JP2002537292A - 二環化合物およびそれらのインテグリン受容体リガンドとしての使用 - Google Patents
二環化合物およびそれらのインテグリン受容体リガンドとしての使用Info
- Publication number
- JP2002537292A JP2002537292A JP2000599745A JP2000599745A JP2002537292A JP 2002537292 A JP2002537292 A JP 2002537292A JP 2000599745 A JP2000599745 A JP 2000599745A JP 2000599745 A JP2000599745 A JP 2000599745A JP 2002537292 A JP2002537292 A JP 2002537292A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- compound
- optionally substituted
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000002619 bicyclic group Chemical group 0.000 title claims description 8
- 108010044426 integrins Proteins 0.000 title abstract description 18
- 102000006495 integrins Human genes 0.000 title abstract description 18
- 239000003446 ligand Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 221
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 111
- -1 and R 4 is Bond Chemical group 0.000 claims abstract description 107
- 239000001257 hydrogen Substances 0.000 claims abstract description 53
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 239000002253 acid Chemical group 0.000 claims abstract description 39
- 239000000651 prodrug Substances 0.000 claims abstract description 34
- 229940002612 prodrug Drugs 0.000 claims abstract description 34
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 25
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 23
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 19
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 7
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 6
- 125000000732 arylene group Chemical group 0.000 claims abstract description 5
- 125000002993 cycloalkylene group Chemical group 0.000 claims abstract description 4
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 76
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000003342 alkenyl group Chemical group 0.000 claims description 22
- 238000011282 treatment Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 230000021164 cell adhesion Effects 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000003435 aroyl group Chemical group 0.000 claims description 6
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 6
- 125000005312 heteroarylalkynyl group Chemical group 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 5
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 5
- 125000005110 aryl thio group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005977 Ethylene Substances 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000005239 aroylamino group Chemical group 0.000 claims description 4
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 2
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 abstract description 19
- 108010067306 Fibronectins Proteins 0.000 abstract description 12
- 102000016359 Fibronectins Human genes 0.000 abstract description 12
- 230000003993 interaction Effects 0.000 abstract description 9
- 150000004677 hydrates Chemical class 0.000 abstract description 7
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 100
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 75
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 150000002148 esters Chemical class 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 239000000377 silicon dioxide Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 11
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 11
- 238000000105 evaporative light scattering detection Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000011347 resin Substances 0.000 description 10
- 229920005989 resin Polymers 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 9
- 150000003254 radicals Chemical class 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 230000006978 adaptation Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000000335 thiazolyl group Chemical group 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 125000005018 aryl alkenyl group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 5
- 210000002744 extracellular matrix Anatomy 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
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- 125000004447 heteroarylalkenyl group Chemical group 0.000 description 5
- 125000003367 polycyclic group Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- JYKYYPPZLPVIBY-UHFFFAOYSA-N 1-isothiocyanato-2-methylbenzene Chemical compound CC1=CC=CC=C1N=C=S JYKYYPPZLPVIBY-UHFFFAOYSA-N 0.000 description 4
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 4
- 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
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- 239000002671 adjuvant Substances 0.000 description 4
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- JMMZYEHPYZGZOK-SECBINFHSA-N ethyl (3r)-3-(4-aminophenyl)butanoate Chemical compound CCOC(=O)C[C@@H](C)C1=CC=C(N)C=C1 JMMZYEHPYZGZOK-SECBINFHSA-N 0.000 description 4
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
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- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
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- 108010049003 Fibrinogen Proteins 0.000 description 3
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
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- 206010061218 Inflammation Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 3
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 108010058846 Ovalbumin Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- KUYMVWXKHQSIAS-UHFFFAOYSA-N tert-butyl 2-chloroacetate Chemical compound CC(C)(C)OC(=O)CCl KUYMVWXKHQSIAS-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
-
- 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
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9903532.1A GB9903532D0 (en) | 1999-02-16 | 1999-02-16 | Chemical compounds |
| US14144599P | 1999-06-29 | 1999-06-29 | |
| US9903532.1 | 1999-06-29 | ||
| US60/141,445 | 1999-06-29 | ||
| PCT/GB2000/000553 WO2000049005A1 (en) | 1999-02-16 | 2000-02-16 | Bicyclic compounds and their use as integrin receptor ligands |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002537292A true JP2002537292A (ja) | 2002-11-05 |
| JP2002537292A5 JP2002537292A5 (enExample) | 2007-04-05 |
Family
ID=26315145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000599745A Pending JP2002537292A (ja) | 1999-02-16 | 2000-02-16 | 二環化合物およびそれらのインテグリン受容体リガンドとしての使用 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US6593354B2 (enExample) |
| EP (1) | EP1153017B1 (enExample) |
| JP (1) | JP2002537292A (enExample) |
| AT (1) | ATE325105T1 (enExample) |
| AU (1) | AU775208B2 (enExample) |
| CA (1) | CA2362862A1 (enExample) |
| DE (1) | DE60027700T2 (enExample) |
| DK (1) | DK1153017T3 (enExample) |
| ES (1) | ES2263447T3 (enExample) |
| PT (1) | PT1153017E (enExample) |
| WO (1) | WO2000049005A1 (enExample) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002541257A (ja) * | 1999-04-12 | 2002-12-03 | アベンティス・フアーマ・リミテッド | インテグリンアンタゴニストとしての置換された二環式ヘテロアリール化合物 |
| JP2007520466A (ja) * | 2003-12-23 | 2007-07-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 摂食障害を治療するためのｍｃｈアンタゴニスト（メラニン含有ホルモン）の形態で使用される３−（４−ピペリジン−１−イルメチル−フェニル）−プロピオン酸−フェニルアミド誘導体及び関連化合物 |
| JP2007525516A (ja) * | 2004-02-27 | 2007-09-06 | アムジエン・インコーポレーテツド | 代謝疾患の治療に使用するための、化合物、薬学的組成物及び方法 |
| JP2009536629A (ja) * | 2006-05-11 | 2009-10-15 | サノフィ−アベンティス | フェニルアミノ−ベンゾオキサゾール置換カルボン酸類、それらの製造方法、及び医薬品としての使用 |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR0010599A (pt) * | 1999-04-12 | 2002-02-13 | Aventis Pharma Ltd | Compostos de heteroarila bicìclicos substituìdos como antagonistas de integrina |
| GB0001346D0 (en) * | 2000-01-21 | 2000-03-08 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004686D0 (en) * | 2000-02-28 | 2000-04-19 | Aventis Pharma Ltd | Chemical compounds |
| US7157487B2 (en) | 2000-12-28 | 2007-01-02 | Daiichi Pharmaceutical Co., Ltd. | Vla-4 inhibitors |
| US7351719B2 (en) | 2002-10-31 | 2008-04-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds |
| ES2382806T3 (es) | 2003-07-24 | 2012-06-13 | Daiichi Sankyo Company, Limited | Compuesto ácido ciclohexanocarboxílico |
| US7592373B2 (en) | 2003-12-23 | 2009-09-22 | Boehringer Ingelheim International Gmbh | Amide compounds with MCH antagonistic activity and medicaments comprising these compounds |
| US7524862B2 (en) | 2004-04-14 | 2009-04-28 | Boehringer Ingelheim International Gmbh | Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds |
| DE102004017934A1 (de) | 2004-04-14 | 2005-11-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Alkin-Verbindungen mit MCH-antagonistischer Wirkung und diese Verbindungen enthaltende Arzneimittel |
| US20070021612A1 (en) * | 2004-11-04 | 2007-01-25 | University Of Notre Dame Du Lac | Processes and compounds for preparing histone deacetylase inhibitors and intermediates thereof |
| US7235688B1 (en) | 2004-11-04 | 2007-06-26 | University Of Notre Dame Du Lac | Process for preparing histone deacetylase inhibitors and intermediates thereof |
| UY32138A (es) * | 2008-09-25 | 2010-04-30 | Boehringer Ingelheim Int | Amidas sustituidas del ácido 2-(2,6-dicloro-fenilamino)-6-fluoro-1-metil-1h-bencimidazol-5-carboxílico y sus sales farmacéuticamente aceptables |
| UY32470A (es) | 2009-03-05 | 2010-10-29 | Boehringer Ingelheim Int | Derivados de 2-{2-cloro-5-[(sustituido) metil]fenilamino} -1-metil]fenilamino}-1-metilbencimidazol-5-carboxamidas-n-(sustituidas) y sus sales fisiológicamente aceptables, composiciones conteniéndolos y aplicaciones |
| US8586604B2 (en) | 2010-08-20 | 2013-11-19 | Boehringer Ingelheim International Gmbh | Inhibitors of the microsomal prostaglandin E2 synthase-1 |
| US8759537B2 (en) | 2010-08-20 | 2014-06-24 | Boehringer Ingelheim International Gmbh | 3H-imidazo [4, 5-C] pyridine-6-carboxamides as anti-inflammatory agents |
| US8674113B2 (en) | 2010-12-10 | 2014-03-18 | Boehringer Ingelheim International Gmbh | Compounds |
| US8466186B2 (en) | 2010-12-10 | 2013-06-18 | Boehringer Ingelheim International Gmbh | Compounds |
| US8486968B2 (en) | 2010-12-10 | 2013-07-16 | Boehringer Ingelheim International Gmbh | Compounds |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4025637A (en) | 1973-10-23 | 1977-05-24 | Lilly Industries, Ltd. | 2,5 OR 2,6 Disubstituted benzoxazoles |
| US4100168A (en) | 1974-09-20 | 1978-07-11 | Lilly Industries Ltd. | 2,5 OR 2,6-Disubstituted benzoxazoles |
| US6306840B1 (en) | 1995-01-23 | 2001-10-23 | Biogen, Inc. | Cell adhesion inhibitors |
| PT889877E (pt) * | 1996-03-29 | 2002-02-28 | Searle & Co | Derivados fenileno meta substituidos e sua utilizacao como antagonitas ou inibidores integrina alfa v beta3 |
| JPH10330369A (ja) | 1997-04-04 | 1998-12-15 | Sumitomo Pharmaceut Co Ltd | 複素環化合物 |
| GB9723789D0 (en) | 1997-11-12 | 1998-01-07 | Zeneca Ltd | Chemical compounds |
| GB9916374D0 (en) * | 1998-07-23 | 1999-09-15 | Zeneca Ltd | Chemical compounds |
| WO2000005223A2 (en) * | 1998-07-23 | 2000-02-03 | Astrazeneca Ab | Heterocyclic derivatives and their use as integrin inhibitors |
-
2000
- 2000-02-16 EP EP00903864A patent/EP1153017B1/en not_active Expired - Lifetime
- 2000-02-16 AT AT00903864T patent/ATE325105T1/de not_active IP Right Cessation
- 2000-02-16 DE DE60027700T patent/DE60027700T2/de not_active Expired - Fee Related
- 2000-02-16 DK DK00903864T patent/DK1153017T3/da active
- 2000-02-16 CA CA002362862A patent/CA2362862A1/en not_active Abandoned
- 2000-02-16 PT PT00903864T patent/PT1153017E/pt unknown
- 2000-02-16 ES ES00903864T patent/ES2263447T3/es not_active Expired - Lifetime
- 2000-02-16 AU AU25617/00A patent/AU775208B2/en not_active Ceased
- 2000-02-16 WO PCT/GB2000/000553 patent/WO2000049005A1/en not_active Ceased
- 2000-02-16 JP JP2000599745A patent/JP2002537292A/ja active Pending
-
2001
- 2001-08-09 US US09/925,110 patent/US6593354B2/en not_active Expired - Lifetime
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002541257A (ja) * | 1999-04-12 | 2002-12-03 | アベンティス・フアーマ・リミテッド | インテグリンアンタゴニストとしての置換された二環式ヘテロアリール化合物 |
| JP4864206B2 (ja) * | 1999-04-12 | 2012-02-01 | アベンティス・フアーマ・リミテッド | インテグリンアンタゴニストとしての置換された二環式ヘテロアリール化合物 |
| JP2007520466A (ja) * | 2003-12-23 | 2007-07-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 摂食障害を治療するためのｍｃｈアンタゴニスト（メラニン含有ホルモン）の形態で使用される３−（４−ピペリジン−１−イルメチル−フェニル）−プロピオン酸−フェニルアミド誘導体及び関連化合物 |
| JP2007525516A (ja) * | 2004-02-27 | 2007-09-06 | アムジエン・インコーポレーテツド | 代謝疾患の治療に使用するための、化合物、薬学的組成物及び方法 |
| JP2009536629A (ja) * | 2006-05-11 | 2009-10-15 | サノフィ−アベンティス | フェニルアミノ−ベンゾオキサゾール置換カルボン酸類、それらの製造方法、及び医薬品としての使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1153017A1 (en) | 2001-11-14 |
| DE60027700T2 (de) | 2007-05-03 |
| PT1153017E (pt) | 2006-07-31 |
| ATE325105T1 (de) | 2006-06-15 |
| DE60027700D1 (de) | 2006-06-08 |
| EP1153017B1 (en) | 2006-05-03 |
| AU2561700A (en) | 2000-09-04 |
| US20020137782A1 (en) | 2002-09-26 |
| US6593354B2 (en) | 2003-07-15 |
| WO2000049005A1 (en) | 2000-08-24 |
| CA2362862A1 (en) | 2000-08-24 |
| AU775208B2 (en) | 2004-07-22 |
| DK1153017T3 (da) | 2006-07-17 |
| ES2263447T3 (es) | 2006-12-16 |
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