (I)/(IA) include those exemplified herein both in free base form and as pharmaceutically acceptable salts.
According to the invention there is also provided a process for the preparation of compound (I) which comprises reaction of a compound of formula (II):
R5 N R4 ~N
J
R6 N NH, dn where R*, R® and R® are as defined in formula (I) or are protected derivatives thereof with a compound of formula (II): rR! i
RZ $=0
LG
Rr3 10) where R!, R? and R? are as defined in formula (I) or are protected derivatives thereof and
LG is a leaving group, and optionally thereafter
* removing any protecting groups, . » forming a pharmaceutically acceptable salt. i Preferred leaving groups LG include halogen such as chloro. Preferably the reaction s between compounds (II) and (Il) is carried out by treating compound (II) with a base such as sodium hydride or potassium tert-butoxide in a suitable solvent such as 1,2- dimethoxyethane or tetrahydrofuran.
Where R* is C,.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group; : Cs.6 alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with hydroxy or NR'R!%:
OC\.6 alkyl-X-C. alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC, alkyIR"!, or OC, alkyl-X-R'! where the alkyl group may form a 3-6 membered - saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'R"?, SR", S(0),R", S(O)R"?; or
OC. alkyIR'S; compounds of formula (IT) can be prepared by treating a compound of the formula (IV), where LG is a leaving group (such as chlorine or bromine):
RA. N_ _LG ~ 1 1
R N NH, (v) with a compound of formula (V)
R*-H
Vv) in a suitable solvent (such as 1,2-dimethoxyethane, N,N-dimethylformamide or ) tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
Where R” is C;.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or . may be substituted with 1-3 fluorine atoms or a cyano group;
Ci. alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with . hydroxy or NR*R">;
OC, alkyl-X-C, alkyl where the alkyl groups may form a 3-6 membered saturated ring;
OC, 6 alkyIR", or OCs alkyl-X-R" where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR"“R"’, SR", S(O),R", S(O)R"; or
OC, alkylR'¢; compounds of formula (I) can be prepared by treating a compound of the formula (V1), where LG is a leaving group (such as chlorine or bromine): :
Ri. _N._ _LG
AN
BD bg
R N NH
0=S8=0 “0
RZ TR’ (V1) with a compound of formula (V) in a suitable solvent (such as 1,2-dimethoxyethane, N, N-dimethylformamide or tetrahydrofuran) with a suitable base such as sodium hydride or potasssium tert-butoxide at a suitable temperature such as 25°C to 60°C.
Compounds of structure (V111) can be prepared by taking a compound of formula (V1) where LG is a leaving group (such as chlorine or bromine) and protecting the sulfonamide as for example the trimethylsilyethoxymethyl ether (SEM) or methoxymethy] ether . 2s (MOM) by the standard literature methods (such as SEM-chloride or MOM-chloride) in a suitable solvent (such as tetrahydrofuran) with a suitable base (such as triethylamine) at a . suitable temperature (such as 0-20°C) to afford compound of the formula (V111):
® 1
LG. _N : 4 or rr
N Ps : R P
R® N NH Rr Nd } O0=8=0 0=8=0
R® R’ Rr’ R’ (Vi) (vi)
Compound of formula (VIII) could then be treated with compounds of formulae (1X):
R*-H (1x) where R>-H is a primary or secondary amine, thiol or alcohol as defined above (i.e. where
R’isa group containing an X moiety where X is NR'?, O or 8), in a suitable solvent (such as tetrahydrofuran or acetonitrile) with or without a suitable base (such as sodium hydride, caesium carbonate or triethylamine) at a suitable temperature ranging from 25-85°C to afford compound of the formula (X):
RA_ _N_ _R
IX
= P
R*” ON N” 0=8=0 2 R®
R
X) : The protecting group (P) can then be removed by standard methods to afford compound of formula (1).
Compounds of structure (11) or (1), where R’ is an optionally substituted aryl or heteroaryl ring as defined in the claims, can be prepared by taking a compound of formula (X1) or (VII) where LG is a suitable leaving group such as bromine, chlorine or iodine and reacting
® 12 it with an aryl or heteroaryl boronic acid such as phenyl boronic acid, a palladium catalyst . such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride, a suitable base such as caesium fluoride, sodium acetate or caesium carbonate and a suitable solvent such as i methanol or ethanol and heating between 40-80°C 4 5 4
R N R
Tr TT ~~ 6 —
R° N™ NH, R N™ “NH, (xX 4) : RL. N_ _R*
Or TX — 2
RS NT NH . RT ONT TH 0=8=0 0=S=0 1 3 3 2 R
R? R R (VID) 0)
Compounds of formula (11) and (1) where R® or R® is CO,R"® can be prepared by reacting a compound of formula (11) or (1), where R® or R® is bromine or iodine, in a suitable solvent 1s such as ROH or dioxane containing R'> OH, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C.
Compounds of formula (11) and (1) where R® or RS is CONRMR'® can be prepared by reacting a compound of formula (11) or (1), where R® or R® is bromine or iodine, in a suitable solvent such as dioxane containing NHR'“R'%, a suitable tertiary amine such as triethylamine, a suitable palladium catalyst such as [1,1°-bis(diphenylphosphino)ferrocene]palladium (11) chloride under an atmosphere of carbon monoxide usually at 2-10 bar, ideally at 4-6 bar and at a temperature of 70-120 °C, 2s Compounds of formula (1) where R’ or R® is CH,OH can be prepared from compounds of formula (I) where R® or R®is COR" by reduction using a suitable reducing agent such as
® E lithium triethylborohydride in a suitable solvent such as tetrahydrofuran at a temperature of - 0-10°C. - Compounds of formula (1) where R® or R° is CHO can be prepared from compounds of formula (1) where R® or R® is CH,OH by oxidation using a suitable oxidising agent such as manganese dioxide or pyridinium chlorochromate (PCC) in a suitable solvent such as tetrahydrofuran or dichloromethane at a temperature of 0-50°C.
Compounds of formula (I) where R® or R® is CH(OH)R'' or CH(OH)(C1-5)alkyl can be prepared from compounds of formula (1) where R® or R® is CHO by reaction with a compound of formula (XII) where M is a metal such as magnesium or lithium in a suitable solvent such as tetrahydrofuran or diethyl ether at a temperature of 0-10°C
Cys alkylM or R''M (X11)
RA. _N_ _R ii RNS
TN O0—=s=0 : Bi 1 x i ’ <0) RON NH
R N LG
R? 3 0=8=0 “0
Rr R’ xin (XIV) (XV)
A compound of formula (XV) can be made by reacting a compound of formula (XIII), where R’ is preferrably chloro, bromo or alkoxy and LG is a suitable leaving group such as chloro or bromo, with a compound of formula (XIV) using a suitable base such as potassium carbonate or caesium carbonate in a suitable solvent such as N,N- dimethylformamide at a temperature of 40-90°C
Intermediate compounds of formula (II) and (III) can be prepared using standard chemistry : 25 or are available commercially. : It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compound may need to be protected by protecting groups. Thus, the preparation of the compound of formula (I) may involve, at an appropriate stage, the [
® y removal of one or more protecting groups. The protection and deprotection of functional
E groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F.
McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’, 2nd edition, : T. W. Greene & P. G. M. Wuts, Wiley—Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of formula (II) and (III) are believed to be novel and form a further aspect of the invention.
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably a basic addition salt such as sodium, potassium, calcium, aluminium, lithinm, magnesium, zine, benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, ethyldiamine, meglumine, tromethamine or procaine, or an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
The compounds of formula (I) has activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR4) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.
Examples of such conditions/diseases include: (1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, ; intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, . atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa
® 15 (hay fever) and vasomotor rhinitis; sarcoidosis, farmer’s lung and related - diseases, fibroid lung and idiopathic interstitial pneumonia; : (2) (bone and joints) gout, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and
Reiter’s disease), Behcet's disease, Sjogren’s syndrome and systemic sclerosis; (3) (skin) pruritis, scleroderma, otitus, psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, ~~.
Alopecia areata and vernal conjunctivitis, lupus; (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, inflammatory bowel diseases such as Crohn’s disease, ulcerative colitis, ileitis and enteritis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema, (5) (central and peripheral nervous system) Neurodegenerative diseases and dementia disorders, e.g. Alzheimer’s disease, amyotrophic lateral sclerosis and other motor neuron diseases, Creutzfeldt-Jacob’s disease and other prion diseases, HIV encephalopathy (AIDS dementia complex), Huntington’s disease, frontotemporal dementia, Lewy body dementia and vascular dementia; polyneuropathies, e.g. Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, plexopathies; CNS demyelination, e.g. multiple sclerosis, acute disseminated/haemorrhagic encephalomyelitis, and subacute sclerosing panencephalitis; neuromuscular disorders, e.g. myasthenia gravis and Lambert-
Eaton syndrome; spinal diorders, e.g. tropical spastic paraparesis, and stiff-man syndrome: paraneoplastic syndromes, e.g. cerebellar degeneration and . encephalomyelitis; CNS trauma; migraine; stroke and correctum diseases such as meningitis (6) (other tissues and systemic disease) hepatitis, vasculitis, spondyloarthopathies, vaginitis, glomerulonephritis, myositis, atherosclerosis,
Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus,
® 16 systemic lupus, erythematosus, Hashimoto’s thyroiditis, type I diabetes, ; nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, and idiopathic thrombocytopenia pupura; post-operative adhesions, . and sepsis. (7) (allograft and xenograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease; (8) Cancer, carcinoma & tumour metastasis, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, especially non-small cell lung cancer (NSCLC), malignant melanoma, prostate cancer and squamous sarcoma. Hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B cell lymphoma and Burketts lymphoma, Hodgkins Lymphoma, Acute Lymphoblastic Leukemia.
Hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia. Tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma, and other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma. (9) All diseases that result from a general inbalance of the immune system and resulting in increased atopic inflammatory reactions. (10) Cystic fibrosis, re-perfusion injury in the heart, brain, peripheral limbs and other organs. (11) Burn wounds & chronic skin ulcers 3 (12) Reproductive Diseases (e.g. Disorders of ovulation, menstruation and implantation, Pre-term labour, Endometriosis) (13) thrombosis (14) infectious diseases such as HIV infection and other viral infections, bacterial infections.
® 17
Thus, the present invention provides a compound of formula (I), or a pharmaceutically- ; acceptable salt or solvate thereof, as hereinbefore defined for use in therapy. . Preferably the compound of the invention are used to treat diseases in which the chemokine receptor belongs to the CC chemokine receptor subfamily, more preferably the target chemokine receptor is the CCR4 receptor.
Particular conditions which can be treated with the compound of the invention are asthma, rhinitis and inflammatory skin disorders, diseases in which there are raised TARC, MDC or CCR4 levels. It is preferred that the compound of the invention is used to treat asthma and rhinitis, especially asthma.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In a still further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity, particularly CCR4 activity, is beneficial.
In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.
Co.
The invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a chemokine (especially CCR4) receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
The invention also provides a method of treating a respiratory disease, such as athma and rhinitis, especially asthma, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
Claims (1)
- PCT/SE03/00041 PS 154 Claims1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: R' 0 [l 3 (3 = rR” NT TR oy in which: R!, R? and R? are independently hydrogen, halogen, cyano, CFs, OCFs, OCy. alkyl or Ci. alkyl; R*is halogen, COR,C..¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;Cs.¢ alkenyloxy or Cj. alkynyloxy where either may be optionally substituted with hydroxy or NR™R";OC,.¢ alkyl-X-C1.6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;OC. alkylR'!, or OC. alkyl-X-R'! where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NRY“R", SR", S(0),R", S(O)R"* or COR";OC. alkylR'®; CLEAN COPYPCT/SE03/00041 @: and R® are independently hydrogen, cyano, halogen, CO,R'2, CONRMR";Ci.¢ alkyl optionally substituted by hydroxy, NRYRY, or 1-3 fluorines;Cy. alkylR"" or XCH(R'")C\. alkyl or XCH(R'®)Cy.s alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NR'“R"; NRM“RY: N(R'R"; X-(CHy)gNR“R"’; (CH2)nNR'“R'’; NHC(O)C,.6 alky! optionally substituted by one or more hydroxy groups,"Cs. alkynyl or C36 alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O; R': XR": X-R'% X-CyealkylR'S; X-R'S; X-(CH)nCO;R'%; X-(CH2)nCONR'“R"; X-(CHpnR'"; X-(CH2)nCN; X-(CH,)qOR'2; (CHz)nOR'%; (CHy)n-X-R''; X-(CH;)gNHC(O)NHR '%; X-(CH,)qNHC(O)R'%; X-(CHz)qNHS(0);R 2; X-(CH;)gNHS(0),R"'; X-Cj. alkenyl; X-Cs.salkynyl; nis 1,2,3,40r5; qis2,3,4,50r6; X is NR", 0, S, S(0), S(O); R!! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR'R", C(O)OR'?, hydroxy, =O, =, CN, NO, COR", NR“RY, X(CH,)qNR"R", (CH;)nNR“R", (CH)nOH, SR", S(O)R", S(O).R"Ci. alkyl-X-C, 6 alkyl, Cy alkyl or Cy. alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NRM“RY, SR", S(O)R"?, S(O).R"; R'2and R" are independently hydrogen or C.¢ alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered ring; R'" and R" are independently hydrogen, C6 alkyl, Cs. cycloalkyl or (CH;)qOH, CLEAN COPYPCT/SE03/00041 @- R' and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by Ci.¢ alkyl, C1. alkyl-OH, or hydroxy; and R'® is a 4-8 membered saturated rin g containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O, provided that: e when R* is halogen or C;4alkoxy and RS is hydrogen, halogen, Caalkyl,C,.;alkoxy, Cj.zalkylthio, trifluoromethyl or ethynyl and when one R!, R? or R}is Ci. salkyl or C,.¢alkoxy and is meta to the sulphonamide group then the group ortho to both the sulphonamide group and the Cy.alkyl or C,.¢alkoxy group is not hydrogen, e when R* is halogen or Cj4alkoxy and R’ is hydrogen, halogen, Cy.4alkyl, Cy.qalkoxy,'C,.;alkylthio, trifluoromethyl, or ethynyl and when one of R!, R2orR%is C,.¢alky! orC.¢alkoxy and is ortho to the sulphonamide group then the group ortho to the C,. salkyl or Cj.¢alkoxy and also meta to the sulphonamide group is not hydrogen, e when two of R', R% R? are hydrogen and the other is a methyl group para to the sulphonamide and R* is methoxy then R’ is not hydrogen or bromo, e when R® is methyl and R*is methoxy and one of R', R2 or R? is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group, e when R’ is methyl and R® is methoxy and one of R', R? or R® is bromo or iodo and the other two are both hydrogen, then the bromo or iodo group is not ortho to the sulphonamide group, e and the compound is nut 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 5-phenyl-2-(2-(N-phenyl-N-methylamino)ethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine : 2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N -methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(piperidin- 1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine : AMENDED SHEETPCT/SE03/000419... yclopentylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphen ylsulfonylamino)pyrazine 2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-c yclohexylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphen ylsulfonylamino)pyrazine 2-(cyclopentylmethylox y)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fl uorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfon ylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsutfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonyl amino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-bromophenylsulfonylamin o)pyrazine 2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfon ylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-phenoxyeth yloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N -phenylamino)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfon ylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 6-(perhydroazepin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclobutylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclopentylaminocarbonyl-2-((pyridin-3 -yh)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine | . 6-cyclohexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(pyrrolidin-1 -ybcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-hydroxypyrrolidin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/000417 ylpiperazin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(morpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(thiomorpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1 ,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,3-dimethylbutyl)ami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-meth ylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1 -ethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- ] methylphenylsulfonylamino)pyrazine 6-(1-meth ylbutyl)aminocarbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-pentylami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dimethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-diethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-propylamino)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dipropylaminocarbonyl-2-((pyridin-3-yl)methylox y)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/00041 outta nocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfon ylamino)pyrazine 6-ethylaminocarbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-(3-hydroxypiperidin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-meth yl-N-(2-methylpropyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-meth yl-N-pentylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(1 -methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylethyl)aminocarbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((1R)-1-methyl-2-h ydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -ethyl-N-(2-hydroxyethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxymeth ylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpiperidin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylpiperidin-1-yl)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(4-methylpiperidin-1 -ylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylpropyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylbutylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-dimethylaminoethyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxyethyl)aminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylbutyl)aminocarbonyl-2-((pyri din-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/00041@:.3-dimethylaminopropylyaminocarbonyl-2-((pyridin-3-yDmethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-hexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazin 6-(N-meth yl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-dimethylaminoethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-(1-methylethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(1-hydroxyethyl)-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((2R)-2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -ethy]-N-methylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(2-hydroxyethyl)-N -propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-carboxy-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine or 6-methoxylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine.2. A compound according to claim 1 in which one of R!, R? and R?is hydrogen and the other is chloro, bromo or methyl.3. A compound according to claim 1 or 2, in which R! and R*are chloro at the 2- and 3- positions of the phenyl ring and R? is hydrogen, or R! and R? are chloro at the 2- and 4- positions of the phenyl ring and R?is hydrogen, or R! is chloro at the 2-position and Ris methyl at the 3-position of the phenyl ring and R3is hydrogen.4. A compound according to any one of claims 1to 3 in which R* is C; alkoxy such as methoxy, 2-furanylmethoxy, bromo, chloro, 2-methoxyethoxy, (5-methyl-3- isoxazolyl)methoxy, pyridylmethoxy, 3-pyridazinylmethoxy, methoxy, 2-(1- imidazolyl)ethoxy, (2-methyl-4-oxazolyl)methoxy and 4-methoxyphenylmethoxy. AMENDED SHEETPCT/SE03/00041 o A compound according to any one of claims 1 to 4 in which R* is methoxy.6. A compound according to any one of claims 1 to 5 in which R’ is hydrogen, halogen such as bromo and chloro, phenyl,-C,.¢ alkyl such as methyl, CH,OH, cyano and 2-aminothanethiol7. A compound according to any one of claims 1 to 6 in which R® is hydrogen,C..6 alkyl, CH,OH and halogen.8. A compound according to claim 1 in which is: 2,3-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)-benzenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,3,4-tifluorobenzenesulphonamide 3-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)-2-methylbenzenesulphonamide2.3-Dichloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide2.3-Dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,5-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3,4-dichlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-4-chlorobenzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)-3-chlorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-fluorobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)benzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-2-iodobenzenesulphonamide N-(3-Methoxy-5-methyl-2-pyrazinyl)-3-fluorobenzenesulphonamide 2-[[(3-Methoxy-5-methyl-2-pyrazinyl)amino]sulphonyl]benzonitrile N-(5-Bromo-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Bromo-3-methoxy-2-pyrazinyl)2-iodobenzenesulphonamide2.3-Dichloro-N-[3-(2-furanylmethoxy)-5-methyl-2-pyrazinyl Jbenzenesulphonamide2.3-Dichloro-N-[5-methyl-3-(5-methyl-3-isoxazolylmethoxy)-2- pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[5-methyl-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[5-methyl-3-(6-methyl-2-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(3-pyridinylmethoxy)-2-pyrazinyl Jbenzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(4-pyridinylmethoxy)-2-pyrazinyl Jbenzenesulphonamide AMENDED SHEETPCT/SE03/00041 @ coro N-(5-methyl-3-(3-methyl-2-pyridinylmethoxy)-2- pyrazinyl}benzenesulphonamide 2,3-Dichloro-N-[5-methyl-3-(3-pyridazin ylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(3 -pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide N-[5 -Bromo-3-(2-pyrazinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(1-methyl-6-oxo-1,6-dihydro-3-pyridinylmethox y)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide N-[5-Bromo-3-(3 -pyridazinylimethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(3 -pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N _[5-Bromo-3-(5-pyrimidinylmethoxy)-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Chloro-3-(5-pyrimidinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(6-chloro-3-methoxy-2-pyrazinyl)benezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-2,4-dichlorobenezenesulphonamide N-(6-Chloro-3-methoxy-2-pyrazinyl)-3 ,4-dichlorobenezenesulphonamide 3-Chloro-N-(3 -methoxy-5-methyl-2-pyrazinyl)-2-methylbenezenesulphonamide 2-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 4-Chloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 2 4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide 3 4-Dichloro-N-(3-methoxy-5-methyl-2-pyrazinyl)benezenesulphonamide N-(5-B romo-3-methoxy-2-pyrazinyl)-2-trifiuoromethoxybenezenesulphonamide 3-Chloro-N-(5-chloro-3-methox y-2-pyrazinyl)-2-methylbenzenesulphonamide 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide3.Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Chloro-3 -methoxy-2-pyrazinyl)-2,4-dichlorobenzenesulphonamide2.3-Dichloro-N-[3-methoxy-5-(4-morpholinyl)-2-pyrazinylJbenzenesulphonamide2.3-Dichloro-N-[3,5-dimethoxy-2-pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[3-methoxy-5-(1 -pyrrolinyl)-2-pyrazinylJbenzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-p yrazinyl)-2-methylbenzenesulphonamide 2,3-Dichloro-N-(5 ,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 2-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 3-Chloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)benzenesulphonamide 4-Chloro-N-(5,6-dichloro-3-methox y-2-pyrazinyl)benzenesulphonamide AMENDED SHEETPCT/SE03/00041 ®, 1 chior0.-(5.6.dichlore-3-methoxy-2-pyrazinylbenzenesulphonamide 3,4-Dichloro-N-(5,6-dichloro-3 -methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(3-methoxy-5,6-dimethyl-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(6-chloro-3 ,5-dimethoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3 -methoxy-5-(4-morpholinyl)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{6-chloro-5-(2-hydroxyethylami no)-3-methoxy-2- pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[6-chloro-5-dimethylamino-3-methox y-2-pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[6-chloro-3-methoxy-5-(2-methoxyethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-5-hydroxy-3-methox y-2-pyraziny!]benzenesulphonamide 2,3-Dichloro-N-[6-methoxy-5-([2,2’ Ibipyrazinylyl)]benzenesulphonamide 4-{5-(2,3-Dichlorobenzenesul phonylamino)-6-methoxy-2-pyrazinyloxy]benzoic acid2.3-Dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide2.3-Dichloro-N-{6-chloro-3-methoxy-5-([2-methoxyeth yl)amino}-2- pyrazinyl }benzenesulphonamide N-{ 2-[3-Chloro-5-(2,3-dichlorobenzenesulphonylamino)-6-methoxy-2- pyrazinylaminoJethyl } acetamide2.3-Dichloro-N-[5-(4-hydroxymethyl-1-piperidinyl)-3 -methoxy-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5 _cyano-3-(3-pyridinylmethoxy)-2-pyrazinyljbenzenesulphonamide2.3-Dichloro-N-(6-chloro-3-methoxy-5-methylamino-2-pyrazinyl )benzenesuiphonamide 2,3-Dichloro-N-(3 -methoxy-5-methylsulphanyl-2-pyraziny!)benzenesulphonamide2.3-Dichloro-N-[5-(2,4-diflucrophen yl)-3-methoxy-2-pyrazinyl]benzenesulphonamide [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetic acid methyl ester [5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyljacetic acid2.3-Dichloro-N-[5-(2-chlorobenzylsulphanyl)-3 -methoxy-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-5-(3-hydroxy-1 -azetidinyl)-3-methoxy-2- ~ pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-meth yl-3-(1-oxy-3-pyrazinylmethox y)-2-pyrazinylJbenzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(4-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(1-oxy-4-pyridinylmethox y)-2-pyrazinyl}benzenesulphonamide2.3-Dichloro-N-[S-chloro-3-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(2-methylsulphanylethoxy)-2-pyrazinyl]benzenesulphonamide N-(3-Butoxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide2.3-Dichloro-N-[{5-chloro-3-(2-methyl-3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide AMENDED SHEETPCT/SE03/00041 ®, 1 cioro-(5-chioro-3 -(6-methyl-2-pyridinylmethoxy)-2- pyrazinyi]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(1-oxy-2-pyridinylmethox y)-2-pyrazinyl]benzenesulphonamide 3-Chloro-N-[5-chloro-3-(3-pyridin ylmethoxy)-2-pyrazinyl}-2-methylbenzenesulphonamide 3-Chloro-N-[5-chloro-3-(3 -pyridinylmethoxy)-2-pyrazinyl]-2-fluorobenzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(4-methoxyphenylmethox y)-2-pyrazinyl}benzenesulphonamide N-[5 -Bromo-6-chloro-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(3 -pyridinylmethoxy)-2-pyrazinyl}benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(2-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide N-[5-(2-Aminoethylsulphanyl)-3-(2-pyridinylmethoxy)-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(6-methoxy-3-pyridinylmethoxy)-2- pyrazinyl}benzenesulphonamide N-[3-(3-Bromophenylmethoxy)-5-chloro-2-pyrazinyl] -2,3-dichlorobenzenesulphonamide 3-[6-Chloro-3~(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyljbenzoic acid methyl ester 3-[6-Chloro-3-(2,3-dichlorobenzenesulphonylamino)-2-pyrazinyloxymethyl]benzoic acid :2.3-Dichloro-N-[5-chloro-3-(3-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(3-methylaminomethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-{ 3-([2-hydroxyethylamino]methyl)phenylmethoxy }-2- pyrazinyljbenzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(4-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[{S-chloro-3- {4-([2-hydroxyethylamino]methyl)phenylmethoxy }-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(4-h ydroxymethylphenylmethoxy)-2-pyrazinyl}benzenesulphonamide2.3-Dichloro-N-[5-chloro-3-(2-hydroxymethylphenylmethoxy)-2- pyrazinyl]benzenesulphonamide 5-(2,3-Dichlorobenzenesuphonyl amino)-6-methoxypyrazine-2-carboxylic acid, methyl ester 2,3-Dichloro-N-{5-(1-hydroxy-1-methyleth yb)-3-methoxy-2-pyrazinyl}benzenesulphonamide N-[5-(2-Aminoethoxy)-3 -methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-[(2-Aminoeth ylthio]-6-chloro-3-methoxy-2-pyrazinyl }-2,3- dichlorobenzenesulfonamide 3-[(5-{[(2,3-Dichlorophenyl)sulphonyljamino} -6-methoxy-2-pyrazinyl)thio]propanoic acid, methyl ester 2 3-Dichloro-N-[5-bromo-3-methox y-6-methyl-2-pyrazinyl ybenzenesulphonamide AMENDED SHEETPCT/SE03/00041©... 5 Dichiorobenzencsulphonylaming)-6-methoxy-3-methylpyrazine-2-carboxylic aicd, methyl ester 2,3-Dichloro-N-[5-(hydroxymethyl)-3 -methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[5,6-dichloro-3-(3-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide 3-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-2-fluorobenzenesulphonamide 3-Chloro-2-fluoro-N-[3-(3-pyridinylmethoxy)-2-pyrazinyl}benzenesulphonamide 3-{[(2,3-Dichlorophenyl)sulphonyl]amino } pyrazine-2-carboxylic acid, methyl ester N-(5-Bromo-6-chloro-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 3-Chloro-5-{[(2,3-dichlorophenyl)sulphonyl]amino }-6-methoxypyrazine-2-carboxylic acid, methyl ester 2,3-Dichloro-N-[6-chloro-5-(hydroxymethyl)-3-methoxypyrazin-2-yl]benzenesulphonamide 2,3-Dichloro-N-{3-[(6-methoxy-3-pyridinyl)methoxy]-2-pyrazinyl }benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-methoxy-5-(methox ymethyl)-2-pyrazinyl]benzenesul phonamide 2-Chloro-N-(5-chloro-3-methoxy-2-pyrazinyl)-3-fluorobenzenesulphonamide 2-Chloro-3 -fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide 2-Chloro-3-methoxy-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide N-[5-Bromo-3-[(25)-2-pyrrolidinylmethoxy]-2-pyrazinyl]-2,3 -dichlorobenzenesulphonamide 5-(2,3-Dichlorobenzenesulphonylamino)-6-(3-pyridinylmethoxy)pyrazine-2-carboxylic acid, methyl ester 5-{[(2,3-Dichlorophenyl)sulphonyl]amino }-6-(3-pyridinylmethoxy)-2-pyrazinecarboxamide2.3-Dichloro-N-[5-(4-pyridinyl)-3-(3-pyridinylmethoxy)-2-pyrazinylJbenzenesulphonamide 2,3-Dichloro-N-[5-(hydroxymethyl)-3-(3-pyridinylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-(hydrox ymethyl)-3-methoxy)-2-pyrazinyl]benzenesulphonamide 4-Amino-2,3-dichloro-N-(5-chloro-3-methoxy-2-pyrazinyl)benzenesulphonamide N-(5-Allyloxy-3-methoxy-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[5-(3-hydroxy-1-propyn yl)-3-methoxy-2-pyrazinyl]benzenesulphonamide N-{3-[(5-Bromo-3-pyridinyl)methoxy}-5-chloro-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide 2 3-Dichloro-N-[5-chloro-3- { [6-(hydrox ymethyl)-2-pyridinylJmethoxy }-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-[(2-methyl-4-oxazolyl)methoxy]-2- pyrazinyl }bénzenesulphonamide 2 3-Dichloro-N-{3-[(2-methyl-4-oxazolyl)methoxy]-2-pyrazinyl }benzenesulphonamide N-[5-Bromo-3-(phen ylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-(2-c yclopropylethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(3-thien ylmethoxy)pyrazinyl]-2,3-dichlorobenzenesulphonamide AMENDED SHEETPCT/SE03/00041 ® 166 N-{5-Bromo-3-[(2-methyl-3-furanyl)methoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-{5-Bromo-3-[(3-furanyl)methoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[(4-fluorophenyl)methoxy}-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[(3-fluorophenyl)methoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-{3-(2-pyridinyl)propoxyl-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(pentyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(propyloxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-methox yethoxy)-2-pyrazinyl}-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-ethox yethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(2-fluoroethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[2-(1 H-imidazol-1-yl)ethoxy}-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(3-pyridinyl)propoxy]-2-pyrazinyl }-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-[2-(methylamino)ethoxy]-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-{5-Bromo-3-[3-(4-hydroxyphenyl)propoxy]-2-pyrazinyl}-2,3- dichlorobenzenesulphonamide N-[5-Bromo-3-(2-phenoxyethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3-(cyclopropylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[5-Bromo-3 -(3-phenoxypropoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2 3-Dichloro-N-(5-ethoxy-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-([1,2,4]-1 -triazolyl)-2-pyrazinyl]benzenesulphonamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]-N- methylacetamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinylsulphanyl]acetamide 2,3-Dichloro-N-[5-(4-fluorobenzylsulphanyl)-3-methoxy-2-pyrazinylJbenzenesulphonamide2.3-Dichloro-N-[5-cyanomethylsulphanyl-3-methoxy-2-pyrazinyl]benzenesulphonamide 2 3-Dichloro-N-[3-methoxy-5-([1,2,4]-3-oxadiazolylmethylsulphanyl)-2- pyrazinyl]benzenesulphonamide N-[5-(2-Aminoethylsulphanyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(5-methyl-3-isoxazolylmethoxy))-2- pyrazinyl]benzenesulphonamide2.3-Dichloro-N-[5-(5-dimethylaminomethyl-2-furanylmethox y)-3-methoxy-2- pyrazinyl]benzenesulphonamide N-[5-Bromo-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2-pyrazinyl] -2,3-dichloro- benzenesulphonamide2.3-Dichloro-N-{5-(2-hydroxyeth ylsulphanyl)-3-methoxy-2-pyrazinyl]benzenesuiphonamide 2 3-Dichloro-N-{5-[2-(ethylureido)ethylsulphanyl]-3-methoxy-2- pyrazinyl}benzenesulphonamide AMENDED SHEETPCT/SE03/00041@. 1 chioro-(3-(5-dimethylaminomethyl-2-furan ylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[6-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide : 2,3-Dichloro-N-[6-chloro-3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-(5-dimethylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(5-methylaminomethyl-2-furanylmethoxy)-2- pyrazinyl]benzenesulphonamide N-(5-Bromo-3-methoxypyrazinyl)-2-cyanobenzenesulphonamide N-(5-Bromo-3-methoxypyrazinyl)-2,3-dichloro-4-fluorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(4-morpholinylmethyl)-2-pyrazinyl Jbenzenesulphonamide N-(3-Allyloxy-5-chloro-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(2-propynyloxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[3-(2-propynyloxy)-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-(5-cyano-3-methoxy-2-pyrazinyl)benzenesulphonamide2.3-Dichloro-N-{3-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-2- pyrazinyl }benzenesulfonamide hydrochloride 2,3-Dichloro-N-{6-chloro-3-methoxy-5-[(2R)-2-pyrrolidinylmethox y]-2- pyrazinyl }benzenesulphonamide Hydrochloride2.3-Dichloro-N-[3-methoxy-5-(2-pyridinylmethoxy)-2-pyrazinyl]benzenesulphonamide Hydrochloride 2,3-Dichloro-N-(3-methoxy-6-methyl-2-pyrazinyl)benzenesulphonamide2.3-Dichloro-N-[3-methoxy-5-(1H-1,2,4-triazol- 1-ylmethyl)-2- pyrazinyl]benzenesulphonamide N-(3-(5-Aminomethyl-2-furanylmethoxy)-5-chloro-2-pyrazinyl)-2,3-dichloro- benzenesulphonamide N-(3-(5-Ami nomethyl-2-furanylmethoxy)-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide 2,3-Dichloro-N-[3-methoxy-5-(2-propyn-1-yloxy)-2-pyrazinylJbenzenesulphonamide {[5-(2,3-Dichlorophenylsulfonylamino)-6-methoxy-2-pyrazinylJoxy }acetic acid, methyl ester N-[5-(2,3-Dichlorophenylsulphonylamino)-6-methoxy-2-pyrazinyl]-2-hydrox yacetamide 6-(2,3-Dichlorophenylsulphonylamino)-5-methoxy-2-pyrazinecarboxylic acid, methyl ester2.3-Dichloro-N-[6-(hydroxymethyl)-3-methoxy-2-pyrazinyl]benzenesulphonamide2.3-Dichloro-N-(5-methanesulphonyl-3-methoxy-2-pyrazinyl)benzenesulphonamide 2-[5-(2,3-Dichlorobenzenesulphonylamino)-6-methoxy-2-pyrazinyloxy]-N,N-diethyl- acetamide AMENDED SHEETPCT/SE03/00041Qo. 5-[2-(dimethylamino)ethylsulphanyl]-3-methoxy-2- pyrazinyl }benzenesulphonamide 2,3-Dichloro-N-(5-difluoromethyl-3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-4-fluoro-N-(3-methoxy-2-pyrazinyl)benzenesulphonamide 2,3-Dichloro-N-{5-chloro-3-[ 1-(cyclopropyl)ethoxy]-2-pyrazinyl } benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-formyl-2-furanylmethoxy)-2-pyrazinyl]benzenesulphonamide 2,3-Dichloro-N-[5-chloro-3-(5-cyclopropylaminomethyl-2-furanylmethoxy)-2-pyrazinyl]- benzenesulphonamide N-[5 ,6-bis-(Hydroxymethyl)-3-methoxy-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide N-[3-[(2-amino-4-oxazolyl)methoxy]-5-chloro-2-pyrazinyl]-2,3- dichlorobenzenesulphonamide and pharmaceutically acceptable salts and solvates thereof. :9. A process for the preparation of compound (I) which comprises: (a) reaction of a compound of formula (II): RS N R4 j AN TX R6 N NH, ety) where R*, R® and R® are as defined in formula (I) or are protected derivatives thereof with a compound of formula (III): R! i R2 $=0 LG Rr? (IIT) a where R', R? and R? are as defined in formula (I) or are protected derivatives thereof and LG is a leaving group, or (b) for compounds where R* is C\.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a cyano group;Cs. alkenyloxy or Cs. alkynyloxy where either may be optionally substituted with hydroxy or NR"R"; AMENDED SHEETPCT/SE03/00041 LN alkyl-X-C.¢ alkyl where the alkyl groups may form a 3-6 membered saturated ring; OC, alkylR"", or OC, alkyl-X-R'' where the alkyl group may form a 3-6 membered saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR"“R", SR", S(0),R", S(O)R"; orOC. alkyIR'S; treating a compound of the formula (V1), where LG is a leaving group:RA. _N._ LGaN XX R N NH 0=S=0 R! RR (V1) with a compound of formula (V) in the presence of a suitable base, or (c) for compounds of structure (1), where R? is an optionally substituted aryl or heteroaryl ring as defined above, reacting a compound of formula (X1) or (VII) where LG is a leaving group with an aryl or heteroaryl boronic acid in the presence of a palladium catalyst and a suitable base at elevated temperature: 4 RA. N._ _R* TX JX BD | _ R*” TNT TNH RYN NH (o— =0 0=S=0 3 Rr? Rr3 R2 R . (V1) 0) and optionally thereafter process (a), (b) or (c) e removing any protecting groups, AMENDED SHEETPCT/SEQ3/00041 ¢ e converting a compound of formula (I) to a further compound of formula (I) forming a pharmaceutically acceptable salt.10. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.11. A process for the preparation of a pharmaceutical composition as claimed in claim 10 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.12. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof for use in therapy.13. A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof: R! 0) I Eo 3 6 = rR ONT CR (IB) in which:R'. R? and R® are independently hydrogen, halogen, cyano, CFs, or Cy alkyl; R*is halogen, COR",C,.¢ alkoxy where the alkyl group may form a 3-6 membered saturated ring or may be substituted with 1-3 fluorine atoms or a Cyano group,C;. alkenyloxy or Ci. alkynyloxy where either may be optionally substituted with hydroxy or NR“R"; AMENDED SHEETPCT/SE03/00041 ® 171 OC, alkyl-X-Cy.6 alkyl where the alkyl groups may form a 3-6 membered saturated ring;OC. alkylR"!, or OCa.6 alkyl-X-R'! where the alkyl group may form a 3-6 membered : saturated ring and is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR“RY, SR", S(0)R", S(OOR";OC. alkylR'%; R’ and R® are independently hydrogen, cyano, halogen, CO2R'2, CONRMRY;C..¢ alkyl optionally substituted by hydroxy, NR"RY, or 1-3 fluorines; Cre alkylR"! or XCH(R")C 16 alkyl or XCH(R'®)Cy. alkyl where the alkyl group may be optionally substituted with 1-3 groups selected from hydroxy, and NRUR"; NRMR'; NR')R"'; X-(CH;)qNR"R'; (CHz)nNR“R";Ci. alkynyl or Cs.¢ alkenyl optionally branched and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O; R': XR: X-R'%, X-CpalkylR'®; X-R'S; X-(CH)nCOR'; X-(CH)nCONRMR'; X-(CHp)nR'"; X-(CH,)nCN; X-(CH2)qOR'%; (CH-)nOR'™; (CHpn-X-R'!; X-(CH)qNHC(O)NHR '%; X-(CHz)qNHC(O)R'; X-(CH)gNHS(O)R'%; X-(CH2)gNHS(O)R''; X-Cs.salkenyl; X-Cs.qalkynyl; nis 1,2,3,4o0r5; qis2,3,4,50r6; X is NR", 0, S, S(0), S(O)z; R!! is an aryl group or a 5-7 membered heteraromatic ring containing 1-4 heteroatoms selected from nitrogen, oxygen or sulphur each of which can be optionally substituted by 1-3 groups selected from halogen, C(O)NR"“R", C(O)OR'?, hydroxy, =O, =S, CN, NO, NRU“R'S, X(CH)GNR “RY, (CH,)nNRR", (CH2)nOH, SR", S(O)R", S(O)R"Ci. alkyl-X-C 6 alkyl, C6 alky! or Cy. alkoxy where the alkyl group may form a 3-6 membered ring or is optionally substituted with 1-3 groups selected from hydroxy, halogen, NR'“RY, SR", S(O)R", S(0):R"; AMENDED SHEET® 172 PCT/SE03/00041 R'2and R" are independently hydrogen or Ci.6 alkyl where the alkyl group may be substituted with 1-3 fluorine atoms or may form a saturated 3-6 membered fing; R' and R" are independently hydrogen, Ci alkyl, Css cycloalkyl or (CH;)qOH, or R™ and R" together with the nitrogen atom to which they are attached form a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur and optionally substituted by C16 alkyl, Cy.¢ alkyl-OH, or hydroxy; and R!S is a 4-8 membered saturated ring containing 1-3 heteroatoms selected from nitrogen, oxygen or sulphur and optionally substituted with 1-3 groups selected from hydroxy, cyano, halogen and =O provided that the compound is not 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine5.phenyl-2-(2-(N-phenyl-N-methylamino)ethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-benzylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N _methyl-N-phenylamino)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-((tetrahydrofuran-2-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclohexylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(piperidin-1-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclopentylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(morpholin-4-yl)ethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclopropylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-cyclohexylethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(3-(piperidin-1-yl)propyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-fluorophenylsulfonylamino)pyrazine 3-(2(N-methyl-N-phenylamino)ethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/00041@ 2-(2-phenoxyethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine2-(c yclopentylmethyloxy)-3-(4-chlorophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phen ylamino)ethyloxy)-3-(4-bromophenylsulfon ylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-bromophenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylamino)ethyloxy)-3-(4-ethylphenylsulfon ylamino)pyrazine 2-(2-phenoxyeth yloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-ethylphenylsulfonylamino)pyrazine 2-(2-(N-methyl-N-phenylami no)ethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-propylphenylsulfonylamino)pyrazine 2-(2-phenoxyethyloxy)-3-(4-(1-methylethyl)phen ylsulfonylamino)pyrazine 2-(cyclopentylmethyloxy)-3-(4-(1 -methylethyl)phenylsulfonylamino)pyrazine 6-(perhydroazepin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-cyclobutylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine6-c yclopentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine6-cyclohexylaminocarbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine6-(pyrrolidin-1 -yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3 -(4-methylphenylsulfonylamino)pyrazine6-(3-hydroxypyrrolidin-1-yl)c arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine6-(4-methylpiperazin-1-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine6-(morpholin-4-yl)carbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine6-(thiomorpholin-4-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine6-(1,1-dimethylethyl)ami nocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine6-(1,2-dimethylpropyl)aminoc arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazineAMENDED SHEET17 PCT/SE03/0004 1® 6.(1.3-dimethylbutylaminocarbonyl-2-((pyridin-3-yDmethyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-ethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1-methylbutyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2,2-dimethylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxypropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpropyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-pentylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dimethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-diethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N -propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-dipropylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-butylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-ethylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine 6-(3-hydroxypiperidin- 1-yl)carbonyl-2-((pyridin-3-yl)meth yloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-methylpropyl)amino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N -methyl-N-pentylamino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(1-methylethyl)amino)carbonyl-2-((pyridin-3-y)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/00041® 6-(1-methylethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((1R)-1-methyl-2-hydroxyeth yl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N -(2-hydroxyethylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxymethylpyrrolidin- 1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-methylpiperidin-1- yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3 -(4- methylphenylsulfonylamino)pyrazine 6-(3-methylpiperidin-1-yl)c arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(4-methylpiperidin-1-yl)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(1,1-dimethylpropyl)aminocarbonyl-2-((pyridin-3 -yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine - 6-(2-methylbutylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-dimethylaminoethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(2-hydroxyethyl)aminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-methylbutyl)aminoc arbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(3-dimethylami nopropyl)aminocarbonyl-2-((pyridin-3-yl)methylox y)-3-(4- methylphenylsulfonylamino)pyrazine 6-hexylaminocarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazin 6-(N-meth yl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-butylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-methyl-N-(2-dimethylaminoethylamino)carbon yl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine AMENDED SHEETPCT/SE03/00041® 6.-(N-ethyl.N-(1-methylethylamino)carbonyl.2-((pyridin-3-ymethyloxy)-3-(d- methylphenylsulfonylamino)pyrazine 6-(N-(1-hydroxyethyl)-N-(1 -methylethyl)amino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-((2R)-2-hydroxymethylpyrrolidin-1-yl)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-ethyl-N-methylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-(N-(2-hydroxyethyl)-N-propylamino)carbonyl-2-((pyridin-3-yl)methyloxy)-3-(4- methylphenylsulfonylamino)pyrazine 6-carboxy-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine or 6-methox ylcarbonyl-2-((pyridin-3-yl)methyloxy)-3-(4-methylphenylsulfonylamino)pyrazine.14. Use according to claim 12 in which the chemokine receptor belongs to the CCR chemokine receptor subfamily.15. Use according to claim 13 or 14 in which the chemokine receptor is the CCR4 receptor.16. Use of a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 13 in the manufacture of a medicament for treating an inflammatory disease in a patient suffering from, or at risk of, said disease.17. Use according to claim 16, wherein the disease is asthma.18. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treatment of an illness, disease, disorder or condition.19. A substance or composition for use in a method of treatment, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering said substance or composition. AMENDED SHEETPCT/SE03/00041 ® 17720. A substance or composition for use in a method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine receptors, said substance or composition comprising a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof as defined in claim 11, and said method comprising administering to a patient a therapeutically effective amount of said substance or composition.21. A substance or composition for use in a method of treatment according to claim 18 in which the chemokine receptor belongs to the CCR chemokine receptor subfamily.22. A substance or composition for use in a method of treatment according to claim 18 or 19 in which the chemokine receptor is the CCR4 receptor.23. A substance or composition for use in a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising a compound of formula (IB), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 11, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.24. A substance or composition for use in a method of treatment according to claim 23, wherein the disease is asthma.25. A compound according to any one of claims 1 to 8 or claim 12, substantially as herein described and illustrated.26. A process according to claim 9, substantially as herein described and illustrated.27. A composition according to claim 10, substantially as herein described and illustrated.28. A process according to claim 11, substantially as herein described and illustrated. AMENDED SHEETPCT/SE03/00041 ® 29. Use according to any one of claims 13 to 18, substantially as herein described and . tlustrated.30. A substance or composition for use in a method of treatment according to any one of claims 19 to 24, substantially as herein described and illustrated.31. A new compound, a new process for preparing a compound, a new composition, a new process for preparing a composition, a new use of a compound as defined in any one of claims 13 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0200119A SE0200119D0 (en) | 2002-01-16 | 2002-01-16 | Novel compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
ZA200405260B true ZA200405260B (en) | 2005-10-03 |
Family
ID=20286679
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200405260A ZA200405260B (en) | 2002-01-16 | 2004-07-01 | N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. |
Country Status (3)
Country | Link |
---|---|
SE (1) | SE0200119D0 (en) |
UA (1) | UA79255C2 (en) |
ZA (1) | ZA200405260B (en) |
-
2002
- 2002-01-16 SE SE0200119A patent/SE0200119D0/en unknown
-
2003
- 2003-01-14 UA UA20040705311A patent/UA79255C2/en unknown
-
2004
- 2004-07-01 ZA ZA200405260A patent/ZA200405260B/en unknown
Also Published As
Publication number | Publication date |
---|---|
UA79255C2 (en) | 2007-06-11 |
SE0200119D0 (en) | 2002-01-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1458715B1 (en) | Novel compounds | |
US20100081670A1 (en) | N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases | |
US9597317B2 (en) | Substituted indazole derivatives active as kinase inhibitiors | |
CN107592861B (en) | Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof | |
US20120157433A1 (en) | Heteroaryl Compounds as Kinase Inhibitors | |
AU2005300736B2 (en) | Anthranilamide pyridinureas as VEGF receptor kinase inhibitors | |
US7572794B2 (en) | Anthranilamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors | |
US20120165306A1 (en) | Pyrazinylpyridines useful for the treatment of proliferative diseases | |
CN111936503A (en) | Oxazin monoacylglycerol lipase (MAGL) inhibitors | |
CA2483890A1 (en) | Substituted 3-amino-thieno[2,3-b]pyridine-2-carboxylic acid amide compounds and processes for preparing and their uses | |
JP2015533177A (en) | Substituted benzene compounds | |
KR20120092586A (en) | Bipyridines useful for the treatment of proliferative diseases | |
JPWO2006004027A1 (en) | Pyrazole derivative | |
US20070185163A1 (en) | Imidazol derivatives of piperidine as histamine antagonists | |
TW200524903A (en) | Quinazoline derivatives | |
CN102395583A (en) | Isoxazole derivatives | |
JPWO2004094407A1 (en) | 5-membered heterocyclic derivatives | |
JP2010515728A (en) | Pyridine compounds and their use as P2Y12 antagonists (new pyridine analogue IX519) | |
CN110818641A (en) | Pyridazine-3-formamide compound, preparation method and application thereof in medicine and pharmacology | |
ZA200405260B (en) | N-pyrazinyl-phenylsulphonamides and their use in the treatment of chemokine mediated diseases. |