ES2391178T3 - Procedimientos y productos intermedios para la preparación de derivados de la purina útiles en el tratamiento de (entre otros) cáncer, asma y diarrea - Google Patents
Procedimientos y productos intermedios para la preparación de derivados de la purina útiles en el tratamiento de (entre otros) cáncer, asma y diarrea Download PDFInfo
- Publication number
- ES2391178T3 ES2391178T3 ES04811022T ES04811022T ES2391178T3 ES 2391178 T3 ES2391178 T3 ES 2391178T3 ES 04811022 T ES04811022 T ES 04811022T ES 04811022 T ES04811022 T ES 04811022T ES 2391178 T3 ES2391178 T3 ES 2391178T3
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- Prior art keywords
- formula
- compound
- ethyl
- methyl
- amino
- 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.)
- Expired - Lifetime
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- 238000002360 preparation method Methods 0.000 title claims abstract description 74
- 238000000034 method Methods 0.000 title claims abstract description 54
- 208000006673 asthma Diseases 0.000 title description 10
- 206010012735 Diarrhoea Diseases 0.000 title description 6
- 206010028980 Neoplasm Diseases 0.000 title description 5
- 201000011510 cancer Diseases 0.000 title description 4
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 233
- 230000008569 process Effects 0.000 claims abstract description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 11
- 125000000732 arylene group Chemical group 0.000 claims abstract description 5
- 125000005549 heteroarylene group Chemical group 0.000 claims abstract description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 108
- -1 pyrazol-4-yl Chemical group 0.000 claims description 99
- 238000006243 chemical reaction Methods 0.000 claims description 82
- 239000000047 product Substances 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 11
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 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
- 239000013067 intermediate product Substances 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- 239000007822 coupling agent Substances 0.000 claims description 7
- 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 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003586 protic polar solvent Substances 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- SYZRCDDKRGGITN-UHFFFAOYSA-N n-(6-amino-1-ethyl-2,4-dioxopyrimidin-5-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxamide Chemical compound O=C1NC(=O)N(CC)C(N)=C1NC(=O)C1=CN(CC=2C=C(C=CC=2)C(F)(F)F)N=C1 SYZRCDDKRGGITN-UHFFFAOYSA-N 0.000 claims description 4
- 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
- 230000001351 cycling effect Effects 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 4
- 239000003377 acid catalyst Substances 0.000 claims 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 description 60
- 125000001072 heteroaryl group Chemical group 0.000 description 52
- 125000003118 aryl group Chemical group 0.000 description 48
- 125000001424 substituent 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 30
- 125000003545 alkoxy group Chemical group 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 28
- 230000002829 reductive effect Effects 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- 229910052736 halogen Inorganic materials 0.000 description 23
- 150000002367 halogens Chemical class 0.000 description 23
- 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
- 125000000623 heterocyclic group Chemical group 0.000 description 21
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 101150078577 Adora2b gene Proteins 0.000 description 17
- 125000000304 alkynyl group Chemical group 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 150000003857 carboxamides Chemical class 0.000 description 16
- 125000000392 cycloalkenyl group Chemical group 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000002947 alkylene group Chemical group 0.000 description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 15
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 14
- 229960005305 adenosine Drugs 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 12
- 201000010099 disease Diseases 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 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
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 125000005110 aryl thio group Chemical group 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 125000004181 carboxyalkyl group Chemical group 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 230000002140 halogenating effect Effects 0.000 description 9
- 125000000468 ketone group Chemical group 0.000 description 9
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 9
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 8
- 125000005553 heteroaryloxy group Chemical group 0.000 description 8
- 125000005368 heteroarylthio group Chemical group 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 125000000033 alkoxyamino group Chemical group 0.000 description 7
- 150000001718 carbodiimides Chemical class 0.000 description 7
- 125000004470 heterocyclooxy group Chemical group 0.000 description 7
- 210000003630 histaminocyte Anatomy 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- 239000002798 polar solvent Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 125000004468 heterocyclylthio group Chemical group 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- UBZZBQIXYQZVDV-UHFFFAOYSA-N 1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC(C(F)(F)F)=C1 UBZZBQIXYQZVDV-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- QHEMDIZENXAVRQ-UHFFFAOYSA-N 6-amino-1-ethylpyrimidine-2,4-dione Chemical compound CCN1C(N)=CC(=O)NC1=O QHEMDIZENXAVRQ-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
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 229940121359 adenosine receptor antagonist Drugs 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000011260 aqueous acid Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- HEXZSEOAILCDMD-UHFFFAOYSA-N 5,6-diamino-1-ethylpyrimidine-2,4-dione Chemical compound CCN1C(N)=C(N)C(=O)NC1=O HEXZSEOAILCDMD-UHFFFAOYSA-N 0.000 description 3
- DRBZCXPJVFOQDO-UHFFFAOYSA-N 5,6-diamino-3-propyl-1h-pyrimidine-2,4-dione Chemical compound CCCN1C(=O)NC(N)=C(N)C1=O DRBZCXPJVFOQDO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000002837 carbocyclic group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000005017 substituted alkenyl group Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-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
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- 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
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- 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
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (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)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| US719102 | 1996-09-24 | ||
| US10/719,102 US7125993B2 (en) | 2001-11-09 | 2003-11-21 | A2B adenosine receptor antagonists |
| PCT/US2004/038136 WO2005051951A1 (en) | 2003-11-21 | 2004-11-15 | A2b adenosine receptor antagonists |
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| ES2391178T3 true ES2391178T3 (es) | 2012-11-22 |
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| ES04811022T Expired - Lifetime ES2391178T3 (es) | 2003-11-21 | 2004-11-15 | Procedimientos y productos intermedios para la preparación de derivados de la purina útiles en el tratamiento de (entre otros) cáncer, asma y diarrea |
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| AU (1) | AU2004292529B2 (https=) |
| CA (1) | CA2546733C (https=) |
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| 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 |
| AU2001238665A1 (en) | 2000-02-23 | 2001-09-03 | Cv Therapeutics, Inc. | Method of identifying partial agonists of the a2a receptor |
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-
2003
- 2003-11-21 US US10/719,102 patent/US7125993B2/en not_active Expired - Lifetime
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- 2004-11-15 CN CNB2004800342770A patent/CN100415748C/zh not_active Expired - Fee Related
- 2004-11-15 ES ES04811022T patent/ES2391178T3/es not_active Expired - Lifetime
- 2004-11-15 RU RU2006117349/04A patent/RU2374247C2/ru not_active IP Right Cessation
- 2004-11-15 NZ NZ547357A patent/NZ547357A/xx not_active IP Right Cessation
- 2004-11-15 WO PCT/US2004/038136 patent/WO2005051951A1/en not_active Ceased
- 2004-11-15 CA CA2546733A patent/CA2546733C/en not_active Expired - Fee Related
- 2004-11-15 KR KR1020067009840A patent/KR101140186B1/ko not_active Expired - Fee Related
- 2004-11-15 EP EP04811022A patent/EP1685132B1/en not_active Expired - Lifetime
- 2004-11-15 MX MXPA06005637A patent/MXPA06005637A/es active IP Right Grant
- 2004-11-15 JP JP2006541295A patent/JP4769728B2/ja not_active Expired - Fee Related
- 2004-11-15 AU AU2004292529A patent/AU2004292529B2/en not_active Ceased
- 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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| Publication number | Publication date |
|---|---|
| US20060281921A1 (en) | 2006-12-14 |
| JP4769728B2 (ja) | 2011-09-07 |
| HK1093736A1 (en) | 2007-03-09 |
| JP2007512335A (ja) | 2007-05-17 |
| US20090137802A1 (en) | 2009-05-28 |
| US7521554B2 (en) | 2009-04-21 |
| TWI365879B (en) | 2012-06-11 |
| NZ547357A (en) | 2009-08-28 |
| CA2546733A1 (en) | 2005-06-09 |
| KR101140186B1 (ko) | 2012-05-23 |
| AU2004292529B2 (en) | 2011-04-14 |
| RU2374247C2 (ru) | 2009-11-27 |
| AU2004292529A1 (en) | 2005-06-09 |
| WO2005051951A1 (en) | 2005-06-09 |
| CN100415748C (zh) | 2008-09-03 |
| EP1685132A1 (en) | 2006-08-02 |
| US7125993B2 (en) | 2006-10-24 |
| ZA200604046B (en) | 2007-11-28 |
| IL175759A0 (en) | 2006-09-05 |
| CN1882588A (zh) | 2006-12-20 |
| TW200530237A (en) | 2005-09-16 |
| EP1685132B1 (en) | 2012-08-29 |
| KR20060100434A (ko) | 2006-09-20 |
| RU2006117349A (ru) | 2007-11-27 |
| US20040176399A1 (en) | 2004-09-09 |
| CA2546733C (en) | 2015-03-17 |
| MXPA06005637A (es) | 2006-08-17 |
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