IL94763A - R) - (Quinuclidinol esters of converted azacycloalkanoic acids in position 1, their preparation and pharmaceutical preparations containing them - Google Patents
R) - (Quinuclidinol esters of converted azacycloalkanoic acids in position 1, their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL94763A IL94763A IL9476390A IL9476390A IL94763A IL 94763 A IL94763 A IL 94763A IL 9476390 A IL9476390 A IL 9476390A IL 9476390 A IL9476390 A IL 9476390A IL 94763 A IL94763 A IL 94763A
- Authority
- IL
- Israel
- Prior art keywords
- carboxylate
- oxo
- compounds
- absent
- compound
- Prior art date
Links
- IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical class C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 239000002253 acid Substances 0.000 title claims description 14
- 150000007513 acids Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 29
- -1 3-quinuclidinyl Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 150000001450 anions Chemical class 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 239000005864 Sulphur Substances 0.000 claims abstract description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 27
- 239000004480 active ingredient Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229940102396 methyl bromide Drugs 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 230000001148 spastic effect Effects 0.000 claims description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010006482 Bronchospasm Diseases 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 3
- 230000007885 bronchoconstriction Effects 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- 206010006458 Bronchitis chronic Diseases 0.000 claims description 2
- 206010007645 Cardiospasm Diseases 0.000 claims description 2
- 206010010774 Constipation Diseases 0.000 claims description 2
- 206010014561 Emphysema Diseases 0.000 claims description 2
- 208000000289 Esophageal Achalasia Diseases 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 206010046543 Urinary incontinence Diseases 0.000 claims description 2
- 201000000621 achalasia Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 210000003445 biliary tract Anatomy 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 206010006451 bronchitis Diseases 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 208000007451 chronic bronchitis Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 230000000414 obstructive effect Effects 0.000 claims description 2
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 2
- 206010037628 pylorospasm Diseases 0.000 claims description 2
- 210000002345 respiratory system Anatomy 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 210000001635 urinary tract Anatomy 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- 239000003149 muscarinic antagonist Substances 0.000 abstract description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 3
- 208000018569 Respiratory Tract disease Diseases 0.000 abstract description 3
- 230000002496 gastric effect Effects 0.000 abstract description 3
- 125000004185 ester group Chemical group 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 150000001721 carbon Chemical group 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000003480 eluent Substances 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 238000004458 analytical method Methods 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- 229960004132 diethyl ether Drugs 0.000 description 16
- 239000000725 suspension Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000006243 chemical reaction Methods 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
- 229960004633 pirenzepine Drugs 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- CELPHAGZKFMOMR-UHFFFAOYSA-N azanium;dichloromethane;methanol;hydroxide Chemical compound [NH4+].[OH-].OC.ClCCl CELPHAGZKFMOMR-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products 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 4
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 4
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 210000003710 cerebral cortex Anatomy 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 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 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- 230000003551 muscarinic effect Effects 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- 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 2
- XTWASPQZSASCGU-UHFFFAOYSA-N CCOC(C(CCCN1C)(C2=CC=CC=C2)C1=O)=O Chemical compound CCOC(C(CCCN1C)(C2=CC=CC=C2)C1=O)=O XTWASPQZSASCGU-UHFFFAOYSA-N 0.000 description 2
- MAZXAQJHGDHACF-UHFFFAOYSA-N CCOC(CCC(C(OCC)=O)(C1=CC=CC=C1)C#N)=O Chemical compound CCOC(CCC(C(OCC)=O)(C1=CC=CC=C1)C#N)=O MAZXAQJHGDHACF-UHFFFAOYSA-N 0.000 description 2
- 102000017926 CHRM2 Human genes 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- FZBCOCPXJJBHEG-UHFFFAOYSA-N O=C1NCC(CC1)(C(=O)OC(CC)CCCCC)C1=CC=CC=C1 Chemical compound O=C1NCC(CC1)(C(=O)OC(CC)CCCCC)C1=CC=CC=C1 FZBCOCPXJJBHEG-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000009858 acid secretion Effects 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000001022 anti-muscarinic effect Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- LWZBDTQYCJMNPJ-UHFFFAOYSA-N ethyl 2-cyano-2-pyridin-2-ylacetate Chemical compound CCOC(=O)C(C#N)C1=CC=CC=N1 LWZBDTQYCJMNPJ-UHFFFAOYSA-N 0.000 description 2
- YMBBAZTUKIDXBV-UHFFFAOYSA-N ethyl 2-oxo-3-phenylpiperidine-3-carboxylate Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCCNC1=O YMBBAZTUKIDXBV-UHFFFAOYSA-N 0.000 description 2
- SXIRJEDGTAKGKU-UHFFFAOYSA-N ethyl phenylcyanoacetate Chemical compound CCOC(=O)C(C#N)C1=CC=CC=C1 SXIRJEDGTAKGKU-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 229940098462 oral drops Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 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 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- 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
-
- 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
- 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
- A61P11/08—Bronchodilators
-
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT8920929A IT1230881B (it) | 1989-06-20 | 1989-06-20 | Derivati del r(-) 3-chinuclidinolo |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL94763A0 IL94763A0 (en) | 1991-04-15 |
| IL94763A true IL94763A (en) | 1994-08-26 |
Family
ID=11174223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9476390A IL94763A (en) | 1989-06-20 | 1990-06-18 | R) - (Quinuclidinol esters of converted azacycloalkanoic acids in position 1, their preparation and pharmaceutical preparations containing them |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5164386A (fr) |
| EP (1) | EP0404737A3 (fr) |
| JP (1) | JPH0331279A (fr) |
| KR (1) | KR910000720A (fr) |
| AU (1) | AU634787B2 (fr) |
| CA (1) | CA2019251A1 (fr) |
| DD (1) | DD300105A5 (fr) |
| FI (1) | FI94131C (fr) |
| HU (1) | HUT54151A (fr) |
| IE (1) | IE902208A1 (fr) |
| IL (1) | IL94763A (fr) |
| IT (1) | IT1230881B (fr) |
| NO (1) | NO174053C (fr) |
| NZ (1) | NZ234157A (fr) |
| PL (1) | PL164218B1 (fr) |
| PT (1) | PT94408A (fr) |
| RU (1) | RU2034843C1 (fr) |
| YU (1) | YU47356B (fr) |
| ZA (1) | ZA904736B (fr) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9106571D0 (en) * | 1991-03-27 | 1991-05-15 | Erba Carlo Spa | Derivatives of substituted imidazol-2-one and process for their preparation |
| AU7618991A (en) * | 1990-05-14 | 1991-11-14 | Syntex (U.S.A.) Inc. | Novel tricyclic compounds |
| US5202318A (en) * | 1990-05-14 | 1993-04-13 | Syntex (U.S.A.) Inc. | Tricyclic compounds acting at serotonin receptor subtypes |
| AU652407B2 (en) * | 1991-01-10 | 1994-08-25 | Pfizer Inc. | N-alkyl quinuclidinium salts as substance P antagonists |
| US5340826A (en) * | 1993-02-04 | 1994-08-23 | Pfizer Inc. | Pharmaceutical agents for treatment of urinary incontinence |
| US7214686B2 (en) * | 1997-06-30 | 2007-05-08 | Targacept, Inc. | Pharmaceutical compositions and methods for effecting dopamine release |
| EE05404B1 (et) | 2000-12-28 | 2011-04-15 | Almirall Prodesfarma Ag | Kinuklidiini derivaat, selle saamine ja kasutamine ravimi valmistamiseks, mis on ette nhtud respiratoorsete, kuseelundite v?i mao-soolte haiguste ravimiseks, ning seda sisaldav ravimkompositsioon |
| WO2014105655A1 (fr) | 2012-12-24 | 2014-07-03 | Neurogastrx, Inc. | Méthodes de traitement d'affections du tractus digestif |
| WO2015200369A1 (fr) | 2014-06-24 | 2015-12-30 | Neurogastrx, Inc. | Promédicaments de métopimazine |
| KR102423577B1 (ko) | 2017-04-07 | 2022-07-21 | 삼성전자주식회사 | 가전기기 |
| US10836757B1 (en) | 2020-04-02 | 2020-11-17 | Neurogastrx, Inc. | Polymorphic forms of metopimazine |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3290316A (en) * | 1962-08-03 | 1966-12-06 | Hoffmann La Roche | Alpha-3-pyridylmandelic acid and derivatives thereof |
| DE3429830A1 (de) * | 1983-08-26 | 1985-03-07 | Sandoz-Patent-GmbH, 7850 Lörrach | Automatische carbonsaeure- und sulfonsaeureester oder -amide |
| CA1307790C (fr) * | 1987-08-04 | 1992-09-22 | Ian Anthony Cliffe | Ethers |
| IL87674A (en) * | 1987-09-08 | 1993-08-18 | Lilly Co Eli | Azabicycloalkyl esters and amides of heterocyclic acids, their preparation and pharmaceutical compositions containing them |
| US4921982A (en) * | 1988-07-21 | 1990-05-01 | Eli Lilly And Company | 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids useful as intermediates for 5-HT3 antagonists |
| IT1231413B (it) * | 1987-09-23 | 1991-12-04 | Angeli Inst Spa | Derivati dell'acido benzimidazolin-2-osso-1-carbossilico utili come antagonisti dei recettori 5-ht |
| US4975437A (en) * | 1989-12-14 | 1990-12-04 | Marion Laboratories, Inc. | Isomers of 1-azabicyclo(2.2.2)oct-3-yl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-nitropyridine-3-carboxylate |
-
1989
- 1989-06-20 IT IT8920929A patent/IT1230881B/it active
-
1990
- 1990-06-18 IL IL9476390A patent/IL94763A/en not_active IP Right Cessation
- 1990-06-18 PL PL90285669A patent/PL164218B1/pl unknown
- 1990-06-18 DD DD341777A patent/DD300105A5/de unknown
- 1990-06-19 YU YU120290A patent/YU47356B/sh unknown
- 1990-06-19 KR KR1019900008991A patent/KR910000720A/ko not_active Application Discontinuation
- 1990-06-19 EP EP19900830281 patent/EP0404737A3/fr not_active Withdrawn
- 1990-06-19 JP JP2161192A patent/JPH0331279A/ja active Pending
- 1990-06-19 IE IE220890A patent/IE902208A1/en unknown
- 1990-06-19 FI FI903077A patent/FI94131C/fi not_active IP Right Cessation
- 1990-06-19 NO NO902710A patent/NO174053C/no unknown
- 1990-06-19 PT PT94408A patent/PT94408A/pt not_active Application Discontinuation
- 1990-06-19 HU HU903908A patent/HUT54151A/hu unknown
- 1990-06-19 ZA ZA904736A patent/ZA904736B/xx unknown
- 1990-06-19 CA CA002019251A patent/CA2019251A1/fr not_active Abandoned
- 1990-06-20 NZ NZ234157A patent/NZ234157A/xx unknown
- 1990-06-20 US US07/541,106 patent/US5164386A/en not_active Expired - Fee Related
- 1990-06-20 AU AU57649/90A patent/AU634787B2/en not_active Ceased
-
1992
- 1992-03-10 RU SU925011061A patent/RU2034843C1/ru active
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0331279A (ja) | 1991-02-12 |
| NO174053B (no) | 1993-11-29 |
| FI903077A0 (fi) | 1990-06-19 |
| NZ234157A (en) | 1992-09-25 |
| EP0404737A3 (fr) | 1992-03-11 |
| ZA904736B (en) | 1992-02-26 |
| AU634787B2 (en) | 1993-03-04 |
| NO902710L (no) | 1990-12-21 |
| FI94131B (fi) | 1995-04-13 |
| US5164386A (en) | 1992-11-17 |
| PT94408A (pt) | 1991-02-08 |
| PL164218B1 (pl) | 1994-07-29 |
| RU2034843C1 (ru) | 1995-05-10 |
| IE902208L (en) | 1990-12-20 |
| IE902208A1 (en) | 1991-01-02 |
| IT8920929A0 (it) | 1989-06-20 |
| YU47356B (sh) | 1995-01-31 |
| IT1230881B (it) | 1991-11-08 |
| NO902710D0 (no) | 1990-06-19 |
| YU120290A (sh) | 1992-12-21 |
| HU903908D0 (en) | 1990-11-28 |
| PL285669A1 (en) | 1991-03-11 |
| IL94763A0 (en) | 1991-04-15 |
| EP0404737A2 (fr) | 1990-12-27 |
| AU5764990A (en) | 1991-01-03 |
| DD300105A5 (de) | 1992-05-21 |
| NO174053C (no) | 1994-03-16 |
| FI94131C (fi) | 1995-07-25 |
| CA2019251A1 (fr) | 1990-12-20 |
| HUT54151A (en) | 1991-01-28 |
| KR910000720A (ko) | 1991-01-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RH | Patent void |