WO2002020484A1 - Chemical compounds - Google Patents
Chemical compounds Download PDFInfo
- Publication number
- WO2002020484A1 WO2002020484A1 PCT/SE2001/001869 SE0101869W WO0220484A1 WO 2002020484 A1 WO2002020484 A1 WO 2002020484A1 SE 0101869 W SE0101869 W SE 0101869W WO 0220484 A1 WO0220484 A1 WO 0220484A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- alkoxy
- halogen
- compound
- substituted
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 126
- 206010039083 rhinitis Diseases 0.000 claims abstract description 35
- 208000006673 asthma Diseases 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 148
- -1 nitro, hydroxy Chemical group 0.000 claims description 117
- 125000000217 alkyl group Chemical group 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 37
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 36
- 125000004122 cyclic group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 17
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 125000002541 furyl group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 15
- 239000001301 oxygen Chemical group 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- 239000005864 Sulphur Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 claims description 4
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 claims description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 3
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 2
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005509 dibenzothiophenyl group Chemical group 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- RCCPEORTSYDPMB-UHFFFAOYSA-N hydroxy benzenecarboximidothioate Chemical compound OSC(=N)C1=CC=CC=C1 RCCPEORTSYDPMB-UHFFFAOYSA-N 0.000 claims description 2
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 102000009410 Chemokine receptor Human genes 0.000 abstract description 5
- 108050000299 Chemokine receptor Proteins 0.000 abstract description 5
- 102000003834 Histamine H1 Receptors Human genes 0.000 abstract 1
- 108090000110 Histamine H1 Receptors Proteins 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 117
- 239000000047 product Substances 0.000 description 97
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- 238000001819 mass spectrum Methods 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 238000002360 preparation method Methods 0.000 description 47
- 238000005160 1H NMR spectroscopy Methods 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- 239000002904 solvent Substances 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 238000002844 melting Methods 0.000 description 28
- 230000008018 melting Effects 0.000 description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 23
- 230000008020 evaporation Effects 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 241000282414 Homo sapiens Species 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 238000004007 reversed phase HPLC Methods 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 208000010668 atopic eczema Diseases 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 230000000172 allergic effect Effects 0.000 description 10
- 229960004132 diethyl ether Drugs 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 9
- 229960001340 histamine Drugs 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 210000003979 eosinophil Anatomy 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 6
- 208000030507 AIDS Diseases 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 206010025135 lupus erythematosus Diseases 0.000 description 6
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
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- 239000000284 extract Substances 0.000 description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
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- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 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
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- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 2
- KUTBMATZUQWFSR-UHFFFAOYSA-N 3-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC(C(O)=O)=C1 KUTBMATZUQWFSR-UHFFFAOYSA-N 0.000 description 2
- UZEGQEQFRRYLRK-UHFFFAOYSA-N 3-sulfinobenzoic acid Chemical compound OC(=O)C1=CC=CC(S(O)=O)=C1 UZEGQEQFRRYLRK-UHFFFAOYSA-N 0.000 description 2
- DQNSSLUVUXZLEO-UHFFFAOYSA-N 4-(3,4-dichlorophenoxy)piperidine Chemical compound C1=C(Cl)C(Cl)=CC=C1OC1CCNCC1 DQNSSLUVUXZLEO-UHFFFAOYSA-N 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 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
- 208000015943 Coeliac disease Diseases 0.000 description 2
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- YFOLZBRFYNXOPZ-UHFFFAOYSA-N n-[2-[4-(2-chloro-4-fluorophenoxy)piperidin-1-yl]ethyl]-6-pyrazol-1-ylpyridine-3-carboxamide Chemical compound ClC1=CC(F)=CC=C1OC1CCN(CCNC(=O)C=2C=NC(=CC=2)N2N=CC=C2)CC1 YFOLZBRFYNXOPZ-UHFFFAOYSA-N 0.000 description 1
- GPQGIHNZCGMCEF-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-(4-hydroxyphenyl)acetamide Chemical compound C1=CC(O)=CC=C1CC(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 GPQGIHNZCGMCEF-UHFFFAOYSA-N 0.000 description 1
- XWGXSKAUSHJAMU-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-(methanesulfonamido)benzamide;hydrochloride Chemical compound Cl.CS(=O)(=O)NC1=CC=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 XWGXSKAUSHJAMU-UHFFFAOYSA-N 0.000 description 1
- YXXNZQBRWPDFSP-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-2-hydrazinyl-2-oxoacetamide Chemical compound C1CN(CCNC(=O)C(=O)NN)CCC1OC1=CC=C(Cl)C(Cl)=C1 YXXNZQBRWPDFSP-UHFFFAOYSA-N 0.000 description 1
- MYSCYFCKXSILMS-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-(2-hydroxyethoxy)benzamide;hydrochloride Chemical compound Cl.OCCOC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 MYSCYFCKXSILMS-UHFFFAOYSA-N 0.000 description 1
- COHJVAXADJURQT-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-(methanesulfonamido)benzamide Chemical compound CS(=O)(=O)NC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 COHJVAXADJURQT-UHFFFAOYSA-N 0.000 description 1
- OUQZBRUIAYDLNF-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-(methylsulfonylmethyl)benzamide Chemical compound CS(=O)(=O)CC1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 OUQZBRUIAYDLNF-UHFFFAOYSA-N 0.000 description 1
- MAAIXHFSHZGPAM-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-3-sulfamoylbenzamide Chemical compound NS(=O)(=O)C1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 MAAIXHFSHZGPAM-UHFFFAOYSA-N 0.000 description 1
- YEPUGGHAUDYUTI-UHFFFAOYSA-N n-[2-[4-(3,4-dichlorophenoxy)piperidin-1-yl]ethyl]-4-methylsulfonylbenzamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)NCCN1CCC(OC=2C=C(Cl)C(Cl)=CC=2)CC1 YEPUGGHAUDYUTI-UHFFFAOYSA-N 0.000 description 1
- CRYOVYYDBRPHMA-UHFFFAOYSA-N n-[2-[4-(3,4-difluorophenoxy)piperidin-1-yl]ethyl]-2,2,2-trifluoro-n-methylacetamide Chemical compound C1CN(CCN(C)C(=O)C(F)(F)F)CCC1OC1=CC=C(F)C(F)=C1 CRYOVYYDBRPHMA-UHFFFAOYSA-N 0.000 description 1
- XCYLLWPISXNJPA-UHFFFAOYSA-N n-[2-[4-(3,4-difluorophenoxy)piperidin-1-yl]ethyl]-3-methoxy-n-methylbenzamide;hydrochloride Chemical compound Cl.COC1=CC=CC(C(=O)N(C)CCN2CCC(CC2)OC=2C=C(F)C(F)=CC=2)=C1 XCYLLWPISXNJPA-UHFFFAOYSA-N 0.000 description 1
- WNDKMEFGGFFTKC-UHFFFAOYSA-N n-[2-[4-(3,4-difluorophenoxy)piperidin-1-yl]ethyl]-3-methylsulfonylbenzamide;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC=CC(C(=O)NCCN2CCC(CC2)OC=2C=C(F)C(F)=CC=2)=C1 WNDKMEFGGFFTKC-UHFFFAOYSA-N 0.000 description 1
- AFILRJSCXIQNOT-UHFFFAOYSA-N n-[2-[4-(4-chloro-3-methylphenoxy)piperidin-1-yl]ethyl]-6-pyrazol-1-ylpyridine-3-carboxamide Chemical compound C1=C(Cl)C(C)=CC(OC2CCN(CCNC(=O)C=3C=NC(=CC=3)N3N=CC=C3)CC2)=C1 AFILRJSCXIQNOT-UHFFFAOYSA-N 0.000 description 1
- CJANIEIPEWSGCT-UHFFFAOYSA-N n-[3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propyl]-3-methylsulfonylbenzamide;hydrochloride Chemical compound Cl.CS(=O)(=O)C1=CC=CC(C(=O)NCCCN2CCC(CC2)OC=2C=C(Cl)C(Cl)=CC=2)=C1 CJANIEIPEWSGCT-UHFFFAOYSA-N 0.000 description 1
- SQBCGUPFPORBQY-UHFFFAOYSA-N n-ethylethanesulfonamide Chemical group CCNS(=O)(=O)CC SQBCGUPFPORBQY-UHFFFAOYSA-N 0.000 description 1
- UHNHTTIUNATJKL-UHFFFAOYSA-N n-methylmethanesulfonamide Chemical group CNS(C)(=O)=O UHNHTTIUNATJKL-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000004634 pharmacological analysis method Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000036515 potency Effects 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
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940081330 tena Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FKRKGPPELQBYCJ-UHFFFAOYSA-N tert-butyl 4-(3,4-dichlorophenoxy)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(Cl)C(Cl)=C1 FKRKGPPELQBYCJ-UHFFFAOYSA-N 0.000 description 1
- BDSJWKPEVPYPQJ-UHFFFAOYSA-N tert-butyl 4-(3,4-difluorophenoxy)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=CC=C(F)C(F)=C1 BDSJWKPEVPYPQJ-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- IOKGWQZQCNXXLD-UHFFFAOYSA-N tert-butyl n-(3-bromopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCBr IOKGWQZQCNXXLD-UHFFFAOYSA-N 0.000 description 1
- NUNMDLSYBHBIGO-UHFFFAOYSA-N tert-butyl n-[3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propyl]carbamate Chemical compound C1CN(CCCNC(=O)OC(C)(C)C)CCC1OC1=CC=C(Cl)C(Cl)=C1 NUNMDLSYBHBIGO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000005062 tracheal ring Anatomy 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
Definitions
- the present invention concerns piperidine derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
- Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. 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 molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif.
- the chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C- C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
- the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP -2).
- IL-8 interleukin-8
- NAP -2 neutrophil-activating peptide 2
- the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as 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 l ⁇ and l ⁇ (MlP-l ⁇ and MlP-l ⁇ ).
- 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, CXCR1, CXCR2, CXCR3 and CXCR4.
- G protein-coupled receptors among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
- Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and is formed from histidine by histidine decarboxylase. It is found in most tissues of the body, but is present in high concentrations in the lung, skin and in the gastrointestinal tract. At the cellular level inflammatory cells such as mast cells and basopbils store large amounts of Hstarnine. It is recognised that the degranulation of mast cells and basopbils and the subsequent release of histamine is a fundamental mechanism responsible for the clinical manifestation of an allergic process. Histamine produces its actions by an effect on specific histamine G- protein coupled receptors, which are of three main types, HI, H2 and H3.
- Histamine HI antagonists comprise the largest class of medications used in the treatment of patients with allergic disorders, especially rhinitis and urticaria. HI antagonists are useful in controlling the allergic response by for example blocking the action of histamine on post-capillary venule smooth muscle, resulting in decreased vascular permeability, exudation and oedema. The antagonists also produce blockade of the actions of histamine on the HI receptors on c-type nociceptive nerve fibres, resulting in decreased itching and sneezing.
- the present invention provides a compound of formula (I):
- R 5 is a 3- to 10-membered saturated or unsaturated ring system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the
- Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
- the present invention covers all such isomers and mixtures thereof in all proportions.
- Suitable salts include acid addition salts .such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate orjc-toluenesulphonate.
- the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
- Halogen includes fluorine, chlorine, bromine and iodine.
- Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl, iso-propyl, iso-butyl or tert-butyl.
- Alkenyl group are; for example, vinyl or allyl.
- Cycloalkyl is, for example, cyclopropyl, cyclopentyl or cyclohexyl; and cycloalkylalkyl is, for example cyclopropyhnethyl.
- Alkoxy includes methoxy, ethoxy, n- propoxy, iso-propoxy and tert-butoxy;
- alkoxycarbonyl includes methoxy- and ethoxy-, carbonyl;
- haloalkyl includes trifluoromethyl; haloalkoxy includes trifluoromethoxy;
- cycloalkylamino includes cyclopropyl-, cyclobutyl-, cyclopentyl- or cyclohexylamino;
- alkylthio includes methyl- or ethylthio;
- alkylfhioalkyl includes methylthiomethyl;
- alkylcarbonylamino includes methyl- or ethylcarbonylamino;
- the 3- to 10-membered saturated or unsaturated ring system in the group R 5 may be monocyclic or polycyclic comprising 2 or more fused rings, examples of which include cyclobutyl, cyclopentyl, cyclohexyl, norbornylenyl, adamantyl, phenyl, naphthyl, furyl, thienyl, pynolyl, 2,5-dihydro-lH-pynolyl (also know as ⁇ 3 -pynoline), thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for example in 6-oxo-l,6-dihydro-pyridinyl), pyrimidinyl (for example a pyrimidinedione), pyrazinyl, pyridazinyl
- the 3- to 10-membered saturated or unsaturated ring system in the group R 5 may be monocyclic or polycyclic comprising 2 or more fused rings, examples of which include cyclobutyl, cyclopentyl, cyclohexyl, norbornylenyl, adamantyl, piperidyl, phenyl, naphthyl, naphthyridinyl, 1,3-benzodioxolyl, pyrazolyl, furanyl, pyridyl, thienyl, indolyl, benzthiazolyl, benzthienyl, 1,2,3-benzthiadiazolyl, benzoxazolyl, benzothiazolyl, chromonyl, imidazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, pyrimidinyl, pyrazolopyrimidinyl, tfaenopyrimidinyl, tMa
- m and q are both 0.
- R 1 is phenyl optionally substituted by halogen (such as chloro or fiuoro), C 1- alkyl (such as methyl) or C 1-4 alkoxy (such as methoxy).
- halogen such as chloro or fiuoro
- C 1- alkyl such as methyl
- C 1-4 alkoxy such as methoxy
- R 2 is hydrogen.
- R 3 is hydrogen.
- R 4 is hydrogen or C 1- alkyl; and R 5 is a 3- to 10-membered saturated or unsaturated ring system which may comprise up to two ring carbon atoms that form carbonyl groups and which may comprise up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, the ring system being substituted by at least one of C ⁇ -6 alkyl (substituted with S(O) 2 (C 1-6 alkyl), NHS(O) 2 (C 1-6 alkyl) or S(O) 2 NR 13 R 14 ), S(O) 2 (C 1-6 alkyl), S(O) 2 NH(C 1-6 alkyl), NHC(O)(C 1-6 alkyl) or NHS(O) (C 1-6 alkyl); and optionally further substituted with a substituent selected from the group comprising: halogen, cyano, nitro, hydroxy, C 1- alkyl, C
- R 10 is hydroxy or NR ⁇ R 12 group; and, R 6 , R 7 R 8 , R 9 , R u , R 12 , R 13 and R 14 are independently hydrogen or C 1-6 alkyl.
- R 4 is hydrogen or C 1- alkyl
- R 5 is phenyl substituted by at least one of C 1-6 alkyl (substituted with S(O) 2 (C 1-6 alkyl), NHS(O) 2 (C ⁇ -6 alkyl) or S(O) 2 NR 13 R 14 ), S(O) 2 (C 1-6 alkyl), S(O) 2 NH(C 1-6 alkyl), NHC(O)(C 1-6 alkyl) or NHS(O) 2 (C 1- alkyl); and optionally further substituted with a substituent selected from the group comprising: halogen, cyano, nitro, hydroxy, C 1-6 alkyl, C 3 .
- R 6 cycloalkyl, C 1-6 alkoxy, C ⁇ -6 alkoxycarbonyl, C ⁇ - haloalkyl, C 1-6 haloalkoxy, NR 6 R 7 , C -6 cycloalkylamino, C 1-6 alkylthio, C 1-6 alkylthio(C 1-6 alkyl), C 1-6 alkylcarbonylamino, C(O)NR 8 R 9 , sulphonamido (S(O) 2 NH 2 ), (di)C ⁇ - alkylsulphonamido and C(O)R 10 -substituted C 1-6 alkyl or Cj- alkoxy groups;
- R 10 is hydroxy or NR n R 12 group; and, R 6 , R 7 R 8 , R 9 , R 11 , R 12 , R 13 and R 14 are independently hydrogen or C 1-6 alkyl.
- R 4 is hydrogen.
- R 5 is phenyl mono-substituted by C ⁇ -6 alkyl (substituted with
- R 13 and R 14 are independently hydrogen or C 1-6 alkyl.
- the invention provides any compound described in a Table or an Example herein, or a pharmaceutically acceptable salt thereof.
- the present invention provides the a compound listed in Table II or a pharmaceutically acceptable salt thereof, or a solvate of a salt thereof.
- compounds of Table II can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers) the present invention covers all such isomers and mixtures thereof in all proportions.
- Suitable salts include acid addition salts such as a hydrochloride, dihydrochloride, hydrobromide, phosphate, acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or y -toluenesulphonate.
- the compounds of the invention can be prepared by reacting a compound of formula (III):
- a compound of formula (III) can be prepared by reacting a compound of formula (V):
- compounds of the invention can be prepared by adapting the methods provided in the Examples below.
- Compounds of formula (III), (IN), (N) and (NI) can be prepared by using or adapting methods described in the art or by adapting the methods provided in the Examples below.
- the present invention provides processes for the preparation of the compounds of the invention.
- the compounds of the invention have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CCR3) activity, and may be used in the treatment of autoimmune, inflammatory, proliferatfve or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)).
- chemokine receptor especially CCR3
- the compounds of the invention are also HI antagonists and may be used in the treatment of allergic disorders. Examples of these conditions are:
- obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer
- COPD chronic
- arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarifiropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis;
- Alzheimer's disease multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle.
- AIDS Acquired Immunodeficiency Syndrome
- Lupus disorders such as lupus erythematosus or systemic lupus
- erythematosus Hashimoto's thyroiditis
- myasthenia gravis myasthenia gravis
- type I diabetes nephrotic syndrome
- eosinophilia fascitis hyper I
- a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
- a method for modulating chemokine receptor activity in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof.
- a method for antagonising HI in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof.
- the invention also provides a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament.
- the present invention provides the use of a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR3 receptor activity) or antagonising HI in a warm blooded animal, such as man, or both).
- the invention further provides the use of a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
- COPD chronic obstructive pulmonary disease
- asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma
- bronchitis such as eosinophilic bronchitis ⁇
- acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa
- membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis
- seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis
- sarcoidosis farmer's lung and related diseases
- nasal polyposis fibroid lung, idiopathic interstitial pneumonia, antitussive activity, treatment of chronic cough associated with inflammatory conditions of the airways or iatrogenic induced cough
- (2) (bone and joints) arthrides including
- Alzheimer's disease multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; in a warm blooded animal, such as man.
- AIDS Acquired Immunodeficiency Syndrome
- Lupus disorders such as lupus erythematosus or systemic lupus
- erythematosus Hashimoto's thyroiditis
- myasthenia gravis myasthenia gravis
- type I diabetes nephrotic syndrome
- a compound of the invention, or a pharmaceutically acceptable salt thereof is useful in the treatment of asthma ⁇ such as bronchial, allergic, mtrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; or rhinitis ⁇ including acute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ .
- asthma such as bronchial, allergic, mtrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma
- a compound of the invention, or a pharmaceutically acceptable salt thereof is useful in the treatment of asthma.
- the present invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma or rhinitis.
- the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR3 mediated disease state, especially asthma) or an HI mediated disease state (such as an allergic disorder) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or solvate thereof.
- a chemokine mediated disease state especially a CCR3 mediated disease state, especially asthma
- an HI mediated disease state such as an allergic disorder
- a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR3 receptor) activity or antagonising HI
- said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- the present invention provides a pharmaceutical composition which comprises a compound as hereinbefore defined or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
- a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
- the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
- compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
- topical such as to the lung and/or airways or to the skin
- the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
- a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between O.lmg and lg of active ingredient.
- composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
- Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of O.Olmgkg "1 to lOOmgkg "1 of the compound, preferably in the range of O.lmgkg "1 to 20mgkg _1 of this invention, the composition being administered 1 to 4 times per day.
- the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
- the intravenous dose may be given by continuous infusion over a period of time.
- each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
- Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ - cyclodextrin may be used to aid formulation.
- the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
- the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
- mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H) + ;
- Example 1 This Example illustrates the preparation of 4-(3,4-dichlorophenoxy)piperidine.
- Step a tert-Butyl 4-(3,4-dichlorophenoxy)-l-piperidinecarboxylate.
- Example 2 This Example illustrates the preparation of N- ⁇ 3-[4-(3,4-dichlorophenoxy)-l- piperidinyl]propyl ⁇ -3-(methylsulfonyl)benzamide hydrochloride (a salt of Compound 20 of Table I).
- Step a tert-butyl 3-[4-(3,4-dichlorophenoxy)-l-piperidinyl]propylcarbamate
- Step b 3 - [4-(3 ,4-dichlorophenoxy)- 1 -piperidinyljpropylamine
- Step (b) The product of Step (b) (0.15g) was dissolved in DMF (4ml). 3-Methylsulphonyl- benzoic acid (0.1 lOg), triethylamine (0.250ml) and PyBrop® (0.350g) were added. After 8 hours at room temperature the solvents were evaporated and the residue redissolved in ethyl acetate. The organics were washed with H 2 O, dried with MgSO 4 and concentrated.
- Example 3 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidmyl]etl ⁇ yl ⁇ -3-(me1hylsulfonyl)benzamide hydrochloride (a salt of Compound 19 of Table I).
- Step a fert-Butyl 2-[4-(3,4-dichlorophenoxy)-l-piperidinyl]ethylcarbamate
- Step b 2-[4-(3,4-dicMorophenoxy)-l- ⁇ iperidmyl]ethylamine
- Step c N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l-piperidmyl]e yl ⁇ -3-(methylsulfonyl)benzamide hydrochloride
- Step b The product of Step b (0.200g) was dissolved in DMF (5ml). 3-Methylsul ⁇ honyl- benzoic acid (0.132g), triethylamine (0.250ml) and PyBrop® (0.420g) were added. After 24 hours at room temperature the solvents were evaporated and the residue redissolved in ethyl acetate. The organics were washed with H 2 O, dried with MgSO 4 and concentrated.
- Example 4 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -3-[(methylsulfonyl)methyl]benzamide (Compound 5 of Table I).
- Example 5 This Example illustrates the preparation of N- ⁇ 2-[4-(3 ,4-dichlorophenoxy)- 1 - ⁇ iperidinyl]emyl ⁇ -4-[(methylsulfonyl)methyl]benzarnide (Compound 7 of Table I).
- Example 6 This Example illustrates the preparation of N-(cyclopropylmethyl)-N- ⁇ 2-[4-(3,4- difluorophenoxy)-l-piperidinyl]ethyl ⁇ -4-fluoro-3-methoxybenzamide (Compound 15 of Table I).
- Step a tert-Butyl 4-(3,4-difluorophenoxy)-l-piperidinecarboxylate
- Step b The product of Step b (5g) was dissolved in DMF (27ml) and triethylamine (7.7ml) was added. tert-Butyl 2-bromoethylcarbamate (5.8g) was added and the solution stirred at room temperature for 24 hrs. The solvent was evaporated and the residue dissolved in ethyl acetate and washed with water. The organic phase separated, dried and evaporated. Purification by flash chromatography (dichloromethane : methanol 97:3) gave the sub-title product as an oil (lOg) containing a small amount of DMF. MS: APCI(+ve): 357 (M+H)
- Step c The product of Step c (lOg) was dissolved in dioxane (114ml) and HC1 (6N) (114ml) was added and the reaction stirred for 2 hours. Organic solvent was evaporated and aqueous NaOH (2M) added. The product was extracted with ethyl acetate, the combined organic extracts dried with Na 2 SO 4 and concentrated to give the sub-title product as an oil (4.65g).
- Step e N-(Cyclopropylmethyl)-N- ⁇ 2-[4-(3,4-difluorophenoxy)-l-piperidmyl]ethyl ⁇ amine
- Step d The product of Step d (0.4g) dissolved in MeOH (6ml) was added to cyclopropanecarbaldehyde (0.116ml) and the resulting mixture was stined for 4 hours. The solvent was evaporated, the residue re-dissolved in methanol (6ml) and ⁇ aBH 4 (0.095g) added and the mixture left for 30 minutes. Aqueous sodium hydroxide (IN) was added and the aqueous extracted with diethyl ether. The organic extracts were dried with Na 2 SO 4 , filtered and concentrated to give the sub-title product as an oil (0.493g).
- Step f N-(Cyclo ⁇ ro ⁇ ylmethyl)-N- ⁇ 2-[4-(3,4-difiuorophenoxy)- 1 -piperidmyljethyl ⁇ -4- fluoro-3 -methoxybenzamide
- Example 7 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-difluorophenoxy)-l- piperidinyl]ethyl ⁇ -3-(methylsulfonyl)benzamide hydrochloride (a salt of Compound 16 of Table I).
- the product of Example 6, Step d (0.200g) was dissolved in THF (4ml), 3- methylsulphonylbenzoic acid (0.156g , ⁇ , ⁇ -di-isopropylethylamine (0.407ml) and PyBrop® (0.401g) were added. After 18 hours at room temperature ethyl acetate and aqueous NaHCO 3 solution were added. The product was extracted with ethyl acetate, the combined organic extracts dried with MgSO and concentrated. Purification by reverse phase HPLC (with a gradient eluent system 45% MeCN/NH OAc aq (0.1%) to 95%
- Example 8 This Example illustrates the preparation of N- ⁇ 3-[4-(3,4-dichlorophenoxy)-l- piperidinyl]propyl ⁇ -2-(2,5-dmydro-l/ -pynol-l-yl)-l,3-benzotm-azole-6-carboxamide (Compound 17 of Table I). Prepared in a similar manner to the method of Example 6, Step fusing the product, of Example 2, Step b and2-(2,5-d ydro-l-H r -pynol-l-yl)-l,3-benzothiazole-6-carboxyhc acid to give the title compound as a solid (0.026g).
- Step a N- ⁇ 2-[4-(3,4-Difluorophenoxy)- 1 -piperidinyljethyl ⁇ -2,2,2-trifluoroacetamide
- Step b N- ⁇ 2-[4-(3,4-Difluorophenoxy)- 1 -piperidinyl] ethyl ⁇ -2,2,2-trifluoro-N- methylacetamide
- Step d N- ⁇ 2-[4-(3,4-difluorophenoxy)-l-piperidinyl]ethyl ⁇ -3-methoxy-N- methylbenzamide hydrochloride
- Example 10 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -3-hydroxybenzamide (Compound 8 of Table II).
- Step a N- ⁇ 2-[4-(3,4-dicUorophenoxy)-l-piperidmyl]ethyl ⁇ -3-methoxybenzamide
- Step b N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l-piperidinyl]ethyl ⁇ -3-hydroxybenzamide
- Example 11 The present Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)- l-piperidinyl]ethyl ⁇ -3-[2-(dimethylanrmo)-2-oxoethoxy]bejizamide acetate (a salt of Compound 86 of Table II).
- Example 12 This Example illustrates the preparation of methyl ⁇ 3-[( ⁇ 2-[4-(3,4- dichlorophenoxy)- 1 -piperidinyl] ethyl ⁇ amino)carbonyl]phenoxy ⁇ acetate hydrochloride (a salt of Compound 87 of Table II).
- Step b a solution of the product from Example 10, Step b (0.250g) and methyl chloroacetate (0.066g) in dimethylformamide (10ml) under nitrogen was added caesium carbonate (0.4g). The reaction was left to stir for 24hours. Water was added and organics extracted into ethyl acetate and dried with MgSO 4 .
- Example 13 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -3-(2-hydroxyethoxy)benzamide hydrochloride (a salt of Compound 21 of Table I).
- the isolated product was then converted to title product by dissolving in diethylether, adding ethereal hydrochloric acid and Iriturating from diethylether to give the titled product (0.069g).
- Example 14 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]emyl ⁇ -3-[(2-hydroxyemyl)sulfonyl]benzamide acetate (a salt of Compound 22 of Table I).
- Step a 3- ⁇ [2-(tetrahydro-2J ' -pyran-2-yloxy)ethyl]sulfonyl ⁇ benzoic acid
- Step b N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l-piperidinyl]ethyl ⁇ -3-[(2-hydroxyethyl)- sulfonyljbenzamide acetate
- Step a To a solution of the product of Step a (0.20g), the product of Example 3, Step b (0.25g) and diisopropylethyl amine (0.33ml) in dichloromethane (5ml) was added PyBrOP® (0.37g) and the mixture stirred for 24 hours. Purification by Biotage® 40M eluting 20% MeC ⁇ /2% 880 ammonia/ 78% dichloromethane gave a colourless oil (0.49g) which was dissolved in trifluoroacetic acid (9ml) and water (1ml) and stined for 15 minutes.
- Example 16 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidmyl]ethyl ⁇ -3-(2-methoxyethoxy)benzamide hydrochloride (A salt of Compound 12 of Table I).
- Example 17 This Example illustrates the preparation of tert-butyl 2- ⁇ 3-[( ⁇ 2-[4-(3,4- dichlorophenoxy)- 1 -piperidinyl]ethyl ⁇ amino)carbonyl]phenoxy ⁇ ethylcarbamate acetate (a salt of Compound 23 of Table I).
- Step a Methyl 3- ⁇ 2-[(tert-butoxycarbonyl)amino]ethoxy ⁇ benzoate
- Step b 3- ⁇ 2-[(tert-butoxycarbonyl)amino]ethoxy ⁇ benzoic acid
- Step c tert-butyl 2- ⁇ 3-[( ⁇ 2-[4-(3,4-dichlorophenoxy)- 1 -piperidinyljethyl ⁇ amino)- carbonyljphenoxy ⁇ ethylcarbamate acetate
- Example 18 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -3-[(methylsulfonyl)amino]benzamide (Compound 24 of Table I).
- Step a 3-amino-N- ⁇ 2-[4-(3,4-dichlorophenoxy) ⁇ 1 -piperidinyl]ethyl ⁇ benzamide
- Step b 3-amino-N- ⁇ 2-[4-(3,4-dichlorophenoxy) ⁇ 1 -piperidinyl]ethyl ⁇ benzamide
- Step b N- ⁇ 2-[4-(3,4-dicMorophenoxy)-l-piperidinyl]ethyl ⁇ -3-[(methylsulfonyl)amino]- benzamide
- Example 19 This Example illustrates the preparation of 3 -(2-aminoethoxy)-N- ⁇ 2-[4-(3 ,4- dichlorophenoxy)-l-piperidinyl] ethyl ⁇ benzamide dihydrochloride (a salt of Compound 25 of Table I).
- step b (0.848g) was then added and the reaction left to stir for 24 hrs.
- Aqueous NaHCO 3 solution was added and the product extracted with CH 2 C1 2 .
- the organic phase was washed with H 2 O dried with Na 2 SO and purification by flash chromatography (ethyl acetate: isohexane 30:70) gave the sub-title compound (0.650g).
- Step b (lS)-2-[4-(3,4-difluorophenoxy)-l-piperidinyl]-2-oxo-l-phenylethylarnine
- step a (0.650g) was dissolved in dichloromethane
- Step c ( 1 S)-2-[4-(3 ,4-difluorophenoxy)- 1 -piperidinyl]- 1 -phenylethylamine
- step b) The product from Example 20, step b) (0.544g) was dissolved in THF (5ml) and borane [10.05ml (IM in THF)] was added. The reaction was heated at reflux for 2 hours. The reaction was quenched slowly with MeOH and the solvents evaporated. Aqueous HCl (5ml Concentrated HCl: 5ml H 2 O) was added and the reaction heated at 70°C for lhour. NaOH (2M) was added until pH 9 was reached. The product was extracted with CH 2 C1 2 and the combined organics washed with saturated aqueous NaHCO , dried with Na 2 SO and solvents evaporated.
- Example 22 This Example illustrates the preparation of 3-(aminosulfonyl)-N- ⁇ 2-[4-(3,4- dichlorophenoxy)-l-piperidinyl]ethyl ⁇ benzamide.
- Example 23 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl] ethyl ⁇ - 1 -ethyl-7-methyl-4-oxo- 1 ,4-dihydro [ 1 , 8]naphthyridine-3 -carboxamide. Prepared in a similar manner to Example 7 using the product of Example 3, Step b. MS: APCI(+ve): 503 (M+H)
- Example 24 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -2-(4-hydroxyphenyl)acetamide.
- Example 27 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidmyl]ethyl ⁇ -5-(methylsulfonyl)-2-tMophenecarboxamide.
- Example 29 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l- piperidinyl]ethyl ⁇ -4-(methylsulfonyl)benzamide.
- Step a N- ⁇ 2-[4-(3,4-dichlorophenoxy)piperidin-l-yl]ethyl ⁇ -2-hydrazino-2-oxoacetamide.
- Step b (0.85g) and triethylamine
- Step b 5-(2-chloroamiino)-N- ⁇ 2-[4-(3,4-dichlorophenoxy)-l-piperidinyl]ethyl ⁇ -l,3,4- oxadiazole-2 -carboxamide.
- Step a 4-(2-C oro-4-fluorophenoxy)piperidine.
- DEAD (0.90ml) was added to a solution of triphenylphosphine (1.44g), 2-chloro-4- fluorophenol (0.806g) and 4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester(l.Og) in THF at RT.
- the reaction was stined for 16hrs, HCl (2ml, 4M in dioxan) added and the mixture stirred at RT for 16 hrs.
- Step b 2-[4-(2-Chloro-4-fluorophenoxy)piperidin-l-yl]ethylamine.
- Potassium carbonate (1.02g, 0.0074 mol) was added to a solution of the 2-chloro-4- fluorophenoxypiperidine (1.7g, 0.0074 mol) and tert-butyl 2-bromoethylcarbamate (1.65g, 0.0074 mol) strirring at RT.
- the resulting mixture was stined at RT for 24 hours, diluted with ethyl acetate (200ml) and washed with saturated brine solution (3 x 100ml).
- the organic layer was dried with MgSO and evaporated under reduced pressure.
- Step c N- ⁇ 2-[4-(2-Chloro-4-fluorophenoxy)-l-piperidinyl]ethyl ⁇ -6-(lH-pyrazol-l- yl)nicotinamide.
- Example 33 This Example illustrates the preparation of N- ⁇ 2-[4-(2-chloro-4-fiuorophenoxy)- 1 - piperidinyl]ethyl ⁇ -3-(methylsulfonyl)benzamide.
- Step b 2- [4-(2,4-Dichloro-3 -methylphenoxy)piperidin- 1 -yl] ethylamine.
- the sub-titled compound was prepared in a similar manner to Example 32, Step b.
- Step c N- ⁇ 2-[4-(2,4-DicUoro-3-methylphenoxy)-l-piperidinyl]ethyl ⁇ -4- (methylsulfonyl)benzamide.
- Example 35 This Example illustrates the preparation of N- ⁇ 2-[4-(2,4-dichloro-3- methylphenoxy)-l-piperidmyl]ethyl ⁇ -5-(methylsulfonyl)-2-t ophenecarboxamide.
- the title compound was prepared in a similar manner to Example 7 using the product of Example 34, step b.
- Example 36 This Example illustrates the preparation of N- ⁇ 2-[4-(2,4-dichloro-3- metnylphenoxy)-l-piperidinyl]ethyl ⁇ -2-(methylsulfonyl)benzamide.
- the title compound was prepared in a similar manner to Example 7 using the product of Example 34, step b.
- Example 37 This Example illustrates the preparation of N- ⁇ 2-[4-(4-chloro-3-methylphenoxy)-l- piperidinyl] ethyl ⁇ -4-(methylsulfonyl)benzamide. Step a: 4-(4-Chloro-3-methylphenoxy)piperidine.
- Step b 2-[4-(4-CMoro-3-me ylphenoxy)piperidm-l-yl]ethylamine.
- This Example illustrates the preparation of N- ⁇ 2-[4-(4-chloro-3-methylphenoxy)-l- piperidinyl]ethyl ⁇ -6-(lH-pyrazol-l-yl)nicotinamide.
- Example 39 This Example illustrates the preparation of N- ⁇ 2-[4-(4-chloro-3-methylphenoxy)-l- piperidinyl]eti ⁇ yl ⁇ -2-(methylsulfonyl)benzamide.
- Example 41 This Example illustrates the preparation of 2-cyano-N- ⁇ 2-[4-(3,4- difluorophenoxy)- 1 -piperidinyl]ethyl ⁇ benzamide.
- the title compound was prepared in a similar manner to Example 7 using the product of Example 6, Step d.
- Example 42 This Example illustrates the preparation of 2-chloro-N- ⁇ 2-[4-(3,4- difluorophenoxy)- 1 -piperidinyl]ethyl ⁇ -4-(methylsulfonyl)benzamide.
- Example 43 This Exampleillustrates the preparation of 3-cyano-N- ⁇ 2-[4-(3,4- difluorophenoxy)- 1 -piperidinyl] ethyl ⁇ benzamide.
- Example 44 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-difluorophenoxy)-l- piperidinyl] ethyl ⁇ -4- [(methy lsulfony l)methyl]b enzamide.
- the title compound was prepared in a similar manner to Example 7 using the product of Example 6, Step d.
- Example 45 This Example illustrates the preparation of N- ⁇ 2-[4-(3,4-difluorophenoxy)-l- piperidinyl] ethyl ⁇ -6-( 1 H-pyrazol- 1 -yl)mcotinamide.
- Human eosinophil chemotaxis Human eosinophil chemotaxis Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at lOxlO 6 ml "1 in RPMI containing 200 IU/ml penicillin, 200 ⁇ g/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.
- Eosinophils 700 ⁇ l were pre-incubated for 15 mins at 37° C with 7 ⁇ l of either vehicle or compound (lOOx required final concentration in 10% DMSO).
- the chemotaxis plate (ChemoTx, 3 ⁇ m pore, Neuroprobe) was loaded by adding 28 ⁇ l of a concentration of eotaxin (0.1 to lOOnM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate.
- the filter was then placed over the wells and 25 ⁇ l of eosinophil suspension were added to the top of the filter.
- the plate was incubated for 1 hr at 37° C in a humidified incubator with a 95% air/5% CO 2 atmosphere to allow chemotaxis.
- the medium containing cells that had not migrated, was carefully aspirated from above the filter and discarded.
- the filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells.
- Cells that had migrated through the filter were pelleted by centrifugation (300xg for 5 rnins at room temperature) and the filter removed and the supernatant transfened to each well of a 96-well plate (Costar).
- the pelleted cells were lysed by the addition of 28 ⁇ l of PBS containing 0.5% Triton xl 00 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant.
- the number of eosinophils n ⁇ grating was quantified according to the method of Strath et al., J. Immunol Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.
- Certain compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis.
- the buffer was maintained at 37°C and gassed with 5% CO 2 in oxygen.
- Indomethacin (2.8 ⁇ M) was added to the Krebs solution to prevent development of smooth muscle tone due to the synthesis of cyclo- oxygenase products.
- the tracheal rings were suspended between two parallel tungsten wire hooks, one attached to an Ormed beam isometric force transducer and the other to a stationary support in the organ bath. Changes in isometric force were recorded on 2-channel Sekonic flat bed chart recorders.
- E/[A] histamine concentration effect
Abstract
Description
Claims
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JP2002525106A JP2004508355A (en) | 2000-09-04 | 2001-08-30 | Chemical compound |
AU2001284584A AU2001284584A1 (en) | 2000-09-04 | 2001-08-30 | Chemical compounds |
US10/344,758 US7304077B2 (en) | 2000-09-04 | 2001-08-30 | Chemical compounds |
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EP (1) | EP1322611A1 (en) |
JP (1) | JP2004508355A (en) |
AU (1) | AU2001284584A1 (en) |
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US20040102432A1 (en) | 2004-05-27 |
JP2004508355A (en) | 2004-03-18 |
AU2001284584A1 (en) | 2002-03-22 |
GB0021670D0 (en) | 2000-10-18 |
US7304077B2 (en) | 2007-12-04 |
EP1322611A1 (en) | 2003-07-02 |
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