JPH06504520A - 選択的ロイコトリエンb↓4拮抗剤活性を示す置換された二環式アリール化合物 - Google Patents
選択的ロイコトリエンb↓4拮抗剤活性を示す置換された二環式アリール化合物Info
- Publication number
- JPH06504520A JPH06504520A JP3516161A JP51616191A JPH06504520A JP H06504520 A JPH06504520 A JP H06504520A JP 3516161 A JP3516161 A JP 3516161A JP 51616191 A JP51616191 A JP 51616191A JP H06504520 A JPH06504520 A JP H06504520A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- phenethyl
- tables
- formula
- formulas
- 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.)
- Granted
Links
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 title claims description 15
- 239000005557 antagonist Substances 0.000 title claims description 10
- 230000000694 effects Effects 0.000 title description 17
- 150000001875 compounds Chemical class 0.000 claims description 135
- -1 haloal (kyl Chemical group 0.000 claims description 112
- 238000000034 method Methods 0.000 claims description 89
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims description 68
- 239000000203 mixture Substances 0.000 claims description 63
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 239000000126 substance Substances 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 150000002431 hydrogen Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 150000001408 amides Chemical group 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 229940047583 cetamide Drugs 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 claims description 3
- 208000026935 allergic disease Diseases 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 230000009610 hypersensitivity Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- ZYNRDTBRGYLTLA-UHFFFAOYSA-N 2-(3-formyl-4-phenylmethoxyindol-1-yl)-n-methyl-n-(2-phenylethyl)acetamide Chemical compound C1=C(C=O)C2=C(OCC=3C=CC=CC=3)C=CC=C2N1CC(=O)N(C)CCC1=CC=CC=C1 ZYNRDTBRGYLTLA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims 7
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims 5
- 125000004414 alkyl thio group Chemical group 0.000 claims 4
- MYJPHTSXARMVLO-UHFFFAOYSA-N 2-[[1-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-5-phenylmethoxyindol-3-yl]methylidene]butanoic acid Chemical compound C12=CC=C(OCC=3C=CC=CC=3)C=C2C(C=C(CC)C(O)=O)=CN1CC(=O)N(C)CCC1=CC=CC=C1 MYJPHTSXARMVLO-UHFFFAOYSA-N 0.000 claims 1
- BIBOYBNEOWGFQZ-UHFFFAOYSA-N 2-methyl-3-[1-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-5-phenylmethoxyindol-3-yl]prop-2-enoic acid Chemical compound C1=C(C=C(C)C(O)=O)C2=CC(OCC=3C=CC=CC=3)=CC=C2N1CC(=O)N(C)CCC1=CC=CC=C1 BIBOYBNEOWGFQZ-UHFFFAOYSA-N 0.000 claims 1
- 241001024304 Mino Species 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 173
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 239000000243 solution Substances 0.000 description 60
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 239000000047 product Substances 0.000 description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 41
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- UDIXOGYXZXPLRV-UHFFFAOYSA-N n-indol-1-ylacetamide Chemical compound C1=CC=C2N(NC(=O)C)C=CC2=C1 UDIXOGYXZXPLRV-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 239000000872 buffer Substances 0.000 description 18
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 18
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 208000024780 Urticaria Diseases 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 229920002554 vinyl polymer Polymers 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 241000700198 Cavia Species 0.000 description 10
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 210000000224 granular leucocyte Anatomy 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 241000700199 Cavia porcellus Species 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000009870 specific binding Effects 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000002776 aggregation Effects 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 150000002617 leukotrienes Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BCASKZVFUNEWAL-UHFFFAOYSA-N 2-(1h-indol-5-yloxy)-n-methyl-n-(2-phenylethyl)acetamide Chemical compound C=1C=C2NC=CC2=CC=1OCC(=O)N(C)CCC1=CC=CC=C1 BCASKZVFUNEWAL-UHFFFAOYSA-N 0.000 description 5
- KAZWWBYOCSMDMA-UHFFFAOYSA-N 5-benzyl-1,3-dihydroindol-2-one Chemical compound C=1C=C2NC(=O)CC2=CC=1CC1=CC=CC=C1 KAZWWBYOCSMDMA-UHFFFAOYSA-N 0.000 description 5
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical compound OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- GYLYBMJFTWUCEB-UHFFFAOYSA-N 2-bromo-n-methyl-n-(2-phenylethyl)acetamide Chemical compound BrCC(=O)N(C)CCC1=CC=CC=C1 GYLYBMJFTWUCEB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
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- 239000008188 pellet Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000000159 protein binding assay Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 4
- DMYWEGNUGASNRA-UHFFFAOYSA-N 4-(2-phenylethenyl)-1h-indole Chemical compound C=1C=CC=2NC=CC=2C=1C=CC1=CC=CC=C1 DMYWEGNUGASNRA-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
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- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
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- 201000004681 Psoriasis Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 229940114079 arachidonic acid Drugs 0.000 description 3
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- 229910052786 argon Inorganic materials 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
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- 125000002837 carbocyclic group Chemical group 0.000 description 3
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- 210000004379 membrane Anatomy 0.000 description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 3
- 238000005192 partition Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
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- 208000024891 symptom Diseases 0.000 description 3
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- 210000001519 tissue Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- XAWPKHNOFIWWNZ-UHFFFAOYSA-N 1h-indol-6-ol Chemical group OC1=CC=C2C=CNC2=C1 XAWPKHNOFIWWNZ-UHFFFAOYSA-N 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
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- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
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- 150000003180 prostaglandins Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- 229910052703 rhodium Inorganic materials 0.000 description 1
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- 238000013391 scatchard analysis Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
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- 239000008227 sterile water for injection Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NFEGNISFSSLEGU-UHFFFAOYSA-N tert-butyl 2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)CC(=O)OC(C)(C)C NFEGNISFSSLEGU-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N trifluoromethanesulfonic anhydride Substances FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000001521 two-tailed test Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
Description
Claims (38)
- 1.選択的なLTB4拮抗剤特性を有し、かつアミド置換基、末端にカルボン酸 又はそれらの誘導体を有する置換基、及び親油性置換基を含む、二環式アリール 化合物。
- 2.二環式環系が、下記式の6.6又は6.5環系である、請求の範囲第1項記 載の化合物: ▲数式、化学式、表等があります▼▲数式、化学式、表等があります▼(式中、 T,U,V及びW、並びにT,U,V及びWは、CR1R2、NR2、O及びS から選択する;但し、この二環系のそれぞれの環は0〜2個の異種原子を含み、 この異種原子はvic−酸素及び/又はvic−イオウ原子ではない;X及びZ はそれぞれ独立に、CR1R2、NR2、O又はSで;YはCR1R2又はNR 3であり; R1は、水素、アルキル、又はvic−R1と共に炭素−炭素二重結合を形成す るか、もしくはvic−R2と共に炭素−窒素二重結合を形成することができ; 該アミド置換基が、式▲数式、化学式、表等があります▼であるR2又はR3の どちらか一方であり、 該末端がカルボン酸で置換された基が、式▲数式、化学式、表等があります▼で あるR2又はR2のどちらか一方であり;かつ、該親油性置換基が、式▲数式、 化学式、表等があります▼であるR2又はR2のどちらか一方であり、 (R2は、)水素、アルキル、アルケニル、フェニル、ルコキシ、アミノ、モノ ー及びジ−アルキルアミノ、メルカプト、アルキルチオ、ハロ、又はハロアルキ ルであり; R2は、水素又はアルキルであり; Aは、−CRR、O、S、NR′、SO又はSO2;B及びGは、それぞれ独立 に置換された又は未置換の単環又は二環のアリールで;D及びFは、それぞれ独 立に、結合、O、S、NR′、SO、SO2、−C(O)NR′−、−NR′C O−、−CRR、−O−(CRR)1、−(CRR)1−O−、−O−(CRR )1−CR=CR−、−CR=CR−(CRR)1−O−(jは1〜4)、又は (CR=CR)x(xは0〜2)、又はC≡C;Eは、−COOR′、−CON R′R′▲数式、化学式、表等があります▼(yは2〜5)、−CN、−CON HSO2R′、▲数式、化学式、表等があります▼、テトラゾリル又は置換され たテトラゾリル(置換基はアルキル、カルボキシアルキル又はカルバルコキシア ルキル);Rは水素又は−(CH1)m−R2(mは0〜5)、もしくはvic −R基又はvic−R′基と共に飽和又は部分的に不飽和である4〜7員環を形 成し;R′は水素、アルキル又はアラルキル;a,b,d,e,f及びgは、d +f+g+x≠0の条件で、それぞれ独立に0〜4である。);もしくはそれら の医薬として許容できる塩である化合物。
- 3.二環式アリール環が、下記式である請求の範囲第2項記載の化合物:▲数式 、化学式、表等があります▼ (式中、X,Y及びZの少なくとも一つがCR1R2である条件で、X,Y及び Zは、CR1R2又はNR3で;T,U,V及びWの少なくとも二つがCR1R 2である条件で、T,U,V及びWは、CR1R2又はNR3である;R1は、 水素、又はvic−R1と共に炭素−炭素二重結合を形成する、もしくはvic −R3と共に炭素−窒素二重結合を形成することができ;R2又はR3の少なく とも一つは、▲数式、化学式、表等があります▼;R2又はR2の他の少なくと も一つは、▲数式、化学式、表等があります▼;R2又はR2の他の少なくとも 一つは、▲数式、化学式、表等があります▼であり;B及び/又はGは、1から 約3のR′′基と任意に置換することができ;かつR′′は、アルキル、ハロア ルキル、アルコキシ、ハロ又はニトロである。)。
- 4.下記式化合物: ▲数式、化学式、表等があります▼ (式中、R4,R5,R6,R7,R8,R9又はR10の少なくとも一つは、 ▲数式、化学式、表等があります▼; R4,R5,R6,R7,R8,R9又はR10の少なくとも一つは、▲数式、 化学式、表等があります▼;並びにR4,R5,R6,R7,R8,R9又はR 10の少なくとも一つは、▲数式、化学式、表等があります▼;残りのR4,R 5,R6,R7,R8,R9及びR10基は、水素であり;Aは−CRR又は0 ; Bは、フェニル、もしくは置換されたフェニル(置換基は、アルキル、ハロアル キル、アルコキシ又はハロ)であり; Dは、結合、O、CRR、−O−(CRR)1、−(CRR)1−O−、−O− (CRR)1−CR=CR−、−CR=CR−(CRR)1−O−(jは1〜4 )、又は−(CR=CR)x(xは1又は2);Eは、−COOR′、−CON R′R′▲数式、化学式、表等があります▼(yは2〜5)、−CN、−CON HSO2R′、▲数式、化学式、表等があります▼、テトラゾリル、もしくは置 換されたテトラゾリル(置換基はアルキル、カルボキシアルキル又はカルバルコ キシアルキル)であり;Fは、結合、O、−CRR、−NR′又は−(CR=C R)x(xは0〜2);Gは、フェニル、又は置換されたフェニル(置換基は、 アルキル、ハロアルキル、アルコキシ又はハロ)で; Rは、水素又は−(CH2)mR2(mは0〜5);R2は、水素、アルキル、 アルケニル、フェニル、アルコキシ、アミノ、モノ−及びジ−アルキルアミノ、 メルカプト、アルキルチオ、ハロ又はハロアルキル;R′は、水素、アルキル又 はアラルキル;並びにa,b,d,e,f,及びgはそれぞれ独立に0〜4であ る。);又は、それらの医薬として許容できる塩。
- 5.請求の範囲第4項記載の化合物: (式中、Aは−CHR、又は0; B及びGは、フェニル、又は置換されたフェニル(置換基は、低級アルキル又は 低級アルコキシ)であり; Dは、結合、O、−CHR、−O−(CRR)1、−(CRR)1−O−、−O −(CRR)1−CR=CR−、−CR=CR−(CRR)1O−(jは1〜4 )、又は−(CR=CR)x(xは1又は2);Eは、−COOR′又はテトラ ゾリル;Fは、結合、0又は−CHR; Rは、水素、低級アルキル又はアリール;R′は、水素、低級アルキル又は低級 アラルキル;かつ、a,b,d,e,f及びgはそれぞれ独立に0〜4である。 )。
- 6.請求の範囲第5項記載の化合物: (式中、▲数式、化学式、表等があります▼は、▲数式、化学式、表等がありま す▼及び▲数式、化学式、表等があります▼から選択する: R′は、水素、低級アルキル;及び、 R′′は、水素、低級アルキル又は低級アルコキシ;▲数式、化学式、表等があ ります▼は、−(CRR)d−(CRR)e−E(d及びeは0〜4)、−(C R=CR)x−E(xは1〜2)、−O−(CRR)d−(CRR)e−E(d 及びeは1〜4)、かつ−O−(CRR)j−CR=CR−E(jは1〜4)で 、並びにRは、水素又は低級アルキル、及びEは、−COOH又は▲数式、化学 式、表等があります▼;かつ▲数式、化学式、表等があります▼は、▲数式、化 学式、表等があります▼又は▲数式、化学式、表等があります▼から選択し、こ こでgは0〜4、Rは水素又は低級アルキル、かつR′′は水素、低級アルキル 又は低級アルコキシである。)。
- 7.請求の範囲第6項記載の化合物: (式中、R4は、▲数式、化学式、表等があります▼;R6は、▲数式、化学式 、表等があります▼;R■は、▲数式、化学式、表等があります▼;かつR6、 R7、R8及びR10は全て水素である。)。
- 8.請求の範囲第6項記載の化合物: (式中、R4は、▲数式、化学式、表等があります▼;R6は、▲数式、化学式 、表等があります▼;R7は、▲数式、化学式、表等があります▼;並びにR6 、R8、R9及びR10は全て水素である。)。
- 9.請求の範囲第7項記載の化合物、N−メチル−N−フェネチル−2−[5− ベンジルオキシ−3−(2−カルボキシビニル)インドール−1−イル]−アセ トアミド、又はその医薬として許容できる塩。
- 10.請求の範囲第9項記載の化合物で、シス異性体。
- 11.請求の範囲第9項記載の化合物で、トランス異性体。
- 12.請求の範囲第7項記載の化合物、N−メチル−N−フェネチル−2−[5 −ベンジルオキシ−3−(2−カルボキシ−2−メチルビニル)インドール−1 −イル]−アセトアミド、又はその医薬として許容できる塩。
- 13.請求の範囲第12項記載の化合物で、シス異性体。
- 14.請求の範囲第12項記載の化合物で、トランス異性体。
- 15.請求の範囲第8項記載の化合物、N−メチル−N−フェネチル−2−[4 −ベンジルオキシ−3−(2−カルボキシビニル)インドール−1−イル]−ア セトアミド、又はその医薬として許容できる塩。
- 16.請求の範囲第15項記載の化合物で、シス異性体。
- 17.請求の範囲第15項記載の化合物で、トランス異性体。
- 18.請求の範囲第8項記載の化合物、N−メチル−N−フェネチル−2−(4 −ベンジルオキシ−3−(2−カルボキシ−2−メチルビニル)インドール−1 −イル)−アセトアミド、又はその医薬として許容できる塩。
- 19.請求の範囲第18項記載の化合物で、シス異性体。
- 20.請求の範囲第18項記載の化合物で、トランス異性体。
- 21.請求の範囲第6項記載の化合物、N−メチル−N−フェネチル−2−(5 −ベンジルオキシ−2−カルボキシインドール−1−イル)−アセトアミド、又 はその医薬として許容できる塩。
- 22.請求の範囲第7項記載の化合物、N−メチル−N−フェネチル−2−[5 −ベンジルオキシ−3−(2−カルボキシ−2−エチルビニル)インドール−1 −イル]−アセトアミド、又はその医薬として許容できる塩。
- 23.請求の範囲第22項記載の化合物で、シス異性体。
- 24.請求の範囲第22項記載の化合物で、トランス異性体。
- 25.請求の範囲第8項記載の化合物、N−メチル−N−フェネチル−2−[( 4−ベンジルオキシ−3−カルボキシ)インドール−1−イル]−アセトアミド 、又はその医薬として許容できる塩。
- 26.請求の範囲第7項記載の化合物、N−メチル−N−フェネチル−2−[5 −フェノキシ−3−(2−カルボキシビニル)インドール−1−イル]−アセト アミド、又はその医薬として許容できる塩。
- 27.請求の範囲第7項記載の化合物、N−メチル−N−フェネチル−2−[5 −フェニル−3−(2−カルボキシビニル)インドール−1−イル]−アセトア ミド、又はその医薬として許容できる塩。
- 28.下記式の化合物: ▲数式、化学式、表等があります▼ (式中、R11,R12,R13,R14,R15,R16,R17又はR18 の少なくとも一つは、▲数式、化学式、表等があります▼,であり;R11,R 12,R13,R14,R15,R16,R17又はR18の少なくとも一つは 、▲数式、化学式、表等があります▼であり;及びR11,R12,R13,R 14,R15,R16,R17又はR18の少なくとも一つは、▲数式、化学式 、表等があります▼であり;残りのR11,R12,R13,R14,R15, R16,R17又はR18基は、水素であり;Aは−CRR,又は0; Bは、フェニル、又はは置換されたフェニル(置換基は、アルキル、ハロアルキ ル、アルコキシ又はハロ)であり; Dは、結合、O、CRR、−O−(CRR)1、−(CRR)1−O−、−O− (CRR)1−CR=CR−、−CR=CR−(CRR)1−O−(jは1〜4 )、又は−(CR=CR)x(xは1又は2);Eは、−COOR′、−CON R′R′、▲数式、化学式、表等があります▼(yは2〜5)、−CN、−CO NRSO2R′、▲数式、化学式、表等があります▼、テトラゾリル、又は置換 されたテトラゾリル(置換基は、アルキル、カルボキシアルキル又はカルバルコ キシアルキル)であり;Fは、O、−CRR、−NR′又は−(CR=CR)x (xは0〜2);Gは、フェニル、又は置換されたフェニル(置換基は、アルキ ル、ハロアルキル、アルコキシ又はハロ)であり; Rは、水素又は−(CH2)m−R2(mは0〜5);R2は、水素、アルキル 、アルケニル、フェニル、アルコキシ、アミノ、モノ−及びジ−アルキルアミノ 、メルカプト、アルキルチオ、ハロ又はハロアルキル;R′は、水素、アルキル 又はアラルキルであり;かつ、a,b,d,e,f,及びgはそれぞれ独立に0 〜4である。);又はそれらの医薬として許容できる塩。
- 29.請求の範囲第28項記載の化合物、4−[(N−メチル−N−フェネチル )−カルバモイルメチル]−7−ベンジルオキシ−2−ナフトエ酸、又はその医 薬として許容できる塩。
- 30.請求の範囲第28項記載の化合物、4−[(N−メチル−N−フェネチル )カルバモイルメチル]−7−ベンジルオキシ−2−ナフトエ酸、又はその医薬 として許容できる塩。
- 31.下記式の化合物: ▲数式、化学式、表等があります▼(式中、Aは−CRR;B及びGは、1〜約 3のR′′で任意に置換することができる、単環又は二環式アリール環系からな る群から、それぞれ独立に選択し;Fは、O、S、NR′、SO、SO2、−C (O)NR′−、NR′CO−、−CRR、−(CR=CR)x(xは1〜2) 、又はC≡Cからなる群から選択し;Rは、水素又は−(CH2)m−R2(m は0〜5);R2は、水素、アルキル、アルケニル、フェニル、アルコキシ、ア ミノ、モノ−及びジ−アルキルアミノ、メルカプト、アルキルチオ、ハロ又はハ ロアルキルからなる群から選択し; vic−R基が共に、及び/又はvic−R及びvic−R′基が共に、−(C H2)n−(nは2〜5)であることができ、その結果、飽和又は部分的に不飽 和の4〜7員環が形成され;R′は、水素、アルキル又はアラルキル;R′′は 、それぞれ独立に水素、アルキル、ハロアルキル、アルコキシ、ハロ又はニトロ ; a,b,f,及びgはそれぞれ独立に0〜4である。);又は、それらの塩。
- 32.請求の範囲第26項記載の化合物:(式中、 ▲数式、化学式、表等があります▼ は、 ▲数式、化学式、表等があります▼及び▲数式、化学式、表等があります▼から 選択し、 R′は、水素、低級アルキル;及び、 R′′は、水素、低級アルキル又は低級アルコキシ;▲数式、化学式、表等があ ります▼は、▲数式、化学式、表等があります▼(gは1〜4)、及び▲数式、 化学式、表等があります▼(gは1〜4)から選択し、Rは、水素又は低級アル キルでかつR′′は、水素、低級アルキル又は低級アルコキシである。)。
- 33.下記式を有する、請求の範囲第27項記載の化合物:▲数式、化学式、表 等があります▼
- 34.請求の範囲第30項記載の化合物、N−メチル−N−フェネチル−2−( 4−ベンジルオキシ−3−ホルミルインドール−1−イル)アセトアミド。
- 35.請求の範囲第1項記載の式の化合物を有効な量投与する事を含む、ヒト及 び哺乳類の過敏症疾患の治療法。
- 36.請求の範囲第1項記載の式の化合物を有効な量投与する事を含む、ヒト及 び哺乳類の炎症性疾患の治療法。
- 37.炎症性疾患が炎症性腸疾患である、請求の範囲第36項記載の方法。
- 38.活性成分は、請求の範囲第1項記載の化合物であり、医薬担体との混合物 である医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US58024390A | 1990-09-10 | 1990-09-10 | |
US580,243 | 1990-09-10 | ||
PCT/US1991/006447 WO1992004321A1 (en) | 1990-09-10 | 1991-09-06 | Substituted bicyclic aryl compounds exhibiting selective leukotriene b4 antagonist activity |
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JPH06504520A true JPH06504520A (ja) | 1994-05-26 |
JP3334087B2 JP3334087B2 (ja) | 2002-10-15 |
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JP51616191A Expired - Lifetime JP3334087B2 (ja) | 1990-09-10 | 1991-09-06 | 選択的ロイコトリエンb▲4▼拮抗剤活性を示す置換された二環式アリール化合物 |
Country Status (9)
Country | Link |
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US (1) | US5468898A (ja) |
EP (1) | EP0548250B1 (ja) |
JP (1) | JP3334087B2 (ja) |
AT (1) | ATE136026T1 (ja) |
AU (1) | AU8641991A (ja) |
CA (1) | CA2091257A1 (ja) |
DE (1) | DE69118388T2 (ja) |
MX (1) | MX9203775A (ja) |
WO (1) | WO1992004321A1 (ja) |
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JP2005008631A (ja) * | 2003-05-29 | 2005-01-13 | New Industry Research Organization | ベンゾフラン化合物、およびそれを含有してなる医薬組成物 |
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JPH10287647A (ja) * | 1997-04-11 | 1998-10-27 | Higeta Shoyu Co Ltd | 新規インドールアルカロイド系化合物 0089−d |
US7064114B2 (en) * | 1999-03-19 | 2006-06-20 | Parker Hughes Institute | Gel-microemulsion formulations |
WO2001032621A1 (fr) * | 1999-10-29 | 2001-05-10 | Wakunaga Pharmaceutical Co., Ltd. | Nouveaux derives d'indole, et medicaments contenant lesdits derives comme principe actif |
CA2424222A1 (en) * | 2000-10-02 | 2002-04-11 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
US6770259B2 (en) | 2000-11-03 | 2004-08-03 | Bristol-Myers Squibb Pharma Company | Simultaneous dual isotope imaging of cardiac perfusion and cardiac inflammation |
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US20050256117A1 (en) * | 2002-06-14 | 2005-11-17 | Meng Hsin Chen | Ophthalmic compositions for treating ocular hypertension |
US20040259926A1 (en) * | 2003-06-05 | 2004-12-23 | Bruendl Michelle M. | 3-Aryloxy and 3-heteroaryloxy substituted benzo[b]thiophenes as therapeutic agents |
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JP2006526614A (ja) * | 2003-06-05 | 2006-11-24 | ワーナー−ランバート カンパニー リミティド ライアビリティー カンパニー | 治療用剤としての3−アリールスルファニル及び3−ヘテロアリールスルファニル置換ベンゾ[b]チオフェン |
CA2527934A1 (en) * | 2003-06-05 | 2004-12-16 | Warner-Lambert Company Llc | Tetrazol benzofurancarboxamides with p13k activity as therapeutic agents |
EP1644360A1 (en) * | 2003-06-05 | 2006-04-12 | Warner-Lambert Company LLC | 3-substituted indoles and derivatives thereof as therapeutic agents |
ITRM20030355A1 (it) * | 2003-07-18 | 2005-01-19 | Sigma Tau Ind Farmaceuti | Composti ad attivita' citotossica derivati della combretastatina. |
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-
1991
- 1991-09-06 EP EP91917468A patent/EP0548250B1/en not_active Expired - Lifetime
- 1991-09-06 CA CA002091257A patent/CA2091257A1/en not_active Abandoned
- 1991-09-06 DE DE69118388T patent/DE69118388T2/de not_active Expired - Lifetime
- 1991-09-06 AU AU86419/91A patent/AU8641991A/en not_active Abandoned
- 1991-09-06 AT AT91917468T patent/ATE136026T1/de not_active IP Right Cessation
- 1991-09-06 WO PCT/US1991/006447 patent/WO1992004321A1/en active IP Right Grant
- 1991-09-06 US US07/777,246 patent/US5468898A/en not_active Expired - Lifetime
- 1991-09-06 JP JP51616191A patent/JP3334087B2/ja not_active Expired - Lifetime
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1992
- 1992-06-29 MX MX9203775A patent/MX9203775A/es unknown
Cited By (1)
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JP2005008631A (ja) * | 2003-05-29 | 2005-01-13 | New Industry Research Organization | ベンゾフラン化合物、およびそれを含有してなる医薬組成物 |
Also Published As
Publication number | Publication date |
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ATE136026T1 (de) | 1996-04-15 |
DE69118388T2 (de) | 1996-11-14 |
EP0548250A1 (en) | 1993-06-30 |
JP3334087B2 (ja) | 2002-10-15 |
US5468898A (en) | 1995-11-21 |
MX9203775A (es) | 1992-07-01 |
WO1992004321A1 (en) | 1992-03-19 |
EP0548250A4 (en) | 1993-10-27 |
AU8641991A (en) | 1992-03-30 |
CA2091257A1 (en) | 1992-03-11 |
DE69118388D1 (de) | 1996-05-02 |
EP0548250B1 (en) | 1996-03-27 |
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