JP2005525398A - ブラジキニン受容体モジュレーターとして有用な新規なヘテロアリールアルキルアミド誘導体 - Google Patents
ブラジキニン受容体モジュレーターとして有用な新規なヘテロアリールアルキルアミド誘導体 Download PDFInfo
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- JP2005525398A JP2005525398A JP2003584046A JP2003584046A JP2005525398A JP 2005525398 A JP2005525398 A JP 2005525398A JP 2003584046 A JP2003584046 A JP 2003584046A JP 2003584046 A JP2003584046 A JP 2003584046A JP 2005525398 A JP2005525398 A JP 2005525398A
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- alkyl
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- 102000010183 Bradykinin receptor Human genes 0.000 title claims description 24
- 108050001736 Bradykinin receptor Proteins 0.000 title claims description 24
- -1 pain Chemical compound 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 348
- 150000001875 compounds Chemical class 0.000 claims description 311
- 125000003118 aryl group Chemical group 0.000 claims description 138
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 96
- 238000000034 method Methods 0.000 claims description 84
- 125000003545 alkoxy group Chemical group 0.000 claims description 59
- 125000004434 sulfur atom Chemical group 0.000 claims description 55
- 125000002950 monocyclic group Chemical group 0.000 claims description 47
- 229910052717 sulfur Inorganic materials 0.000 claims description 46
- 229910052760 oxygen Inorganic materials 0.000 claims description 45
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 40
- 150000002367 halogens Chemical group 0.000 claims description 40
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 33
- 229920006395 saturated elastomer Polymers 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 19
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 18
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 12
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004001 thioalkyl group Chemical group 0.000 claims description 12
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 6
- 125000005551 pyridylene group Chemical group 0.000 claims description 6
- 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 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000005556 thienylene group Chemical group 0.000 claims description 5
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- 101800004538 Bradykinin Proteins 0.000 abstract description 33
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 abstract description 33
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 abstract description 33
- 208000002193 Pain Diseases 0.000 abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 208000035475 disorder Diseases 0.000 abstract description 9
- 206010020751 Hypersensitivity Diseases 0.000 abstract description 6
- 230000007815 allergy Effects 0.000 abstract description 6
- 208000006673 asthma Diseases 0.000 abstract description 6
- 229940122155 Bradykinin receptor antagonist Drugs 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 4
- 239000003366 bradykinin receptor agonist Substances 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 102100035792 Kininogen-1 Human genes 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 363
- 238000006243 chemical reaction Methods 0.000 description 210
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 159
- 239000000047 product Substances 0.000 description 145
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 129
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 126
- 239000002904 solvent Substances 0.000 description 113
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 106
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000000243 solution Substances 0.000 description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 100
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 70
- 229910052757 nitrogen Inorganic materials 0.000 description 69
- 239000000843 powder Substances 0.000 description 67
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 57
- 239000007787 solid Substances 0.000 description 57
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- 239000000203 mixture Substances 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- 238000010992 reflux Methods 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 238000010898 silica gel chromatography Methods 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 102400000967 Bradykinin Human genes 0.000 description 31
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 239000011734 sodium Substances 0.000 description 26
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 21
- 238000002955 isolation Methods 0.000 description 21
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 18
- 239000002585 base Substances 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- 238000003786 synthesis reaction Methods 0.000 description 16
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 150000002431 hydrogen Chemical class 0.000 description 13
- 150000007530 organic bases Chemical class 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 239000003826 tablet Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000007664 blowing Methods 0.000 description 12
- 230000005587 bubbling Effects 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 12
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 12
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000376 reactant Substances 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 239000003610 charcoal Substances 0.000 description 10
- 239000012320 chlorinating reagent Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- XFTJDGAYMRFSDJ-UHFFFAOYSA-N 2-[5-(4-cyanobenzoyl)-1h-pyrrol-2-yl]-n-[2,4-dichloro-3-[(2-methylquinolin-8-yl)oxymethyl]phenyl]-n-methylacetamide Chemical compound C=1C=C(Cl)C(COC=2C3=NC(C)=CC=C3C=CC=2)=C(Cl)C=1N(C)C(=O)CC(N1)=CC=C1C(=O)C1=CC=C(C#N)C=C1 XFTJDGAYMRFSDJ-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- XDTTUTIFWDAMIX-UHFFFAOYSA-N 3-methyl-4-nitrobenzoic acid Chemical compound CC1=CC(C(O)=O)=CC=C1[N+]([O-])=O XDTTUTIFWDAMIX-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- 108010093008 Kinins Proteins 0.000 description 7
- 102000002397 Kinins Human genes 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 206010052428 Wound Diseases 0.000 description 7
- 208000027418 Wounds and injury Diseases 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000007127 saponification reaction Methods 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- UAGTWDQQWBGJCI-UHFFFAOYSA-N 1h-pyrrol-2-yl acetate Chemical class CC(=O)OC1=CC=CN1 UAGTWDQQWBGJCI-UHFFFAOYSA-N 0.000 description 6
- JJPSZKIOGBRMHK-UHFFFAOYSA-N 2,6-dimethylquinoline Chemical compound N1=C(C)C=CC2=CC(C)=CC=C21 JJPSZKIOGBRMHK-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- QOHMWDJIBGVPIF-UHFFFAOYSA-N n',n'-diethylpropane-1,3-diamine Chemical compound CCN(CC)CCCN QOHMWDJIBGVPIF-UHFFFAOYSA-N 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000002098 pyridazinyl group Chemical group 0.000 description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 0 ***Ic1c(*)ccc(*)c1* Chemical compound ***Ic1c(*)ccc(*)c1* 0.000 description 5
- NBYLBWHHTUWMER-UHFFFAOYSA-N 2-Methylquinolin-8-ol Chemical compound C1=CC=C(O)C2=NC(C)=CC=C21 NBYLBWHHTUWMER-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 5
- 239000011149 active material Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 125000002757 morpholinyl group Chemical group 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 125000004193 piperazinyl group Chemical group 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 5
- 230000008733 trauma Effects 0.000 description 5
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- IKBZKTIWBYTIOT-UHFFFAOYSA-N 2-[5-(4-aminobenzoyl)-1-methylpyrrol-2-yl]-n-[2,4-dichloro-3-[(2-methylquinolin-8-yl)oxymethyl]phenyl]-n-methylacetamide Chemical compound C=1C=C(Cl)C(COC=2C3=NC(C)=CC=C3C=CC=2)=C(Cl)C=1N(C)C(=O)CC(N1C)=CC=C1C(=O)C1=CC=C(N)C=C1 IKBZKTIWBYTIOT-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- USEDMAWWQDFMFY-UHFFFAOYSA-N 4-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(C#N)C=C1 USEDMAWWQDFMFY-UHFFFAOYSA-N 0.000 description 4
- FMEBIWNKYZUWFV-UHFFFAOYSA-N 6-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)N=C1 FMEBIWNKYZUWFV-UHFFFAOYSA-N 0.000 description 4
- 206010048962 Brain oedema Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000012659 Joint disease Diseases 0.000 description 4
- 206010033645 Pancreatitis Diseases 0.000 description 4
- 206010033647 Pancreatitis acute Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 206010040070 Septic Shock Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 4
- 201000003229 acute pancreatitis Diseases 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
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- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical group O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US37135002P | 2002-04-10 | 2002-04-10 | |
| PCT/US2003/009974 WO2003087090A2 (en) | 2002-04-10 | 2003-03-31 | Novel heteroaryl alkylamide derivatives useful as bradykinin receptor modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2005525398A true JP2005525398A (ja) | 2005-08-25 |
| JP2005525398A5 JP2005525398A5 (enExample) | 2006-05-25 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003584046A Withdrawn JP2005525398A (ja) | 2002-04-10 | 2003-03-31 | ブラジキニン受容体モジュレーターとして有用な新規なヘテロアリールアルキルアミド誘導体 |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US6958349B2 (enExample) |
| EP (1) | EP1495017A2 (enExample) |
| JP (1) | JP2005525398A (enExample) |
| AU (1) | AU2003226188A1 (enExample) |
| CA (1) | CA2481855A1 (enExample) |
| WO (1) | WO2003087090A2 (enExample) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516132A (ja) * | 2002-12-19 | 2006-06-22 | エラン ファーマシューティカルズ,インコーポレイテッド | 置換n−フェニルスルホンアミドブラジキニン拮抗薬 |
| JP2016514141A (ja) * | 2013-03-14 | 2016-05-19 | シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド | B2−ブラジキニン受容体媒介の血管浮腫の治療方法 |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004233898B2 (en) | 2003-04-25 | 2010-12-23 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
| ES2363160T3 (es) | 2004-07-27 | 2011-07-22 | Gilead Sciences, Inc. | Conjugados de fosfonato nucelosidico como agentes anti-vih. |
| WO2008026018A1 (en) * | 2006-09-01 | 2008-03-06 | Topotarget Switzerland Sa | New method for the treatment of inflammatory diseases |
| TWI407960B (zh) | 2007-03-23 | 2013-09-11 | Jerini Ag | 小分子緩激肽b2受體調節劑 |
| US7807629B1 (en) | 2007-06-05 | 2010-10-05 | Alcon Research, Ltd. | Use of bradykinin and related B2R agonists to treat ocular hypertension and glaucoma |
| US8173668B1 (en) | 2007-06-05 | 2012-05-08 | Alcon Research, Ltd. | Use of non-peptidic bradykinin receptor agonists to treat ocular hypertension and glaucoma |
| JP5620376B2 (ja) | 2008-07-08 | 2014-11-05 | ギリアード サイエンシーズ, インコーポレイテッド | Hiv阻害剤化合物の塩 |
| EP2830643A1 (en) | 2012-03-26 | 2015-02-04 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for prevention or treatment of ischemia related organ damage |
| JP6603712B2 (ja) * | 2014-07-01 | 2019-11-06 | ミレニアム ファーマシューティカルズ, インコーポレイテッド | Sumo活性化酵素の阻害薬として有用なヘテロアリール化合物 |
| ES2892402T3 (es) | 2017-08-01 | 2022-02-04 | Gilead Sciences Inc | Formas cristalinas de ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-il)-4-fluoro-2,5-dihidrofuran-2-il)oxi)metil)(fenoxi)fosforil)-L-alaninato de etilo para tratar infecciones virales |
| LT3713928T (lt) | 2017-11-24 | 2022-05-10 | Pharvaris Netherlands B.V. | Nauji bradikinino b2 receptoriaus antagonistai |
| AR118982A1 (es) | 2019-05-23 | 2021-11-17 | Pharvaris Gmbh | Antagonistas cíclicos del receptor b2 de bradiquinina |
| UY38707A (es) | 2019-05-23 | 2020-12-31 | Pharvaris Gmbh | Nuevos antagonistas cíclicos del receptor b2 de bradiquinina |
| TW202345810A (zh) | 2022-03-25 | 2023-12-01 | 瑞士商帕法瑞斯有限責任公司 | 包含緩激肽b2受體拮抗劑之固態延長釋放組成物 |
| IL315699A (en) | 2022-03-25 | 2024-11-01 | Pharvaris Gmbh | A solid composition comprising dissolved bradykinin B2 receptor antagonists |
| EP4499100A1 (en) | 2022-03-25 | 2025-02-05 | Pharvaris GmbH | Therapeutic uses of bradykinin b2-receptor antagonists |
| CN117342963B (zh) * | 2023-09-28 | 2025-06-17 | 上海予君生物科技发展有限公司 | 一种1,4-二羰基化合物、及其制备方法和应用 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574042A (en) * | 1992-11-02 | 1996-11-12 | Fujisawa Pharmaceutical Co., Ltd | Imidazo [1,2-a] pyridines and their pharmaceutical use |
| AU686115B2 (en) * | 1992-11-02 | 1998-02-05 | Fujisawa Pharmaceutical Co., Ltd. | Imidazo (I,2-a) pyridine derivatives as bradykinin antagonists, pharmaceuticals and processes for their preparation |
| AU680870B2 (en) * | 1993-04-28 | 1997-08-14 | Astellas Pharma Inc. | New heterocyclic compounds |
| GB9519077D0 (en) | 1995-09-18 | 1995-11-15 | Fujisawa Pharmaceutical Co | New heterocyclic compounds |
| DE19610784A1 (de) * | 1996-03-19 | 1997-09-25 | Hoechst Ag | Fluoralkyl- und Fluoralkoxysubstituierte heterocyclische Bradykinin-Antagonisten, Verfahren zu ihrer Herstellung und ihre Verwendung |
| DE19712960A1 (de) * | 1997-03-27 | 1998-10-01 | Hoechst Ag | Benzyloxy-substituierte, anellierte N-Heterocyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Bradykininrezeptorantagonisten |
| JP3775780B2 (ja) * | 1997-09-18 | 2006-05-17 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 薬剤の経口的バイオアベイラビリテイを向上させるための縮合イミダゾール誘導体 |
| WO1999051235A1 (en) * | 1998-04-03 | 1999-10-14 | Alcon Laboratories, Inc. | Non-peptide bradykinin receptor antagonists for use in controlling intraocular pressure and treating glaucoma |
| WO2000023439A1 (en) * | 1998-10-21 | 2000-04-27 | Fujisawa Pharmaceutical Co., Ltd. | Vitreous form of known bradykinin antagonist |
-
2003
- 2003-03-31 CA CA002481855A patent/CA2481855A1/en not_active Abandoned
- 2003-03-31 AU AU2003226188A patent/AU2003226188A1/en not_active Abandoned
- 2003-03-31 EP EP03746573A patent/EP1495017A2/en not_active Withdrawn
- 2003-03-31 JP JP2003584046A patent/JP2005525398A/ja not_active Withdrawn
- 2003-03-31 US US10/403,186 patent/US6958349B2/en not_active Expired - Lifetime
- 2003-03-31 WO PCT/US2003/009974 patent/WO2003087090A2/en not_active Ceased
-
2004
- 2004-12-16 US US11/014,471 patent/US7358261B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006516132A (ja) * | 2002-12-19 | 2006-06-22 | エラン ファーマシューティカルズ,インコーポレイテッド | 置換n−フェニルスルホンアミドブラジキニン拮抗薬 |
| JP2016514141A (ja) * | 2013-03-14 | 2016-05-19 | シャイアー ヒューマン ジェネティック セラピーズ インコーポレイテッド | B2−ブラジキニン受容体媒介の血管浮腫の治療方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003226188A8 (en) | 2003-10-27 |
| CA2481855A1 (en) | 2003-10-23 |
| WO2003087090A2 (en) | 2003-10-23 |
| US6958349B2 (en) | 2005-10-25 |
| WO2003087090A3 (en) | 2003-12-11 |
| US7358261B2 (en) | 2008-04-15 |
| EP1495017A2 (en) | 2005-01-12 |
| US20050159443A1 (en) | 2005-07-21 |
| US20040192720A1 (en) | 2004-09-30 |
| AU2003226188A1 (en) | 2003-10-27 |
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