HRP20040690A2 - Novel fluorene carboxylic acid esters, methods for the production thereof, and use of the same as pharmaceuticals - Google Patents
Novel fluorene carboxylic acid esters, methods for the production thereof, and use of the same as pharmaceuticals Download PDFInfo
- Publication number
- HRP20040690A2 HRP20040690A2 HR20040690A HRP20040690A HRP20040690A2 HR P20040690 A2 HRP20040690 A2 HR P20040690A2 HR 20040690 A HR20040690 A HR 20040690A HR P20040690 A HRP20040690 A HR P20040690A HR P20040690 A2 HRP20040690 A2 HR P20040690A2
- Authority
- HR
- Croatia
- Prior art keywords
- compounds
- methyl
- hydroxy
- acid
- general formula
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 6
- 238000000034 method Methods 0.000 title description 12
- HTPXFGUCAUTOEL-UHFFFAOYSA-N 9h-fluorene-1-carboxylic acid Chemical class C1C2=CC=CC=C2C2=C1C(C(=O)O)=CC=C2 HTPXFGUCAUTOEL-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 90
- -1 hydroxy, methyl Chemical group 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000013543 active substance Substances 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Chemical group 0.000 claims description 12
- 229910052731 fluorine Chemical group 0.000 claims description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229940043355 kinase inhibitor Drugs 0.000 claims description 10
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 8
- 230000003454 betamimetic effect Effects 0.000 claims description 8
- 150000001450 anions Chemical class 0.000 claims description 7
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 7
- 239000003246 corticosteroid Substances 0.000 claims description 6
- 229960001334 corticosteroids Drugs 0.000 claims description 6
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 6
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 239000000043 antiallergic agent Substances 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 5
- 208000007101 Muscle Cramp Diseases 0.000 claims description 4
- 208000005392 Spasm Diseases 0.000 claims description 4
- 239000005557 antagonist Substances 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 2
- 108010081348 HRT1 protein Hairy Chemical group 0.000 claims description 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 2
- 206010040741 Sinus bradycardia Diseases 0.000 claims description 2
- 230000003266 anti-allergic effect Effects 0.000 claims description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 2
- 239000000812 cholinergic antagonist Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 2
- 230000002175 menstrual effect Effects 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- 239000013312 porous aromatic framework Substances 0.000 claims description 2
- 230000033764 rhythmic process Effects 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims 1
- 239000004202 carbamide Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 150000002148 esters Chemical group 0.000 description 17
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 13
- 239000003380 propellant Substances 0.000 description 13
- 239000007789 gas Substances 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 10
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 235000015165 citric acid Nutrition 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- PUPWRKQSVGUBQS-UHFFFAOYSA-N 9-methylfluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C)(C(O)=O)C3=CC=CC=C3C2=C1 PUPWRKQSVGUBQS-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000001530 fumaric acid Chemical class 0.000 description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000003755 preservative agent Substances 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 5
- GXAMYUGOODKVRM-UHFFFAOYSA-N Flurecol Chemical compound C1=CC=C2C(C(=O)O)(O)C3=CC=CC=C3C2=C1 GXAMYUGOODKVRM-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 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 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 5
- 229960002848 formoterol Drugs 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000011976 maleic acid Substances 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- 229940102396 methyl bromide Drugs 0.000 description 5
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229960004017 salmeterol Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000015424 sodium Nutrition 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 229940037001 sodium edetate Drugs 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000002906 tartaric acid Nutrition 0.000 description 5
- 239000011975 tartaric acid Substances 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- BHEFSGMUMYBJRZ-UHFFFAOYSA-N 9-fluorofluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)(F)C3=CC=CC=C3C2=C1 BHEFSGMUMYBJRZ-UHFFFAOYSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000011668 ascorbic acid Substances 0.000 description 4
- 229960005070 ascorbic acid Drugs 0.000 description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical class O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940052760 dopamine agonists Drugs 0.000 description 4
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000026030 halogenation Effects 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 235000014655 lactic acid Nutrition 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- OBRNDARFFFHCGE-PERKLWIXSA-N (S,S)-formoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@H](C)NC[C@@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-PERKLWIXSA-N 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 3
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960000686 benzalkonium chloride Drugs 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229960003728 ciclesonide Drugs 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 229960003449 epinastine Drugs 0.000 description 3
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 3
- 229960002714 fluticasone Drugs 0.000 description 3
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 3
- 229960000193 formoterol fumarate Drugs 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 229960001664 mometasone Drugs 0.000 description 3
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 3
- 238000004172 nitrogen cycle Methods 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229960003089 pramipexole Drugs 0.000 description 3
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 2
- MNJNSRQVLNIPFN-UHFFFAOYSA-N 4-[2-[[4-(benzimidazol-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-2-[(4-methoxyphenyl)methylamino]phenol Chemical compound C1=CC(OC)=CC=C1CNC1=CC(C(O)CNC(C)(C)CCN2C3=CC=CC=C3N=C2)=CC=C1O MNJNSRQVLNIPFN-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 102000017925 CHRM3 Human genes 0.000 description 2
- 101150060249 CHRM3 gene Proteins 0.000 description 2
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- ZCGOMHNNNFPNMX-YHYDXASRSA-N Levocabastinum Chemical compound C1([C@@]2(C(O)=O)CCN(C[C@H]2C)C2CCC(CC2)(C#N)C=2C=CC(F)=CC=2)=CC=CC=C1 ZCGOMHNNNFPNMX-YHYDXASRSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229940125907 SJ995973 Drugs 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229960004574 azelastine Drugs 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- 229940092705 beclomethasone Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229960001803 cetirizine Drugs 0.000 description 2
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 229960001971 ebastine Drugs 0.000 description 2
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- 229960003592 fexofenadine Drugs 0.000 description 2
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- IHPSWTZHVWAGFX-UHFFFAOYSA-N methyl 9-methylfluorene-9-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)(C)C3=CC=CC=C3C2=C1 IHPSWTZHVWAGFX-UHFFFAOYSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229960001144 mizolastine Drugs 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- DPHDSIQHVGSITN-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-2-[1-[(4-fluorophenyl)methyl]-5-hydroxyindol-3-yl]-2-oxoacetamide Chemical compound C1=C(C(=O)C(=O)NC=2C(=CN=CC=2Cl)Cl)C2=CC(O)=CC=C2N1CC1=CC=C(F)C=C1 DPHDSIQHVGSITN-UHFFFAOYSA-N 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 2
- 229960002586 roflumilast Drugs 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 229950008418 talipexole Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DYRRBMLFLLRLKB-UHFFFAOYSA-N 1-(5-tert-butyl-2-methylpyrazol-3-yl)-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound CN1N=C(C(C)(C)C)C=C1NC(=O)NC(C1=CC=CC=C11)=CC=C1OCCN1CCOCC1 DYRRBMLFLLRLKB-UHFFFAOYSA-N 0.000 description 1
- UQDWAVPZBOQOCI-UHFFFAOYSA-N 1-[5-tert-butyl-2-(4-methylphenyl)pyrazol-3-yl]-3-[4-[2-(1-oxo-1,4-thiazinan-4-yl)ethoxy]naphthalen-1-yl]urea Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCS(=O)CC3)=CC=2)=CC(C(C)(C)C)=N1 UQDWAVPZBOQOCI-UHFFFAOYSA-N 0.000 description 1
- OBWCIXSXYKHZQK-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methoxypyridin-3-yl)pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound C1=NC(OC)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 OBWCIXSXYKHZQK-UHFFFAOYSA-N 0.000 description 1
- APRDOMOEBUWBDX-UHFFFAOYSA-N 1-[5-tert-butyl-2-(6-methylpyridin-3-yl)pyrazol-3-yl]-3-[4-(2-pyridin-4-ylethoxy)naphthalen-1-yl]urea Chemical compound C1=NC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCC=3C=CN=CC=3)=CC=2)=CC(C(C)(C)C)=N1 APRDOMOEBUWBDX-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- DBCKRBGYGMVSTI-UHFFFAOYSA-N 2-oxo-7-[2-[2-[3-(2-phenylethoxy)propylsulfonyl]ethylazaniumyl]ethyl]-3h-1,3-benzothiazol-4-olate Chemical compound C1=2SC(=O)NC=2C(O)=CC=C1CCNCCS(=O)(=O)CCCOCCC1=CC=CC=C1 DBCKRBGYGMVSTI-UHFFFAOYSA-N 0.000 description 1
- ZMPRRFPMMJQXPP-UHFFFAOYSA-N 2-sulfobenzoic acid Chemical class OC(=O)C1=CC=CC=C1S(O)(=O)=O ZMPRRFPMMJQXPP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- YLLRPQWLASQXSI-UHFFFAOYSA-N 3-(4b,8a,9,9a-tetrahydro-4aH-pyrido[2,3-b]indol-4-ylamino)phenol Chemical compound Oc1cccc(NC2=CC=NC3NC4C=CC=CC4C23)c1 YLLRPQWLASQXSI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- RTLJQOLVPIGICL-UHFFFAOYSA-N 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(methylsulfonylmethyl)phenol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CS(C)(=O)=O)=C1 RTLJQOLVPIGICL-UHFFFAOYSA-N 0.000 description 1
- KOTMQCNDGLTIHR-UHFFFAOYSA-N 4-[2-[[4-(benzimidazol-1-yl)-2-methylbutan-2-yl]amino]-1-hydroxyethyl]-3-fluorophenol Chemical compound C1=NC2=CC=CC=C2N1CCC(C)(C)NCC(O)C1=CC=C(O)C=C1F KOTMQCNDGLTIHR-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- DNVJGJUGFFYUPT-UHFFFAOYSA-N 9h-fluorene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)C3=CC=CC=C3C2=C1 DNVJGJUGFFYUPT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 240000002470 Amphicarpaea bracteata Species 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical class C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical class C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical class OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000004097 EU approved flavor enhancer Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical class CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- AJKQZRAAQMBNKM-UHFFFAOYSA-N Flurenol methyl ester Chemical compound C1=CC=C2C(C(=O)OC)(O)C3=CC=CC=C3C2=C1 AJKQZRAAQMBNKM-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- ZCVMWBYGMWKGHF-UHFFFAOYSA-N Ketotifene Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CC(=O)C2=C1C=CS2 ZCVMWBYGMWKGHF-UHFFFAOYSA-N 0.000 description 1
- JGPJQFOROWSRRS-UHFFFAOYSA-N LSM-2613 Chemical compound S1C=2N3C(C)=NN=C3CN=C(C=3C(=CC=CC=3)Cl)C=2C=C1CCC(=O)N1CCOCC1 JGPJQFOROWSRRS-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- NZPJYPTZUPYUJT-LJQANCHMSA-N N-[7-cyclopropyl-2-methoxy-4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]-4-morpholin-4-ylbut-2-enamide Chemical compound C1([C@@H](C)NC=2N=C(N=C3C=C(C(NC(=O)C=CCN4CCOCC4)=CC3=2)C2CC2)OC)=CC=CC=C1 NZPJYPTZUPYUJT-LJQANCHMSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910004879 Na2S2O5 Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 1
- BKRGVLQUQGGVSM-KBXCAEBGSA-N Revanil Chemical compound C1=CC(C=2[C@H](N(C)C[C@H](C=2)NC(=O)N(CC)CC)C2)=C3C2=CNC3=C1 BKRGVLQUQGGVSM-KBXCAEBGSA-N 0.000 description 1
- RUOGJYKOQBFJIG-UHFFFAOYSA-N SCH-351591 Chemical compound C12=CC=C(C(F)(F)F)N=C2C(OC)=CC=C1C(=O)NC1=C(Cl)C=[N+]([O-])C=C1Cl RUOGJYKOQBFJIG-UHFFFAOYSA-N 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- JOAHPSVPXZTVEP-YXJHDRRASA-N Terguride Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NC(=O)N(CC)CC)=C3C2=CNC3=C1 JOAHPSVPXZTVEP-YXJHDRRASA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- WKHOPHIMYDJVSA-UHFFFAOYSA-N [3-[2-(tert-butylamino)-1-hydroxyethyl]-5-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate Chemical compound CC(C)C(=O)OC1=CC(OC(=O)C(C)C)=CC(C(O)CNC(C)(C)C)=C1 WKHOPHIMYDJVSA-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- ANZXOIAKUNOVQU-UHFFFAOYSA-N bambuterol Chemical compound CN(C)C(=O)OC1=CC(OC(=O)N(C)C)=CC(C(O)CNC(C)(C)C)=C1 ANZXOIAKUNOVQU-UHFFFAOYSA-N 0.000 description 1
- 229960003060 bambuterol Drugs 0.000 description 1
- 229960002526 bamipine Drugs 0.000 description 1
- VZSXTYKGYWISGQ-UHFFFAOYSA-N bamipine Chemical compound C1CN(C)CCC1N(C=1C=CC=CC=1)CC1=CC=CC=C1 VZSXTYKGYWISGQ-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- FWYVRZOREBYLCY-UHFFFAOYSA-N bepafant Chemical compound C1C=2SC=3N4C(C)=NN=C4CN=C(C=4C(=CC=CC=4)Cl)C=3C=2CC1C(=O)N1CCOCC1 FWYVRZOREBYLCY-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960004620 bitolterol Drugs 0.000 description 1
- FZGVEKPRDOIXJY-UHFFFAOYSA-N bitolterol Chemical compound C1=CC(C)=CC=C1C(=O)OC1=CC=C(C(O)CNC(C)(C)C)C=C1OC(=O)C1=CC=C(C)C=C1 FZGVEKPRDOIXJY-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 239000001273 butane Chemical class 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 229960004596 cabergoline Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960001386 carbuterol Drugs 0.000 description 1
- KEMXXQOFIRIICG-UHFFFAOYSA-N carbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(NC(N)=O)=C1 KEMXXQOFIRIICG-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960003686 chlorphenoxamine Drugs 0.000 description 1
- KKHPNPMTPORSQE-UHFFFAOYSA-N chlorphenoxamine Chemical compound C=1C=C(Cl)C=CC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KKHPNPMTPORSQE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229960001117 clenbuterol Drugs 0.000 description 1
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 229940126115 compound 4f Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- PBUNVLRHZGSROC-VTIMJTGVSA-N dihydro-alpha-ergocryptine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1 PBUNVLRHZGSROC-VTIMJTGVSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- MVMQESMQSYOVGV-UHFFFAOYSA-N dimetindene Chemical compound CN(C)CCC=1CC2=CC=CC=C2C=1C(C)C1=CC=CC=N1 MVMQESMQSYOVGV-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- MVCOAUNKQVWQHZ-UHFFFAOYSA-N doramapimod Chemical compound C1=CC(C)=CC=C1N1C(NC(=O)NC=2C3=CC=CC=C3C(OCCN3CCOCC3)=CC=2)=CC(C(C)(C)C)=N1 MVCOAUNKQVWQHZ-UHFFFAOYSA-N 0.000 description 1
- 229960005178 doxylamine Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 229960000325 emedastine Drugs 0.000 description 1
- KBUZBQVCBVDWKX-UHFFFAOYSA-N emedastine Chemical compound N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCN(C)CC1 KBUZBQVCBVDWKX-UHFFFAOYSA-N 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZEVMEEXSRCFQAC-UHFFFAOYSA-N ethyl 3-[[4-[[4-(3-chloro-4-fluoroanilino)-7-cyclopropyl-2-methoxyquinazolin-6-yl]amino]-4-oxobut-2-enyl]-(2-ethoxy-2-oxoethyl)amino]propanoate Chemical compound N1=C(OC)N=C2C=C(C3CC3)C(NC(=O)C=CCN(CCC(=O)OCC)CC(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ZEVMEEXSRCFQAC-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019264 food flavour enhancer Nutrition 0.000 description 1
- 235000010855 food raising agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 229960000708 hexoprenaline Drugs 0.000 description 1
- OXLZNBCNGJWPRV-UHFFFAOYSA-N hexoprenaline Chemical compound C=1C=C(O)C(O)=CC=1C(O)CNCCCCCCNCC(O)C1=CC=C(O)C(O)=C1 OXLZNBCNGJWPRV-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- YXOKBHUPEBNZOG-UHFFFAOYSA-N hydron;4-hydroxy-7-[2-[2-[3-(2-phenylethoxy)propylsulfonyl]ethylamino]ethyl]-3h-1,3-benzothiazol-2-one;chloride Chemical compound Cl.C1=2SC(=O)NC=2C(O)=CC=C1CCNCCS(=O)(=O)CCCOCCC1=CC=CC=C1 YXOKBHUPEBNZOG-UHFFFAOYSA-N 0.000 description 1
- 229950002451 ibuterol Drugs 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940041682 inhalant solution Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical class OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229920005610 lignin Polymers 0.000 description 1
- 229960003587 lisuride Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- NMJORVOYSJLJGU-UHFFFAOYSA-N methane clathrate Chemical compound C.C.C.C.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O NMJORVOYSJLJGU-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960001383 methylscopolamine Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- ZIISKCSUEHVFLY-AWEZNQCLSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[2-[(2s)-2-methyl-6-oxomorpholin-4-yl]ethoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1NC(=O)C=C ZIISKCSUEHVFLY-AWEZNQCLSA-N 0.000 description 1
- QLVAINZHTQIWQM-QHCPKHFHSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[2-[4-[(2s)-5-oxooxolane-2-carbonyl]piperazin-1-yl]ethoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCN3CCN(CC3)C(=O)[C@H]3OC(=O)CC3)=C(NC(=O)C=C)C=C12 QLVAINZHTQIWQM-QHCPKHFHSA-N 0.000 description 1
- MPIZUARKKMOKKZ-INIZCTEOSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[4-[(2s)-2-methyl-6-oxomorpholin-4-yl]butoxy]quinazolin-6-yl]prop-2-enamide Chemical compound C1C(=O)O[C@@H](C)CN1CCCCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1NC(=O)C=C MPIZUARKKMOKKZ-INIZCTEOSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 239000001294 propane Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- 229950000366 roxindole Drugs 0.000 description 1
- BKTTWZADZNUOBW-UHFFFAOYSA-N roxindole Chemical compound C=12[CH]C(O)=CC=C2N=CC=1CCCCN(CC=1)CCC=1C1=CC=CC=C1 BKTTWZADZNUOBW-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 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
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 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
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229950007862 sulfonterol Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960004558 terguride Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- 230000008719 thickening Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/06—Anti-spasmodics
-
- 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
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. ***e
Description
Predloženi izum odnosi se na nove estere fluorenkarbonske kiseline opće formule 1 The proposed invention relates to new fluorenecarboxylic acid esters of the general formula 1
[image] [image]
u kojoj where
X- i skupine A, R, R1, R2, R3, R1', R4 i R4' mogu imati značenja navedena u zahtjevima i u opisu, na postupke za njihovu pripravu kao i na njihova upotrebu kao lijeka. X- and the groups A, R, R1, R2, R3, R1', R4 and R4' can have the meanings given in the claims and in the description, to the processes for their preparation as well as to their use as a medicine.
Opis izuma Description of the invention
Predloženi izum se odnosi spojeve opće formule 1 The proposed invention relates to compounds of the general formula 1
[image] [image]
u kojoj where
A predstavlja dvovalentan ostatak odabran iz skupine koju čine A represents a divalent residue selected from the group they comprise
[image] [image]
X- je anion s jednostrukim negativnim nabojem, ponajprije anion odabran iz skupine koju čine klorid, bromid, jodid, sulfat, fosfat, metansulfonat, nitrat, maleat, acetat, citrat, fumarat, tartarat, oksalat, sukcinat, benzoat i p-toluolsulfonat; X- is an anion with a single negative charge, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate;
R je vodik, hidroksi, metil, etil, -CF3, CHF2 ili fluor; R is hydrogen, hydroxy, methyl, ethyl, -CF3, CHF2 or fluorine;
R1 i R2 su jednaki ili različiti i predstavljaju -C1-C5-alkil, koji prema potrebi može biti supstituiran sa -C3-C6-cikloalkilom, hidroksi ili halogenim, ili R1 and R2 are the same or different and represent -C1-C5-alkyl, which can be substituted with -C3-C6-cycloalkyl, hydroxy or halogen if necessary, or
R1 i R2 tvore zajedno -C3-C5-alkilenski most; R1 and R2 together form a -C3-C5-alkylene bridge;
R3, R4, R3' i R4'su jednaki ili različiti i predstavljaju vodik, -C1-C4-alkil, -C1-C4-alkiloksi, hidroksi, -CF3, -CHF2, CN, NO2 ili halogen. R3, R4, R3' and R4' are the same or different and represent hydrogen, -C1-C4-alkyl, -C1-C4-alkyloxy, hydroxy, -CF3, -CHF2, CN, NO2 or halogen.
Prednost se daje spojevima opće formule 1 u kojoj Preference is given to compounds of the general formula 1 in which
A predstavlja dvovalentan ostatak odabran iz skupine koju čine A represents a divalent residue selected from the group they comprise
[image] [image]
X- je anion s jednostrukim negativnim nabojem odabran iz skupine koju čine klorid, bromid, 4-toluolsulfonat i metansulfonat, ponajprije bromid; X- is an anion with a single negative charge selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide;
R je hidroksi, metil ili fluor; R is hydroxy, methyl or fluoro;
R1 i R2 su jednaki ili različiti i predstavljaju metil, etil ili fluoretil; R1 and R2 are the same or different and represent methyl, ethyl or fluoroethyl;
R3, R4, R3' i R4' su jednak ili različiti i predstavljaju vodik, metil, metiloksi, hidroksi, -CF3, -CHF2 ili fluor. R3, R4, R3' and R4' are the same or different and represent hydrogen, methyl, methyloxy, hydroxy, -CF3, -CHF2 or fluorine.
Posebnu prednost imaju spojevi opće formule i u kojoj A je dvovalentan ostatak odabran iz skupine koju čine Particular preference is given to compounds of the general formula and in which A is a divalent residue selected from the group they comprise
[image] [image]
X- je anion s jednostrukim negativnim nabojem odabran iz skupine koju čine klorid, bromid i metansulfonat, ponajprije bromid; X- is an anion with a single negative charge selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide;
R je hidroksi, metil ili fluor, ponajprije metil ili hidroksi; R is hydroxy, methyl or fluoro, preferably methyl or hydroxy;
R1 i R2 su jednaki ili različiti i predstavljaju metil ili etil, ponajprije metil; R1 and R2 are the same or different and represent methyl or ethyl, preferably methyl;
R3, R4, R3' i R4' su jednaki ili različiti i predstavljaju vodik, -CF3, -CHF2 ili fluor, ponajprije vodik ili fluor. R3, R4, R3' and R4' are the same or different and represent hydrogen, -CF3, -CHF2 or fluorine, preferably hydrogen or fluorine.
Prema izumu posebno značenje imaju spojevi opće formule 1 u kojoj According to the invention, the compounds of general formula 1 in which
A predstavlja dvovalentan ostatak odabran iz skupine koju čine A represents a divalent residue selected from the group they comprise
[image] [image]
X- je bromid; X- is bromide;
R je hidroksi ili metil, ponajprije metil; R is hydroxy or methyl, preferably methyl;
R1 i R2 su jednaki ili različiti i predstavljaju metil ili etil, ponajprije metil; R1 and R2 are the same or different and represent methyl or ethyl, preferably methyl;
R3, R4, R3' i R4' su jednaki ili različiti i predstavljaju vodik ili fluor. R3, R4, R3' and R4' are the same or different and represent hydrogen or fluorine.
Predmet izuma su u svakom slučaju i spojevi formule 1 prema potrebi u obliku pojedinačnih optičkih izomera, smjesa pojedinačnih enantiomera ili racemata. The subject of the invention is in any case also the compounds of formula 1 as necessary in the form of individual optical isomers, mixtures of individual enantiomers or racemates.
U spojevima opće formule 1, ostaci R3, R4, R3' i R4', ako ne predstavljaju vodik, mogu se nalaziti u svakom slučaju u orto, meta ili para položaju prema mjestu spajanja skupine "-C-R"-. Ako nijedan od ostataka R3, R4, R3 i R4' nije vodik, tada su R3 i R3' povezani ponajprije u para položaju, a R4 i R4' su povezani ponajprije u orto ili meta položaju, posebno povoljno u meta položaju. Ako jedan od ostataka R3 i R4 i jedan od ostataka R3' i R4' predstavlja vodik, tada je u svakom slučaju drugi ostatak povezan ponajprije u meta ili para položaju, posebno povoljno u para položaju. Ako nijedan od ostataka R3, R4, R i R4' nije vodik, tada prema izumu posebnu prednost imaju spojevi opće formule 1 u kojoj ostaci R3, R4, R3' i R4' imaju isto značenje. In the compounds of the general formula 1, the residues R3, R4, R3' and R4', if they do not represent hydrogen, can be located in any case in the ortho, meta or para position according to the point of attachment of the group "-C-R"-. If none of the residues R 3 , R 4 , R 3 and R 4' is hydrogen, then R 3 and R 3' are preferably connected in the para position, and R 4 and R 4' are preferably connected in the ortho or meta position, particularly preferably in the meta position. If one of the residues R3 and R4 and one of the residues R3' and R4' represents hydrogen, then in any case the second residue is connected preferably in the meta or para position, especially preferably in the para position. If none of the residues R3, R4, R and R4' is hydrogen, then compounds of the general formula 1 in which the residues R3, R4, R3' and R4' have the same meaning are particularly preferred according to the invention.
Prema izumu posebno značenje imaju, nadalje, oni spojevi opće formule 1, u kojoj se esterski supstituent nalazi na dušikovom biciklu α. Ti spojevi odgovaraju općoj formuli 1-α According to the invention, those compounds of the general formula 1, in which the ester substituent is located on the nitrogen cycle α, have a special meaning. These compounds correspond to the general formula 1-α
[image] [image]
Prema izumu posebno značenje imaju slijedeći spojevi: According to the invention, the following compounds have special meaning:
9-hidroksi-fluoren-9-karbonska kiselina tropenol ester metobromid; 9-hydroxy-fluorene-9-carboxylic acid tropenol ester methobromide;
9-fluor-fluoren-9-karbonska kiselina tropenol ester metobromid; 9-fluoro-fluorene-9-carboxylic acid tropenol ester methobromide;
9-hidroksi-fluoren-9-karbonske kiseline skopin ester metobromid; 9-hydroxy-fluorene-9-carboxylic acid scopine ester methobromide;
9-fluor-fluoren-9-karbonske kiseline skopin ester metobromid; 9-fluoro-fluorene-9-carboxylic acid scopine ester methobromide;
9-metil-fluoren-9-karbonske kiseline tropenol ester metobromid; 9-methyl-fluorene-9-carboxylic acid tropenol ester methobromide;
9-metil-fluoren-9-karbonske kiseline skopin ester metobromid. 9-methyl-fluorene-9-carboxylic acid scopine ester methobromide.
Kao alkilne skupine, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate alkilne skupine koje imaju od 1 do 5 ugljikovih atoma. Navode se, na primjer, metil, etil, propil ili butil. Za označavanje skupina metil, etil, propil ili također butil upotrebljavaju se prema potrebi također i kratice Me, Et, Prop ili Bu. Ako nije navedeno drugačije, definicije propila i butila obuhvaćaju također i sve zamislive izomerne oblike dotičnih ostataka. Tako na primjer propil obuhvaća n-propil i izo-propil, butil obuhvaća izo-butil, sek-butil i terc-butil itd. Alkyl groups, unless stated otherwise, are branched and unbranched alkyl groups having from 1 to 5 carbon atoms. Examples include methyl, ethyl, propyl or butyl. To indicate methyl, ethyl, propyl or also butyl groups, the abbreviations Me, Et, Prop or Bu are also used as necessary. Unless otherwise stated, the definitions of propyl and butyl also include all conceivable isomeric forms of the respective residues. So for example propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.
Kao alkilenske skupine, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate dvovalentne skupine s alkilnim mostovima koje imaju od 1 do 4 ugljikova atoma. Navode se, na primjer, metilen, etilen, propilen ili butilen. Alkylene groups, unless otherwise stated, are branched and unbranched divalent groups with alkyl bridges having from 1 to 4 carbon atoms. Methylene, ethylene, propylene or butylene are mentioned, for example.
Kao alkilen-halogene skupine, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate dvovalentne skupine s alkilnim mostovima koje imaju od 1 do 4 ugljikova atoma, koje su jednostruko, dvostruko ili trostruko, ponajprije dvostruko supstituirane s helogenim. S tim u skladu, kao skupine alkilen-OH, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate dvovalentne skupine s alkilnim mostovima koje imaju od 1 do 4 ugljikova atoma, koje su jednostruko, dvostruko ili trostruko, ponajprije jednostruko supstituirane s hidroksi. Alkylene-halogen groups, unless otherwise stated, are branched and unbranched divalent groups with alkyl bridges having from 1 to 4 carbon atoms, which are singly, doubly or triply, preferably doubly substituted with halogen. In accordance with this, alkylene-OH groups, unless otherwise stated, denote branched and unbranched divalent groups with alkyl bridges having from 1 to 4 carbon atoms, which are singly, doubly or triply, preferably singly substituted with hydroxy.
Kao alkiloksi skupine, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate skupine s 1 do 4 ugljikova atoma koje su povezane preko kisikovog atoma. Navode se, na primjer, metiloksi, etiloksi, propiloksi ili butiloksi. Za označavanje skupina metiloksi, etiloksi, propiloksi ili također butiloksi upotrebljavaju se prema potrebi također i kratice MeO-, EtO-, PropO- ili BuO-. Ako nije navedeno drugačije, definicije propiloksi i butiloksi obuhvaćaju sve zamislive izomerne oblike dotičnih ostataka. Tako na primjer propiloksi obuhvaća n-propiloksi i izo-propiloksi, butiloksi obuhvaća izo-butiloksi, sek-butiloksi i terc-butiloksi, itd. Prema potrebi, u okviru predloženog izuma, umjesto oznake alkiloksi koristi se također i oznaku alkoksi. Za označavanje skupina metiloksi, etiloksi, propiloksi ili također butiloksi, odgovarajuće se prema potrebi također koriste i izrazi metoksi, etoksi, propoksi ili butoksi. Alkyloxy groups, unless stated otherwise, are branched and unbranched groups with 1 to 4 carbon atoms that are connected through an oxygen atom. Examples include methyloxy, ethyloxy, propyloxy or butyloxy. The abbreviations MeO-, EtO-, PropO- or BuO- are also used to indicate the groups methyloxy, ethyloxy, propyloxy or also butyloxy, if necessary. Unless otherwise stated, the definitions of propyloxy and butyloxy include all conceivable isomeric forms of the respective residues. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec-butyloxy and tert-butyloxy, etc. If necessary, within the scope of the proposed invention, instead of the designation alkyloxy, the designation alkoxy is also used. To denote methyloxy, ethyloxy, propyloxy or also butyloxy groups, the terms methoxy, ethoxy, propoxy or butoxy are also used as appropriate.
Kao alkilen-alkiloksi skupine, ako nije navedeno drugačije, označavaju se razgranati i nerazgranati dvovalentni alkilni mostovi s 1 do 4 ugljikova atoma, koji su jednostruko, dvostruko ili trostruko, ponajprije jednostruko supstituirani s alkiloksi skupinom. Alkylene-alkyloxy groups, if not stated otherwise, denote branched and unbranched divalent alkyl bridges with 1 to 4 carbon atoms, which are singly, doubly or triply, preferably singly substituted with an alkyloxy group.
Kao -O-CO-alkilne skupine, ako nije navedeno drugačije, označavaju se razgranate i nerazgranate alkilne skupine s 1 do 4 ugljikova atoma, koje su povezane preko esterske skupine. Pri tome, alkilne skupine su povezane izravno na karbonilni ugljik esterske skupine. Branched and unbranched alkyl groups with 1 to 4 carbon atoms, which are connected via an ester group, are denoted as -O-CO-alkyl groups, if not stated otherwise. In this case, the alkyl groups are connected directly to the carbonyl carbon of the ester group.
Analogno se podrazumijeva i oznaku skupine -O-CO-alkil-halogen. The designation of the group -O-CO-alkyl-halogen is understood analogously.
Skupina-O-CO-CF3 predstavlja trifluoracetat. The group-O-CO-CF3 represents trifluoroacetate.
U okviru predloženog izuma halogen je fluor, klor, brom ili jod. Ako nije navedeno drugačije, kao halogeni prednost imaju fluor i brom. In the context of the proposed invention, halogen is fluorine, chlorine, bromine or iodine. Unless otherwise specified, fluorine and bromine are preferred as halogens.
Skupina CO označava karbonilnu skupinu. Priprava spojeva prema izumu može se objasniti kao u nastavku, djelomično analogno postupcima koji su već poznati iz stanja tehnike (shema 1) . Derivati karbonske kiseline formule 3 su poznati iz stanja tehnike ili se mogu dobiti postupcima sinteze koji su poznati iz stanja tehnike. Ako su iz stanja tehnike poznate samo supstituirane karbonske kiseline, spojevi formule 3 se mogu također dobiti izravno iz njih esterifikacijom s odgovarajućim alkoholima uz kiseli ili bazični katalizator ili halogeniranjem s odgovarajućim reagentima za halogeniranje. The CO group denotes a carbonyl group. The preparation of the compounds according to the invention can be explained as follows, partially analogous to procedures already known from the state of the art (scheme 1). Carboxylic acid derivatives of formula 3 are known from the state of the art or can be obtained by synthesis procedures that are known from the state of the art. If only substituted carboxylic acids are known from the prior art, the compounds of formula 3 can also be obtained directly from them by esterification with suitable alcohols with an acidic or basic catalyst or by halogenation with suitable halogenation reagents.
Shema 1: Scheme 1:
[image] [image]
Kako se vidi iz sheme l, kao polazni proizvodi za pripravu spojeva formule 1 služe spojevi formule 2. Ti spojevi su poznati iz stanja tehnike. As can be seen from scheme 1, compounds of formula 2 serve as starting products for the preparation of compounds of formula 1. These compounds are known from the state of the art.
Počevši od spojeva formule 2 dolazi se do estera opće formule 4 reakcijom s derivatima karbonske kiseline formule 3, u kojima R1 predstavlja, na primjer, klor ili ostatak C1-C4-alkil-oksi. U slučaju da R1 predstavlja C1-C4-alkiloksi, tu reakciju se može provesti, na primjer, u natrijevoj talini, pri povišenoj temperaturi, ponajprije pri pribl. 50-150°C, posebno povoljno pri otprilike 90-100°C, pod nižom tlakom, ponajprije pod tlakom ispod 500 mbara, posebno povoljno pod tlakom ispod 75 mbara. Alternativno tome, umjesto derivata 3, u kojima R' predstavlja C1-C4-alkiloksi, također se mogu upotrijebiti odgovarajući kiselinski kloridi (R je Cl). Starting from compounds of formula 2, esters of general formula 4 are obtained by reaction with carboxylic acid derivatives of formula 3, in which R1 represents, for example, chlorine or a C1-C4-alkyloxy residue. In case R1 represents C1-C4-alkyloxy, this reaction can be carried out, for example, in a sodium melt, at an elevated temperature, preferably at approx. 50-150°C, particularly advantageously at about 90-100°C, under lower pressure, preferably under pressure below 500 mbar, particularly preferably under pressure below 75 mbar. Alternatively, instead of derivatives 3, in which R' represents C1-C4-alkyloxy, the corresponding acid chlorides (R is Cl) can also be used.
Tako dobiveni spojevi formule 4. mogu se prevesti u željene spojeve formule 1 reakcijom sa spojevima R2-X, u kojima R i X mogu imati gore navedena značenja. Također, provedba tog stupnja sinteze vrši se analogno primjerima sinteze koji su opisani u WO 92/16528. U slučaju da R1 i R2 zajedno tvore alkilenski most, dodatak reagenta R2 -X nije potreban, kao što je to stručnjaku jasno. U tom slučaju, spojevi formule 4 imaju odgovarajuće supstituirani ostatak R1 (na primjer -C3-C5-alkilen-halogen) koji odgovara gore navedenoj definiciji i priprava spojeva formule 1 vrši se intramolekularnom kvarternizacijom amina. The thus obtained compounds of formula 4 can be converted into the desired compounds of formula 1 by reaction with compounds R2-X, in which R and X can have the above-mentioned meanings. Also, the implementation of this stage of synthesis is carried out analogously to the synthesis examples described in WO 92/16528. In the event that R 1 and R 2 together form an alkylene bridge, the addition of the reagent R 2 -X is not necessary, as is clear to the person skilled in the art. In this case, the compounds of formula 4 have a suitably substituted residue R1 (for example -C3-C5-alkylene-halogen) which corresponds to the above definition and the preparation of compounds of formula 1 is carried out by intramolecular quaternization of amines.
Alternativno postupku prikazanom u shemi 1 za sintezu spojeva formule 4 mogu se pripraviti derivati 4, u kojima dušikov bicikl predstavlja derivat skupina, oksidacijom (epoksidiranjem) spojeva formule 4, u kojima dušikov bicikl predstavlja tropenilni ostatak. U tu svrhu, prema izumu se postupa kako slijedi. Spoj 4, u kojem A predstavlja -CH=CH-, suspendira se u polarnom organskom otapalu, ponajprije u otapalu odabranom iz skupine koju čine N-metil-2-pirolidon (NMP), dimetilacetamid i dimetilformamid, ponajprije dimetilformamid, i zatim se zagrije na temperaturu od pribl. 30-90°C, ponajprije 40-70°C. Zatim se doda prikladno oksidacijsko sredstvo i pri konstantnoj temperaturi se miješa 2 do 8 sati, ponajprije 3 do 6 sati. Kao oksidacijsko sredstvo za upotrebu u obzir dolazi ponajprije vanadijev pentoksid u mješavini s H2O2, posebno povoljno kompleks H2O2-urea u kombinaciji s vanadijevim pentoksidom. Obrada se vrši na uobičajen način. Čišćenje proizvoda može se provesti, ovisno o sklonosti prema kristalizaciji, kristalizacijom ili kromatografijom. Alternatively to the procedure shown in scheme 1 for the synthesis of compounds of formula 4, derivatives 4, in which the nitrogen cycle represents a derivative group, can be prepared by oxidation (epoxidation) of compounds of formula 4, in which the nitrogen cycle represents a tropenyl residue. For this purpose, the invention is handled as follows. Compound 4, where A represents -CH=CH-, is suspended in a polar organic solvent, preferably a solvent selected from the group consisting of N-methyl-2-pyrrolidone (NMP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then heated to a temperature of approx. 30-90°C, preferably 40-70°C. A suitable oxidizing agent is then added and stirred at a constant temperature for 2 to 8 hours, preferably 3 to 6 hours. Vanadium pentoxide in a mixture with H2O2, particularly advantageously the H2O2-urea complex in combination with vanadium pentoxide, comes into consideration as an oxidizing agent for use. Processing is done in the usual way. Purification of the product can be carried out, depending on the tendency towards crystallization, by crystallization or chromatography.
Alternativno tome, spojevi formule 4, u kojima R predstavlja halogen, mogu se također dobiti na način prikazan u shemi 2. Alternatively, compounds of formula 4, wherein R is halogen, can also be obtained in the manner shown in Scheme 2.
Shema 2: Scheme 2:
[image] [image]
U tu svrhu, spojevi formule 4 u kojima R predstavlja hidroksi, prevedu se u spojeve 4 u kojima R predstavlja halogen upotrebom odgovarajućih reagenata za halogeniranje. Reakcija prema shemi 2 za provedbu halogeniranja dovoljno je poznata iz stanja tehnike. For this purpose, compounds of formula 4 in which R is hydroxy are converted into compounds 4 in which R is halogen using appropriate halogenation reagents. The reaction according to scheme 2 for carrying out halogenation is sufficiently known from the state of the art.
Kako se vidi u shemi 1, središnji značaj imaju intermedijarni proizvodi opće formule 4. S tim u skladu, daljnji aspekt predloženog izuma odnosi se na intermedijate formule 4 As can be seen in scheme 1, intermediate products of general formula 4 are of central importance. Accordingly, a further aspect of the proposed invention relates to intermediates of formula 4
[image] [image]
u kojoj ostataci A, R, R1, R3, R3', R4 i R4' mogu imati gore navedena značenja, prema potrebi u obliku njihovih kiselinskih adicijskih soli. in which the residues A, R, R1, R3, R3', R4 and R4' may have the above meanings, optionally in the form of their acid addition salts.
Pri tome, pod kiselinskim adicijskim solima podrazumijevaju se soli odabrane iz skupine koju čine hidroklorid, hidrobromid, hidrojodid, hidrosulfat, hidrofosfat, hidrometansulfonat, hidronitrat, hidromaleat, hidroacetat, hidrocitrat, hidrofumarat, hidrotartrat, hidrooksalat, hidrosukcinat, hidrobenzoat i hidro-p-toluolsulfonat, ponajprije hidroklorid, hidrobromid, hidrosulfat, hidrofosfat, hidrofumarat i hidrometan-sulfonat. In addition, under acid addition salts are meant salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate , especially hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethane sulfonate.
Kao u spojevima opće formule 1, u spojevima opće formule 4 ostaci R3, R4, R3' i R4' , ako oni ne predstavljaju vodik, mogu također biti u svakom slučaju u orto, meta ili para položaju u odnosu na mjesto veze prema skupini "-C-R"-. Ako nijedan od ostataka R3, R4, R3' i R4' nije vodik, tada su R3 i R3' povezani ponajprije u para položaju, a R4 i R4' su ponajprije u orto ili meta položaju, posebno povoljno u meta položaju. Ako jedan od ostataka R3 i R4 i jedan od ostataka R3' i R4' predstavlja vodik, tada je u svakom slučaju drugi ostatak povezan ponajprije u meta ili para položaju, posebno povoljno u para položaju. Ako nijedan od ostataka R3, R4, R3' i R4' nije vodik, prema izumu imaju posebnu prednost oni spojevi opće formule 4 u kojima ostaci R3, R4, R3' i R4' imaju isto značenje. As in the compounds of the general formula 1, in the compounds of the general formula 4 the residues R3, R4, R3' and R4', if they do not represent hydrogen, can also be in any case in the ortho, meta or para position in relation to the point of connection to the group " -C-R"-. If none of the residues R3, R4, R3' and R4' is hydrogen, then R3 and R3' are preferably connected in the para position, and R4 and R4' are preferably in the ortho or meta position, particularly preferably in the meta position. If one of the residues R3 and R4 and one of the residues R3' and R4' represents hydrogen, then in any case the second residue is connected preferably in the meta or para position, especially preferably in the para position. If none of the residues R3, R4, R3' and R4' is hydrogen, compounds of the general formula 4 in which the residues R3, R4, R3' and R4' have the same meaning are particularly preferred according to the invention.
Kao polazni materijali prema izumu se upotrebljavaju ponajprije spojevi formule 4 koji imaju α oblik konfiguracije. Ti spojevi α konfiguracije su stoga prema izumu posebno značajni i oni odgovaraju općoj formuli 4-α. As starting materials according to the invention, compounds of formula 4 which have an α form of configuration are primarily used. Those compounds of the α configuration are therefore particularly important according to the invention and they correspond to the general formula 4-α.
[image] [image]
Daljnji aspekt predloženog izuma odnosi se na upotrebu spojeva opće formule 2 za pripravu spojeva opće formule 4. Nadalje, predloženi izum odnosi se na upotrebu spojeva opće formule 2 kao polanog materijala za pripravu spojeva opće formule 1. Nadalje, predloženi izum odnosi se na upotrebu spojeva opće formule 4 kao intermedijarnih proizvoda u pripravi spojeva opće formule 1. A further aspect of the proposed invention relates to the use of compounds of general formula 2 for the preparation of compounds of general formula 4. Furthermore, the proposed invention relates to the use of compounds of general formula 2 as a filling material for the preparation of compounds of general formula 1. Furthermore, the proposed invention relates to the use of compounds of general formula 4 as intermediate products in the preparation of compounds of general formula 1.
Slijedeći primjere sinteze, koji su opisani u nastavku, dalje objašnjavaju predloženi izum. Njih treba shvatiti u svakom slučaju samo kao zorni prikaz postupaka za daljnje objašnjenje izuma, koji se sam na ograničava na te opisane primjere. Following synthesis examples, which are described below, further illustrate the proposed invention. They should be understood in any case only as a clear presentation of procedures for further explanation of the invention, which itself is limited to those described examples.
Primjer 1 Example 1
9-hidroksv-fluoren-9-karbonska kiselina tropenol ester metobromid 9-Hydroxv-fluorene-9-carboxylic acid tropenol ester methobromide
[image] [image]
1.1 1.1
9-hidroksi-fluoren-9-karbonska kiselina metil ester 3a 9-hydroxy-fluorene-9-carboxylic acid methyl ester 3a
50,4 g (0,223 mola) 9-hidroksi-9-fluorenkarbonske kiseline otopi se u 500 ml metanola, pomiješa se s 5 ml (0,089 mola) konc. sumporne kiseline i grije se 1 sat pod refluksom. Kad se ohladi, doda se 100 ml otopine natrijevog hidrogen karbonata (pribl. pH 8) i metanol se maksimalno ispari. Ekstrahira se s diklormetanom i vodom, organsku fazu se osuši i ispari do suhog. Čišćenje se vrši prekristalizacijom iz etil acetata. Iskorištenje: 50,0 g bijelih kristala (= 93% od teorijskog). 50.4 g (0.223 mol) of 9-hydroxy-9-fluorenecarboxylic acid is dissolved in 500 ml of methanol, mixed with 5 ml (0.089 mol) of conc. sulfuric acid and heated for 1 hour under reflux. When cooled, 100 ml of sodium hydrogen carbonate solution (approx. pH 8) is added and the methanol is maximally evaporated. It is extracted with dichloromethane and water, the organic phase is dried and evaporated to dryness. Purification is done by recrystallization from ethyl acetate. Yield: 50.0 g of white crystals (= 93% of theory).
1.2 1.2
9-hidroksi-fluoren-9-karbonska kiselina tropenol ester 4a 13,4 g (0,056 mola) metil estera 3a, 11,65 g (0,084 mola) tropenola i 0,3 g natrija grije se kao talina 4 sata pod 75 mbara na kipućoj vodenoj kupelji uz povremeno mućkanje. Kad se ohladi, ostaci natrija se otope s aceto-nitrilom, otopinu se ispari do suhog i ostatak se ekstrahira s diklormetan/vodom. Organsku fazu se ispere s vodom, osuši se preko MgSO4 i otapalo se izdestilira. Čišćenje proizvoda se vrši prekristalizacijom iz dietil etera. 9-hydroxy-fluorene-9-carboxylic acid tropenol ester 4a 13.4 g (0.056 mol) methyl ester 3a, 11.65 g (0.084 mol) tropenol and 0.3 g sodium are heated as a melt for 4 hours at 75 mbar boiling water bath with occasional shaking. When cooled, the sodium residue was dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4 and the solvent is distilled off. The product is purified by recrystallization from diethyl ether.
Iskorištenje: 11,40 g bijelih kristala (= 59% od teorijskog). Yield: 11.40 g of white crystals (= 59% of theory).
1.3 1.3
9-hidroksi-fluoren-9-karbonska kiselina tropenol ester metobromid 9-hydroxy-fluorene-9-carboxylic acid tropenol ester methobromide
1,75 g (0,005 mola) spoja 4a se stavi u 30 ml diklor-metana i 15 ml acetonitrila i pomiješa se s 2,85 g (0,015 mola) 50%-tne otopine metil bromida u acetonitrilu. Reakcijsku smjesu se pusti stajati 3 dana pri sobnoj temperaturi, pri čemu proizvod kristalizira. Izlučeni kristali se odvoje i za čišćenje se prekristaliziraju iz dietil etera. 1.75 g (0.005 mol) of compound 4a was placed in 30 ml of dichloromethane and 15 ml of acetonitrile and mixed with 2.85 g (0.015 mol) of a 50% solution of methyl bromide in acetonitrile. The reaction mixture is allowed to stand for 3 days at room temperature, during which the product crystallizes. The precipitated crystals are separated and recrystallized from diethyl ether for purification.
Iskorištenje: 1,95 g bijelih kristala (= 88% od teorijekog); Yield: 1.95 g of white crystals (= 88% of theory);
talište: 250°C. melting point: 250°C.
Elementarna analiza: Elementary analysis:
izračunato: C (62,45) H (5,47) N (3,17) calculated: C (62.45) H (5.47) N (3.17)
nađeno: C (61,53) H (5,84) N (3,22). found: C (61.53) H (5.84) N (3.22).
Primjer 2 Example 2
9-fluor-fluoren-9-karbonska kiselina tropenol ester metobromid 9-fluoro-fluorene-9-carboxylic acid tropenol ester methobromide
[image] [image]
2.1 2.1
9-fluor-fluoren-9-karbonska kiselina tropenol ester 4b 9-fluoro-fluorene-9-carboxylic acid trophenol ester 4b
1,66 ml (0,009 mola) bis- (2-metoksietil)-amino-sumpor-trifluorida stavi se u 10 ml diklormetana i pri 15-20°C pomiješa se tijekom 20 minuta, kap po kap, s otopinom od 2,4 g (0,007 mola) spoja 4a u 25 ml diklormetana. Miješa se 20 h pri sobnoj temperaturi, ohladi se na 0°C i oprezno se pomiješa s 80 ml vode uz dobro miješanje. Zatim se oprezno namjesti na pH 8 s vodenom otopinom NaHCO3, organsku fazu se odvoji, vodenu fazu se ponovno ekstrahira s diklor-metanom, sjedinjene organske faze se isperu s vodom, osuše preko MgSO4 i ispare do suhog. Izlučeni hidroklorid se prekristalizira iz acetonitril/dietil etera. Zatim se slobodnu bazu oslobodi pomoću 10%-tne vodene otopine natrijevog karbonata. 1.66 ml (0.009 mol) of bis-(2-methoxyethyl)-amino-sulphur-trifluoride is placed in 10 ml of dichloromethane and mixed at 15-20°C for 20 minutes, drop by drop, with a solution of 2.4 g (0.007 mol) of compound 4a in 25 ml of dichloromethane. It is stirred for 20 h at room temperature, cooled to 0°C and carefully mixed with 80 ml of water with good mixing. It is then carefully adjusted to pH 8 with an aqueous solution of NaHCO3, the organic phase is separated, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over MgSO4 and evaporated to dryness. The secreted hydrochloride is recrystallized from acetonitrile/diethyl ether. Then the free base is released using a 10% aqueous solution of sodium carbonate.
Iskorištenje: 1,05 g svjetlo žutih kristala (= 53% od teorijskog). Yield: 1.05 g of light yellow crystals (= 53% of theory).
2.2 2.2
9-fluor-fluoren-9-karbonska kiselina tropenol ester metobromid 9-fluoro-fluorene-9-carboxylic acid tropenol ester methobromide
1,05 g (0,003 mola) spoja 4b se stavi u 20 ml aceto-nitrila i analogno stupnju 1.3 reagira s 1,71 g (0,009 mola) 50%-tne otopine metil bromida u acetonitrilu. Za čišćenje se prekristalizira iz acetonitrila. Iskorištenje: 0,80 g bijelih kristala (= 60% od teorijskog); talište: 252°C. 1.05 g (0.003 mol) of compound 4b is placed in 20 ml of acetonitrile and reacted analogously to step 1.3 with 1.71 g (0.009 mol) of a 50% solution of methyl bromide in acetonitrile. For purification, it is recrystallized from acetonitrile. Yield: 0.80 g of white crystals (= 60% of theoretical); melting point: 252°C.
Elementarna analiza: Elementary analysis:
izračunato: C (62,17) H (5,22) N (3,15) calculated: C (62.17) H (5.22) N (3.15)
nađeno: C (62,04) H (5,23) N (3,15). found: C (62.04) H (5.23) N (3.15).
Primjer 3 Example 3
9-hidroksi-fluoren-9-karbonska kiselina skopin ester metobromid 9-hydroxy-fluorene-9-carboxylic acid scopine ester methobromide
[image] [image]
3.1 3.1
9-hidroksi-fluoren-9-karbonska kiselina skonin ester 4c 9-hydroxy-fluorene-9-carboxylic acid sconene ester 4c
9,0 g (0,026 mola) tropenol estera 4a suspendira se u 90 ml dimetilformamida i pomiješa se s 0,47 g (0,003 mola) vanadijevog(V) oksida. Pri 60°C dokaplje se otopinu iz 4,89 g (0,052 mola) H2O2-uree u 20 ml vode i miješa se 6 sati pri 60°C. Kad se ohladi na 20°C nastali talog se odsisa, filtrat se namjesti na pH 2 sa 4 N solnom kiselinom i pomiješa se s Na2S2O5 otopljenim u vodi. Tako dobivenu otopinu se ispari do suhog i ostatak se ekstrahira s diklormetan/vodom. Kiselu vodenu fazu se namjesti bazičnom s Na2CO3, ekstrahira se s diklormetanom i organsku fazu se osuši preko Na2SO4 i koncentrira. Zatim se doda l ml acetil klorida pri sobnoj temperaturi i miješa se l sat. Nakon ekstrakcije s l N solnom kiselinom, vodenu fazu se namjesti bazičnom, ekstrahira se s diklormetanom organsku fazu se ispere s vodom i osuši preko MgSO4. Zatim se otapalo odstrani destilacijom. Čišćenje sirovog proizvoda vrši se prekristalizacijom iz dietil etera. 9.0 g (0.026 mol) of trophenol ester 4a was suspended in 90 ml of dimethylformamide and mixed with 0.47 g (0.003 mol) of vanadium(V) oxide. At 60°C, a solution of 4.89 g (0.052 mol) H2O2-urea in 20 ml of water is added dropwise and stirred for 6 hours at 60°C. When it cools down to 20°C, the resulting precipitate is suctioned off, the filtrate is adjusted to pH 2 with 4 N hydrochloric acid and mixed with Na2S2O5 dissolved in water. The solution thus obtained is evaporated to dryness and the residue is extracted with dichloromethane/water. The acidic aqueous phase is made basic with Na2CO3, extracted with dichloromethane and the organic phase is dried over Na2SO4 and concentrated. Then 1 ml of acetyl chloride is added at room temperature and stirred for 1 hour. After extraction with 1 N hydrochloric acid, the aqueous phase is made basic, extracted with dichloromethane, the organic phase is washed with water and dried over MgSO4. Then the solvent was removed by distillation. The crude product is purified by recrystallization from diethyl ether.
Iskorištenje: 2,8 g bijelih kristala (= 30% od teorijskog). Yield: 2.8 g of white crystals (= 30% of theoretical).
3.2 3.2
9-hidroksi-fluoren-9-karbonska kiselina skopin ester metobromid 9-hydroxy-fluorene-9-carboxylic acid scopine ester methobromide
1,3 g (0,004 mol) spoja 4c stavi se u 20 ml kloroforma i 20 ml acetonitrila i s 2,279 g (0,012 mola) 50%-tne otopine metil bromida u acetonitrilu reagira analogno stupnju 1.3. Za čišćenje se prekristalizira iz aceto-nitrila. 1.3 g (0.004 mol) of compound 4c is placed in 20 ml of chloroform and 20 ml of acetonitrile and reacted analogously to step 1.3 with 2.279 g (0.012 mol) of a 50% solution of methyl bromide in acetonitrile. For purification, it is recrystallized from acetonitrile.
Iskorištenje: 1,25 g svjetlo bež kristala (= 68% od teorijskog); talište: 243-244°C. Yield: 1.25 g of light beige crystals (= 68% of theoretical); melting point: 243-244°C.
Elementarna analiza: Elementary analysis:
izračunato: C (60,27) H (5,28) N (3,06) calculated: C (60.27) H (5.28) N (3.06)
nađeno: C (60,03) H (5,35) N (3,55). found: C (60.03) H (5.35) N (3.55).
Primjer 4 Example 4
9-fluor-fluoren-9-karbonska kiselina skopin ester metobromid 9-fluoro-fluorene-9-carboxylic acid scopine ester methobromide
[image] [image]
4.1 4.1
9-fluor-fluoren-9-karbonska kiselina skopin ester 4d 9-fluoro-fluorene-9-carboxylic acid scopine ester 4d
0,885 ml (0,005 mola) bis-(2-metoksietil)-amino-sumportrifluorida stavi se u 25 ml diklormetana i analogno prethodnom postupku 2.1 reagira s 1,42 g (0,004 mola) spoja 4c. 0.885 ml (0.005 mol) of bis-(2-methoxyethyl)-amino-sulfur trifluoride is placed in 25 ml of dichloromethane and reacted analogously to the previous procedure 2.1 with 1.42 g (0.004 mol) of compound 4c.
Iskorištenje: 1,1 g bež kristala (= 75% od teorijskog) Yield: 1.1 g of beige crystals (= 75% of theoretical)
4.2 4.2
9-fluor-fluoren-9-karbonska kiselina skopin ester metobromid 9-fluoro-fluorene-9-carboxylic acid scopine ester methobromide
1,1 g (0,003 mola) spoja 4d stavi se u 30 ml aceto-nitrila i s 1,71 g (0,009 mola) 50%-tne otopine metil bromida u acetonitrilu reagira analogno stupnju 1.3. Za čišćenje se prekristalizira iz izopropanola. 1.1 g (0.003 mol) of compound 4d is placed in 30 ml of acetonitrile and reacted analogously to step 1.3 with 1.71 g (0.009 mol) of a 50% solution of methyl bromide in acetonitrile. For cleaning, it is recrystallized from isopropanol.
Iskorištenje: 0,45 g bijelih kristala (= 33% od teorijskog); talište: 200-201°C. Yield: 0.45 g of white crystals (= 33% of theory); melting point: 200-201°C.
Elementarna analiza: Elementary analysis:
izračunato: C (60,01) H (5,04) N (3,04) calculated: C (60.01) H (5.04) N (3.04)
nađeno: C (59,91) H (5,18) N (3,10). found: C (59.91) H (5.18) N (3.10).
Primjer 5 Example 5
9-metil-fluoren-9-karbonska kiselina tropenol ester metobromid 9-methyl-fluorene-9-carboxylic acid tropenol ester methobromide
[image] [image]
5.1 5.1
9-metil-fluoren-9-karbonska kiselina 3b 9-methyl-fluorene-9-carboxylic acid 3b
a) 9-metil-fluoren-9-karbonska kiselina metil ester a) 9-methyl-fluorene-9-carboxylic acid methyl ester
Iz 7,6 g (0,33 mola) natrija i 300 ml etanola pripravi se otopinu natrijevog metilata koju se u obrocima doda u 69,6 g (0,33 mola) 9-fluorenkarbonske kiseline. Po završenom dodavanju miješa se 2,5 sata pri sobnoj temperaturi. A sodium methylate solution is prepared from 7.6 g (0.33 mol) of sodium and 300 ml of ethanol, which is added in portions to 69.6 g (0.33 mol) of 9-fluorenecarboxylic acid. After the addition is complete, it is stirred for 2.5 hours at room temperature.
Zatim se ispari do suhog, ostatak se suspendira u 600 ml dimetilformamida i dokaplje se 93,96 g (0,662 mola) metil jodida. Miješa se još 3 sata pri konstantnoj temperaturi. Mutnu otopinu se uz hlađenje umiješa u 500 ml vode i 300 ml dietil etera i ekstrahira se, organsku fazu se ispere s vodom i s 10%-tnom otopinom natrijevog karbonata, osuši i ispari do suhog. Ostatak se očisti pomoću kromatografije na stupcu s protočnim sredstvom cikloheksan/etil acetatom 96:4. It is then evaporated to dryness, the residue is suspended in 600 ml of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide is added dropwise. It is mixed for another 3 hours at a constant temperature. After cooling, the cloudy solution is mixed with 500 ml of water and 300 ml of diethyl ether and extracted, the organic phase is washed with water and with a 10% sodium carbonate solution, dried and evaporated to dryness. The residue was purified by column chromatography eluting with cyclohexane/ethyl acetate 96:4.
Iskorištenje: 12,61 g bijelih kristala (= 16% od teorijskog); talište: 108 -109°C. Yield: 12.61 g of white crystals (= 16% of theory); melting point: 108 -109°C.
b) 9-metil-fluoren-9-karbonska kiselina 3b b) 9-methyl-fluorene-9-carboxylic acid 3b
12,6 g (0,053 mola) 9-metil-fluoren-9-karbonska kiselina metil estera i 53 ml 2 molarne vodene otopine natrijevog hidroksida miješa se 24 sata u 120 ml 1,4-dioksana 24 sata pri sobnoj temperaturi. Dioksan se izdestilira, pomiješa se s vodom na ukupni volumen od 300 ml i ekstrahira se s dietil eterom. Vodenu fazu se zakiseli s 3 molarnom, vodenom HC1, kristalizira i profiltrira. Iskorištenje: 11,25 g bijelih kristala (= 95% od teorijskog); talište: 168-169°C. 12.6 g (0.053 mol) of 9-methyl-fluorene-9-carboxylic acid methyl ester and 53 ml of a 2 molar aqueous solution of sodium hydroxide were mixed for 24 hours in 120 ml of 1,4-dioxane for 24 hours at room temperature. Dioxane is distilled off, mixed with water to a total volume of 300 ml and extracted with diethyl ether. The aqueous phase is acidified with 3 molar aqueous HCl, crystallized and filtered. Yield: 11.25 g of white crystals (= 95% of theory); melting point: 168-169°C.
5.2 5.2
9-metil-fluoren-9-karbonska kiselina tropenol ester 4e 6,73 g (0,03 mola) spoja 3b suspendira se u 60 ml diklormetana, pomiješa se s 5,0 g oksalil klorida i l kapi dimetilformamida, zatim se miješa jedan sat pri sobnoj temperaturi i zatim se otapalo izdestilira. Zaostali kiselinski klorid se bez daljnjeg čišćenja upotrebljava u slijedećem stupnju. 9-methyl-fluorene-9-carboxylic acid trophenol ester 4e 6.73 g (0.03 mol) of compound 3b is suspended in 60 ml of dichloromethane, mixed with 5.0 g of oxalyl chloride and 1 drop of dimethylformamide, then stirred for one hour at room temperature and then the solvent is distilled off. The remaining acid chloride is used in the next stage without further cleaning.
4,18 g (0,03 mola) tropenola i 4,27 g (0,033 mola) diizopropiletilamina suspendira se u 100 ml dikloretana, pri 35-40°C dokaplje se kiselinski klorid u 30 ml diklor-etana i zatim se miješa 24 sata pri 40°C. Suspenziju se razrijedi s diklormetanom i ekstrahira se s razrijeđenom solnom kiselinom. Organsku fazu se zatim ispere s vodom, osuši se preko MgSO4 i proizvod se prevede u hidroklorid s otopinom HC1 u dietil eteru. Zatim se odstrani otapalo. Za čišćenje se istaloženi hidroklorid preuzme u vodu i ekstrahira s dietil eterom. Vodenu fazu se namjesti lužnatom s 10%-tnom otopinom natrijevog karbonata i ekstrahira s diklormetanom. Organsku fazu se osuši preko MgSO4 i otapalo se izdestilira. 4.18 g (0.03 mol) of tropenol and 4.27 g (0.033 mol) of diisopropylethylamine are suspended in 100 ml of dichloroethane, at 35-40°C acid chloride is added dropwise in 30 ml of dichloroethane and then stirred for 24 hours at 40°C. The suspension is diluted with dichloromethane and extracted with dilute hydrochloric acid. The organic phase is then washed with water, dried over MgSO4 and the product is converted into the hydrochloride with a solution of HCl in diethyl ether. Then the solvent was removed. For cleaning, the precipitated hydrochloride is taken up in water and extracted with diethyl ether. The aqueous phase is made alkaline with a 10% sodium carbonate solution and extracted with dichloromethane. The organic phase is dried over MgSO4 and the solvent is distilled off.
Iskorištenje: 4,40 g žutog ulja (= 42% od teorijskog). Yield: 4.40 g of yellow oil (= 42% of theoretical).
5.3 5.3
9-metil-fluoren-9-karbonska kiselina tropenol ester metobromid 9-methyl-fluorene-9-carboxylic acid tropenol ester methobromide
1,8 g (0,005 mola) slobodne baze 4e reagira analogno postupku iz stupnja 1.3. Čišćenje se vrši prekristalizacijom iz acetona. 1.8 g (0.005 mol) of free base 4e react analogously to the procedure from step 1.3. Cleaning is done by recrystallization from acetone.
Iskorištenje: 1,80 g bijelih kristala (= 82% od teorijskog); talište: 258-259°C. Yield: 1.80 g of white crystals (= 82% of theory); melting point: 258-259°C.
Elementarna analiza: Elementary analysis:
izračunato: C (65,46) H (5,95) N (3,18) nađeno: C (64,15) H (5,95) N (3,18). calcd: C (65.46) H (5.95) N (3.18) found: C (64.15) H (5.95) N (3.18).
Primjer 6 Example 6
9-metil-fluoren-9-karbonska kiselina skopin ester metobromid 9-methyl-fluorene-9-carboxylic acid scopine ester methobromide
[image] [image]
6.1 6.1
9-metil-fluoren-9-karbonska kiselina skopin ester 4f 9-methyl-fluorene-9-carboxylic acid scopine ester 4f
2,5 g (0,007 mol) tropenol estera 4e reagira s 0,13 g (0,001 mola) vanadijevog(V) oksida i 1,43 g (0,015 mola) H2O2-uree analogno postupku iz stupnja 3.1. 2.5 g (0.007 mol) of trophenol ester 4e is reacted with 0.13 g (0.001 mol) of vanadium(V) oxide and 1.43 g (0.015 mol) of H2O2-urea analogously to the procedure from step 3.1.
Iskorištenje: 1,8 g bijelih kristala (= 71% od teorijskog). Yield: 1.8 g of white crystals (= 71% of theory).
6.2 6.2
9-metil-fluoren-9-karbonska kiselina skopin ester metobromid 9-methyl-fluorene-9-carboxylic acid scopine ester methobromide
1,8 g (0,005 mola) spoja 4f stavi se u 30 ml aceto-nitrila i s 2,848 g (0,015 mola) 50%-tne otopine metil bromida u acetonitrilu reagira analogno stupnju 1.3. Iskorištenje: 1,6 g bijelih kristala (= 70% od teorijskog); talište: 214°C. Elementarna analiza: 1.8 g (0.005 mol) of compound 4f is placed in 30 ml of acetonitrile and reacted analogously to step 1.3 with 2.848 g (0.015 mol) of a 50% solution of methyl bromide in acetonitrile. Yield: 1.6 g of white crystals (= 70% of theoretical); melting point: 214°C. Elementary analysis:
izračunato: C (62,13) H (5,93) N (4,26) calculated: C (62.13) H (5.93) N (4.26)
nađeno: C (62,23) H (6,05) N (4,32). found: C (62.23) H (6.05) N (4.32).
Kako je bilo pronađeno, spojevi formule 1 predstavljaju antagoniste M3 receptora (podtip 3 muskarinskog receptora}. Što se tiče afiniteta prema M3 receptoru, spojevi prema izumu imaju Ki vrijednost manju od 10 nM. Ta vrijednost je utvrđena u skladu s postupkom koji je opisan u nastavku. As it was found, the compounds of the formula 1 are antagonists of the M3 receptor (subtype 3 of the muscarinic receptor}. Regarding the affinity for the M3 receptor, the compounds according to the invention have a Ki value of less than 10 nM. This value was determined in accordance with the procedure described in continuation.
Kemikalije Chemicals
3H-NMS je dobiven od tvrtke Amersham, Braunschweig, sa specifičnom radioaktivnošću od 3071 GBq/mmolu (83 Ci/mmolu). Svi ostali reagenti dobivei su od tvrtke Serva, Heidelberg i Merck, Darmstadt. 3H-NMS was obtained from Amersham, Braunschweig, with a specific radioactivity of 3071 GBq/mmole (83 Ci/mmole). All other reagents were obtained from Serva, Heidelberg and Merck, Darmstadt.
Stanične membrane Cell membranes
Upotrijebljene su stanične membrane CHO stanica (Chinese hamster ovary) koje su bile transficirane s odgovarajućim genima humanih muskarinskih podtipova receptora hml do hm5 (BONNER). Stanične membrane željenog podtipa su otopljene, ponovno suspendirane ručno sa staklenim homogenizatorom i s puferom HEPES su razrijeđene na krajnju koncentraciju od 20-30 mg proteina/ml. Cell membranes of CHO cells (Chinese hamster ovary) transfected with the corresponding genes of human muscarinic receptor subtypes hml to hm5 (BONNER) were used. Cell membranes of the desired subtype were solubilized, resuspended manually with a glass homogenizer, and diluted with HEPES buffer to a final concentration of 20-30 mg protein/ml.
Proučavanje vezanja receptora Study of receptor binding
Pokus vezanja izvršen je u krajnjem volumenu od l ml i 1 sastojao se je iz 100 μl neobilježene tvari u različitim koncentracijama, 100 μl radioliganda (3H-N-metilskopolamin 2 nmola/1 (3H-NMS), 200 μl membranskog pripravka i 600 μl pufera HEPES (20 mmolova/1 HEPES-a, 10 mmolova/1 MgCl2, 100 mmolova/1 Nad, i s l molom/1 NaOH namješteno je na pH 7,4). The binding experiment was performed in a final volume of 1 ml and consisted of 100 μl of unlabeled substance in different concentrations, 100 μl of radioligand (3H-N-methylscopolamine 2 nmole/1 (3H-NMS), 200 μl of membrane preparation and 600 μl of HEPES buffer (20 mmol/l HEPES, 10 mmol/l MgCl2, 100 mmol/l Nad, and with 1 mol/l NaOH adjusted to pH 7.4).
Nespecifično vezanje utvrđeno je s 10 μmola/1 atropina. Non-specific binding was determined with 10 μmol/l atropine.
Inkubacija od 45 min izvršena je pri 37°C u mikro-titarskim pločicama s 96 jamica (Beckman, Polγstirol, br. 267001) kao dvostruko određivanje. Inkubacija je završena filtracijom pomoću Inotech Zellernter (Tip IH 110) preko filtera Whatman G-7. Filteri su isprani s 3 ml ledeno hladnog HEPES-a i osušeni prije mjerenja. Incubation for 45 min was performed at 37°C in 96-well micro-titer plates (Beckman, Polγstyrene, no. 267001) as a duplicate determination. Incubation was completed by filtration using an Inotech Zellernter (Type IH 110) through a Whatman G-7 filter. Filters were washed with 3 ml of ice-cold HEPES and dried before measurement.
Određivanje radioaktivitnosti Determination of radioactivity
Radioaktivnost filterskih hasura mjerenja je istovremeno pomoću dvodimenzionalnog, digitalnog autoradiografa (Berthold, Wildbad, Tip 3052). The radioactivity of the filter particles was measured simultaneously using a two-dimensional, digital autoradiograph (Berthold, Wildbad, Type 3052).
Prikaz rezultata Display of results
Ki vrijednosti izračunate su iz posrednih jednadžbi, koje su izravno izvedene iz zakona učinka mase, s modelom za reakciju za l receptor 2 liganda (programski paket SγsFit, SCHITTKOWSKI). Ki values were calculated from intermediate equations, which were directly derived from the law of mass effect, with a reaction model for l receptor 2 ligand (program package SγsFit, SCHITTKOWSKI).
Literatura Literature
BONNER TI, New suptγpes of muscarinic acetγlcholine receptors, Trends Pharmacol. Sci. 10, Suppl.: 11-15 (1989); SCHITTKOVJSKI K, Parameter estimation in sγstems of nonlinear equations Numer Math. 68: 129-142 (1994). BONNER TI, New suspects of muscarinic acetylcholine receptors, Trends Pharmacol. Sci. 10, Suppl.: 11-15 (1989); SCHITTKOVJSKI K, Parameter estimation in systems of nonlinear equations Numer Math. 68: 129-142 (1994).
Spojevi formule 1 prema izumu odlikuju se višestrukim mogućnostima primjene na području terapije. The compounds of formula 1 according to the invention are characterized by multiple possibilities of application in the field of therapy.
Prema izumu se ističu takove mogućnosti primjene u kojima se spojevi formule 1 prema izumu mogu upotrijebiti zbog njihove farmaceutske učinkovitosti, ponajprije kao antiholinergici. According to the invention, such application possibilities are emphasized in which the compounds of formula 1 according to the invention can be used due to their pharmaceutical effectiveness, primarily as anticholinergics.
To se odnosi, na primjer, na terapiju astme ili COPD-a (chroriic obstructive pulmonari disease = kronična opstrukcijska bolest pluća). Spojevi opće formule 1 mogu se, nadalje, upotrijebiti za liječenje vagalno uzrokovanih sinusnih bradikardija i za liječenje poremećaja srčanog ritma. Općenito, spojevi prema izumu upotrebljavaju se teraputski korisno, nadalje, za liječenje spazmi, na primjer u gastrointestinalnom traktu. Oni se mogu upotrijebiti, nadalje, za liječenje spazmi u putevima za odvođenje urina, kao i na primjer kod menstruacijskih tegoba. This applies, for example, to the treatment of asthma or COPD (chronic obstructive pulmonary disease). The compounds of general formula 1 may further be used for the treatment of vagally induced sinus bradycardia and for the treatment of heart rhythm disorders. In general, the compounds of the invention are used therapeutically advantageously, furthermore, for the treatment of spasms, for example in the gastrointestinal tract. They can also be used to treat spasms in the urinary tract, as well as, for example, menstrual problems.
Od gore navedenih primjera područja indikacija, poseban značaj ima terapija astme i COPD-a pomoću spojeva formule 1 prema izumu. Of the above-mentioned examples of the field of indications, the therapy of asthma and COPD using the compounds of formula 1 according to the invention is of particular importance.
Spojevi opće formule 1 mogu se primijeniti sami ili u kombinaciji s drugim aktivnim tvarima formule 1 prema izumu. The compounds of general formula 1 can be used alone or in combination with other active substances of formula 1 according to the invention.
Prema potrebi, spojevi opće formule 1 mogu se također primijeniti u kombinaciji s daljnjim farmakološki aktivnim tvarima. Pri tome, radi se posebno o betamimeticima, antialergicima, PAF antagonistima, inhibitorima PDE IV, leukotrien antagonistima, inhibitorima p38 kinaze, inhibitorima EGFR kinaze i kortikosteroidima, kao i o kombinacijama tih aktivnih tvari. If necessary, the compounds of general formula 1 can also be used in combination with further pharmacologically active substances. In this, it is especially about betamimetics, antiallergics, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, as well as combinations of these active substances.
Kao primjeri betamimetika, koji se mogu upotrijebiti kao kombinacija sa spojevima formule 1 prema izumu, mogu se navesti spojevi odabrani iz skupine koju čine bambuterol, bitolterol, karbuterol, klenbuterol, fenoterol, formoterol, heksoprenalin, ibuterol, pirbuterol, prokaterol, reproterol, salmeterol, sulfonterol, terbutalin, tolubuterol, 4-hidroksi-7-[2-{[2-{[3-(2-feniletoksi)-propil]sulfonil}etil]-amino}etil]-2(3H)-benzotiazolon, 1-(2-fluor-4-hidroksifenil)-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol, 1-[3-(4-metoksibenzil-amino}-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butil-amino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-N,N-dimetilaminofenil)-2-metil-2-propilamino]-etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-metoksifenil)-2-metil-2-propilamino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butil-oksifenil)-2-metil-propilamino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-{4-[3-(4-metoksifenil)-l,2,4-triazol-3-il]-2-metil-2-butilamino}etanol, 5-hidroksi-8-(1-hidroksi-2-izopropilaminobutil)-2H-1,4-benzoksazin-3-(4H)-on, 1-(4-amino-3-klor-5-trifluormetil-fenikl)-2-terc-butilamino)etanol i 1-(4-etoksikarbonil-amino-3-cijano-5-fluorfenil)-2-(terc-butilamino)etanol, prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera, kao i prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli i hidrata. U kombinaciji sa spojevima formule 1. kao betamimetici se upotrebljavaju posebno povoljno takove aktivne tvari koje su odabrane iz skupine koju čine fenoterol, formoterol, salmeterol, 1-[3-(4-metoksibenzil-amino)-4-hidroksifenil]-2-[4-(1-benzimidazolil)-2-metil-2-butilamino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benz-oksazin-8-il]-2-[3-(4-N,N-di-metilaminofenil)-2-metil-2-propilamino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benz-oksazin-8-il]-2-[3-(4-metoksi-fenil)-2-metil-2-propil-amino]etanol, 1-[2H-5-hidroksi-3-okso-4H-1,4-benzoksazin-8-il]-2-[3-(4-n-butiloksifenil)-2-metil-2-propilamino]etanol, 1-[-2H-5-hidroksi-3-okso-4H-benzoksazin-8-ol]-2-{4-[3-4-metoksifenil)-1,2,4-triazol-3-il]-2-metil-2-butilamino}-etanol, prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera, kao i prema potrebi njihovih farmakološki nedvojbenih kiselinskih adicijskih soli i hidrata. Od prethodno navedenih betamimetika ovdje poseban značaj imaju spojevi formoterol i salmeterol, prema potrebi u obliku njihovih racemata, njihovih enantiomera, njihovih diastereomera, kao i prema potrebi u obliku njihovih farmakološki nedvojbenih kiselinskih adicijskih soli i hidrata. As examples of betamimetics, which can be used in combination with compounds of formula 1 according to the invention, compounds selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulfonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)-propyl]sulfonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino}-4-hydroxyphenyl]-2 -[4-(1-benzimidazolyl)-2-methyl-2-butyl-amino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2- [3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]-ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]- 2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[ 3-(4-n-butyl-oxyphenyl)-2-methyl-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4 -[3-(4-methoxy iphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazine- 3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert-butylamino)ethanol and 1-(4-ethoxycarbonyl-amino-3-cyano-5-fluorophenyl) )-2-(tert-butylamino)ethanol, if necessary in the form of their racemates, their enantiomers, their diastereomers, as well as if necessary their pharmacologically unambiguous acid addition salts and hydrates. In combination with the compounds of formula 1, active substances selected from the group consisting of fenoterol, formoterol, salmeterol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[ 4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benz-oxazin-8-yl]-2-[3 -(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benz-oxazin-8-yl] -2-[3-(4-methoxy-phenyl)-2-methyl-2-propyl-amino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl ]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[-2H-5-hydroxy-3-oxo-4H-benzoxazin-8-ol]-2- {4-[3-4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}-ethanol, as necessary in the form of their racemates, their enantiomers, their diastereomers, as well as according to the need of their pharmacologically unquestionable acid addition salts and hydrates. Of the previously mentioned betamimetics, the compounds formoterol and salmeterol are of special importance here, as necessary in the form of their racemates, their enantiomers, their diastereomers, as well as, if necessary, in the form of their pharmacologically unambiguous acid addition salts and hydrates.
Prema izumu prednost se daje kiselinskim adicijskim solima betamimetika koje su odabrane iz skupine koju čine hidroklorid, hidrobromid, sulfat, fosfat, fumarat, metansulfonat i ksinafoat. U slučaju salmeterola, posebno povoljne su soli odabrane između hidroklorida, sulfata i ksinofoata, od kojih je ksinofoat posebno povoljan. U slučaju formoterola, posebno povoljne su soli odabrane između hidroklorida, sulfata i fumarata, od kojih su posebno povoljni hidroklorid i fumarat. Prema izumu istaknuto značenje ima formoterol fumarat. According to the invention, preference is given to acid addition salts of betamimetics selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate. In the case of salmeterol, particularly preferred salts are selected from the hydrochloride, sulfate and xinofoate, of which xinofoate is particularly preferred. In the case of formoterol, particularly preferred salts are selected from the hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are particularly preferred. According to the invention, formoterol fumarate has a prominent meaning.
U okviru predloženog izuma, pod kortikosteroidima koji se mogu upotrijebiti prema potrebi u kombinaciji sa spojevima formule 1 podrazumijevaju se spojevi odabrani iz skupine koju čine flunizolid, beklometazon, triamikinilon, budenozid, flutikazon, mometazon, ciklezonid, rofleponif, GW 215864, KSR 592, ST-126 i deksametazon. U opsegu predloženog izuma prednost se daje kortikosteroidima odabranim iz skupine koju čine flunizolid, beklometazon, triamkinolon, budenozid, flutikazon, mometazon, ciklezonid i deksametazon, pri čemu se ovdje posebno značenje daje budenozidu, flutikazobu, mometazonu i ciklezonidu, naročito budenozidu i flutikazonu. Prema potrebi, u okviru predložene patentne prijave umjesto naziva kortikosteroida upotrebljava se također i samo naziv steroidi. Within the scope of the proposed invention, corticosteroids that can be used as necessary in combination with compounds of formula 1 are understood to mean compounds selected from the group consisting of flunizolid, beclomethasone, triamiquinilone, budenoside, fluticasone, mometasone, ciclesonide, rofleponif, GW 215864, KSR 592, ST -126 and dexamethasone. Within the scope of the proposed invention, preference is given to corticosteroids selected from the group consisting of flunizolid, beclomethasone, triamquinolone, budenoside, fluticasone, mometasone, ciclesonide and dexamethasone, whereby special meaning is given here to budenoside, fluticasob, mometasone and ciclesonide, especially budenoside and fluticasone. If necessary, in the framework of the proposed patent application, instead of the name corticosteroids, only the name steroids is also used.
Uzimanje u obzir steroida, uključenih u opseg predloženog izuma, uključuje njihove soli ili derivate, koje steroidi mogu tvoriti. Kao moguće soli ili derivati mogu se navesti na primjer: natrijeve soli, sulfobenzoati, fosfati, izonikotinati, acetati, propionati, dihidrogen fosfati, palmitat, pivalato ili furoati. Prema potrebi, kortikosteroidi mogu biti također i u obliku njihovih hidrata. Consideration of steroids included within the scope of the present invention includes salts or derivatives thereof, which the steroids may form. Examples of possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitate, pivalato or furoates. If necessary, corticosteroids can also be in the form of their hydrates.
Kao primjeri PDE-IV inhibitora, koji se prema izumu mogu upotrijebiti sa spojevim formule J. kao kombinacija mogu se navesti spojevi koji su odabrani iz skupine koju čine enprofilin, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591) , V-11294A i AWD-12-281. Ponajprije, PDE-IV inhibitori su odabrani iz skupine koju čine enprofilin, roflumilast, ariflo i AWD-12-281, pri čemu AMD-12-281 kao sudionik kombinacije sa spojevima formule 1. prema izumu ima posebnu prednost. Uzimanje u obzir gore navedenenih PDE-IV inhibitora u opsegu predloženog izuma uključuje prema potrebi i njihove postojeće farmakološki podnošljive kiselinske adicijske soli. Pod fiziološki podnošljivim kiselinskim adicijskim solima koje mogu tvoriti gore navedeni PDE-IV inhibitori, podrazumijevaju se prema izumu farmaceutski podnošljive soli koje su odabrane između soli solne kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline, metansulfonske kiseline, octene kiseline, fumarne kiseline, jantarne kiseline, mliječne kiseline, limunske kiseline, vinske kiseline ili maleinske kiseline. Prema izumu, u tom pogledu prednost se daje solima odabranim iz skupine koju čine acetat, hidroklorid, hidrobromid, sulfat, fosfat i metansulfonat. As examples of PDE-IV inhibitors, which according to the invention can be used with compounds of formula J. as a combination, compounds selected from the group consisting of enprofilin, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 can be mentioned (Sch-351591) , V-11294A and AWD-12-281. First of all, PDE-IV inhibitors are selected from the group consisting of enprofilin, roflumilast, ariflo and AWD-12-281, whereby AMD-12-281 as a participant in the combination with compounds of formula 1 according to the invention has a particular advantage. Consideration of the above-mentioned PDE-IV inhibitors within the scope of the proposed invention includes, as appropriate, their existing pharmacologically tolerable acid addition salts. According to the invention, the physiologically tolerable acid addition salts that can be formed by the above-mentioned PDE-IV inhibitors mean pharmaceutically tolerable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid acid, lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, in this regard, preference is given to salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate.
U opsegu predloženog izuma kao dopamin agonisti koji se prema potrebi mogu upotrijebiti u kombinaciji sa spojevima formule 1, podrazumijevaju se spojevi odabrani iz skupine koju čine bromokriptin, kabergolin, alfa-dihidro-ergokriptin, lisurid, pergolid, pramipeksol, roksindol, ropinirol, talipeksol, tergurid i viozan. Ponajprije, u opsegu predloženog izuma, kao sudionici kombinacije sa spojevima formule 1 upotrebljavaju se dopamin agonisti odabrani iz skupine koju čine pramipeksol, talipeksol i viozan, pri čemu pramipeksol ima posebno značenje. Gore navedeni dopamin agonisti, koji su uzeti u obzir u opsegu predloženog izuma, uključuju prema potrebi i njihove postojeće farmakološki podnošljive kiselinske adicijske soli i prema potrebi njihove hidrate. Pod fiziološki podnošljivim kiselinskim adicijskim solima, koje mogu tvoriti prethodno navedeni dopamin agonisti, podrazumijevaju se, na primjer, farmaceutski podnošljive soli odabrane između soli solne kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline, metan-sulfonske kiseline, octene kiseline, fumarne kiseline, jantarna kiseline, mliječne kiseline, limunske kiseline, vinske kiseline i maleinske kiseline. Within the scope of the proposed invention, dopamine agonists that can be used in combination with compounds of formula 1, if necessary, include compounds selected from the group consisting of bromocriptine, cabergoline, alpha-dihydro-ergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viosan. First of all, within the scope of the proposed invention, dopamine agonists selected from the group consisting of pramipexole, talipexole and viozan are used as participants in the combination with the compounds of formula 1, whereby pramipexole has a special meaning. The above-mentioned dopamine agonists, which are considered within the scope of the present invention, include, as appropriate, their existing pharmacologically tolerable acid addition salts and, as appropriate, their hydrates. Physiologically tolerable acid addition salts, which can be formed by the aforementioned dopamine agonists, are meant, for example, pharmaceutically tolerable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Kao primjeri antialergika koji se prema izumu mogu upotrijebiti u kombinaciji sa spojevima formule 1, mogu se navesti epinastin, cetirizin, azelastin, feksofenadin, levokabastin, loratadir, mizolastin, ketotifen, emedastin, dimetinden, klemastin, bamipin, ceksklorfeniramin, feniramin, doksilamin, klorfenoksamin, dimenhidrinat, difenhidramin, prometazin, ebastin, desloratidin i meklozin. Ponajprije, antialergici koji se u opsegu predloženog izuma mogu upotrijebiti u kombinaciji sa spojevima formule 1 prema izumu odabrani su iz skupine koju čine epinastin, cetirizin, azelastin, feksofenadin,levokabastin, loratadin, ebastin, desloratidin i mizolastin, pri čemu se posebnu prednost daje epinastinu i desloratidinu. Uzimanje u obzir gore navedenih antialergika u opsegu predloženog izuma uključuje prema potrebi i njihove postojeće farmakološki podnošljive kiselnske adicijske soli. As examples of antiallergic drugs that can be used according to the invention in combination with compounds of formula 1, epinastine, cetirizine, azelastine, fexofenadine, levocabastin, loratadir, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine can be mentioned. , dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. First of all, the antiallergic drugs that can be used in the scope of the proposed invention in combination with the compounds of formula 1 according to the invention are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastin, loratadine, ebastine, desloratidine and mizolastine, whereby epinastine is particularly preferred and desloratidine. Consideration of the above-mentioned antiallergic agents in the scope of the proposed invention includes, as necessary, their existing pharmacologically tolerable acid addition salts.
Kao primjeri PAF antagonista, koji se mogu upotrijebiti kao kombinacija sa spojevima formule 1 prema izumu, mogu se navesti 4-(2-klorfenil)-9-metil-2-[3(4-morfolinil)-3-propanon-1-il]-6H-tieno-[3,2-f][1,2,4]-triazolo[4,3-a] [1,4]-diazepin i 6-(2-klorfenil)-8,9-dihidro-1-metil-8-[(4-morfolinil)karbonil]-4H,7H-ciklo-penta-[4,5]tieno-[3,2-f]-[1,2,4]triazolo[4,3-a] [1,4]-diazepin. As examples of PAF antagonists, which can be used in combination with compounds of formula 1 according to the invention, 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl ]-6H-thieno-[3,2-f][1,2,4]-triazolo[4,3-a] [1,4]-diazepine and 6-(2-chlorophenyl)-8,9-dihydro -1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f]-[1,2,4]triazolo[4, 3-a] [1,4]-diazepine.
Kao primjeri inhibitora EGFR kinaze, koji se mogu upotrijebiti u kombinaciji sa spojevima formule 1 prema izumu, mogu se navesti kao posebno povoljni 4-[(3-klor-4-fluor-fenil)aminoj-7-[4-((R)-6-metil-2-okso-morfolin-4-il)-butiloksi]-6-[(vinilkarbonil)amino]-kinazolin, 4-[(3-klor-4-fluor-fenil)amino]-7-[4-((S)-6-metil-2-okso-morfolin-4-il)-butiloksi]-6-[(vinilkarbonil)amino]-kinazolin, 4-[(3-klor-4-fluor-fenil)amino]-7-(2-{4-[(S)-(2okso-tetrahidro-furan-5-il)karbonil]-piperazin-1-il}-etoksi)-6-[(vinilkarbonil)amino]kinazolin, 4-[{3-klor-4-fluor-fenil)amino]-7-[2-((S)-6-metil-2-okso-morfolin-4il)-etoksi]-6-[(vinilkarbonil)amino]-kinazolin, 4-[(3-klor-4-fluorfenil)amino]-6-[(4-{N-[2-(etoksikarbonil)-etil]-N-[(etoksikarbonil)-metil]amino}-1-okso-2-buten-1-il)amino]-7-ciklopropil-metoksi-kinazolin, 4-[(R)-{1-fenil-etil)amino]-6-{[4-(morfolin-4-il)-1-okso-2-buten-1-il]amino}-7-ciklopropil-metoksi-kinazolin i 4-[(3-klor-4-fluorfenil)amino]-6-[3-(morfolin-4-il)-propiloksi]-7-metoksi-kinazolin. Uzimanje u obzir gore navedenih inhibitira EGFR kinaze uključuje u opseg predloženog izuma također i njihove prema potrebi postojeće farmakološki podnošljive kiselinske adicijske soli. Pod fiziološki, odnosno farmakološki podnošljivim kiselinskim adicijskim solima, koje mogu tvoriti inhibitiri EGFR kinaze, podrazumijevaju se prema izumu farmaceutski podnošljive soli koje su odabrane između soli solne kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline, metansulfonske kiseline, octene kiseline, fumarne kiseline, jantarne kiseline, mliječne kiseline, limunske kiseline, vinske kiseline ili maleinske kiseline. Prema izumu, prednost se daje onim solima inhibitora EGFR kinaze koje su odabrane između soli octene kiseline, solne kiseline, bromovodične kiseline, sumporne kiseline, fosforne kiseline i metansulfonske kiseline. As examples of EGFR kinase inhibitors, which can be used in combination with the compounds of formula 1 according to the invention, 4-[(3-chloro-4-fluoro-phenyl)aminoj-7-[4-((R) -6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[ 4-((S)-6-methyl-2-oxo-morpholin-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino]-7-(2-{4-[(S)-(2oxo-tetrahydro-furan-5-yl)carbonyl]-piperazin-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]quinazoline, 4-[{3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholin-4yl)-ethoxy]-6-[(vinylcarbonyl)amino ]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[2-(ethoxycarbonyl)-ethyl]-N-[(ethoxycarbonyl)-methyl]amino}- 1-oxo-2-buten-1-yl)amino]-7-cyclopropyl-methoxy-quinazoline, 4-[(R)-{1-phenyl-ethyl)amino]-6-{[4-(morpholine-4 -yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropyl-methoxy-quinazoline and 4-[(3-chloro-4-fluorophenyl)amino]-6-[3-(morpholine- 4-yl)-propyloxy]-7-methoxy-quinazoline. Consideration of the above-mentioned EGFR kinase inhibitors includes within the scope of the proposed invention also their optionally available pharmacologically tolerable acid addition salts. According to the invention, physiologically or pharmacologically tolerable acid addition salts, which can form EGFR kinase inhibitors, mean pharmaceutically tolerable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, preference is given to those salts of EGFR kinase inhibitors which are selected from salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
Kao primjeri inhibitora p38 kinaze, koji se mogu upotrijebiti u kombinaciji sa spojevima formul 1 prema izumu, mogu se navesti kao posebno povoljni 1-[5-terc-butil-2-p-tolil-2H-pirazol-3-il]-3-[4-(2-morfolin-4-il-etoksi)naftalin-1-il]-urea; 1-[5-terc-butil-2-p-tolil-2H-pirazol-3-il]-3-[4-(2-(1-oksotiomorfolin-4-il}etoksi)-naftalin-1-il]-urea; 1-[5-terc-butil-2-(2-metilpiridin-5-il)-2H-pirazol-3-il]-3-[4-(2-piridin-4-il-etoksi)naftalin-1-il]-urea; 1-[5-terc-butil-2-(2-metoksipiridin-5-il)-2H-pirazol-3-il]-3-[4-(2-morfolin-4-il-etoksi)naftalin-1-il]-urea ili 1-[5-terc-butil-2-metil-2H-pirazol-3-il]-3-[4-(2-morfolin-4-il-etoksi)naftalen-1-il]-urea. Uzimanje u obzir gore navedenih inhibitora p38 kinaze uključenih u opseg predloženog izuma uključuje i prema potrebi njihove postojeće farmakološki podnošljive kiselinske adicijske soli. Pod fiziološki, odnosno farmakološki podnošljivim kiselinskim adicijskim solima koje mogu tvoriti inhibitori p38 kinaze, podrazumijevaju se prema izumu farmaceutski podnošljive soli koje su odabrane između soli solne kiseline, bromovodične kiselina, sumporne kiseline, fosforne kiselina, metansulfonske kiseline, octene kiseline, fumarne kiseline, jantarne kiseline, mliječne kiseline, limunske kiseline, vinske kiseline ili maleinske kiseline. As examples of p38 kinase inhibitors, which can be used in combination with the compounds of formula 1 according to the invention, 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3 -[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]-urea; 1-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(1-oxothiomorpholin-4-yl}ethoxy)-naphthalen-1-yl] -urea; 1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalene -1-yl]-urea; 1-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4- yl-ethoxy)naphthalen-1-yl]-urea or 1-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy )naphthalen-1-yl]-urea. Consideration of the above-mentioned p38 kinase inhibitors included in the scope of the proposed invention also includes, if necessary, their existing pharmacologically tolerable acid addition salts. Under physiologically or pharmacologically tolerable acid addition salts that can be formed by p38 kinase inhibitors , are understood according to the invention to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid ine, tartaric acid or maleic acid.
Ako se spojevi formule 1 upotrebljavaju u kombinaciji s drugim aktivnim tvarima, od gore navedenih razreda spojeva posebnu prednost daje se kombinaciji sa steroidima, PDE IV inhibitorima ili betamimeticima. Pri tome, kombinacija s betamimeticima, naročito s betamimeticima dugotrajnog djelovanja ima posebno značenje. Kao posebno povoljna smatra se kombinacija spojeva formule 1 prema izumu sa salmeterolom ili formoterolom. If the compounds of formula 1 are used in combination with other active substances, of the above-mentioned classes of compounds, particular preference is given to the combination with steroids, PDE IV inhibitors or betamimetics. At the same time, the combination with betamimetics, especially long-acting betamimetics, has a special significance. The combination of the compounds of formula 1 according to the invention with salmeterol or formoterol is considered particularly advantageous.
Prikladni primjenski oblici za aplikaciju spojeva formule 1 jesu, na primjer, tablete, kapsule, čepići, otopine, itd. Suitable application forms for the application of the compounds of formula 1 are, for example, tablets, capsules, suppositories, solutions, etc.
Prema izumu posebno značenje daje se (posebno kod liječenja astme ili COPD-a) inhalacijskoj aplikaciji spojeva prema izumu. Udio farmaceutski učinkovitog spoja (spojeva) mora biti u svakom slučaju u području od 0,05 do 90 mas. %, ponajprije 0,1 do 50 mas. % od ukupnog sastava. Odgovarajuće tablete mogu se dobiti, na primjer, miješanjem jedne ili više aktivnih tvari s poznatim pomoćnim tvarima, na primjer s inertnim sredstvima za razrjeđivanje, kao što su kalcijev karbonat, kalcijev fosfat ili mliječni šećer, sredstva za rastvaranje kao što su kukuruzni škrob ili alginska kiselina, veziva kao škrob ili želatina, klizna sredstva kao magnezijev stearat ili talk, i/ili sredstva za postizanje depot efekta kao karboksimetilceluloza, celulozni acetat ftalat, ili polivinil acetat. Tablete se također mogu sastojati iz više slojeva. According to the invention, special significance is given (especially in the treatment of asthma or COPD) to the inhalation application of the compounds according to the invention. The proportion of pharmaceutically effective compound(s) must in any case be in the range of 0.05 to 90 wt. %, preferably 0.1 to 50 wt. % of the total composition. Suitable tablets can be obtained, for example, by mixing one or more active substances with known excipients, for example with inert diluents such as calcium carbonate, calcium phosphate or milk sugar, dissolving agents such as corn starch or alginate acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc, and/or depot effect agents such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets can also consist of multiple layers.
Odgovarajuće se mogu proizvesti dražeje prevlačenjem jezgri, proizvedenih analogno tabletama, s uobičajenim sredstvima koja se upotrebljavaju za prevlačenje dražeja, kao što su na primjer kolidon ili šelak, guma arabika, talk, titanov dioksid ili šećer. Za postizanje depot efekta ili za izbjegavanje inkompatibilnosti, jezgre se mogu također sastojati iz više slojeva. Također za postizanje depot efekta, čahure za dražeje se mogu sastojati iz više slojeva, pri čemu se mogu upotrijebiti pomoćne tvari koje su gore spomenute kod tableta. Dragees can suitably be produced by coating cores, produced analogously to tablets, with the usual means used for coating dragees, such as for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibility, cores can also consist of multiple layers. Also in order to achieve a depot effect, capsules for dragees can consist of several layers, whereby the excipients mentioned above for tablets can be used.
Sokovi aktivnih tvari prema izumu, odnosno kombinacija aktivnih tvari, mogu dodatno sadržavati sladila kao saharin, ciklamat, glicerin ili šećer, kao i sredstva za poboljšavanje okusa, npr. aromatične tvari kao vaniliju ili ekstrakt naranče. Osim toga, oni mogu sadržavati i pomoćna sredstva za suspendiranje ili zgušnjavanje, kao natrij karboksimetilcelulozu, kvasila, na primjer proizvode kondenzacije masnih alkohola i etilenoksida, ili konzervanse kao p-hidroksibenzoat. Juices of active substances according to the invention, or a combination of active substances, may additionally contain sweeteners such as saccharin, cyclamate, glycerin or sugar, as well as agents for improving taste, for example aromatic substances such as vanilla or orange extract. In addition, they may also contain auxiliaries for suspending or thickening, such as sodium carboxymethylcellulose, leavening agents, for example condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoate.
Otopine se mogu proizvesti na uobičajen način, npr. uz dodatak izotonanata, konzervansa, kao p-hidroksibenzoata, ili stabilizatora, kao alkalijskih soli etilendiamin-tetraoctene kiseline, prema potrebi uz upotrebu emulgatora i/ili disperzanata, pri čemu se, na primjer pri upotrebi vode kao sredstva za razređivanje, prema potrebi mogu upotrijebiti i organska otapala kao sredstva za pospješivanje otapanja, odnosno kao pomoćna otapala, i pune se u bočice za injekcije ili u ampule ili u boce za infuziju. Solutions can be produced in the usual way, e.g. with the addition of isotonants, preservatives, such as p-hydroxybenzoate, or stabilizers, such as alkaline salts of ethylenediamine-tetraacetic acid, if necessary with the use of emulsifiers and/or dispersants, whereby, for example, when using water as diluents, if necessary, organic solvents can also be used as means to promote dissolution, i.e. as auxiliary solvents, and are filled into vials for injections or ampoules or infusion bottles.
Kapsule koje sadrže jednu ili više aktivnih tvari, odnosno kombinaciju aktivnih tvari, mogu se proizvesti na primjer tako da se aktivne tvari pomiješaju s inertnim nosačima, kao što je mliječni šećer ili sorbit, i kapsuliraju se u želatinske kapsule. Capsules containing one or more active substances, or a combination of active substances, can be produced, for example, by mixing the active substances with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.
Prikladni čepići mogu se proizvesti/ na primjer, miješanjem s nosačima predviđenim za tu svrhu, kao što su neutralne masti ili polietilenglikol, odnosno s njihovim derivatima. Suitable suppositories can be produced/ for example, by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol, or with their derivatives.
Kao pomoćne tvari mogu se spomenuti, na primjer voda, farmaceutski nedvojbena organska otapala, kao parafin (npr. frakcije nafte), ulje biljnog porijekla (npr. kikirikijevo ili sezamovo ulje), monovalentni polivalentni alkoholi (npr. etanol ili glicerin), nosači kao npr. prirodno kameno brašno (npr. kaolin, ilovača, talk, kreda) sintetičko brašno (npr. visoko dispergirana silicijeva kiselina i silikati), šećer (npr. od šećerne trske, mliječni ili grožđani), emulgatori (npr. lignin, sufitni saponifikati, metilceluloza, škrob i polivinilpirolidon) i klizna sredstva (npr. magnezijev stearat, talk, stearinska kiselina i natrijev laurilsulfat). Excipients can be mentioned, for example, water, pharmaceutically acceptable organic solvents, such as paraffin (e.g. petroleum fractions), vegetable oil (e.g. peanut or sesame oil), monovalent polyvalent alcohols (e.g. ethanol or glycerin), carriers such as e.g. natural stone flour (e.g. kaolin, loam, talc, chalk) synthetic flour (e.g. highly dispersed silicic acid and silicates), sugar (e.g. sugar cane, milk or grape), emulsifiers (e.g. lignin, suffite saponifiers , methylcellulose, starch and polyvinylpyrrolidone) and glidants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).
U slučaju oralnog davanje, osim navedenenih nosača tablete mogu naravno sadržavati također i dodatke kao npr. natrijev citrat, kalcijev karbonat i dikalcijev fosfat, zajedno s različitim dodatnim tvarima kao što je škrob, ponajprije krumpirov škrob, želatina i slično. Nadalje, za tabletiranje se mogu upotrijebiti klizna sredstva kao magnezijev stearat, natrijev laurilsulfat i talk. U slučaju vodenih suspenzija, osim s gore navedenim pomoćnim tvarima, aktivne tvari se mogu pomiješati s različitim sredstvima za poboljšanje okusa ili s bojilima. In the case of oral administration, apart from the stated carriers, the tablets may of course also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances such as starch, primarily potato starch, gelatin and the like. Furthermore, glidants such as magnesium stearate, sodium lauryl sulfate and talc can be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active substances can be mixed with different flavor enhancers or with colorants.
Pri aplikaciji spojeva formule 1, ponajprije za terapiju astme ili COPD-a, upotrebljavaju se posebno povoljno inhalacijski oblici za davanje, odnosno farmaceutske formulacije koje se mogu aplicirati inhalacijom. When applying the compounds of formula 1, primarily for the treatment of asthma or COPD, inhalation forms for administration, i.e. pharmaceutical formulations that can be administered by inhalation, are especially advantageously used.
Kao inhalacijski oblici za davanje u obzir dolazi inhalacijski prah, aerosoli za doziranje koji sadrže potisni plin ili inhalacijske otopine bez potisnog plina. U opsegu predloženog izuma s pojmom inhalacijske otopine bez potisnog plina obuhvaćeni su također i koncentrati ili sterilne otopine gotove za upotrebu. Oblici za davanje koji se mogu upotrijebiti u okviru predloženog izuma opisat će se s više pojedinosti u slijedećem dijelu opisa. As inhalation forms to be considered are inhalation powders, dosing aerosols containing propellant gas or inhalation solutions without propellant gas. In the scope of the proposed invention, the term inhalation solution without propellant gas also includes concentrates or sterile solutions ready for use. Administration forms that can be used within the scope of the proposed invention will be described in more detail in the following part of the description.
Inhalacijski prah, koji se može upotrijebiti prema predloženom izumu, može sadržavati samo spoj 1 ili spoj 1 u mješavini s prikladnim fiziološki nedvojbenim pomoćnim tvarima. Ako je aktivna tvar 1 sadržana u mješavini s fiziološki nedvojenim pomoćnim tvarima, za pripravu tog inhalacijskog praha prema izumu mogu se upotrijebiti slijedeće fiziološki nedvojbene pomoćne tvari: monosaharidi (npr. glukoza ili arabinoza), disaharidi (npr. laktoza, saharoza, maltoza) , oligo- i polisaharidi (npr. dekstran), polialkoholi (npr. sorbit, manit, ksilit), soli (npr. natrijev klorid, kalcijev karbonat) ili međusobne mješavine tih pomoćnih tvari. Ponajprije se upotrebljavaju mono- ili disaharidi, pri čemu se prednost daje upotrebi laktoze ili glukoze, posebno, ali ne isključivo u obliku njezinog hidrata. Kao posebno povoljnom pomoćnom sredstvu u smislu izuma, najveću prednost daje se upotrebi laktoze mono-hidrata. The inhalation powder, which can be used according to the proposed invention, can contain compound 1 alone or compound 1 in admixture with suitable physiologically unquestionable excipients. If the active substance 1 is contained in a mixture with physiologically unambiguous auxiliary substances, the following physiologically unambiguous auxiliary substances can be used for the preparation of this inhalation powder according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (eg dextran), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mutual mixtures of these excipients. Primarily, mono- or disaccharides are used, with preference being given to the use of lactose or glucose, especially, but not exclusively, in the form of its hydrate. As a particularly favorable auxiliary agent in terms of the invention, the greatest preference is given to the use of lactose monohydrate.
U okviru izuma pomoćne tvari za inhalacijski prah imaju maksimalnu srednju veličinu čestica do 250 μm, ponajprije između 10 i 150 μm, posebno povoljno između 15 i 80 μm. Prema potrebi, može se pokazati smislenim da se umiješaju gore navedene pomoćne tvari s frakcijama pomoćnih tvari sitnijih čestica sa srednjom veličinom čestica od 1 do 9 μm. Potonje navedene sitnije pomoćne tvari su također odabrane iz gore navedene skupine upotrebljivih pomoćnih tvari. Konačno, za pripravu inhalcijskog praha prema izumu u mješavinu pomoćnih tvari može se umiješati mikroniziranu aktivnu tvar _!, ponajprije sa srednjom veličinom čestica od 0,5 do 10 μm, posebno povoljno od 1 do 5 μm. Postupci za pripravu inhalacijskog praha prema izumu mljevenjem i mikronizacijom, kao i završnim miješanjem sastojaka su poznati iz stannja tehnike. Inhalacijski prah prema izumu može se aplicirati pomoću inhalatora koji su poznati iz stanja tehnike. In the context of the invention, excipients for inhalation powder have a maximum mean particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If necessary, it may prove meaningful to mix the above excipients with fractions of excipients of finer particles with an average particle size of 1 to 9 μm. The latter mentioned finer excipients are also selected from the above-mentioned group of usable excipients. Finally, for the preparation of the inhalation powder according to the invention, a micronized active substance can be mixed into the mixture of excipients, preferably with an average particle size of 0.5 to 10 μm, especially preferably from 1 to 5 μm. Procedures for the preparation of the inhalation powder according to the invention by grinding and micronization, as well as the final mixing of the ingredients, are known from the state of the art. The inhalation powder according to the invention can be applied using inhalers known from the state of the art.
Inhalacijski aerosol koji sadrži potisni plin može sadržavati spoj 1 prema izumu otopljen u potisnom plinu ili u dispergiranom obliku. Pri tome, spoj 1 može biti sadržan u odvojenom obliku za davanje ili u zajedničkom obliku za davanje, pri čemu se spoj otapa u obojem, ili se u obojem dispergira ili samo jedna komponenta može biti prisutna otopljena, a druga može biti sadržana dispergirana. An inhalation aerosol containing a propellant gas may contain compound 1 according to the invention dissolved in the propellant gas or in dispersed form. Here, compound 1 can be contained in a separate form for administration or in a common form for administration, whereby the compound dissolves in both, or is dispersed in both, or only one component can be present dissolved, and the other can be contained dispersed.
Potisni plinovi koji se mogu upotrijebiti za pripravu inhalacijskog aerosola su poznati iz stanja tehnike. Prikladni potisni plinovi su odabrani iz skupine koju čine ugljikovodici kao n-propan, n-butan ili izobutan i halogenirani ugljikovodici kao fluorirani derivati metana, etana, propana, butana, ciklopropana ili ciklobutana. Pri tome, gore navedeni potisni plinovi mogu se upotrijebiti sami ili u međusobnim mješavinama. Posebno povoljni potisni plinovi su halogenirani derivati alkana odabrani između TG134a i TG227 i njihove mješavine. Propellant gases that can be used to prepare an inhalation aerosol are known from the state of the art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. In doing so, the above-mentioned propellant gases can be used alone or in mutual mixtures. Particularly favorable propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and their mixtures.
Inhalacijski aerosoli koji sadrže potisni plin mogu, nadalje, sadržavati i daljnje sastojke kao što su ko-otapala, stabilizatori, površinski aktivna sredstva (surfaktanti), antioksidanti, klizna sredstva kao i sredstva za namještanje pH vrijednosti. Svi ti sastojci su poznati iz stanja tehnike. Inhalation aerosols containing propellant gas may also contain additional ingredients such as co-solvents, stabilizers, surface active agents (surfactants), antioxidants, sliding agents as well as agents for adjusting the pH value. All these ingredients are known from the state of the art.
Gore navedeni inhalacijski aerosoli koji sadrže potisni plin mogu se aplicirati pomoću inhalatora koji su poznati iz stanja tehnike (MDIs - metered dose inhalers). The above-mentioned inhalation aerosols containing propellant gas can be applied using inhalers known from the state of the art (MDIs - metered dose inhalers).
Nadalje, moguća je aplikacija aktivne tvari 1 prema izumu u obliku inhalacijskih otopina i inhalacijskih suspenzija bez potisnog plina. Ovdje kao otapala dolaze u obzir vodene ili alkoholne, ponajprije etanolne otopine. Otapalo može biti samo voda ili mješavina vode i etanola. Relativan udio etanola prema vodi nije ograničen, ali je maksimalna granica ponajprije ipak pri do 70 volumnih postotaka, posebno pri do 60 volumnih postotaka, a posebno povoljno do 30 volumnih postotaka. Preostali volumni postoci nadopunjuju se s vodom. Otopine ili suspenzije koje sadrže spoj i namještaju se s prikladnim kiselinama na pH vrijednost 2 do 7, ponajprije od 2 do 5. Za namještanje pH vrijednosti mogu se upotrijebiti kiseline odabrane između anorganskih ili organskih kiselina. Primjeri posebno prikladnih anorganskih kiselina jesu solna kiselina, bromo-vodična kiselina, dušična kiselina, sumporna kiselina i/ili fosforna kiselina. Primjeri posebno prikladnih organskih kiselina jesu askorbinska kiselina, limunska kiselina, jabučna kiselina, vinska kiselina, maleinska kiselina, jantarna kiselina, fumarna kiselina, octena kiselina, mravlja kiselina i/ili propionska kiselina i druge. Anorganske kiseline kojima se daje prednost jesu solna kiselina i sumporna kiselina. Furthermore, it is possible to apply the active substance 1 according to the invention in the form of inhalation solutions and inhalation suspensions without propellant gas. Here, aqueous or alcoholic, preferably ethanolic solutions come into play as solvents. The solvent can be only water or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, especially up to 60% by volume, and especially preferably up to 30% by volume. The remaining volume percentages are supplemented with water. Solutions or suspensions containing the compound are adjusted with suitable acids to a pH value of 2 to 7, preferably from 2 to 5. Acids selected from inorganic or organic acids can be used to adjust the pH value. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others. Preferred inorganic acids are hydrochloric acid and sulfuric acid.
Također se mogu upotrijebiti i kiseline koje s aktivnom tvari već tvore kiselinske adicijske soli. Među organskim kiselinama prednost se daje askorbinskoj kiselini, fumarnoj kiselini i limunskoj kiselini. Prema potrebi također se mogu upotrijebiti i mješavine navedenih kiselina, posebno u slučaju da kiselina, osim njezinih kiselih svojstava ima i neka druga svojstva, npr. kao tvar za okus, antioksidant ili sredstvo za tvorbu kompleksa, kao na primjer limunska kiselina ili askorbinska kiselina. Za namještanje pH vrijednosti prema izumu se posebno povoljno upotrebljava solna kiselina. You can also use acids that already form acid addition salts with the active substance. Among the organic acids, preference is given to ascorbic acid, fumaric acid and citric acid. If necessary, mixtures of the mentioned acids can also be used, especially if the acid has other properties besides its acidic properties, for example as a flavoring agent, antioxidant or complex forming agent, such as citric acid or ascorbic acid. Hydrochloric acid is especially advantageously used to adjust the pH value according to the invention.
U ovim formulacijama može se prema potrebi izostaviti dodatak editinske kiseline (EDTA) ili neke njezine poznate soli, natrijevog edetata, kao stabilizatora ili sredstva za tvorbu kompleksa. Drugi izvedbeni oblici sadrže ovaj spoj (spojeve). U takovom povoljnom izvedbenom obliku sadržaj natrijevog edetata je ispod 100 mg/100 ml, ponajprije ispod 50 mg/100 ml, posebno povoljno ispod 20 mg/100 ml. Općenito, takove inhalacijske otopine sadrže ponajprije 0 do 10 mg/100 ml natrijevog edetata. In these formulations, the addition of editic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complex forming agent, can be omitted if necessary. Other embodiments contain this compound(s). In such an advantageous embodiment, the content of sodium edetate is below 100 mg/100 ml, preferably below 50 mg/100 ml, particularly preferably below 20 mg/100 ml. In general, such inhalation solutions preferably contain 0 to 10 mg/100 ml sodium edetate.
Inhalcijskim otopinama bez potisnog plina mogu se dodati ko-otapala i/ili daljnje pomoćne tvari. Povoljna ko-otapala su ona koja sadrže hidroksilne skupine ili druge polarne skupine, na primjer alkoholi, posebno izopropilni alkohol, glikoli, posebno propilenglikol, polietilenglikol, polipropilenglikol, glikol eter, glicerol, polioksi-etilenalkoholi i esteri polioksietilen-masnih kiselina. Co-solvents and/or further excipients can be added to inhalation solutions without propellant gas. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
U ovom smislu kao pomoćna i dodatna tvar podrazumijeva se svaka farmakološki podnošljiva tvar koja nije aktivna tvar, ali koja se zajedno s aktivnnom tvari (tvarima) može formulirati u farmakološki prikladnom otapalu da bi se poboljšalo kvalitetu formulacije aktivne tvari. U smislu ciljane terapije, te tvari ponajprije nemaju nikakvog značajnog ili u najmanju ruku nemaju nikakvog neželjenog farmakološkog učinka. U pomoćne i dodatne tvari ubrajaju se npr. površinski aktivne tvari, kao npr. soja lecitin, uljna kiselina, sorbitan esteri, kao polisorbati, polivinil-pirolidon i drugi stabilizatori, sredstva za tvorbu kompleksa, antioksidanti i/ili konzervansi, koji omogućuju ili produljuju vijek upotrebe gotove formulacije lijeka, tvari za korekciju okusa, vitamini i/ili drugi dodaci poznati iz stanja tehnike. In this sense, auxiliary and additional substance means any pharmacologically tolerable substance that is not an active substance, but which together with the active substance (substances) can be formulated in a pharmacologically suitable solvent in order to improve the quality of the formulation of the active substance. In terms of targeted therapy, these substances first of all do not have any significant or at least no unwanted pharmacological effect. Auxiliary and additional substances include, for example, surface-active substances, such as soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinyl-pyrrolidone and other stabilizers, agents for the formation of complexes, antioxidants and/or preservatives, which enable or prolong the shelf life of the finished formulation of the drug, substances for taste correction, vitamins and/or other additives known from the state of the art.
U dodatne tvari ubrajaju se također i farmakološki nedvojbene soli, kao na primjer natrijev klorid, kao izotonanti. Additives also include pharmacologically unambiguous salts, such as sodium chloride, as isotonants.
U pomoćne tvari kojima se daje prednost ubrajaju se antioksidanti, kao na primjer askorbinska kiselina, ako ona već nije upotrijebljena za namještanje pH vrijednosti, vitamin A, vitamin E, tokoferol i slični vitamini ili provitamini, koji se pojavljuju u ljudskom organizmu. Preferred auxiliary substances include antioxidants, such as ascorbic acid, if it is not already used to adjust the pH value, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins, which occur in the human body.
Konzervansi se mogu upotrijebiti da bi se formulaciju zaštitilo od kontaminacije s klicama. Kao konzervansi prikladni su oni koji su poznati iz stanja tehnike, posebno cetilpiridinijev klorid, benzalkonijev klorid ili benzojeva kiselina, odnosno benzoati kao natrijev benzoat koncentracije koja je poznata iz stanja tehnike. Gore navedeni konzervansi sadržani su ponajprije koncentracijama do 50 mg/100 ml, posebno povoljno između 5 i 20 mg/100 ml. Preservatives can be used to protect the formulation from germ contamination. Suitable preservatives are those known from the state of the art, especially cetylpyridinium chloride, benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate of a concentration known from the state of the art. The above-mentioned preservatives are preferably contained in concentrations of up to 50 mg/100 ml, particularly preferably between 5 and 20 mg/100 ml.
Formulacije kojima se daje prednost osim vode kao otapala i ektivne tvari 1 sadrže samo još benzalkonijev klorid i natrijev edetat. In addition to water as solvent and active ingredient 1, preferred formulations contain only benzalkonium chloride and sodium edetate.
U obliku izvedbe kojoj se daje prednost natrijev edetat je izostavljen. In a preferred embodiment sodium edetate is omitted.
Doziranje spojeva prema izumu jako ovisi naravno o načinu aplikacije i o bolesti koju se liječi. Kod inhalacijske aplikacije spojevi formule i odlikuju se visokom učinkovitošću već pri dozama u području μg. Spojevi formule 1 mogu se također smisleno upotrijebiti i u području iznad μg. Tada doziranje može također biti na primjer i u području grama. Posebno, kod ne-inhalacijske aplikacije spojevi prema izumu mogu se aplicirati s višim doziranjem (na primjer, ali bez ograničenja, u području od 1 do 1000 mg). The dosage of the compounds according to the invention depends, of course, on the method of application and on the disease being treated. For inhalation application, the compounds of formula i are characterized by high efficiency even at doses in the μg range. The compounds of formula 1 can also be usefully used in the range above μg. Then the dosage can also be in the range of grams, for example. In particular, for non-inhalational application, the compounds according to the invention can be administered at a higher dosage (for example, but without limitation, in the range of 1 to 1000 mg).
Slijedeći primjeri formulacija prikazuju predloženi izum koji se međutim ne ograničava na njihov opseg. The following examples of formulations illustrate the proposed invention, but are not limited to their scope.
Primjeri farmaceutskih formulacija Examples of pharmaceutical formulations
A) Tablete A) Tablets
1 tableta sadrži: 1 tablet contains:
aktivna tvar 1 100 mg active substance 1 100 mg
mliječni šećer 140 mg milk sugar 140 mg
kukuruzni škrob 240 mg corn starch 240 mg
polivinilpirolidon 15 mg polyvinylpyrrolidone 15 mg
magnezijev stearat 5 mg magnesium stearate 5 mg
Međusobno se pomiješa 500 mg fino samljevene aktivne tvari, mliječni šećer i dio kukuruznog škroba. Smjesu se prosije, zatim se navlaži s otopinom polivinilpirolidona u vodi, prognječi se, mokro se granulira i osuši. Granulat, ostatak kukuruznog škroba i magnezijev stearat se prosiju i međusobno pomiješaju. Smjesu se ispreša u tablete odgovarajućeg oblika i veličine. 500 mg of finely ground active substance, milk sugar and part of corn starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granulate, the rest of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is pressed into tablets of the appropriate shape and size.
B) Tablete B) Tablets
1 tableta sadrži: 1 tablet contains:
aktivna tvar 1 80 mg active substance 1 80 mg
mliječni šećer 55 mg milk sugar 55 mg
kukuruzni škrob 190 mg corn starch 190 mg
mikrokristalinična celuloza 35 mg microcrystalline cellulose 35 mg
polivinilpirolidon 15 mg polyvinylpyrrolidone 15 mg
natrijev karboksimetil škrob 23 mg sodium carboxymethyl starch 23 mg
magnezijev stearat 2 mg magnesium stearate 2 mg
Međusobno se pomiješa 400 mg fino samljevene aktivne tvari, dio kukuruznog škroba, mliječni šećer, mikrokristalinična celuloza i polivinilpirolidon, smjesu se prosije i s ostatkom kukuruznog škroba i vode se preradi u granulat koji se osuši i prosije. K tome se doda natrijev karboksimetil škrob i magnezijev stearat, pomiješa se i ispreša u tablete odgovarajućeg oblika i veličine. 400 mg of finely ground active substance, part of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and with the rest of corn starch and water it is processed into a granulate that is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this, mixed and crushed into tablets of the appropriate shape and size.
C) Otopina za ampule C) Solution for ampoules
aktivna tvar 1 50 mg active substance 1 50 mg
natrijev klorid 50 mg sodium chloride 50 mg
voda za injekcije 5 ml water for injections 5 ml
Aktivnu tvar se otopi u vodi pri vlastom pH ili prema potrebi pri pH 5,5 do 6,5 i pomiješa se s natrijevim kloridom kao izotonantom. Dobivenu otopinu se profiltrira bez pirogena i filtrat se puni u ampule pod aseptičkim uvjetima. Zatim se ampule steriliziraju i zatale. Ampule sadrže po 5 mg, 25 mg i 50 mg aktivne tvari. The active substance is dissolved in water at its own pH or, as needed, at pH 5.5 to 6.5 and mixed with sodium chloride as an isotonant. The resulting solution is filtered without pyrogen and the filtrate is filled into ampoules under aseptic conditions. Then the ampoules are sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg of active substance each.
D) Aerosol za doziranje D) Aerosol for dosing
aktivna tvar 1 0,005 active substance 1 0.005
sorbitan trioleat 0,1 sorbitan trioleate 0.1
monofluortriklormetan i difluordiklormetan 2:3 do 100 monofluorotrichloromethane and difluorodichloromethane 2:3 to 100
Suspenziju se puni u uobičajene spremnike za aerosol s ventilom za doziranje. S jednim aktiviranjem izlazi ponajprije 50 μl suspenzije. Aktivna tvar se po želji može također dozirati i većom količinom (npr. 0,02 mas. %). The suspension is filled in conventional aerosol containers with a dosing valve. With one activation, at least 50 μl of suspension comes out. If desired, the active substance can also be dosed in a larger amount (e.g. 0.02 wt. %).
E) Otopine (u mg/100 ml) E) Solutions (in mg/100 ml)
Aktivna tvar 1 333,3 mg Active substance 1,333.3 mg
formoterol fumarat 333,3 mg formoterol fumarate 333.3 mg
benzalkonijev klorid 10,0 mg benzalkonium chloride 10.0 mg
EDTA 50,0 mg EDTA 50.0 mg
HCl (1 n) do pH 3,4 HCl (1 N) to pH 3.4
Ovu otopinu se može pripraviti na uobičajen način. This solution can be prepared in the usual way.
F) Prah za inhalaciju F) Powder for inhalation
Aktivna tvar 1 6 μg Active substance 1 6 μg
Formoterol fumarat 6 μg Formoterol fumarate 6 μg
Laktoza monohidrat do 25 mg Lactose monohydrate up to 25 mg
Priprava inhalcijskog praha vrši se na uobičajen način miješanjem pojedinačnih sastojaka. The inhalation powder is prepared in the usual way by mixing the individual ingredients.
G) Prah za inhalaciju G) Powder for inhalation
Aktivna tvar 110 μg Active substance 110 μg
Laktoza monohidrat do 5 mg Lactose monohydrate up to 5 mg
Priprava inhalcijskog praha vrši se na uobičajen način miješanjem pojedinačnih sastojaka. The inhalation powder is prepared in the usual way by mixing the individual ingredients.
Claims (12)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10203741A DE10203741A1 (en) | 2002-01-31 | 2002-01-31 | New fluorene carboxylic acid esters, process for their preparation and their use as medicaments |
PCT/EP2003/000534 WO2003064419A1 (en) | 2002-01-31 | 2003-01-21 | Novel fluorene carboxylic acid esters, methods for the production thereof, and use of the same as pharmaceuticals |
Publications (2)
Publication Number | Publication Date |
---|---|
HRP20040690A2 true HRP20040690A2 (en) | 2005-10-31 |
HRP20040690B1 HRP20040690B1 (en) | 2012-09-30 |
Family
ID=27588159
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HRP20040690AA HRP20040690B1 (en) | 2002-01-31 | 2004-07-29 | Novel fluorene carboxylic acid esters, methods for the production thereof, and use of the same as pharmaceuticals |
Country Status (29)
Country | Link |
---|---|
EP (2) | EP1561751A1 (en) |
JP (1) | JP4484522B2 (en) |
KR (1) | KR100950869B1 (en) |
CN (1) | CN100348598C (en) |
AR (1) | AR038379A1 (en) |
AT (1) | ATE299880T1 (en) |
AU (1) | AU2003210172C1 (en) |
BR (1) | BR0307294A (en) |
CA (1) | CA2472149C (en) |
DE (2) | DE10203741A1 (en) |
EA (1) | EA006966B1 (en) |
EC (1) | ECSP045209A (en) |
ES (1) | ES2245443T3 (en) |
HK (1) | HK1082376A1 (en) |
HR (1) | HRP20040690B1 (en) |
IL (1) | IL162527A0 (en) |
ME (1) | MEP43408A (en) |
MX (1) | MXPA04007245A (en) |
MY (1) | MY134582A (en) |
NO (1) | NO328929B1 (en) |
NZ (1) | NZ534784A (en) |
PE (1) | PE20031029A1 (en) |
PL (1) | PL209037B1 (en) |
PT (1) | PT1472251E (en) |
RS (1) | RS50918B (en) |
TW (1) | TWI352077B (en) |
UA (1) | UA78544C2 (en) |
UY (1) | UY27633A1 (en) |
WO (1) | WO2003064419A1 (en) |
Families Citing this family (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2316996T3 (en) * | 2003-07-28 | 2009-04-16 | Boehringer Ingelheim International Gmbh | MEDICINES FOR INHALATION, UNDERSTANDING BETAMIMETICS AND AN ANTI-POLINERGIC AGENT. |
WO2005013967A1 (en) * | 2003-07-28 | 2005-02-17 | Boehringer Ingelheim International Gmbh | Medicaments comprising pde iv inhibitors and a novel anticholinergic and their use for treating respiratory disorders |
ES2326320T3 (en) * | 2003-07-28 | 2009-10-07 | Boehringer Ingelheim International Gmbh | INHALATION DRUGS THAT INCLUDE STEROIDS AND NEW ESTER OF FLUORENCARBOXILIC ACID. |
CA2534120C (en) * | 2003-07-31 | 2012-09-11 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising anticholinergics and a betamimetic |
DE102004001607A1 (en) * | 2004-01-09 | 2005-08-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New drug combinations based on scopin or tropic acid esters with EGFR kinase inhibitors |
US7507745B2 (en) * | 2004-02-20 | 2009-03-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions based on fluorenecarboxylic acid esters and soluble TNF receptor fusion proteins |
CA2552903A1 (en) * | 2004-02-20 | 2005-09-01 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions based on anticholinergics and pegsunercept |
DE102004016179A1 (en) * | 2004-03-30 | 2005-10-20 | Boehringer Ingelheim Pharma | Compounds for the treatment of proliferative processes |
US20060034776A1 (en) * | 2004-08-10 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Inhalable medicaments containing a new anticholinergic, corticosteroids, and betamimetics |
DE102004038885A1 (en) * | 2004-08-10 | 2006-02-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol formulation for inhalation containing an anticholinergic |
ES2322148T3 (en) * | 2004-08-11 | 2009-06-17 | BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG | MEDICINES CONTAINING ANTI-POLINERGIC FOR TREATMENT IN URINARY ROADS. |
DE102005001297A1 (en) * | 2005-01-12 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol formulation for inhalation containing an anticholinergic |
JP2008530177A (en) * | 2005-02-16 | 2008-08-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Pharmaceutical composition comprising an anticholinergic and etiprednol |
WO2006094924A2 (en) * | 2005-03-09 | 2006-09-14 | Boehringer Ingelheim International Gmbh | New pharmaceutical compositions based on anticholinergics and pde 5-inhibitors |
WO2006128847A2 (en) * | 2005-05-31 | 2006-12-07 | Boehringer Ingelheim International Gmbh | Medicament containing a betamimetic in conjunction with an anticholinergic and a pde iv inhibitor |
DE102005030733A1 (en) | 2005-07-01 | 2007-01-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New drug combinations for the treatment of respiratory diseases containing long-acting beta-2 agonists and at least one other active ingredient |
US7423146B2 (en) | 2005-11-09 | 2008-09-09 | Boehringer Ingelheim International Gmbh | Process for the manufacturing of pharmaceutically active 3,1-benzoxazine-2-ones |
US20090324510A1 (en) | 2006-08-07 | 2009-12-31 | Boehringer Ingelheim International Gmbh | Drug combinations for the treatment of respiratory tract diseases |
UY30550A1 (en) | 2006-08-22 | 2008-03-31 | Boehringer Ingelheim Int | NEW BETA-AGANISTAS ENANTIOMÉRICAMENTE PUROS, PROCEDURES FOR ITS PREPARATION AND ITS USE AS MEDICATIONS |
EP1925296A1 (en) * | 2006-11-22 | 2008-05-28 | Boehringer Ingelheim Pharma GmbH & Co. KG | Stable powder formulation containing a new antichinolinergic agent |
EP1997819A1 (en) * | 2007-05-25 | 2008-12-03 | Boehringer Ingelheim Pharma GmbH & Co. KG | Method for manufacturing scopinium esters |
ES2569359T3 (en) | 2007-07-06 | 2016-05-10 | Vectura Delivery Devices Limited | Inhaler |
US20100234411A1 (en) * | 2007-07-18 | 2010-09-16 | Boehringer Ingelheim Intermational Gmbh | New Combination for the Treatment of Respiratory Diseases |
EP2082771A1 (en) | 2008-01-24 | 2009-07-29 | Vectura Delivery Devices Limited | Inhaler |
EP2082767A1 (en) | 2008-01-24 | 2009-07-29 | Vectura Delivery Devices Limited | Inhaler |
EP2082766A1 (en) | 2008-01-24 | 2009-07-29 | Vectura Delivery Devices Limited | Blister Strip Coil Forming |
EP2082772A1 (en) | 2008-01-24 | 2009-07-29 | Vectura Delivery Devices Limited | Inhaler |
EP2082768A1 (en) | 2008-01-24 | 2009-07-29 | Vectura Delivery Devices Limited | Inhaler |
EP2093219A1 (en) | 2008-02-22 | 2009-08-26 | Boehringer Ingelheim International Gmbh | Crystalline enantiomer free salt form of a betamimetic and its use as medicine |
GB0918450D0 (en) | 2009-10-21 | 2009-12-09 | Innovata Ltd | Composition |
CN102876318B (en) * | 2012-09-28 | 2014-07-16 | 宁波大学 | Fluorene acid ester fluorescent material and preparation method thereof |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
CA3128468A1 (en) | 2017-10-05 | 2019-04-11 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce dux4 and downstream gene expression for the treatment of fshd |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2221828A (en) * | 1936-04-25 | 1940-11-19 | Merck & Co Inc | Esters of amino alcohols with 9-hydroxyfluorene-9-carboxylic acid and processes for their production |
DE4108393A1 (en) * | 1991-03-15 | 1992-09-17 | Boehringer Ingelheim Kg | NEW ESTERS BI-AND TRICYCLIC AMINO ALCOHOLS, THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS |
-
2002
- 2002-01-31 DE DE10203741A patent/DE10203741A1/en not_active Withdrawn
-
2003
- 2003-01-21 EP EP05004525A patent/EP1561751A1/en not_active Withdrawn
- 2003-01-21 NZ NZ534784A patent/NZ534784A/en not_active IP Right Cessation
- 2003-01-21 AU AU2003210172A patent/AU2003210172C1/en not_active Ceased
- 2003-01-21 WO PCT/EP2003/000534 patent/WO2003064419A1/en active IP Right Grant
- 2003-01-21 RS YUP-656/04A patent/RS50918B/en unknown
- 2003-01-21 JP JP2003564042A patent/JP4484522B2/en not_active Expired - Lifetime
- 2003-01-21 CA CA2472149A patent/CA2472149C/en not_active Expired - Fee Related
- 2003-01-21 EA EA200400878A patent/EA006966B1/en not_active IP Right Cessation
- 2003-01-21 DE DE50300813T patent/DE50300813D1/en not_active Expired - Lifetime
- 2003-01-21 KR KR1020047011881A patent/KR100950869B1/en not_active IP Right Cessation
- 2003-01-21 PL PL369396A patent/PL209037B1/en unknown
- 2003-01-21 PT PT03734600T patent/PT1472251E/en unknown
- 2003-01-21 EP EP03734600A patent/EP1472251B1/en not_active Expired - Lifetime
- 2003-01-21 BR BR0307294-0A patent/BR0307294A/en active Pending
- 2003-01-21 ES ES03734600T patent/ES2245443T3/en not_active Expired - Lifetime
- 2003-01-21 CN CNB038030004A patent/CN100348598C/en not_active Expired - Fee Related
- 2003-01-21 AT AT03734600T patent/ATE299880T1/en active
- 2003-01-21 IL IL16252703A patent/IL162527A0/en not_active IP Right Cessation
- 2003-01-21 UA UA20040807067A patent/UA78544C2/en unknown
- 2003-01-21 MX MXPA04007245A patent/MXPA04007245A/en active IP Right Grant
- 2003-01-21 ME MEP-434/08A patent/MEP43408A/en unknown
- 2003-01-29 PE PE2003000092A patent/PE20031029A1/en not_active Application Discontinuation
- 2003-01-29 TW TW092101968A patent/TWI352077B/en active
- 2003-01-29 MY MYPI20030303A patent/MY134582A/en unknown
- 2003-01-30 UY UY27633A patent/UY27633A1/en not_active Application Discontinuation
- 2003-01-31 AR ARP030100288A patent/AR038379A1/en active Pending
-
2004
- 2004-07-28 EC EC2004005209A patent/ECSP045209A/en unknown
- 2004-07-29 HR HRP20040690AA patent/HRP20040690B1/en not_active IP Right Cessation
- 2004-08-30 NO NO20043612A patent/NO328929B1/en not_active IP Right Cessation
-
2005
- 2005-11-02 HK HK05109744A patent/HK1082376A1/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
HRP20040690A2 (en) | Novel fluorene carboxylic acid esters, methods for the production thereof, and use of the same as pharmaceuticals | |
CA2425557C (en) | Anticholinergic agents that can be used as medicaments and method for the production thereof | |
US7429600B2 (en) | Fluorenecarboxylic acid esters, process for the manufacture thereof, and use thereof as medicaments | |
AU2003206760B2 (en) | Anticholinergic agents, method for producing the same and use thereof as medicaments | |
CA2471578C (en) | Xanthene-carboxylic acid esters of tropenol and scopine as m3 antagonists, method for producing the same and use thereof as medicaments | |
US6696462B2 (en) | Anticholinergics, processes for the preparation thereof, and pharmaceutical compositions | |
US7429601B2 (en) | Esters of hydroxyl-substituted nitrogen heterocycles, processes for the preparation thereof as well as the use thereof as pharmaceutical compositions | |
ES2254925T3 (en) | NEW ESTERES OF HYDROXISUBSTITUTED NITROGEN HETERICICLES, AS AN MUSCARINE RECEIVER M3 ANTAGONISTS, PROCEDURE FOR OBTAINING IT AS ITS EMPLOYMENT AS MEDICATIONS. | |
US7405224B2 (en) | Xanthenecarboxylates, processes for preparing them, and their use as pharmaceutical compositions | |
US20030229227A1 (en) | New difurylglycolic acid esters, processes for the preparation thereof as well as the use thereof as pharmaceutical compositions | |
ES2272947T3 (en) | TROPENOL ESTERS OF THE DIFURILGLICOLIC ACID, AS ANTI-POLINERGIC. | |
ZA200404366B (en) | Novel fluorene carboxylic acid esters methods for the production thereof and use of the same as pharmaceuticals |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A1OB | Publication of a patent application | ||
ARAI | Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application | ||
B1PR | Patent granted | ||
ODRP | Renewal fee for the maintenance of a patent |
Payment date: 20150112 Year of fee payment: 13 |
|
PBON | Lapse due to non-payment of renewal fee |
Effective date: 20160121 |