NZ500029A - Compounds and compositions of carboxamide derivatives associated with the treatment of rheumatoid arthritis, conjunctivitis and/ or syncytial virus infections - Google Patents

Info

Publication number

NZ500029A

NZ500029A NZ500029A NZ50002997A NZ500029A NZ 500029 A NZ500029 A NZ 500029A NZ 500029 A NZ500029 A NZ 500029A NZ 50002997 A NZ50002997 A NZ 50002997A NZ 500029 A NZ500029 A NZ 500029A

Authority

NZ

New Zealand

Prior art keywords

benzoimidazol

ethyl

alkyl

compound

methyl

Prior art date

1997-04-07

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims description 355
• 239000000203 mixture Substances 0.000 title claims description 141
• 238000011282 treatment Methods 0.000 title description 15
• 230000009385 viral infection Effects 0.000 title description 6
• 206010039073 rheumatoid arthritis Diseases 0.000 title description 4
• 206010010741 Conjunctivitis Diseases 0.000 title description 2
• 229940053202 antiepileptics carboxamide derivative Drugs 0.000 title 1
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 375
• WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 176
• -1 amino, carboxy, carbamoyl Chemical group 0.000 claims description 128
• 125000000217 alkyl group Chemical group 0.000 claims description 123
• 235000011468 Albizia julibrissin Nutrition 0.000 claims description 96
• 241001070944 Mimosa Species 0.000 claims description 96
• 125000005842 heteroatom Chemical group 0.000 claims description 75
• 239000001257 hydrogen Substances 0.000 claims description 65
• 229910052739 hydrogen Inorganic materials 0.000 claims description 65
• 125000003118 aryl group Chemical group 0.000 claims description 64
• 239000005711 Benzoic acid Substances 0.000 claims description 62
• 235000010233 benzoic acid Nutrition 0.000 claims description 62
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 51
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 49
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 44
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 40
• 125000004429 atom Chemical group 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 38
• 125000002947 alkylene group Chemical group 0.000 claims description 37
• 125000003545 alkoxy group Chemical group 0.000 claims description 36
• 125000005843 halogen group Chemical group 0.000 claims description 32
• 125000001424 substituent group Chemical group 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 29
• 239000000651 prodrug Substances 0.000 claims description 26
• 229940002612 prodrug Drugs 0.000 claims description 26
• 125000003282 alkyl amino group Chemical group 0.000 claims description 25
• 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 25
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 24
• 125000001931 aliphatic group Chemical group 0.000 claims description 20
• 125000004432 carbon atom Chemical group C* 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 125000002723 alicyclic group Chemical group 0.000 claims description 17
• 229910052799 carbon Inorganic materials 0.000 claims description 16
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 16
• SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 claims description 14
• OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical class N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 12
• 239000000443 aerosol Substances 0.000 claims description 12
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
• 125000004423 acyloxy group Chemical group 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 10
• 125000003943 azolyl group Chemical group 0.000 claims description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 9
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 9
• 101100240516 Caenorhabditis elegans nhr-10 gene Proteins 0.000 claims description 7
• 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
• 150000001204 N-oxides Chemical class 0.000 claims description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims description 6
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 6
• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 5
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
• 125000004104 aryloxy group Chemical group 0.000 claims description 4
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• 239000000843 powder Substances 0.000 claims description 4
• 239000000048 adrenergic agonist Substances 0.000 claims description 3
• 125000001118 alkylidene group Chemical group 0.000 claims description 3
• 125000002619 bicyclic group Chemical group 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 3
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
• 230000000699 topical effect Effects 0.000 claims description 3
• XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 claims description 2
• LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 claims description 2
• NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 2
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
• 229960001022 fenoterol Drugs 0.000 claims description 2
• 229960002848 formoterol Drugs 0.000 claims description 2
• BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 229960002052 salbutamol Drugs 0.000 claims description 2
• 229960000195 terbutaline Drugs 0.000 claims description 2
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
• WPYMKLBDIGXBTP-VQEHIDDOSA-N benzoic acid Chemical compound OC(=O)C1=CC=C[13CH]=C1 WPYMKLBDIGXBTP-VQEHIDDOSA-N 0.000 claims 7
• WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims 6
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
• 238000001819 mass spectrum Methods 0.000 description 205
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 110
• 238000005160 1H NMR spectroscopy Methods 0.000 description 98
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
• 239000000243 solution Substances 0.000 description 57
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
• 239000007787 solid Substances 0.000 description 40
• 239000002244 precipitate Substances 0.000 description 39
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 32
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 29
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
• 229920006395 saturated elastomer Polymers 0.000 description 27
• 208000006673 asthma Diseases 0.000 description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
• 150000003254 radicals Chemical class 0.000 description 24
• 238000001914 filtration Methods 0.000 description 23
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• 201000010099 disease Diseases 0.000 description 22
• 229910052757 nitrogen Inorganic materials 0.000 description 22
• 102000001400 Tryptase Human genes 0.000 description 21
• 108060005989 Tryptase Proteins 0.000 description 21
• 239000011780 sodium chloride Substances 0.000 description 16
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
• 241001494479 Pecora Species 0.000 description 14
• 238000006243 chemical reaction Methods 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 13
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 208000027866 inflammatory disease Diseases 0.000 description 12
• 230000002829 reductive effect Effects 0.000 description 12
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
• 238000005481 NMR spectroscopy Methods 0.000 description 11
• 239000002253 acid Substances 0.000 description 11
• 235000019441 ethanol Nutrition 0.000 description 11
• 210000003630 histaminocyte Anatomy 0.000 description 11
• 235000017557 sodium bicarbonate Nutrition 0.000 description 11
• 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• 125000000753 cycloalkyl group Chemical group 0.000 description 10
• 239000003921 oil Substances 0.000 description 10
• 210000001519 tissue Anatomy 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• 241001465754 Metazoa Species 0.000 description 9
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 230000004047 hyperresponsiveness Effects 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• 125000006239 protecting group Chemical group 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 8
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• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
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• 208000024891 symptom Diseases 0.000 description 8
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 230000004054 inflammatory process Effects 0.000 description 7
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
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• 239000000427 antigen Substances 0.000 description 6
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• 238000009472 formulation Methods 0.000 description 6
• 150000002431 hydrogen Chemical class 0.000 description 6
• QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 6
• 239000010410 layer Substances 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
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• 238000002560 therapeutic procedure Methods 0.000 description 6
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• 230000001225 therapeutic effect Effects 0.000 description 5
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• 239000004215 Carbon black (E152) Substances 0.000 description 4
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
• RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
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• ZAKAONRTRWRIJT-UHFFFAOYSA-N ethyl 3-ethoxy-3-iminopropanoate Chemical compound CCOC(=N)CC(=O)OCC ZAKAONRTRWRIJT-UHFFFAOYSA-N 0.000 description 4
• 238000003818 flash chromatography Methods 0.000 description 4
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• 239000012362 glacial acetic acid Substances 0.000 description 4
• 229960000789 guanidine hydrochloride Drugs 0.000 description 4
• PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 4
• 229930195733 hydrocarbon Natural products 0.000 description 4
• 125000001841 imino group Chemical group [H]N=* 0.000 description 4
• 239000000543 intermediate Substances 0.000 description 4
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
• 150000002576 ketones Chemical class 0.000 description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 description 4
• 230000007170 pathology Effects 0.000 description 4
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• 238000010992 reflux Methods 0.000 description 4
• 238000000926 separation method Methods 0.000 description 4
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• 239000002750 tryptase inhibitor Substances 0.000 description 4
• CBCKQZAAMUWICA-UHFFFAOYSA-N 1,4-phenylenediamine Chemical compound NC1=CC=C(N)C=C1 CBCKQZAAMUWICA-UHFFFAOYSA-N 0.000 description 3
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
• 229940044174 4-phenylenediamine Drugs 0.000 description 3
• 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 3
• 206010002198 Anaphylactic reaction Diseases 0.000 description 3
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