BRPI0611763A2 - processo para a preparação de sais de tiotrópio, sais de tiotrópio como tais e composições farmacêuticas dos mesmos - Google Patents

Info

Publication number

BRPI0611763A2

BRPI0611763A2 BRPI0611763-5A BRPI0611763A BRPI0611763A2 BR PI0611763 A2 BRPI0611763 A2 BR PI0611763A2 BR PI0611763 A BRPI0611763 A BR PI0611763A BR PI0611763 A2 BRPI0611763 A2 BR PI0611763A2

Authority

BR

Brazil

Prior art keywords

tiotropium

crystalline

amino

optionally substituted

crystalline tiotropium

Prior art date

2005-06-15

Links

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• Global Dossier
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• LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 title claims abstract description 346
• 238000000034 method Methods 0.000 title claims abstract description 95
• 238000002360 preparation method Methods 0.000 title claims abstract description 78
• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 65
• 230000008569 process Effects 0.000 title claims abstract description 52
• -1 alkenyl sulfate Chemical compound 0.000 claims description 312
• 229940110309 tiotropium Drugs 0.000 claims description 276
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 152
• 239000000843 powder Substances 0.000 claims description 121
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 90
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 78
• 239000003456 ion exchange resin Substances 0.000 claims description 68
• 229920003303 ion-exchange polymer Polymers 0.000 claims description 68
• NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 65
• 239000002904 solvent Substances 0.000 claims description 63
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 56
• 239000013078 crystal Substances 0.000 claims description 48
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 48
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 48
• 239000002253 acid Substances 0.000 claims description 41
• 238000010586 diagram Methods 0.000 claims description 40
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 36
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 30
• 229950000339 xinafoate Drugs 0.000 claims description 30
• 230000002265 prevention Effects 0.000 claims description 28
• 238000012916 structural analysis Methods 0.000 claims description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
• 150000001875 compounds Chemical class 0.000 claims description 26
• HVIDCXBJDYXPTO-JAZONYGRSA-M tiotropium salicylate Chemical compound OC(=O)C1=CC=CC=C1[O-].C([C@H]1[N+]([C@H](C2)[C@H]3[C@@H]1O3)(C)C)C2OC(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 HVIDCXBJDYXPTO-JAZONYGRSA-M 0.000 claims description 26
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 24
• MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 23
• 239000012453 solvate Substances 0.000 claims description 22
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
• 150000004677 hydrates Chemical class 0.000 claims description 20
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 19
• 229940095064 tartrate Drugs 0.000 claims description 19
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 18
• BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 17
• 230000002062 proliferating effect Effects 0.000 claims description 17
• 238000004458 analytical method Methods 0.000 claims description 16
• 150000001450 anions Chemical class 0.000 claims description 16
• 150000004682 monohydrates Chemical class 0.000 claims description 16
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 14
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
• 150000001298 alcohols Chemical class 0.000 claims description 13
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 13
• 230000002452 interceptive effect Effects 0.000 claims description 13
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 13
• BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 12
• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 125000000623 heterocyclic group Chemical group 0.000 claims description 12
• 229940049920 malate Drugs 0.000 claims description 12
• 208000023504 respiratory system disease Diseases 0.000 claims description 12
• 208000024891 symptom Diseases 0.000 claims description 12
• 229940077388 benzenesulfonate Drugs 0.000 claims description 11
• 150000002367 halogens Chemical class 0.000 claims description 11
• 239000001257 hydrogen Substances 0.000 claims description 11
• 229910052739 hydrogen Inorganic materials 0.000 claims description 11
• 125000002950 monocyclic group Chemical group 0.000 claims description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
• 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 10
• 150000008051 alkyl sulfates Chemical class 0.000 claims description 10
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
• 150000004820 halides Chemical class 0.000 claims description 9
• 239000003112 inhibitor Substances 0.000 claims description 9
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 9
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 8
• 150000008052 alkyl sulfonates Chemical class 0.000 claims description 8
• 125000003118 aryl group Chemical group 0.000 claims description 8
• 230000003454 betamimetic effect Effects 0.000 claims description 8
• GEVPUGOOGXGPIO-UHFFFAOYSA-N oxalic acid;dihydrate Chemical compound O.O.OC(=O)C(O)=O GEVPUGOOGXGPIO-UHFFFAOYSA-N 0.000 claims description 8
• 150000003431 steroids Chemical class 0.000 claims description 8
• 238000002441 X-ray diffraction Methods 0.000 claims description 7
• 239000000808 adrenergic beta-agonist Substances 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 230000007774 longterm Effects 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 230000002093 peripheral effect Effects 0.000 claims description 7
• 239000003495 polar organic solvent Substances 0.000 claims description 7
• CAQZTSCRGMRSHX-TYYBGVCCSA-N (e)-but-2-enedioic acid;ethanol Chemical compound CCO.OC(=O)\C=C\C(O)=O CAQZTSCRGMRSHX-TYYBGVCCSA-N 0.000 claims description 6
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 6
• 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 6
• 208000007101 Muscle Cramp Diseases 0.000 claims description 6
• 208000005392 Spasm Diseases 0.000 claims description 6
• 239000005557 antagonist Substances 0.000 claims description 6
• 125000005228 aryl sulfonate group Chemical group 0.000 claims description 6
• HNGDOSBFYRVIEY-UHFFFAOYSA-N ethanesulfonic acid;hydrate Chemical compound O.CCS(O)(=O)=O HNGDOSBFYRVIEY-UHFFFAOYSA-N 0.000 claims description 6
• CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 claims description 6
• 230000001515 vagal effect Effects 0.000 claims description 6
• 150000002170 ethers Chemical class 0.000 claims description 5
• OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 claims description 5
• 229910052757 nitrogen Inorganic materials 0.000 claims description 5
• 239000003960 organic solvent Substances 0.000 claims description 5
• TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 claims description 5
• 125000003107 substituted aryl group Chemical group 0.000 claims description 5
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
• 150000001408 amides Chemical class 0.000 claims description 4
• 230000003444 anaesthetic effect Effects 0.000 claims description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 4
• CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 4
• YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 claims description 4
• 150000002825 nitriles Chemical class 0.000 claims description 4
• FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 claims description 4
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 4
• 208000005374 Poisoning Diseases 0.000 claims description 3
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 3
• 230000035873 hypermotility Effects 0.000 claims description 3
• 231100000572 poisoning Toxicity 0.000 claims description 3
• 230000000607 poisoning effect Effects 0.000 claims description 3
• 238000009101 premedication Methods 0.000 claims description 3
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 3
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 3
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 3
• 239000004480 active ingredient Substances 0.000 claims 1
• 229940121647 egfr inhibitor Drugs 0.000 claims 1
• 150000003839 salts Chemical class 0.000 abstract description 70
• 239000003814 drug Substances 0.000 abstract description 34
• 238000004519 manufacturing process Methods 0.000 abstract description 11
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 179
• 239000000243 solution Substances 0.000 description 123
• 239000000203 mixture Substances 0.000 description 89
• 239000002002 slurry Substances 0.000 description 88
• 210000004027 cell Anatomy 0.000 description 44
• 239000002994 raw material Substances 0.000 description 39
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
• 239000007787 solid Substances 0.000 description 33
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 30
• 238000003756 stirring Methods 0.000 description 29
• 238000009472 formulation Methods 0.000 description 28
• 239000003380 propellant Substances 0.000 description 28
• MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].C[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 description 28
• 239000002245 particle Substances 0.000 description 27
• 239000004810 polytetrafluoroethylene Substances 0.000 description 27
• 229920001343 polytetrafluoroethylene Polymers 0.000 description 27
• 239000011148 porous material Substances 0.000 description 27
• 238000012360 testing method Methods 0.000 description 27
• 229910002651 NO3 Inorganic materials 0.000 description 25
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 25
• 239000013543 active substance Substances 0.000 description 25
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 23
• 238000002844 melting Methods 0.000 description 22
• 230000008018 melting Effects 0.000 description 22
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 21
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical group OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 21
• CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 20
• 239000000725 suspension Substances 0.000 description 20
• 210000004379 membrane Anatomy 0.000 description 19
• 239000012528 membrane Substances 0.000 description 19
• 238000001816 cooling Methods 0.000 description 18
• 238000003860 storage Methods 0.000 description 18
• 239000000443 aerosol Substances 0.000 description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
• 238000012423 maintenance Methods 0.000 description 16
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 16
• 238000001704 evaporation Methods 0.000 description 15
• 230000008020 evaporation Effects 0.000 description 15
• 238000004467 single crystal X-ray diffraction Methods 0.000 description 15
• 125000000217 alkyl group Chemical group 0.000 description 14
• 239000002775 capsule Substances 0.000 description 14
• 238000010438 heat treatment Methods 0.000 description 14
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 13
• 201000010099 disease Diseases 0.000 description 13
• 239000003921 oil Substances 0.000 description 12
• 235000019198 oils Nutrition 0.000 description 12
• 239000000890 drug combination Substances 0.000 description 11
• 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 10
• 229960005070 ascorbic acid Drugs 0.000 description 10
• 235000010323 ascorbic acid Nutrition 0.000 description 10
• 239000011668 ascorbic acid Substances 0.000 description 10
• 235000015165 citric acid Nutrition 0.000 description 10
• 239000007789 gas Substances 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
• 150000007513 acids Chemical class 0.000 description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 8
• 206010035664 Pneumonia Diseases 0.000 description 8
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 8
• 239000000654 additive Substances 0.000 description 8
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 8
• 201000000028 adult respiratory distress syndrome Diseases 0.000 description 8
• 125000004432 carbon atom Chemical group C* 0.000 description 8
• 238000004891 communication Methods 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 239000001530 fumaric acid Substances 0.000 description 8
• 235000011167 hydrochloric acid Nutrition 0.000 description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
• 238000002156 mixing Methods 0.000 description 8
• YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 8
• 239000004094 surface-active agent Substances 0.000 description 8
• YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 7
• IHOXNOQMRZISPV-YJYMSZOUSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]azaniumyl]ethyl]-2-oxo-1h-quinolin-8-olate Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 IHOXNOQMRZISPV-YJYMSZOUSA-N 0.000 description 7
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 7
• OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 7
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
• 208000006673 asthma Diseases 0.000 description 7
• 239000000463 material Substances 0.000 description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
• SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 7
• 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 7
• ULMFXAMQUGLVGA-LJQANCHMSA-N 3-[[2-methoxy-4-[(2-methylphenyl)sulfonylcarbamoyl]phenyl]methyl]-1-methyl-n-[(2r)-4,4,4-trifluoro-2-methylbutyl]indole-5-carboxamide Chemical compound C=1C=C(CC=2C3=CC(=CC=C3N(C)C=2)C(=O)NC[C@H](C)CC(F)(F)F)C(OC)=CC=1C(=O)NS(=O)(=O)C1=CC=CC=C1C ULMFXAMQUGLVGA-LJQANCHMSA-N 0.000 description 6
• FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical class OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• 229920000858 Cyclodextrin Polymers 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
• 206010037423 Pulmonary oedema Diseases 0.000 description 6
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
• 239000003963 antioxidant agent Substances 0.000 description 6
• 235000006708 antioxidants Nutrition 0.000 description 6
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
• 239000000460 chlorine Substances 0.000 description 6
• 239000011737 fluorine Substances 0.000 description 6
• 229910052731 fluorine Inorganic materials 0.000 description 6
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
• NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• 150000007522 mineralic acids Chemical class 0.000 description 6
• OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
• 235000011007 phosphoric acid Nutrition 0.000 description 6
• 238000000634 powder X-ray diffraction Methods 0.000 description 6
• 208000005333 pulmonary edema Diseases 0.000 description 6
• 201000000306 sarcoidosis Diseases 0.000 description 6
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