JP4769728B2 - Ａ２ｂアデノシンレセプターアンタゴニスト - Google Patents
Ａ２ｂアデノシンレセプターアンタゴニスト Download PDFInfo
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- JP4769728B2 JP4769728B2 JP2006541295A JP2006541295A JP4769728B2 JP 4769728 B2 JP4769728 B2 JP 4769728B2 JP 2006541295 A JP2006541295 A JP 2006541295A JP 2006541295 A JP2006541295 A JP 2006541295A JP 4769728 B2 JP4769728 B2 JP 4769728B2
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- formula
- compound
- ethyl
- methyl
- amino
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- 229940121359 adenosine receptor antagonist Drugs 0.000 title description 5
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 title description 5
- 101150078577 Adora2b gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 308
- -1 pyrazol-4-yl Chemical group 0.000 claims description 110
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 108
- 238000006243 chemical reaction Methods 0.000 claims description 92
- 238000000034 method Methods 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 18
- 150000003857 carboxamides Chemical class 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 125000001246 bromo group Chemical group Br* 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 14
- 239000012442 inert solvent Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 13
- 235000010288 sodium nitrite Nutrition 0.000 claims description 10
- 125000002346 iodo group Chemical group I* 0.000 claims description 9
- 239000003586 protic polar solvent Substances 0.000 claims description 9
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 8
- 239000000543 intermediate Substances 0.000 claims description 8
- 239000007822 coupling agent Substances 0.000 claims description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000732 arylene group Chemical group 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 5
- 125000005549 heteroarylene group Chemical group 0.000 claims description 5
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 5
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical group N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- 239000003377 acid catalyst Substances 0.000 claims 2
- 238000002360 preparation method Methods 0.000 description 80
- 125000001072 heteroaryl group Chemical group 0.000 description 52
- 239000000047 product Substances 0.000 description 51
- 125000001424 substituent group Chemical group 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 44
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 29
- 238000007796 conventional method Methods 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 28
- 125000003545 alkoxy group Chemical group 0.000 description 25
- 229910052736 halogen Inorganic materials 0.000 description 23
- 150000002367 halogens Chemical class 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 22
- 125000004181 carboxyalkyl group Chemical group 0.000 description 22
- 125000004093 cyano group Chemical group *C#N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 125000003342 alkenyl group Chemical group 0.000 description 20
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 125000000623 heterocyclic group Chemical group 0.000 description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 20
- 108050000203 Adenosine receptors Proteins 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000003826 tablet Substances 0.000 description 18
- 102000009346 Adenosine receptors Human genes 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 17
- 125000000392 cycloalkenyl group Chemical group 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 125000000304 alkynyl group Chemical group 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 16
- 108020003175 receptors Proteins 0.000 description 16
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 15
- 229960005305 adenosine Drugs 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 13
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 125000004414 alkyl thio group Chemical group 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000004615 ingredient Substances 0.000 description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 229930194542 Keto Natural products 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000004442 acylamino group Chemical group 0.000 description 9
- 125000004423 acyloxy group Chemical group 0.000 description 9
- 125000005110 aryl thio group Chemical group 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 208000006673 asthma Diseases 0.000 description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 description 9
- 125000000468 ketone group Chemical group 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 239000002798 polar solvent Substances 0.000 description 9
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 9
- 150000003573 thiols Chemical class 0.000 description 9
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 8
- 125000000033 alkoxyamino group Chemical group 0.000 description 8
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 8
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000002140 halogenating effect Effects 0.000 description 8
- 125000005368 heteroarylthio group Chemical group 0.000 description 8
- 125000004468 heterocyclylthio group Chemical group 0.000 description 8
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 150000001540 azides Chemical class 0.000 description 7
- 150000001718 carbodiimides Chemical class 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 125000004470 heterocyclooxy group Chemical group 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- QHEMDIZENXAVRQ-UHFFFAOYSA-N 6-amino-1-ethylpyrimidine-2,4-dione Chemical compound CCN1C(N)=CC(=O)NC1=O QHEMDIZENXAVRQ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 210000003630 histaminocyte Anatomy 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229930195734 saturated hydrocarbon Natural products 0.000 description 6
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- 238000012360 testing method Methods 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- KOYXXLLNCXWUNF-UHFFFAOYSA-N 3-ethyl-1-propyl-8-[1-[[3-(trifluoromethyl)phenyl]methyl]pyrazol-4-yl]-7h-purine-2,6-dione Chemical compound N1C=2C(=O)N(CCC)C(=O)N(CC)C=2N=C1C(=C1)C=NN1CC1=CC=CC(C(F)(F)F)=C1 KOYXXLLNCXWUNF-UHFFFAOYSA-N 0.000 description 5
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- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 5
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- LWLBIEJVVPVPMW-UHFFFAOYSA-N 1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole Chemical compound FC(F)(F)C1=CC=CC(CN2N=CC=C2)=C1 LWLBIEJVVPVPMW-UHFFFAOYSA-N 0.000 description 4
- SHKJXAPOAVPNKW-UHFFFAOYSA-N 6-amino-1-ethyl-5-nitrosopyrimidine-2,4-dione Chemical compound CCN1C(N)=C(N=O)C(=O)NC1=O SHKJXAPOAVPNKW-UHFFFAOYSA-N 0.000 description 4
- FPJMMVWPHPRAMW-UHFFFAOYSA-N 6-amino-3-propyl-1h-pyrimidine-2,4-dione Chemical compound CCCN1C(=O)C=C(N)NC1=O FPJMMVWPHPRAMW-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000001593 cAMP accumulation Effects 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
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- 238000001704 evaporation Methods 0.000 description 4
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- SPJDDRUDFQBAOY-UHFFFAOYSA-N n'-(3-ethyl-2,6-dioxo-1-propylpyrimidin-4-yl)-n,n-dimethylmethanimidamide Chemical compound CCCN1C(=O)C=C(N=CN(C)C)N(CC)C1=O SPJDDRUDFQBAOY-UHFFFAOYSA-N 0.000 description 4
- 239000006199 nebulizer Substances 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
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- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000055025 Adenosine deaminases Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- FVKPZGAIJRIYTI-UHFFFAOYSA-N N-[6-amino-4-oxo-3-(2-oxopentan-3-yl)-1,2-dihydropyrimidin-5-yl]-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxamide Chemical compound NC1=C(C(N(CN1)C(C(C)=O)CC)=O)NC(=O)C=1C=NN(C1)CC1=CC(=CC=C1)C(F)(F)F FVKPZGAIJRIYTI-UHFFFAOYSA-N 0.000 description 3
- JTTYIGNOWNZSHC-UHFFFAOYSA-N N-[6-amino-4-oxo-3-(2-oxopropyl)-1,2-dihydropyrimidin-5-yl]-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxamide Chemical compound NC1=C(C(N(CN1)CC(C)=O)=O)NC(=O)C=1C=NN(C1)CC1=CC(=CC=C1)C(F)(F)F JTTYIGNOWNZSHC-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/719,102 US7125993B2 (en) | 2001-11-09 | 2003-11-21 | A2B adenosine receptor antagonists |
| US10/719,102 | 2003-11-21 | ||
| PCT/US2004/038136 WO2005051951A1 (en) | 2003-11-21 | 2004-11-15 | A2b adenosine receptor antagonists |
Publications (3)
| Publication Number | Publication Date |
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| JP2007512335A JP2007512335A (ja) | 2007-05-17 |
| JP2007512335A5 JP2007512335A5 (https=) | 2007-12-13 |
| JP4769728B2 true JP4769728B2 (ja) | 2011-09-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2006541295A Expired - Fee Related JP4769728B2 (ja) | 2003-11-21 | 2004-11-15 | Ａ２ｂアデノシンレセプターアンタゴニスト |
Country Status (15)
| Country | Link |
|---|---|
| US (3) | US7125993B2 (https=) |
| EP (1) | EP1685132B1 (https=) |
| JP (1) | JP4769728B2 (https=) |
| KR (1) | KR101140186B1 (https=) |
| CN (1) | CN100415748C (https=) |
| AU (1) | AU2004292529B2 (https=) |
| CA (1) | CA2546733C (https=) |
| ES (1) | ES2391178T3 (https=) |
| IL (1) | IL175759A0 (https=) |
| MX (1) | MXPA06005637A (https=) |
| NZ (1) | NZ547357A (https=) |
| RU (1) | RU2374247C2 (https=) |
| TW (1) | TWI365879B (https=) |
| WO (1) | WO2005051951A1 (https=) |
| ZA (1) | ZA200604046B (https=) |
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| USRE47351E1 (en) | 1999-06-22 | 2019-04-16 | Gilead Sciences, Inc. | 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists |
| US6403567B1 (en) | 1999-06-22 | 2002-06-11 | Cv Therapeutics, Inc. | N-pyrazole A2A adenosine receptor agonists |
| CA2671940A1 (en) * | 2000-02-23 | 2001-08-30 | Cv Therapeutics, Inc. | Identification of partial agonists of the a2a adenosine receptor |
| US7125993B2 (en) * | 2001-11-09 | 2006-10-24 | Cv Therapeutics, Inc. | A2B adenosine receptor antagonists |
| US20080318983A1 (en) * | 2001-11-09 | 2008-12-25 | Rao Kalla | A2b adenosine receptor antagonists |
| WO2003063800A2 (en) * | 2002-02-01 | 2003-08-07 | King Pharmaceuticals Research And Development, Inc. | 8-heteroaryl xanthine adenosine a2b receptor antagonists |
| NZ537975A (en) * | 2002-07-29 | 2007-08-31 | Cv Therapeutics Inc | Method of producing coronary vasodilation without peripheral vasodilation comprising administering at least 10 mcg of at least one A2A receptor agonist |
| US8470801B2 (en) | 2002-07-29 | 2013-06-25 | Gilead Sciences, Inc. | Myocardial perfusion imaging methods and compositions |
| US20050020915A1 (en) * | 2002-07-29 | 2005-01-27 | Cv Therapeutics, Inc. | Myocardial perfusion imaging methods and compositions |
| EP1799221A1 (en) * | 2004-10-15 | 2007-06-27 | Cv Therapeutics, Inc. | Method of preventing and treating airway remodeling and pulmonary inflammation using a2b adenosine receptor antagonists |
| KR20070083714A (ko) | 2004-10-20 | 2007-08-24 | 씨브이 쎄러퓨틱스, 인코포레이티드 | Ａ2ａ 아데노신 수용체 작용제의 용도 |
| NZ564326A (en) * | 2005-06-16 | 2010-01-29 | Cv Therapeutics Inc | Prodrugs of A2B adenosine receptor antagonists |
| ES2270715B1 (es) * | 2005-07-29 | 2008-04-01 | Laboratorios Almirall S.A. | Nuevos derivados de pirazina. |
| ES2274712B1 (es) * | 2005-10-06 | 2008-03-01 | Laboratorios Almirall S.A. | Nuevos derivados imidazopiridina. |
| US7732595B2 (en) | 2006-02-03 | 2010-06-08 | Gilead Palo Alto, Inc. | Process for preparing an A2A-adenosine receptor agonist and its polymorphs |
| WO2007109547A2 (en) * | 2006-03-17 | 2007-09-27 | Cv Therapeutics, Inc. | Method of preventing and treating hepatic disease using a2b adenosine receptor antagonists |
| US20090081120A1 (en) * | 2006-09-01 | 2009-03-26 | Cv Therapeutics, Inc. | Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods |
| RU2459626C2 (ru) * | 2006-09-01 | 2012-08-27 | Гайлид Сайэнсиз, Инк. | Способы и композиции, повышающие переносимость пациентом методов визуализации миокарда |
| US20080170990A1 (en) * | 2006-09-29 | 2008-07-17 | Cv Therapeutics, Inc. | Methods for Myocardial Imaging in Patients Having a History of Pulmonary Disease |
| ES2303776B1 (es) * | 2006-12-29 | 2009-08-07 | Laboratorios Almirall S.A. | Derivados de 5-fenil-6-piridin-4-il-1,3-dihidro-2h-imidazo(4,5-b)piridin-2-ona utiles como antagonistas del receptor de adenosina a2b. |
| JP2010515081A (ja) * | 2007-01-03 | 2010-05-06 | ギリアード・パロ・アルト・インコーポレイテッド | 心筋灌流画像化 |
| US20110118276A1 (en) * | 2008-07-16 | 2011-05-19 | Edward Leung | Methods of treating atherosclerosis |
| AU2009296235A1 (en) * | 2008-09-29 | 2010-04-01 | Gilead Sciences, Inc. | Combinations of a rate control agent and an A-2-alpha receptor antagonist for use in multidetector computed tomography methods |
| US20120003329A1 (en) | 2010-06-30 | 2012-01-05 | Gilead Sciences, Inc. | Use of A2B Adenosine Receptor Antagonists for Treating Pulmonary Hypertension |
| MX2020009286A (es) | 2018-03-05 | 2020-12-11 | Teon Therapeutics Inc | Antagonistas del receptor de adenosina y usos de los mismos. |
| MX2021008094A (es) | 2019-01-11 | 2021-09-21 | Omeros Corp | Metodos y composiciones para el tratamiento del cancer. |
| CN116322698A (zh) * | 2020-09-04 | 2023-06-23 | 泰昂治疗公司 | 腺苷a2b受体拮抗剂的共晶 |
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| EP0956855A1 (en) * | 1998-04-24 | 1999-11-17 | K.U. Leuven Research & Development | Immunosuppressive effects of 8-substituted xanthine derivatives |
| WO2003042214A2 (en) * | 2001-11-09 | 2003-05-22 | Cv Therapeutics, Inc. | A2b adenosine receptor antagonists |
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| US4452788A (en) * | 1982-04-21 | 1984-06-05 | Warner-Lambert Company | Substituted 8-phenylxanthines |
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| US4593095A (en) * | 1983-02-18 | 1986-06-03 | The Johns Hopkins University | Xanthine derivatives |
| US4558051A (en) * | 1983-10-11 | 1985-12-10 | Richardson-Vicks, Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
| GB8510758D0 (en) * | 1985-04-27 | 1985-06-05 | Wellcome Found | Compounds |
| DE8817122U1 (de) * | 1988-12-22 | 1993-02-04 | Boehringer Ingelheim Kg, 55218 Ingelheim | Neue Xanthinderivate mit Adenosinantogenistischer Wirkung |
| IT1229195B (it) | 1989-03-10 | 1991-07-25 | Poli Ind Chimica Spa | Derivati xantinici ad attivita' broncodilatatrice e loro applicazioni terapeutiche. |
| DE4019892A1 (de) * | 1990-06-22 | 1992-01-02 | Boehringer Ingelheim Kg | Neue xanthinderivate |
| TW252044B (https=) * | 1992-08-10 | 1995-07-21 | Boehringer Ingelheim Kg | |
| US5446046A (en) * | 1993-10-28 | 1995-08-29 | University Of Florida Research Foundation | A1 adenosine receptor agonists and antagonists as diuretics |
| WO1995011681A1 (en) | 1993-10-29 | 1995-05-04 | Merck & Co., Inc. | Human adenosine receptor antagonists |
| DE19535504A1 (de) | 1995-09-25 | 1997-03-27 | Bayer Ag | Substituierte Xanthine |
| GB9703044D0 (en) * | 1997-02-14 | 1997-04-02 | Glaxo Group Ltd | Phenyl xanthine esters and amides |
| US6117878A (en) | 1998-02-24 | 2000-09-12 | University Of Virginia | 8-phenyl- or 8-cycloalkyl xanthine antagonists of A2B human adenosine receptors |
| US6060481A (en) * | 1998-05-28 | 2000-05-09 | The Penn State Research Foundation | Method for improving insulin sensitivity using an adenosine receptor antagonist |
| ES2273487T3 (es) | 1998-06-01 | 2007-05-01 | Astellas Pharma Inc. | Antagonistas a1 de adenosina contra la esterilidad masculina. |
| GB9817623D0 (en) | 1998-08-13 | 1998-10-07 | Glaxo Group Ltd | Pharmaceutical compounds |
| US6545002B1 (en) * | 1999-06-01 | 2003-04-08 | University Of Virginia Patent Foundation | Substituted 8-phenylxanthines useful as antagonists of A2B adenosine receptors |
| US7125993B2 (en) * | 2001-11-09 | 2006-10-24 | Cv Therapeutics, Inc. | A2B adenosine receptor antagonists |
| US6977300B2 (en) * | 2001-11-09 | 2005-12-20 | Cv Therapeutics, Inc. | A2B adenosine receptor antagonists |
-
2003
- 2003-11-21 US US10/719,102 patent/US7125993B2/en not_active Expired - Lifetime
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2004
- 2004-11-15 CA CA2546733A patent/CA2546733C/en not_active Expired - Fee Related
- 2004-11-15 WO PCT/US2004/038136 patent/WO2005051951A1/en not_active Ceased
- 2004-11-15 RU RU2006117349/04A patent/RU2374247C2/ru not_active IP Right Cessation
- 2004-11-15 AU AU2004292529A patent/AU2004292529B2/en not_active Ceased
- 2004-11-15 MX MXPA06005637A patent/MXPA06005637A/es active IP Right Grant
- 2004-11-15 NZ NZ547357A patent/NZ547357A/xx not_active IP Right Cessation
- 2004-11-15 ES ES04811022T patent/ES2391178T3/es not_active Expired - Lifetime
- 2004-11-15 CN CNB2004800342770A patent/CN100415748C/zh not_active Expired - Fee Related
- 2004-11-15 EP EP04811022A patent/EP1685132B1/en not_active Expired - Lifetime
- 2004-11-15 KR KR1020067009840A patent/KR101140186B1/ko not_active Expired - Fee Related
- 2004-11-15 JP JP2006541295A patent/JP4769728B2/ja not_active Expired - Fee Related
- 2004-11-19 TW TW093135764A patent/TWI365879B/zh not_active IP Right Cessation
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2006
- 2006-05-18 IL IL175759A patent/IL175759A0/en active IP Right Grant
- 2006-05-19 ZA ZA200604046A patent/ZA200604046B/en unknown
- 2006-08-22 US US11/508,592 patent/US7521554B2/en not_active Expired - Fee Related
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2009
- 2009-01-28 US US12/361,409 patent/US20090137802A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0956855A1 (en) * | 1998-04-24 | 1999-11-17 | K.U. Leuven Research & Development | Immunosuppressive effects of 8-substituted xanthine derivatives |
| WO2003042214A2 (en) * | 2001-11-09 | 2003-05-22 | Cv Therapeutics, Inc. | A2b adenosine receptor antagonists |
| US20030139428A1 (en) * | 2001-11-09 | 2003-07-24 | Rao Kalla | A2B adenosine receptor antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| US7521554B2 (en) | 2009-04-21 |
| TW200530237A (en) | 2005-09-16 |
| WO2005051951A1 (en) | 2005-06-09 |
| RU2006117349A (ru) | 2007-11-27 |
| TWI365879B (en) | 2012-06-11 |
| KR20060100434A (ko) | 2006-09-20 |
| CA2546733C (en) | 2015-03-17 |
| US20090137802A1 (en) | 2009-05-28 |
| US20060281921A1 (en) | 2006-12-14 |
| CN1882588A (zh) | 2006-12-20 |
| EP1685132A1 (en) | 2006-08-02 |
| AU2004292529A1 (en) | 2005-06-09 |
| NZ547357A (en) | 2009-08-28 |
| HK1093736A1 (en) | 2007-03-09 |
| MXPA06005637A (es) | 2006-08-17 |
| CA2546733A1 (en) | 2005-06-09 |
| US7125993B2 (en) | 2006-10-24 |
| KR101140186B1 (ko) | 2012-05-23 |
| ES2391178T3 (es) | 2012-11-22 |
| ZA200604046B (en) | 2007-11-28 |
| JP2007512335A (ja) | 2007-05-17 |
| US20040176399A1 (en) | 2004-09-09 |
| EP1685132B1 (en) | 2012-08-29 |
| RU2374247C2 (ru) | 2009-11-27 |
| AU2004292529B2 (en) | 2011-04-14 |
| CN100415748C (zh) | 2008-09-03 |
| IL175759A0 (en) | 2006-09-05 |
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