EA018386B1 - Пуриновые соединения - Google Patents
Пуриновые соединения Download PDFInfo
- Publication number
- EA018386B1 EA018386B1 EA201170832A EA201170832A EA018386B1 EA 018386 B1 EA018386 B1 EA 018386B1 EA 201170832 A EA201170832 A EA 201170832A EA 201170832 A EA201170832 A EA 201170832A EA 018386 B1 EA018386 B1 EA 018386B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- methyl
- purine
- pharmaceutically acceptable
- chlorophenyl
- acceptable salt
- Prior art date
Links
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 208000002193 Pain Diseases 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 C1-C2 -fluoroalkyl Chemical group 0.000 claims description 69
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 21
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 9
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 201000008482 osteoarthritis Diseases 0.000 claims description 6
- UCMNDPDJRSEZPL-UHFFFAOYSA-N 8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(oxan-4-yl)purine Chemical compound C1CN(C)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)Cl)N2C1CCOCC1 UCMNDPDJRSEZPL-UHFFFAOYSA-N 0.000 claims description 4
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- PGBKYWIIHKALFL-UHFFFAOYSA-N 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9-(oxan-4-ylmethyl)purine Chemical compound C1CN(CC)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)Cl)N2CC1CCOCC1 PGBKYWIIHKALFL-UHFFFAOYSA-N 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- WGBFSSQNXAZCGW-UHFFFAOYSA-N 2-methyl-6-(4-methylpiperazin-1-yl)-9-(oxan-4-yl)-8-[2-(trifluoromethyl)phenyl]purine Chemical compound C1CN(C)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)C(F)(F)F)N2C1CCOCC1 WGBFSSQNXAZCGW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- PCLIUMMFWRGXRK-UHFFFAOYSA-N methyl azetidine-1-carboxylate Chemical compound COC(=O)N1CCC1 PCLIUMMFWRGXRK-UHFFFAOYSA-N 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 230000008520 organization Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 11
- 239000000556 agonist Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 229960004592 isopropanol Drugs 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 6
- 239000010802 sludge Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QMLHFSMZYWZLBC-UHFFFAOYSA-N 2-(oxolan-3-yl)-7H-purine Chemical compound O1CC(CC1)C1=NC=C2N=CNC2=N1 QMLHFSMZYWZLBC-UHFFFAOYSA-N 0.000 description 5
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000013256 coordination polymer Substances 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- FKRXXAMAHOGYNT-UHFFFAOYSA-N 4,6-dichloro-2-methylpyrimidin-5-amine Chemical compound CC1=NC(Cl)=C(N)C(Cl)=N1 FKRXXAMAHOGYNT-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 150000001412 amines Chemical class 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 210000003127 knee Anatomy 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IAHBIMWHYUOIOH-UHFFFAOYSA-N vanadium hydrochloride Chemical class Cl.[V] IAHBIMWHYUOIOH-UHFFFAOYSA-N 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- MDGBSTWUPNFLOA-UHFFFAOYSA-N 2-(oxan-4-ylmethyl)pyrimidine-4,5-diamine Chemical compound N1=C(N)C(N)=CN=C1CC1CCOCC1 MDGBSTWUPNFLOA-UHFFFAOYSA-N 0.000 description 3
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 3
- PPAULTVPKLVLII-UHFFFAOYSA-N 4,5-diaminopyrimidine Chemical compound NC1=CN=CN=C1N PPAULTVPKLVLII-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000006820 Arthralgia Diseases 0.000 description 3
- 208000022120 Jeavons syndrome Diseases 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 150000003212 purines Chemical class 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 3
- BHFXPKPIPBNKFI-UHFFFAOYSA-N 2,3,4,7,8,8a-hexahydro-1h-pyrrolo[1,2-a]pyrazin-6-one Chemical compound C1NCCN2C(=O)CCC21 BHFXPKPIPBNKFI-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- QJCVRCBTRSHEGC-UHFFFAOYSA-N 2-[2-methyl-6-(4-methylpiperazin-1-yl)-9-(oxan-4-yl)purin-8-yl]benzonitrile Chemical compound C1CN(C)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)C#N)N2C1CCOCC1 QJCVRCBTRSHEGC-UHFFFAOYSA-N 0.000 description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- GNFWMEFWZWXLIN-UHFFFAOYSA-N 2-bromopyridine-3-carbaldehyde Chemical compound BrC1=NC=CC=C1C=O GNFWMEFWZWXLIN-UHFFFAOYSA-N 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- OTGBAKZHSWJFHG-UHFFFAOYSA-N 4-(oxan-4-yl)-1h-pyrimidine-4,5-diamine Chemical compound NC1=CNC=NC1(N)C1CCOCC1 OTGBAKZHSWJFHG-UHFFFAOYSA-N 0.000 description 2
- BALFVHNOVINJPK-UHFFFAOYSA-N 4-(oxan-4-ylmethyl)-1h-pyrimidine-4,5-diamine Chemical compound NC1=CNC=NC1(N)CC1CCOCC1 BALFVHNOVINJPK-UHFFFAOYSA-N 0.000 description 2
- HOXCINBJDCBBLJ-UHFFFAOYSA-N 6-chloro-8-(2-chlorophenyl)-2-methyl-9-(oxan-4-yl)purine Chemical compound C1COCCC1N1C2=NC(C)=NC(Cl)=C2N=C1C1=CC=CC=C1Cl HOXCINBJDCBBLJ-UHFFFAOYSA-N 0.000 description 2
- KLOTXTYTQQWRLN-UHFFFAOYSA-N 6-chloro-8-(2-chlorophenyl)-9-(oxan-4-ylmethyl)purine Chemical compound ClC1=CC=CC=C1C1=NC2=C(Cl)N=CN=C2N1CC1CCOCC1 KLOTXTYTQQWRLN-UHFFFAOYSA-N 0.000 description 2
- NCJNWQRRSXNHLY-UHFFFAOYSA-N 8-(2-bromophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(oxan-4-yl)purine Chemical compound C1CN(C)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)Br)N2C1CCOCC1 NCJNWQRRSXNHLY-UHFFFAOYSA-N 0.000 description 2
- LJQIKJPICVGYFS-UHFFFAOYSA-N 8-(2-bromophenyl)-6-chloro-2-methyl-9-(oxan-4-yl)purine Chemical compound C1COCCC1N1C2=NC(C)=NC(Cl)=C2N=C1C1=CC=CC=C1Br LJQIKJPICVGYFS-UHFFFAOYSA-N 0.000 description 2
- FRNQUEJTMHXRTF-UHFFFAOYSA-N 8-(2-chlorophenyl)-2-methyl-6-(4-methylpiperazin-1-yl)-9-(oxolan-3-ylmethyl)purine Chemical compound C1CN(C)CCN1C1=NC(C)=NC2=C1N=C(C=1C(=CC=CC=1)Cl)N2CC1COCC1 FRNQUEJTMHXRTF-UHFFFAOYSA-N 0.000 description 2
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 2
- 108050007331 Cannabinoid receptor Proteins 0.000 description 2
- 206010065390 Inflammatory pain Diseases 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- KWZSCXIYGVEHOB-UHFFFAOYSA-N oxan-4-amine;hydrochloride Chemical compound [Cl-].[NH3+]C1CCOCC1 KWZSCXIYGVEHOB-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000004544 purin-8-yl group Chemical group N1=CN=C2N=C(NC2=C1)* 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
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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
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13858908P | 2008-12-18 | 2008-12-18 | |
| PCT/US2009/067249 WO2010080306A1 (en) | 2008-12-18 | 2009-12-09 | Purine compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201170832A1 EA201170832A1 (ru) | 2011-12-30 |
| EA018386B1 true EA018386B1 (ru) | 2013-07-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201170832A EA018386B1 (ru) | 2008-12-18 | 2009-12-09 | Пуриновые соединения |
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| WO (1) | WO2010080306A1 (enExample) |
| ZA (1) | ZA201103943B (enExample) |
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| ES2543216T3 (es) * | 2009-03-13 | 2015-08-17 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Moduladores de tiazolopirimidina como agentes inmunosupresores |
| KR20200008045A (ko) | 2009-08-28 | 2020-01-22 | 아레나 파마슈티칼스, 인크. | 칸나비노이드 수용체 조절제 |
| RU2012141536A (ru) * | 2010-03-17 | 2014-04-27 | Ф. Хоффманн-Ля Рош Аг | Имидазопиридины, композиции и способы применения |
| AR080711A1 (es) * | 2010-03-31 | 2012-05-02 | Lilly Co Eli | Compuesto de piperazin-purina composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para el tratamiento o prevencion del dolor |
| KR101432411B1 (ko) * | 2010-03-31 | 2014-08-20 | 일라이 릴리 앤드 캄파니 | Ｃｂ2 효능제로서 사용되는 퓨린 화합물 |
| CN103209695A (zh) | 2010-09-15 | 2013-07-17 | 弗·哈夫曼-拉罗切有限公司 | 氮杂苯并噻唑化合物、组合物及应用方法 |
| KR20140009259A (ko) | 2010-11-19 | 2014-01-22 | 에프. 호프만-라 로슈 아게 | 피라졸로피리딘 및 tyk2 억제제로서 이의 용도 |
| JP6043733B2 (ja) | 2011-02-25 | 2016-12-14 | アリーナ ファーマシューティカルズ， インコーポレイテッド | カンナビノイド受容体モジュレーター |
| MX346533B (es) | 2011-02-25 | 2017-03-14 | Arena Pharm Inc | Formas cristalinas y procesos para la preparacion de azaciclos condensados (moduladores de receptores canabinoides). |
| US9597340B2 (en) | 2011-02-25 | 2017-03-21 | Arena Pharmaceuticals, Inc. | Cannabinoid receptor modulators |
| WO2013041539A1 (en) * | 2011-09-20 | 2013-03-28 | F. Hoffmann-La Roche Ag | Imidazopyridine compounds, compositions and methods of use |
| US9067943B2 (en) * | 2011-11-25 | 2015-06-30 | Hoffmann-La Roche Inc. | [1,2,3]triazolo[4,5-D]pyrimidine derivatives |
| PH12015500315B1 (en) * | 2012-08-16 | 2019-08-07 | Janssen Pharmaceutica Nv | Substituted pyrozales as n-type calcium channel blockers |
| WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
| HRP20171099T1 (hr) * | 2013-05-02 | 2017-10-06 | F. Hoffmann - La Roche Ag | Derivati pirolo[2,3-d]pirimidina kao agonisti cb2 receptora |
| US9453002B2 (en) | 2013-08-16 | 2016-09-27 | Janssen Pharmaceutica Nv | Substituted imidazoles as N-type calcium channel blockers |
| WO2017052394A1 (en) * | 2015-09-23 | 2017-03-30 | Uniwersytet Jagielloński | Imidazopyridine compounds and their use as 5-ht6 receptor ligands |
| WO2018137176A1 (en) * | 2017-01-25 | 2018-08-02 | Eli Lilly And Company | Treatment for nonalcoholic steatohepatitis and fibrosis |
| WO2017184412A1 (en) | 2016-04-18 | 2017-10-26 | Eli Lilly And Company | Purine cannabinoid agonist for treating nonalcoholic steatohepatitis and fibrosis |
| WO2017181317A1 (en) * | 2016-04-18 | 2017-10-26 | Eli Lilly And Company | Treatment for nonalcoholic steatohepatitis and fibrosis |
| JP7071342B6 (ja) * | 2016-12-21 | 2023-12-20 | リサーチ トライアングル インスティテュート | 改善されたバイオアベイラビリティを有するジアリールプリン誘導体 |
| EP3621619B1 (en) | 2017-05-08 | 2023-06-28 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of visceral pain |
| WO2024017227A1 (zh) * | 2022-07-21 | 2024-01-25 | 长春金赛药业有限责任公司 | 取代的稠环大麻素受体化合物及其应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004037823A1 (en) * | 2002-10-28 | 2004-05-06 | Pfizer Products Inc. | Purine compounds and uses thereof as cannabinoid receptor ligands |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS60260579A (ja) * | 1984-01-13 | 1985-12-23 | Yoshitomi Pharmaceut Ind Ltd | プリン誘導体 |
| IL87149A (en) | 1987-07-20 | 1994-05-30 | Merck & Co Inc | 6-Piperazinyl derivatives of purine and its 3- and 9-deaza isosteres, their preparation and pharmaceutical compositions containing them |
| US5057517A (en) * | 1987-07-20 | 1991-10-15 | Merck & Co., Inc. | Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents |
| GB0003960D0 (en) * | 2000-02-18 | 2000-04-12 | Pfizer Ltd | Purine derivatives |
| WO2003022214A2 (en) | 2001-09-06 | 2003-03-20 | Millennium Pharmaceuticals, Inc. | Piperazine and homopiperazine compounds |
| US20030139427A1 (en) * | 2002-08-23 | 2003-07-24 | Osi Pharmaceuticals Inc. | Bicyclic pyrimidinyl derivatives and methods of use thereof |
| US20040224962A1 (en) * | 2003-05-09 | 2004-11-11 | Pfizer Inc | Pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss |
| US20050043327A1 (en) * | 2003-08-21 | 2005-02-24 | Pfizer Inc | Pharmaceutical composition for the prevention and treatment of addiction in a mammal |
| WO2005067546A2 (en) | 2004-01-13 | 2005-07-28 | Ambit Biosciences Corporation | Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases |
| KR20070054737A (ko) * | 2004-10-22 | 2007-05-29 | 화이자 프로덕츠 인코포레이티드 | 퓨린 화합물의 제조 방법 |
| US20070032493A1 (en) | 2005-05-26 | 2007-02-08 | Synta Pharmaceuticals Corp. | Method for treating B cell regulated autoimmune disorders |
| JP5231251B2 (ja) * | 2006-02-02 | 2013-07-10 | ミレニアム ファーマシューティカルズ， インコーポレイテッド | Ｅ１活性化酵素の阻害剤 |
| US20120295915A1 (en) * | 2009-11-24 | 2012-11-22 | Chaudhari Amita M | Azabenzimidazoles as fatty acid synthase inhibitors |
| AR080711A1 (es) * | 2010-03-31 | 2012-05-02 | Lilly Co Eli | Compuesto de piperazin-purina composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para el tratamiento o prevencion del dolor |
-
2009
- 2009-09-12 UA UAA201107563A patent/UA104010C2/ru unknown
- 2009-12-01 AR ARP090104628A patent/AR075104A1/es not_active Application Discontinuation
- 2009-12-01 PA PA20098851501A patent/PA8851501A1/es unknown
- 2009-12-04 TW TW098141555A patent/TWI376378B/zh not_active IP Right Cessation
- 2009-12-09 JP JP2011542246A patent/JP5559812B2/ja not_active Expired - Fee Related
- 2009-12-09 CA CA2746740A patent/CA2746740C/en not_active Expired - Fee Related
- 2009-12-09 EA EA201170832A patent/EA018386B1/ru not_active IP Right Cessation
- 2009-12-09 BR BRPI0923195A patent/BRPI0923195A2/pt not_active Application Discontinuation
- 2009-12-09 ES ES09768474.0T patent/ES2536880T3/es active Active
- 2009-12-09 AU AU2009335997A patent/AU2009335997B2/en not_active Ceased
- 2009-12-09 EP EP09768474.0A patent/EP2379555B1/en not_active Not-in-force
- 2009-12-09 US US12/633,812 patent/US8252798B2/en not_active Expired - Fee Related
- 2009-12-09 WO PCT/US2009/067249 patent/WO2010080306A1/en not_active Ceased
- 2009-12-09 NZ NZ593088A patent/NZ593088A/xx not_active IP Right Cessation
- 2009-12-09 SG SG2011044773A patent/SG172253A1/en unknown
- 2009-12-09 CN CN200980150689.3A patent/CN102256977B/zh not_active Expired - Fee Related
- 2009-12-09 MX MX2011006442A patent/MX2011006442A/es active IP Right Grant
- 2009-12-09 PE PE2011001219A patent/PE20110999A1/es not_active Application Discontinuation
- 2009-12-09 KR KR1020117014000A patent/KR101319630B1/ko not_active Expired - Fee Related
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2011
- 2011-05-26 IL IL213167A patent/IL213167A/en not_active IP Right Cessation
- 2011-05-27 ZA ZA2011/03943A patent/ZA201103943B/en unknown
- 2011-06-09 TN TN2011000291A patent/TN2011000291A1/fr unknown
- 2011-06-14 MA MA33947A patent/MA32904B1/fr unknown
- 2011-06-16 CL CL2011001464A patent/CL2011001464A1/es unknown
- 2011-06-17 DO DO2011000196A patent/DOP2011000196A/es unknown
- 2011-06-17 CR CR20110340A patent/CR20110340A/es unknown
- 2011-06-17 HN HN2011001700A patent/HN2011001700A/es unknown
- 2011-06-17 EC EC2011011151A patent/ECSP11011151A/es unknown
- 2011-06-23 CO CO11079298A patent/CO6390101A2/es active IP Right Grant
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004037823A1 (en) * | 2002-10-28 | 2004-05-06 | Pfizer Products Inc. | Purine compounds and uses thereof as cannabinoid receptor ligands |
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| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
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