ES2890492T3 - Métodos para preparar N-(4-fluorobencil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metilpropiloxi)fenilmetil)carbamida y su sal de tartrato y forma polimórfica C - Google Patents
Métodos para preparar N-(4-fluorobencil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metilpropiloxi)fenilmetil)carbamida y su sal de tartrato y forma polimórfica C Download PDFInfo
- Publication number
- ES2890492T3 ES2890492T3 ES16745321T ES16745321T ES2890492T3 ES 2890492 T3 ES2890492 T3 ES 2890492T3 ES 16745321 T ES16745321 T ES 16745321T ES 16745321 T ES16745321 T ES 16745321T ES 2890492 T3 ES2890492 T3 ES 2890492T3
- Authority
- ES
- Spain
- Prior art keywords
- pimavanserin
- substituted
- group
- formula
- methylpiperidin
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 87
- 150000003892 tartrate salts Chemical class 0.000 title claims description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 title description 28
- 235000013877 carbamide Nutrition 0.000 title description 15
- 239000004202 carbamide Substances 0.000 title description 14
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 claims abstract description 165
- 229960003300 pimavanserin Drugs 0.000 claims abstract description 147
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 24
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 17
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims abstract description 15
- 239000013067 intermediate product Substances 0.000 claims abstract description 14
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims abstract description 14
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 12
- 238000011031 large-scale manufacturing process Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 39
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- QWMUMFXFUCDJJI-UHFFFAOYSA-N 4-(2-methylpropoxy)benzonitrile Chemical compound CC(C)COC1=CC=C(C#N)C=C1 QWMUMFXFUCDJJI-UHFFFAOYSA-N 0.000 claims description 6
- UNIXIBUAGDSVOK-UHFFFAOYSA-N C(C(C)C)OC1=CC=C(CNC(OC2=CC=CC=C2)=O)C=C1 Chemical compound C(C(C)C)OC1=CC=C(CNC(OC2=CC=CC=C2)=O)C=C1 UNIXIBUAGDSVOK-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 5
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 5
- 229940035429 isobutyl alcohol Drugs 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims 1
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 147
- -1 N-methylpiperidin-4-yl Chemical group 0.000 description 87
- 239000000203 mixture Substances 0.000 description 86
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 125000000217 alkyl group Chemical group 0.000 description 61
- 150000001875 compounds Chemical class 0.000 description 47
- 239000000243 solution Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 125000003118 aryl group Chemical group 0.000 description 42
- 229910001868 water Inorganic materials 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 40
- 239000000543 intermediate Substances 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 37
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 35
- 125000004432 carbon atom Chemical group C* 0.000 description 35
- 239000002904 solvent Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 125000002947 alkylene group Chemical group 0.000 description 32
- 125000001424 substituent group Chemical group 0.000 description 32
- 239000001257 hydrogen Substances 0.000 description 30
- 229910052739 hydrogen Inorganic materials 0.000 description 30
- 229940081770 pimavanserin tartrate Drugs 0.000 description 29
- 239000000725 suspension Substances 0.000 description 28
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 26
- 125000000753 cycloalkyl group Chemical group 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 125000000392 cycloalkenyl group Chemical group 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- 125000003710 aryl alkyl group Chemical group 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 125000003342 alkenyl group Chemical group 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 16
- 125000000304 alkynyl group Chemical group 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- JBVKKHDTYSDPHA-UHFFFAOYSA-N [4-(2-methylpropoxy)phenyl]methanamine Chemical compound CC(C)COC1=CC=C(CN)C=C1 JBVKKHDTYSDPHA-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- ROORDVPLFPIABK-UHFFFAOYSA-N diphenyl carbonate Chemical compound C=1C=CC=CC=1OC(=O)OC1=CC=CC=C1 ROORDVPLFPIABK-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 11
- 239000012458 free base Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000011975 tartaric acid Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000002252 acyl group Chemical group 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 125000001188 haloalkyl group Chemical group 0.000 description 9
- 150000002367 halogens Chemical class 0.000 description 9
- 125000004475 heteroaralkyl group Chemical group 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 125000002883 imidazolyl group Chemical group 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 125000005631 S-sulfonamido group Chemical group 0.000 description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 8
- 125000004414 alkyl thio group Chemical group 0.000 description 8
- 125000005110 aryl thio group Chemical group 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 8
- 125000004438 haloalkoxy group Chemical group 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 235000002906 tartaric acid Nutrition 0.000 description 8
- 125000005423 trihalomethanesulfonamido group Chemical group 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 125000004043 oxo group Chemical group O=* 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- 125000003396 thiol group Chemical class [H]S* 0.000 description 7
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 6
- 239000012964 benzotriazole Substances 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 6
- PLYWEOOWONUOBN-UHFFFAOYSA-N n-[(4-fluorophenyl)methyl]-1-methylpiperidin-4-amine Chemical compound C1CN(C)CCC1NCC1=CC=C(F)C=C1 PLYWEOOWONUOBN-UHFFFAOYSA-N 0.000 description 6
- 150000002923 oximes Chemical class 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 6
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 6
- 150000003672 ureas Chemical class 0.000 description 6
- IYXORPUPKMTKBL-UHFFFAOYSA-N 1,3-bis[[4-(2-methylpropoxy)phenyl]methyl]urea Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)NCC1=CC=C(OCC(C)C)C=C1 IYXORPUPKMTKBL-UHFFFAOYSA-N 0.000 description 5
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 5
- PWASYRSZCSTUIW-UHFFFAOYSA-N 4-(2-methylpropoxy)benzaldehyde Chemical compound CC(C)COC1=CC=C(C=O)C=C1 PWASYRSZCSTUIW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000001301 oxygen Chemical group 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- 229910052717 sulfur Chemical group 0.000 description 5
- 239000011593 sulfur Chemical group 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- UJZBSAONPRVEIJ-UHFFFAOYSA-N 2,2,2-trifluoroethyl carbonochloridate Chemical compound FC(F)(F)COC(Cl)=O UJZBSAONPRVEIJ-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 4
- 229920002988 biodegradable polymer Polymers 0.000 description 4
- 239000004621 biodegradable polymer Substances 0.000 description 4
- TZSMWSKOPZEMAJ-UHFFFAOYSA-N bis[(2-methoxyphenyl)methyl] carbonate Chemical compound COC1=CC=CC=C1COC(=O)OCC1=CC=CC=C1OC TZSMWSKOPZEMAJ-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YKGYCKNKCJFIQT-UHFFFAOYSA-N methyl N-[[4-(2-methylpropoxy)phenyl]methyl]carbamate Chemical compound C(C(C)C)OC1=CC=C(CNC(OC)=O)C=C1 YKGYCKNKCJFIQT-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
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- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QAWMIDIJFWHLAQ-UHFFFAOYSA-N methyl 2-(2-methoxycarbonylphenoxy)carbonyloxybenzoate Chemical compound COC(=O)C1=CC=CC=C1OC(=O)OC1=CC=CC=C1C(=O)OC QAWMIDIJFWHLAQ-UHFFFAOYSA-N 0.000 description 1
- NIYSNCNXXGYMEU-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1.COC(=O)C1=CC=CC=C1 NIYSNCNXXGYMEU-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
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- 239000012452 mother liquor Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DVEKCXOJTLDBFE-UHFFFAOYSA-N n-dodecyl-n,n-dimethylglycinate Chemical compound CCCCCCCCCCCC[N+](C)(C)CC([O-])=O DVEKCXOJTLDBFE-UHFFFAOYSA-N 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-M n-octyl sulfate Chemical compound CCCCCCCCOS([O-])(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-M 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940067739 octyl sulfate Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
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- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 229940067631 phospholipid Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002006 poly(N-vinylimidazole) polymer Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001444 polymaleic acid Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- URLJMZWTXZTZRR-UHFFFAOYSA-N sodium myristyl sulfate Chemical compound CCCCCCCCCCCCCCOS(O)(=O)=O URLJMZWTXZTZRR-UHFFFAOYSA-N 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- 235000021055 solid food Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- CSMFSDCPJHNZRY-UHFFFAOYSA-N sulfuric acid monodecyl ester Natural products CCCCCCCCCCOS(O)(=O)=O CSMFSDCPJHNZRY-UHFFFAOYSA-N 0.000 description 1
- UZZYXUGECOQHPU-UHFFFAOYSA-N sulfuric acid monooctyl ester Natural products CCCCCCCCOS(O)(=O)=O UZZYXUGECOQHPU-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
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- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/98—Nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562194725P | 2015-07-20 | 2015-07-20 | |
| PCT/US2016/042933 WO2017015272A1 (en) | 2015-07-20 | 2016-07-19 | Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c |
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|---|---|
| ES2890492T3 true ES2890492T3 (es) | 2022-01-20 |
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| ES16745321T Active ES2890492T3 (es) | 2015-07-20 | 2016-07-19 | Métodos para preparar N-(4-fluorobencil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metilpropiloxi)fenilmetil)carbamida y su sal de tartrato y forma polimórfica C |
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| WO (1) | WO2017015272A1 (cg-RX-API-DMAC7.html) |
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| DK3325444T3 (da) * | 2015-07-20 | 2021-10-04 | Acadia Pharm Inc | Fremgangsmåder til fremstilling af n-(4-fluorbenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamid og dets tartratsalt og polymorf form c |
| WO2017165635A1 (en) | 2016-03-25 | 2017-09-28 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome p450 modulators |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| EP3558311A1 (en) | 2016-12-20 | 2019-10-30 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of alzheimer's disease psychosis |
| EP3615028A1 (en) | 2017-04-28 | 2020-03-04 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| CN107200707B (zh) * | 2017-05-16 | 2020-10-02 | 河北科技大学 | 一种匹莫范色林的制备方法 |
| WO2019008595A1 (en) * | 2017-07-03 | 2019-01-10 | Jubilant Generics Limited (Formerly A Division Of Jubilant Life Sciences Limited) | PROCESS FOR THE PREPARATION OF 1- (4-FLUOROBENZYL) -3- (4-ISOBUTOXYBENZYL) -1- (1-METHYLPIPERIDIN-4-YL) UREA AND ITS SALTS |
| SI3672954T1 (sl) | 2017-08-21 | 2025-11-28 | Acadia Pharmaceuticals Inc. | Spojine, njihove soli in njihova uporaba za zdravljenje bolezni |
| WO2019040106A2 (en) * | 2017-08-21 | 2019-02-28 | Acadia Pharmaceuticals Inc. | COMPOUNDS, RELATED SALTS AND METHODS FOR THE TREATMENT OF DISEASES |
| EP3672960A2 (en) * | 2017-08-21 | 2020-07-01 | Acadia Pharmaceuticals Inc. | Compounds, salts thereof and their use for the treatment of diseases |
| EP3675827A1 (en) | 2017-08-30 | 2020-07-08 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| CN110054583A (zh) * | 2018-01-19 | 2019-07-26 | 广东东阳光药业有限公司 | 一种制备哌马色林或其盐的方法 |
| WO2019207494A1 (en) * | 2018-04-26 | 2019-10-31 | Olon S.P.A. | Method for the preparation of pimavanserin base |
| CN110894186B (zh) * | 2018-09-12 | 2022-05-24 | 浙江京新药业股份有限公司 | 匹莫范色林及其中间体的制备方法 |
| US20220016101A1 (en) | 2018-10-30 | 2022-01-20 | Acadia Pharmaceuticals Inc. | Methods of treating depression, anxiety and sexual dysfunction using the compound pimavanserin |
| CN111320569B (zh) * | 2018-12-17 | 2022-03-08 | 江苏艾立康医药科技有限公司 | 一种哌马色林固态中间体的制备方法 |
| WO2021016369A1 (en) | 2019-07-22 | 2021-01-28 | Acadia Pharmaceuticals Inc. | Pimavanserin for trating schizophrenia or for treating psychosis secondary to neurodegenerative disorders or depressive disorder |
| WO2021030607A1 (en) | 2019-08-15 | 2021-02-18 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating neurodegenerative diseases |
| WO2022094230A1 (en) | 2020-11-02 | 2022-05-05 | Acadia Pharmaceuticals Inc. | Compounds for treating psychosis or depression |
| CN116496496B (zh) * | 2023-04-27 | 2024-11-05 | 中国石油大学(华东) | 一种基于三嗪共价框架材料（CTFs）制备单位点催化剂的制备方法 |
Family Cites Families (123)
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|---|---|---|---|---|
| BE794333A (fr) | 1972-01-20 | 1973-07-19 | Wyeth John & Brother Ltd | Composes heterocycliques azotes therapeutiques |
| GB1507462A (en) | 1974-03-21 | 1978-04-12 | Gallardo Antonio Sa | N-heterocyclic substituted benzamides methods for their preparation and compositions containing them |
| US3983234A (en) | 1974-07-04 | 1976-09-28 | Sandoz Ltd. | Treatment of dyskinesias |
| JPS5152176A (cg-RX-API-DMAC7.html) | 1974-10-12 | 1976-05-08 | Yoshitomi Pharmaceutical | |
| JPS5285174A (en) | 1976-01-05 | 1977-07-15 | Yoshitomi Pharmaceut Ind Ltd | Novel urea or thiourea derivatives |
| GB1586468A (en) | 1976-10-29 | 1981-03-18 | Anphar Sa | Piperidine derivatives |
| CA1140119A (en) | 1978-04-03 | 1983-01-25 | Joseph Torremans | N-heterocyclyl-4-piperidinamines |
| US4255432A (en) | 1979-09-06 | 1981-03-10 | Syntex (U.S.A.) Inc. | 8-[2-3-Indolyl)ethyl]-1-oxa-3-,8-diazaspiro[4.5]decan-2-ones, pharmaceutical compositions thereof and methods of use thereof |
| US4332804A (en) | 1981-03-23 | 1982-06-01 | Syntex (U.S.A.) Inc. | 9-[2-(3-Indolyl)ethyl]-1oxa-4,9-diazaspiro[5.5]undecan-3-ones |
| US4353900A (en) | 1981-10-19 | 1982-10-12 | Syntex (U.S.A.) Inc. | 9-(Arylalkyl or aroylalkyl)-1-oxa-4,9-diazaspiro(5.5)undecan-3-ones |
| US4353901A (en) | 1981-10-19 | 1982-10-12 | Syntex (U.S.A.) Inc. | 9-(1,4-Benzodioxan-2-ylalkyl and hydroxyalkyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-ones |
| GB8527052D0 (en) | 1985-11-02 | 1985-12-04 | Beecham Group Plc | Compounds |
| GB8621892D0 (en) | 1986-09-11 | 1986-10-15 | Lundbeck & Co As H | Organic compound |
| FR2642069B1 (fr) | 1989-01-20 | 1991-04-12 | Rhone Poulenc Sante | Nouveaux derives du benzopyranne, leur preparation et les compositions pharmaceutiques qui les contiennent |
| US5214055A (en) | 1990-05-18 | 1993-05-25 | Adir Et Compagnie | Aminopiperidine 4-oxo-4H-chromen-2-yl compounds |
| US5216165A (en) | 1990-10-03 | 1993-06-01 | American Home Products Corporation | N-substituted aminoquinolines as analgesic agents |
| IT1252227B (it) | 1991-12-17 | 1995-06-05 | Ciba Geigy Spa | Composti tetrametilpiperidinici atti all'impiego come stabilizzanti per materiali organici |
| US5595872A (en) | 1992-03-06 | 1997-01-21 | Bristol-Myers Squibb Company | Nucleic acids encoding microsomal trigyceride transfer protein |
| CA2123728A1 (en) | 1993-05-21 | 1994-11-22 | Noriyoshi Sueda | Urea derivatives and their use as acat inhibitors |
| WO1994027967A1 (en) | 1993-05-26 | 1994-12-08 | Smithkline Beecham Laboratoires Pharmaceutiques | Novel compounds |
| US5707798A (en) | 1993-07-13 | 1998-01-13 | Novo Nordisk A/S | Identification of ligands by selective amplification of cells transfected with receptors |
| DE4404183A1 (de) | 1994-02-10 | 1995-08-17 | Merck Patent Gmbh | 4-Amino-1-piperidylbenzoylguanidine |
| US5795894A (en) | 1995-05-02 | 1998-08-18 | Schering Corporation | Piperazino derivatives as neurokinn antagonists |
| BR9610277A (pt) | 1995-08-31 | 1999-07-06 | Schering Corp | Derivados de piperazino como antagonistas de neurowuinina |
| EP0854869B1 (en) | 1995-09-29 | 2004-08-25 | Eli Lilly And Company | Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation |
| IL124536A (en) | 1995-12-07 | 2001-03-19 | Daniel C Javitt | Pharmaceutical compositions containing a glycine uptake antagonist |
| EP0944388A4 (en) | 1996-04-03 | 2001-08-16 | Merck & Co Inc | INHIBITORS OF FARNESYL PROTEIN TRANSFERASE |
| AU2733997A (en) | 1996-04-17 | 1997-11-07 | Du Pont Pharmaceuticals Company | N-(amidinophenyl)-n'-(subst.)-3h-2,4-benzodiazepin-3-one derivatives as factor xa inhibitors |
| US5869488A (en) | 1996-05-01 | 1999-02-09 | Schering Corporation | Piperazino derivatives as neurokinin antagonists |
| US5877173A (en) | 1996-08-28 | 1999-03-02 | Washington University | Preventing neuronal degeneration in Alzheimer's disease |
| US6344449B1 (en) | 1996-09-10 | 2002-02-05 | Dr. Karl Thomae Gmbh | Modified aminoacids, pharmaceuticals containing these compounds and method for their production |
| DE19643331A1 (de) | 1996-10-21 | 1998-04-23 | Thomae Gmbh Dr K | 1-(4-Piperidinyl)-piperidinylene, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| US6057338A (en) | 1997-04-04 | 2000-05-02 | Merck & Co., Inc. | Somatostatin agonists |
| CN1255162A (zh) | 1997-05-08 | 2000-05-31 | 史密丝克莱恩比彻姆公司 | 蛋白酶抑制剂 |
| GB9718833D0 (en) | 1997-09-04 | 1997-11-12 | Merck Sharp & Dohme | Therapeutic agents |
| IL138192A0 (en) | 1998-03-11 | 2001-11-25 | Smithkline Beecham Plc | Controlled release oral dosage forms |
| DE1071701T1 (de) | 1998-04-14 | 2001-08-23 | Arena Pharmaceuticals, Inc. | Non-endogene, konstitutiv aktivierte humane serotonin-rezeptoren und kleine molekülmodulatoren davon |
| US6140509A (en) | 1998-06-26 | 2000-10-31 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated human serotonin receptors and small molecule modulators thereof |
| GB9816263D0 (en) | 1998-07-24 | 1998-09-23 | Merck Sharp & Dohme | Therapeutic agents |
| US6358698B1 (en) | 1998-10-07 | 2002-03-19 | Acadia Pharmacueticals Inc. | Methods of identifying inverse agonists of the serotonin 2A receptor |
| JP2002527477A (ja) | 1998-10-16 | 2002-08-27 | サントリー株式会社 | 神経細胞保護作用物質としてのアミノフェノキシ酢酸誘導体 |
| US6150393A (en) | 1998-12-18 | 2000-11-21 | Arena Pharmaceuticals, Inc. | Small molecule modulators of non-endogenous, constitutively activated human serotonin receptors |
| EP1013276A1 (en) | 1998-12-23 | 2000-06-28 | Pfizer Inc. | Aminoazacycloalkanes as CCR5 modulators |
| WO2000056335A1 (en) | 1999-03-24 | 2000-09-28 | The Regents Of The University Of California | Methods for treating neurodegenerative disorders using aspartyl protease inhibitors |
| US6399619B1 (en) | 1999-04-06 | 2002-06-04 | Merck & Co., Inc. | Pyrrolidine modulators of chemokine receptor activity |
| CN1356977A (zh) | 1999-05-17 | 2002-07-03 | 诺沃挪第克公司 | 胰高血糖素拮抗剂/反向激动剂 |
| US20040229908A1 (en) | 1999-07-13 | 2004-11-18 | Jodi Nelson | Compositions and methods for the treatment of Parkinson's disease and tardive dyskinesias |
| US20050148018A1 (en) | 1999-10-07 | 2005-07-07 | David Weiner | Methods of identifying inverse agonists of the serotonin 2A receptor |
| FR2802206B1 (fr) | 1999-12-14 | 2005-04-22 | Sod Conseils Rech Applic | Derives de 4-aminopiperidine et leur utilisation en tant que medicament |
| US7022698B2 (en) | 1999-12-28 | 2006-04-04 | U & I Pharmaceuticals, Ltd. | Pharmaceutical compositions containing new polymorphic forms of olanzapine and uses thereof |
| IL151164A0 (en) | 2000-03-06 | 2003-04-10 | Acadia Pharm Inc | Azacyclic compounds for use in the treatment of serotonin related diseases |
| GB0011838D0 (en) | 2000-05-17 | 2000-07-05 | Astrazeneca Ab | Chemical compounds |
| US20020099076A1 (en) | 2000-05-25 | 2002-07-25 | Richard Scheyer D. | Use of (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidinemethanol or its prodrug in the treatment of symptoms of dementia and dopamine induced psychosis |
| DE60141752D1 (de) | 2000-06-30 | 2010-05-20 | Innogenetics Nv | Differentielle diagnose von neurologischen krankheiten |
| HUP0300810A2 (hu) | 2000-07-20 | 2003-08-28 | M.G.V.S. Ltd. | Mesterséges értranszplantátum, valamint ennek létrehozása és alkalmazása |
| HUP0303360A2 (hu) | 2000-09-25 | 2004-01-28 | Actelion Pharmaceuticals Ltd. | Maláriaellenes hatású szubsztituált amino-aza-cikloalkánok és ezeket tartalmazó gyógyszerkészítmények |
| WO2002038142A2 (en) | 2000-11-08 | 2002-05-16 | Massachusetts Institute Of Technology | Serotonergic compositions and methods for treatment of mild cognitive impairment |
| WO2002076464A1 (en) | 2001-03-22 | 2002-10-03 | Arena Pharmaceuticals, Inc. | Anti-psychosis combination |
| GB0108099D0 (en) | 2001-03-30 | 2001-05-23 | Hoffmann La Roche | Aminopiperidine derivatives |
| TWI310034B (en) | 2001-10-02 | 2009-05-21 | Acadia Pharmaceuticais Inc | Benzimidazolidinone derivatives as muscarinic agents |
| KR20100008799A (ko) | 2001-12-28 | 2010-01-26 | 아카디아 파마슈티칼스 인코포레이티드 | 모노아민 수용체 조정자로서의 스피로아자사이클릭 화합물 |
| WO2003062206A2 (en) | 2002-01-23 | 2003-07-31 | Arena Pharmaceuticals, Inc. | Small molecule modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
| UY27668A1 (es) | 2002-02-20 | 2003-10-31 | Pfizer Prod Inc | Composición de ziprasidona y controles sintéticos |
| GB0208279D0 (en) | 2002-04-10 | 2002-05-22 | Glaxo Group Ltd | Novel compounds |
| BR0312217A (pt) | 2002-06-24 | 2005-05-10 | Acadia Pharm Inc | Compostos, métodos de inibição da atividade/ativação de um receptor monoaminérgico e método de tratamento de condição doentia associada a um receptor de monoaminergético |
| US7538222B2 (en) | 2002-06-24 | 2009-05-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| US7253186B2 (en) | 2002-06-24 | 2007-08-07 | Carl-Magnus Andersson | N-substituted piperidine derivatives as serotonin receptor agents |
| WO2004039322A2 (en) | 2002-10-29 | 2004-05-13 | Miicro, Inc. | Novel combination therapy for schizophrenia focused on improved cognition: 5-ht-2a/d2 blockade with adjunctive blockade of prefrontal da reuptake |
| CN101780080B (zh) | 2003-01-16 | 2014-06-04 | 阿卡蒂亚药品公司 | 用于神经退行性疾病的治疗的选择性五羟色胺2a/2c受体反向激动剂 |
| EP1589974A2 (en) | 2003-01-23 | 2005-11-02 | Acadia Pharmaceuticals Inc. | Use of n-desmethylclozapine to treat human neuropsychiatric disease |
| PL1708790T3 (pl) | 2003-12-02 | 2010-10-29 | Pharmaneuroboost N V | Zastosowanie pipamperonu oraz antagonisty receptora D2 lub antagonisty receptora serotoniny/dopaminy do leczenia zaburzeń psychotycznych |
| EP1576985A1 (en) | 2004-03-18 | 2005-09-21 | B&B Beheer NV | Use of D4 and 5-HT2A antagonists, inverse agonists or partial agonists |
| MXPA06007244A (es) | 2003-12-22 | 2006-08-18 | Acadia Pharm Inc | Analogos amino sustituidos de diaril[a,d]ciclohepteno como agonistas muscarinicos y metodos de tratamiento de trastornos neuropsiquiatricos. |
| US20050261278A1 (en) | 2004-05-21 | 2005-11-24 | Weiner David M | Selective serotonin receptor inverse agonists as therapeutics for disease |
| US7820695B2 (en) | 2004-05-21 | 2010-10-26 | Acadia Pharmaceuticals, Inc. | Selective serotonin receptor inverse agonists as therapeutics for disease |
| US7790899B2 (en) | 2004-09-27 | 2010-09-07 | Acadia Pharmaceuticals, Inc. | Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms |
| ES2530258T3 (es) | 2004-09-27 | 2015-02-27 | Acadia Pharmaceuticals Inc. | Síntesis de una forma cristalina de sal tartrato de N-(4-fluorobencil)-N-(1-metilpiperidin-4-il)-N'-(4-(2-metilpropiloxi)fenilmetil)carbamida |
| WO2006096439A2 (en) | 2005-03-04 | 2006-09-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases |
| AU2006229904A1 (en) | 2005-03-30 | 2006-10-05 | Merck Sharp & Dohme Corp. | Glucagon receptor antagonist compounds, compositions containing such compounds and methods of use |
| US20080051429A1 (en) | 2006-04-19 | 2008-02-28 | Van Kammen Daniel | Use of 4-amino-piperidines for treating sleep disorders |
| WO2007124136A1 (en) * | 2006-04-19 | 2007-11-01 | Acadia Pharmaceuticals, Inc. | Use of 4-amino-piperidines for treating sleep disorders |
| CA2652300A1 (en) | 2006-05-15 | 2007-11-22 | Acadia Pharmaceuticals Inc. | Pharmaceutical formulations of pimavanserin |
| WO2008116024A2 (en) | 2007-03-19 | 2008-09-25 | Acadia Pharmaceuticals Inc. | Combinations of 5-ht2a inverse agonists and antagonists with antipsychotics |
| US20080280886A1 (en) | 2007-05-08 | 2008-11-13 | Auspex Pharmaceuticals, Inc. | Substituted ureas |
| EP2173343A1 (en) | 2007-05-18 | 2010-04-14 | Acadia Pharmaceuticals Inc. | Use of pimavanserin in the treatment of parkinson and symptoms thereof |
| US8318813B2 (en) | 2007-09-13 | 2012-11-27 | Lcs Group, Llc | Method of treating binge eating disorder |
| CA2700331A1 (en) | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | Co-administration of pimavanserin with other agents |
| WO2009039461A2 (en) | 2007-09-21 | 2009-03-26 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| WO2010111353A1 (en) | 2009-03-25 | 2010-09-30 | Acadia Pharmaceuticals, Inc. | N-substituted piperidine derivatives as serotonin receptor agents |
| US8927553B2 (en) | 2009-08-10 | 2015-01-06 | Daljit Singh Dhanoa | Deuterium-enriched alkyl sulfonamides and uses thereof |
| AU2010306576A1 (en) | 2009-10-16 | 2012-06-07 | University Of South Florida | Treatment of suicidal ideation or behavior using inhibitors of nicotinic acetylcholine receptors |
| US7816383B1 (en) | 2009-12-04 | 2010-10-19 | Intermune, Inc. | Methods of administering pirfenidone therapy |
| US20130150346A1 (en) | 2010-01-08 | 2013-06-13 | Quest Ventures Ltd. | Use of FAAH Inhibitors for Treating Parkinson's Disease and Restless Legs Syndrome |
| WO2012002583A1 (en) | 2010-07-02 | 2012-01-05 | Vanderbilt University | Method for treating schizophrenia and related diseases with a combination therapy |
| EP2598159A4 (en) | 2010-07-30 | 2014-01-08 | Merck Sharp & Dohme | INHIBITION OF THE CYP3A DRUG MIXTURE EXCHANGE |
| US9737531B2 (en) | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
| EP2556827A1 (en) | 2011-08-11 | 2013-02-13 | Acadia Pharmaceuticals Inc. | Treatment of neurodegenerative diseases |
| WO2014085362A1 (en) | 2012-11-27 | 2014-06-05 | Acadia Pharmaceuticals Inc. | Methods for the treatment of parkinson's disease psychosis using pimavanserin |
| CN105418460B (zh) | 2014-08-11 | 2017-04-12 | 苏州鹏旭医药科技有限公司 | 匹莫范色林及其类似化合物中间体，其制备方法和制备匹莫范色林及其类似化合物的方法 |
| WO2016141003A1 (en) * | 2015-03-02 | 2016-09-09 | Teva Pharmaceutical Industries Ltd. | Processes and intermediates for the preparation of pimavanserin |
| CN104961672B (zh) * | 2015-05-20 | 2017-10-20 | 沈阳药科大学 | 一种n‑(4‑氟苄基)‑n‑(1‑甲基哌啶‑4‑基)‑n’‑(4‑异丁氧基苄基)脲的酒石酸盐的合成方法 |
| CN104844502B (zh) * | 2015-06-05 | 2018-07-31 | 齐鲁师范学院 | 一种匹莫范色林的制备方法 |
| CN109562085A (zh) | 2015-06-12 | 2019-04-02 | 阿速万科学有限责任公司 | 用于预防和治疗rem睡眠行为障碍的二芳基和芳基杂芳基脲衍生物 |
| KR20180064373A (ko) | 2015-07-15 | 2018-06-14 | 엑소반트 사이언시즈 게엠베하 | 신경퇴행성 질환과 관련된 환각의 예방 및 치료에 유용한 5-ht2a 세로토닌 수용체의 조절자로서의 다이아릴 및 아릴헤테로아릴 우레아 유도체 |
| DK3325444T3 (da) | 2015-07-20 | 2021-10-04 | Acadia Pharm Inc | Fremgangsmåder til fremstilling af n-(4-fluorbenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamid og dets tartratsalt og polymorf form c |
| CN105111135A (zh) | 2015-09-09 | 2015-12-02 | 安徽省逸欣铭医药科技有限公司 | 取代的尿素衍生物制备方法 |
| CN106543072A (zh) | 2015-09-21 | 2017-03-29 | 天津市汉康医药生物技术有限公司 | 匹莫范色林化合物 |
| CN105153016B (zh) | 2015-10-12 | 2017-10-03 | 北京诺康达医药科技有限公司 | 一种匹莫范色林的制备方法 |
| CN105481757A (zh) | 2015-12-25 | 2016-04-13 | 北京康立生医药技术开发有限公司 | 一种哌马色林的制备方法 |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| WO2017165635A1 (en) | 2016-03-25 | 2017-09-28 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome p450 modulators |
| US20190117636A1 (en) | 2016-03-29 | 2019-04-25 | Acadia Pharmaceuticals Inc. | 5-ht2a serotonin receptor inverse agonists or antagonists for use in reducing amyloid-beta peptides and accumulation of amyloid plaques |
| EP3436010B1 (en) | 2016-03-29 | 2021-03-10 | Acadia Pharmaceuticals Inc. | 5-ht2a serotonin receptor inverse agonists or antagonists for use in reducing amyloid-beta peptides and accumulation of amyloid plaques |
| CN105820110B (zh) | 2016-05-09 | 2018-07-24 | 杭州科巢生物科技有限公司 | 匹莫范色林合成方法 |
| EP3558311A1 (en) | 2016-12-20 | 2019-10-30 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of alzheimer's disease psychosis |
| EP3615028A1 (en) | 2017-04-28 | 2020-03-04 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| EP3675827A1 (en) | 2017-08-30 | 2020-07-08 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| WO2019177973A1 (en) | 2018-03-13 | 2019-09-19 | Acadia Pharmaceuticals Inc. | Methods for assessing suicidality |
| US20220016101A1 (en) | 2018-10-30 | 2022-01-20 | Acadia Pharmaceuticals Inc. | Methods of treating depression, anxiety and sexual dysfunction using the compound pimavanserin |
| WO2021016369A1 (en) | 2019-07-22 | 2021-01-28 | Acadia Pharmaceuticals Inc. | Pimavanserin for trating schizophrenia or for treating psychosis secondary to neurodegenerative disorders or depressive disorder |
| WO2021030607A1 (en) | 2019-08-15 | 2021-02-18 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating neurodegenerative diseases |
| US20210161880A1 (en) | 2019-12-02 | 2021-06-03 | Acadia Pharmaceuticals Inc. | Methods for treating dementia related psychosis |
| WO2022094230A1 (en) | 2020-11-02 | 2022-05-05 | Acadia Pharmaceuticals Inc. | Compounds for treating psychosis or depression |
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| US10981870B2 (en) | 2021-04-20 |
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| CA2992728A1 (en) | 2017-01-26 |
| PT3325444T (pt) | 2021-09-22 |
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| US11840515B2 (en) | 2023-12-12 |
| US20200165202A1 (en) | 2020-05-28 |
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| US20190047955A1 (en) | 2019-02-14 |
| US10597363B2 (en) | 2020-03-24 |
| WO2017015272A8 (en) | 2017-04-06 |
| SI3325444T1 (sl) | 2021-11-30 |
| CN107848972A (zh) | 2018-03-27 |
| US10981871B2 (en) | 2021-04-20 |
| IL256998B (en) | 2021-12-01 |
| PL3325444T3 (pl) | 2021-12-06 |
| US20200181087A1 (en) | 2020-06-11 |
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