ES2201552T3 - Agonistas del receptor a1 de la adenosina. - Google Patents
Agonistas del receptor a1 de la adenosina.Info
- Publication number
- ES2201552T3 ES2201552T3 ES98955538T ES98955538T ES2201552T3 ES 2201552 T3 ES2201552 T3 ES 2201552T3 ES 98955538 T ES98955538 T ES 98955538T ES 98955538 T ES98955538 T ES 98955538T ES 2201552 T3 ES2201552 T3 ES 2201552T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- alq
- group
- adenosine
- tetrahydro
- 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
Links
- 239000002126 C01EB10 - Adenosine Substances 0.000 title claims description 26
- 229960005305 adenosine Drugs 0.000 title claims description 26
- 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 title description 8
- 239000000556 agonist Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 125000001424 substituent group Chemical group 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
- 150000002367 halogens Chemical group 0.000 claims abstract description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 19
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- 229910052739 hydrogen Chemical group 0.000 claims abstract description 17
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 17
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000004429 atom Chemical group 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 8
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 7
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 6
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 6
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000011593 sulfur Substances 0.000 claims abstract description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 4
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 3
- -1 N- (2-pyridin-4-yl-ethyl) -5'-trifluoromethyl-adenosine Chemical compound 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 26
- 208000002193 Pain Diseases 0.000 claims description 18
- 238000011282 treatment Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 239000000460 chlorine Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052801 chlorine Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 235000021588 free fatty acids Nutrition 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 208000031225 myocardial ischemia Diseases 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 230000008901 benefit Effects 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 201000002859 sleep apnea Diseases 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 208000015114 central nervous system disease Diseases 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- UYSGCRYMJJMGIM-KQYNXXCUSA-N (2r,3r,4s,5r)-2-(6-aminopurin-9-yl)-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COC(F)(F)F)[C@@H](O)[C@H]1O UYSGCRYMJJMGIM-KQYNXXCUSA-N 0.000 claims description 3
- FQPOPTXHKUUAGF-LSCFUAHRSA-N (2r,3r,4s,5r)-2-[2-chloro-6-(oxan-4-ylamino)purin-9-yl]-5-(3-fluoropropoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COCCCF)O[C@H]1N1C2=NC(Cl)=NC(NC3CCOCC3)=C2N=C1 FQPOPTXHKUUAGF-LSCFUAHRSA-N 0.000 claims description 3
- FTCQFWYJINORPS-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[2-methyl-6-(oxan-4-ylamino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound C=12N=CN([C@H]3[C@@H]([C@H](O)[C@@H](COC(F)(F)F)O3)O)C2=NC(C)=NC=1NC1CCOCC1 FTCQFWYJINORPS-XNIJJKJLSA-N 0.000 claims description 3
- KUUUKOXSYSLSLQ-ZRURSIFKSA-N (2r,3r,4s,5r)-2-[6-(2,3-dihydroxypropylamino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(NCC(O)CO)=NC=NC=2N1[C@@H]1O[C@H](COC(F)(F)F)[C@@H](O)[C@H]1O KUUUKOXSYSLSLQ-ZRURSIFKSA-N 0.000 claims description 3
- HIDBVKBAWSBKMO-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-(3,4-difluoroanilino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1N1C2=NC=NC(NC=3C=C(F)C(F)=CC=3)=C2N=C1 HIDBVKBAWSBKMO-XNIJJKJLSA-N 0.000 claims description 3
- XCFCLFQNWLHHMC-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-(3-fluoroanilino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1N1C2=NC=NC(NC=3C=C(F)C=CC=3)=C2N=C1 XCFCLFQNWLHHMC-XNIJJKJLSA-N 0.000 claims description 3
- VLBSROBMFIQHAR-LSCFUAHRSA-N (2r,3r,4s,5r)-2-[6-(4-fluoroanilino)purin-9-yl]-5-(2,2,2-trifluoroethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1N1C2=NC=NC(NC=3C=CC(F)=CC=3)=C2N=C1 VLBSROBMFIQHAR-LSCFUAHRSA-N 0.000 claims description 3
- REAFCJZEBOQFSM-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-(cyclopentylamino)purin-9-yl]-5-(2,2,2-trifluoroethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1N1C2=NC=NC(NC3CCCC3)=C2N=C1 REAFCJZEBOQFSM-XNIJJKJLSA-N 0.000 claims description 3
- GLISGJNMLQTLNU-XNIJJKJLSA-N (2r,3r,4s,5r)-2-[6-(oxan-4-ylamino)purin-9-yl]-5-(2,2,2-trifluoroethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COCC(F)(F)F)O[C@H]1N1C2=NC=NC(NC3CCOCC3)=C2N=C1 GLISGJNMLQTLNU-XNIJJKJLSA-N 0.000 claims description 3
- ZVSMNRNJGJGCHG-SDBHATRESA-N (2r,3r,4s,5r)-2-[6-(oxan-4-ylamino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COC(F)(F)F)O[C@H]1N1C2=NC=NC(NC3CCOCC3)=C2N=C1 ZVSMNRNJGJGCHG-SDBHATRESA-N 0.000 claims description 3
- JZHIJAIIKORZJM-QYVSTXNMSA-N (2r,3r,4s,5r)-2-[6-(tert-butylamino)purin-9-yl]-5-(trifluoromethoxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(NC(C)(C)C)=NC=NC=2N1[C@@H]1O[C@H](COC(F)(F)F)[C@@H](O)[C@H]1O JZHIJAIIKORZJM-QYVSTXNMSA-N 0.000 claims description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 3
- VTGVYJFENKSVFQ-SCFUHWHPSA-N (2r,3s,4r,5r)-2-(3-fluoropropoxymethyl)-5-[6-(oxan-4-ylamino)purin-9-yl]oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](COCCCF)O[C@H]1N1C2=NC=NC(NC3CCOCC3)=C2N=C1 VTGVYJFENKSVFQ-SCFUHWHPSA-N 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 abstract 1
- 229910003827 NRaRb Inorganic materials 0.000 abstract 1
- 125000004430 oxygen atom Chemical group O* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
- 239000000377 silicon dioxide Substances 0.000 description 54
- 239000000243 solution Substances 0.000 description 53
- 239000000203 mixture Substances 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000000543 intermediate Substances 0.000 description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 32
- 238000001819 mass spectrum Methods 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 239000012299 nitrogen atmosphere Substances 0.000 description 23
- 150000002148 esters Chemical class 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 238000010992 reflux Methods 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 239000003921 oil Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 229910021529 ammonia Inorganic materials 0.000 description 16
- 239000006260 foam Substances 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical group ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 125000006345 2,2,2-trifluoroethoxymethyl group Chemical group [H]C([H])(*)OC([H])([H])C(F)(F)F 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 229910052681 coesite Inorganic materials 0.000 description 9
- 229910052906 cristobalite Inorganic materials 0.000 description 9
- 235000012239 silicon dioxide Nutrition 0.000 description 9
- 229910052682 stishovite Inorganic materials 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 229910052905 tridymite Inorganic materials 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- WJYHCYBNUJVCEH-UHFFFAOYSA-N cyclohexane;ethoxyethane Chemical compound CCOCC.C1CCCCC1 WJYHCYBNUJVCEH-UHFFFAOYSA-N 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000000747 cardiac effect Effects 0.000 description 6
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 6
- 208000028867 ischemia Diseases 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 5
- 230000003243 anti-lipolytic effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 208000021070 secondary pulmonary alveolar proteinosis Diseases 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JADDQZYHOWSFJD-FLNNQWSLSA-N N-ethyl-5'-carboxamidoadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NCC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 JADDQZYHOWSFJD-FLNNQWSLSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Applications Claiming Priority (2)
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| GB9723566 | 1997-11-08 | ||
| GBGB9723566.7A GB9723566D0 (en) | 1997-11-08 | 1997-11-08 | Chemical compounds |
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| ES2201552T3 true ES2201552T3 (es) | 2004-03-16 |
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| ES98955538T Expired - Lifetime ES2201552T3 (es) | 1997-11-08 | 1998-11-06 | Agonistas del receptor a1 de la adenosina. |
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| SK (1) | SK6712000A3 (https=) |
| TR (1) | TR200002157T2 (https=) |
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| US6576619B2 (en) * | 1999-05-24 | 2003-06-10 | Cv Therapeutics, Inc. | Orally active A1 adenosine receptor agonists |
| US6784165B1 (en) | 1999-11-23 | 2004-08-31 | Aderis Pharmaceuticals, Inc. | Treatment of heart rhythm disturbances with N6-substituted-5′-(N-substituted) carboxamidoadenosines |
| US6294522B1 (en) * | 1999-12-03 | 2001-09-25 | Cv Therapeutics, Inc. | N6 heterocyclic 8-modified adenosine derivatives |
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| WO1988003147A1 (en) * | 1986-10-31 | 1988-05-05 | Warner-Lambert Company | Selected n6-substituted adenosines having selective a2 binding activity |
| US5561134A (en) * | 1990-09-25 | 1996-10-01 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Compounds having antihypertensive, cardioprotective, anti-ischemic and antilipolytic properties |
| US5652366A (en) * | 1990-09-25 | 1997-07-29 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | DI (1R)-(-)camphosulfonic acid) salt, preparation thereof and use thereof |
| WO1997033591A1 (en) * | 1996-03-13 | 1997-09-18 | Novo Nordisk A/S | A method of treating disorders related to cytokines in mammals |
| GB9610031D0 (en) | 1996-05-14 | 1996-07-17 | Glaxo Group Ltd | Chemical compounds |
| US6232297B1 (en) * | 1999-02-01 | 2001-05-15 | University Of Virginia Patent Foundation | Methods and compositions for treating inflammatory response |
-
1997
- 1997-11-08 GB GBGB9723566.7A patent/GB9723566D0/en not_active Ceased
-
1998
- 1998-11-06 EP EP98955538A patent/EP1027363B1/en not_active Expired - Lifetime
- 1998-11-06 HU HU0004106A patent/HUP0004106A2/hu unknown
- 1998-11-06 SK SK671-2000A patent/SK6712000A3/sk unknown
- 1998-11-06 AP APAP/P/2000/001803A patent/AP2000001803A0/en unknown
- 1998-11-06 HR HR20000276A patent/HRP20000276A2/hr not_active Application Discontinuation
- 1998-11-06 EE EEP200000284A patent/EE200000284A/xx unknown
- 1998-11-06 JP JP2000520458A patent/JP2001522858A/ja active Pending
- 1998-11-06 DE DE69815378T patent/DE69815378T2/de not_active Expired - Fee Related
- 1998-11-06 KR KR1020007004974A patent/KR20010031883A/ko not_active Withdrawn
- 1998-11-06 AU AU12327/99A patent/AU1232799A/en not_active Abandoned
- 1998-11-06 CA CA002309199A patent/CA2309199A1/en not_active Abandoned
- 1998-11-06 EA EA200000393A patent/EA200000393A1/ru unknown
- 1998-11-06 PL PL98341091A patent/PL341091A1/xx unknown
- 1998-11-06 BR BR9813973-8A patent/BR9813973A/pt not_active Application Discontinuation
- 1998-11-06 ES ES98955538T patent/ES2201552T3/es not_active Expired - Lifetime
- 1998-11-06 TR TR2000/02157T patent/TR200002157T2/xx unknown
- 1998-11-06 WO PCT/EP1998/007022 patent/WO1999024450A2/en not_active Ceased
- 1998-11-06 CN CN98812978A patent/CN1285842A/zh active Pending
- 1998-11-06 US US09/530,574 patent/US6407076B1/en not_active Expired - Fee Related
- 1998-11-06 IL IL13596598A patent/IL135965A0/xx unknown
- 1998-11-06 AT AT98955538T patent/ATE242259T1/de not_active IP Right Cessation
-
2000
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- 2000-05-05 NO NO20002360A patent/NO20002360L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1285842A (zh) | 2001-02-28 |
| HRP20000276A2 (en) | 2000-12-31 |
| US6407076B1 (en) | 2002-06-18 |
| DE69815378D1 (de) | 2003-07-10 |
| KR20010031883A (ko) | 2001-04-16 |
| NO20002360D0 (no) | 2000-05-05 |
| JP2001522858A (ja) | 2001-11-20 |
| NO20002360L (no) | 2000-07-05 |
| IL135965A0 (en) | 2001-05-20 |
| BR9813973A (pt) | 2000-09-26 |
| TR200002157T2 (tr) | 2000-11-21 |
| GB9723566D0 (en) | 1998-01-07 |
| DE69815378T2 (de) | 2004-04-29 |
| IS5478A (is) | 2000-05-03 |
| AU1232799A (en) | 1999-05-31 |
| AP2000001803A0 (en) | 2000-06-30 |
| EP1027363A2 (en) | 2000-08-16 |
| EP1027363B1 (en) | 2003-06-04 |
| HUP0004106A2 (hu) | 2001-04-28 |
| SK6712000A3 (en) | 2001-01-18 |
| EE200000284A (et) | 2001-08-15 |
| ATE242259T1 (de) | 2003-06-15 |
| CA2309199A1 (en) | 1999-05-20 |
| WO1999024450A3 (en) | 1999-08-19 |
| EA200000393A1 (ru) | 2000-12-25 |
| PL341091A1 (en) | 2001-03-26 |
| WO1999024450A2 (en) | 1999-05-20 |
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