IL93257A - History of trotocycles containing nitrogen, their preparation and pharmaceutical preparations containing them - Google Patents

History of trotocycles containing nitrogen, their preparation and pharmaceutical preparations containing them

Info

Publication number: IL93257A
Authority: IL; Israel
Prior art keywords: endo; compound; alkyl; methyl; azabicyclo
Prior art date: 1989-02-06

Application number

IL9325790A

Other languages

English (en)

Hebrew (he)

Other versions

IL93257A0 (en

Original Assignee

Boehringer Ingelheim Italia

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1989-02-06

Filing date

1990-02-02

Publication date

1994-07-31

1990-02-02 Application filed by Boehringer Ingelheim Italia filed Critical Boehringer Ingelheim Italia

1990-11-29 Publication of IL93257A0 publication Critical patent/IL93257A0/xx

1994-07-31 Publication of IL93257A publication Critical patent/IL93257A/en

Links

238000002360 preparation method Methods 0.000 title claims abstract description 27
239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
150000001875 compounds Chemical class 0.000 claims abstract description 137
229910052799 carbon Inorganic materials 0.000 claims abstract description 131
238000000034 method Methods 0.000 claims abstract description 23
230000008569 process Effects 0.000 claims abstract description 10
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
125000002252 acyl group Chemical group 0.000 claims abstract description 3
125000004442 acylamino group Chemical group 0.000 claims abstract description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 3
229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
150000002148 esters Chemical class 0.000 claims description 53
-1 oct-3-yl Chemical group 0.000 claims description 33
239000002253 acid Substances 0.000 claims description 32
239000000203 mixture Substances 0.000 claims description 27
238000006243 chemical reaction Methods 0.000 claims description 25
150000003839 salts Chemical class 0.000 claims description 25
239000004480 active ingredient Substances 0.000 claims description 17
125000000217 alkyl group Chemical group 0.000 claims description 17
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 10
239000012312 sodium hydride Substances 0.000 claims description 9
229910000104 sodium hydride Inorganic materials 0.000 claims description 9
239000003795 chemical substances by application Substances 0.000 claims description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
208000035475 disorder Diseases 0.000 claims description 7
125000005843 halogen group Chemical group 0.000 claims description 7
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
230000003213 activating effect Effects 0.000 claims description 5
125000003545 alkoxy group Chemical group 0.000 claims description 5
239000001257 hydrogen Substances 0.000 claims description 5
229910052739 hydrogen Inorganic materials 0.000 claims description 5
125000004430 oxygen atom Chemical group O* 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
230000001148 spastic effect Effects 0.000 claims description 5
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
125000003277 amino group Chemical group 0.000 claims description 3
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
230000000414 obstructive effect Effects 0.000 claims description 3
230000003287 optical effect Effects 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
210000002345 respiratory system Anatomy 0.000 claims description 3
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [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
230000001154 acute effect Effects 0.000 claims description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
125000004414 alkyl thio group Chemical group 0.000 claims description 2
125000004429 atom Chemical group 0.000 claims description 2
210000003445 biliary tract Anatomy 0.000 claims description 2
230000001684 chronic effect Effects 0.000 claims description 2
229910052751 metal Inorganic materials 0.000 claims description 2
239000002184 metal Substances 0.000 claims description 2
230000002485 urinary effect Effects 0.000 claims description 2
210000001635 urinary tract Anatomy 0.000 claims description 2
PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 claims 1
239000003085 diluting agent Substances 0.000 claims 1
210000001035 gastrointestinal tract Anatomy 0.000 claims 1
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 5
125000000623 heterocyclic group Chemical group 0.000 abstract description 4
239000003149 muscarinic antagonist Substances 0.000 abstract description 4
208000018522 Gastrointestinal disease Diseases 0.000 abstract description 3
229910052736 halogen Inorganic materials 0.000 abstract description 3
150000002367 halogens Chemical class 0.000 abstract description 3
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 3
125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract description 2
208000018569 Respiratory Tract disease Diseases 0.000 abstract description 2
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
230000002496 gastric effect Effects 0.000 abstract description 2
239000001301 oxygen Substances 0.000 abstract description 2
229910052760 oxygen Inorganic materials 0.000 abstract description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 5
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
125000003118 aryl group Chemical group 0.000 abstract 2
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 abstract 1
125000006700 (C1-C6) alkylthio group Chemical group 0.000 abstract 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
238000004458 analytical method Methods 0.000 description 56
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 47
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
239000000243 solution Substances 0.000 description 42
239000002904 solvent Substances 0.000 description 30
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
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 25
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
238000003756 stirring Methods 0.000 description 17
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
235000019441 ethanol Nutrition 0.000 description 15
229940093499 ethyl acetate Drugs 0.000 description 15
235000019439 ethyl acetate Nutrition 0.000 description 15
239000007787 solid Substances 0.000 description 15
239000007858 starting material Substances 0.000 description 14
239000011541 reaction mixture Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 11
230000000694 effects Effects 0.000 description 10
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
238000001704 evaporation Methods 0.000 description 9
230000008020 evaporation Effects 0.000 description 9
238000001914 filtration Methods 0.000 description 9
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 8
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000003480 eluent Substances 0.000 description 8
241000700199 Cavia porcellus Species 0.000 description 7
238000003818 flash chromatography Methods 0.000 description 7
230000003551 muscarinic effect Effects 0.000 description 7
229960004633 pirenzepine Drugs 0.000 description 7
239000000725 suspension Substances 0.000 description 7
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
239000000543 intermediate Substances 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
102000005962 receptors Human genes 0.000 description 6
108020003175 receptors Proteins 0.000 description 6
210000001519 tissue Anatomy 0.000 description 6
206010006482 Bronchospasm Diseases 0.000 description 5
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 5
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
230000027455 binding Effects 0.000 description 5
230000007885 bronchoconstriction Effects 0.000 description 5
239000002775 capsule Substances 0.000 description 5
125000004494 ethyl ester group Chemical group 0.000 description 5
239000010410 layer Substances 0.000 description 5
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 5
239000002243 precursor Substances 0.000 description 5
229910002027 silica gel Inorganic materials 0.000 description 5
239000000741 silica gel Substances 0.000 description 5
229960001866 silicon dioxide Drugs 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
239000000010 aprotic solvent Substances 0.000 description 4
239000002585 base Substances 0.000 description 4
239000003054 catalyst Substances 0.000 description 4
210000003710 cerebral cortex Anatomy 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
238000001816 cooling Methods 0.000 description 4
238000001035 drying Methods 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
210000003405 ileum Anatomy 0.000 description 4
238000000338 in vitro Methods 0.000 description 4
239000008101 lactose Substances 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
150000007522 mineralic acids Chemical class 0.000 description 4
150000007524 organic acids Chemical class 0.000 description 4
239000012044 organic layer Substances 0.000 description 4
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
239000011734 sodium Substances 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
229910000029 sodium carbonate Inorganic materials 0.000 description 4
150000003892 tartrate salts Chemical class 0.000 description 4
238000010626 work up procedure Methods 0.000 description 4
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
229920002261 Corn starch Polymers 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 3
108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
238000009835 boiling Methods 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
238000007796 conventional method Methods 0.000 description 3
239000008120 corn starch Substances 0.000 description 3
235000014113 dietary fatty acids Nutrition 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
125000005456 glyceride group Chemical group 0.000 description 3
210000002837 heart atrium Anatomy 0.000 description 3
238000001727 in vivo Methods 0.000 description 3
229910052744 lithium Inorganic materials 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
239000008188 pellet Substances 0.000 description 3
230000000144 pharmacologic effect Effects 0.000 description 3
238000010992 reflux Methods 0.000 description 3
230000004044 response Effects 0.000 description 3
229910052708 sodium Inorganic materials 0.000 description 3
239000001509 sodium citrate Substances 0.000 description 3
239000001117 sulphuric acid Substances 0.000 description 3
235000011149 sulphuric acid Nutrition 0.000 description 3
239000000829 suppository Substances 0.000 description 3
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
YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
102000017926 CHRM2 Human genes 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-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
239000001828 Gelatine Substances 0.000 description 2
239000007995 HEPES buffer Substances 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
241001465754 Metazoa Species 0.000 description 2
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
230000009858 acid secretion Effects 0.000 description 2
150000007513 acids Chemical class 0.000 description 2
125000004423 acyloxy group Chemical group 0.000 description 2
229910052783 alkali metal Inorganic materials 0.000 description 2
125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
125000003368 amide group Chemical group 0.000 description 2
235000011114 ammonium hydroxide Nutrition 0.000 description 2
230000001022 anti-muscarinic effect Effects 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
239000004202 carbamide Substances 0.000 description 2
125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 2
230000000747 cardiac effect Effects 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
125000001309 chloro group Chemical group Cl* 0.000 description 2
229940125846 compound 25 Drugs 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
230000001186 cumulative effect Effects 0.000 description 2
230000003247 decreasing effect Effects 0.000 description 2
229960004132 diethyl ether Drugs 0.000 description 2
238000006073 displacement reaction Methods 0.000 description 2
238000010494 dissociation reaction Methods 0.000 description 2
230000005593 dissociations Effects 0.000 description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
239000007789 gas Substances 0.000 description 2
229920000159 gelatin Polymers 0.000 description 2
235000019322 gelatine Nutrition 0.000 description 2
229940093915 gynecological organic acid Drugs 0.000 description 2
125000002883 imidazolyl group Chemical group 0.000 description 2
238000011534 incubation Methods 0.000 description 2
239000012442 inert solvent Substances 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
230000000297 inotrophic effect Effects 0.000 description 2
210000004731 jugular vein Anatomy 0.000 description 2
239000003446 ligand Substances 0.000 description 2
239000007788 liquid Substances 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
MAFJXAYWVBYUEH-UHFFFAOYSA-N n,n'-bis(4-methoxyphenyl)ethane-1,2-diamine Chemical compound C1=CC(OC)=CC=C1NCCNC1=CC=C(OC)C=C1 MAFJXAYWVBYUEH-UHFFFAOYSA-N 0.000 description 2
230000009871 nonspecific binding Effects 0.000 description 2
NMRPBPVERJPACX-UHFFFAOYSA-N octan-3-ol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 2
235000005985 organic acids Nutrition 0.000 description 2
229910052697 platinum Inorganic materials 0.000 description 2
229910000027 potassium carbonate Inorganic materials 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
239000002287 radioligand Substances 0.000 description 2
239000002994 raw material Substances 0.000 description 2
230000008707 rearrangement Effects 0.000 description 2
230000000241 respiratory effect Effects 0.000 description 2
229920006395 saturated elastomer Polymers 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
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
239000000600 sorbitol Substances 0.000 description 2
238000012360 testing method Methods 0.000 description 2
238000004809 thin layer chromatography Methods 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
210000003437 trachea Anatomy 0.000 description 2
238000005303 weighing Methods 0.000 description 2
SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
HVWQTEPEBQYIFB-PXXJPSRFSA-N (1s,3s,4r,5r)-3-hydroxy-8-methyl-8-azabicyclo[3.2.1]octane-4-carboxylic acid;hydrochloride Chemical compound [Cl-].C1[C@H](O)[C@H](C(O)=O)[C@H]2CC[C@@H]1[NH+]2C HVWQTEPEBQYIFB-PXXJPSRFSA-N 0.000 description 1
PYYRNLDFMZVKCV-UHFFFAOYSA-N (2-nitrophenyl)methanamine Chemical compound NCC1=CC=CC=C1[N+]([O-])=O PYYRNLDFMZVKCV-UHFFFAOYSA-N 0.000 description 1
YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 1
STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
BZZXQZOBAUXLHZ-UHFFFAOYSA-N (c-methylsulfanylcarbonimidoyl)azanium;sulfate Chemical compound CSC(N)=N.CSC(N)=N.OS(O)(=O)=O BZZXQZOBAUXLHZ-UHFFFAOYSA-N 0.000 description 1
KSSXNHGPIDAUAS-UHFFFAOYSA-N 1,4-benzodiazepin-6-one Chemical compound N1=CC=NC=C2C(=O)C=CC=C21 KSSXNHGPIDAUAS-UHFFFAOYSA-N 0.000 description 1
ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
USGPMHRMOOPLFC-UHFFFAOYSA-N 1-methyl-n-[(2-nitrophenyl)methyl]piperidine-4-carboxamide Chemical compound C1CN(C)CCC1C(=O)NCC1=CC=CC=C1[N+]([O-])=O USGPMHRMOOPLFC-UHFFFAOYSA-N 0.000 description 1
UBRKDAVQCKZSPO-UHFFFAOYSA-N 11-[2-[2-(diethylaminomethyl)-1-piperidinyl]-1-oxoethyl]-5H-pyrido[2,3-b][1,4]benzodiazepin-6-one Chemical compound CCN(CC)CC1CCCCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 UBRKDAVQCKZSPO-UHFFFAOYSA-N 0.000 description 1
OVKMCETXCBHMBZ-UHFFFAOYSA-N 2-(aminomethyl)-3-nitrophenol Chemical compound NCC1=C(O)C=CC=C1[N+]([O-])=O OVKMCETXCBHMBZ-UHFFFAOYSA-N 0.000 description 1
LRMCJMFUQDKEPJ-UHFFFAOYSA-N 2-[(2-hydroxy-6-nitrophenyl)methyl]isoindole-1,3-dione Chemical compound OC1=CC=CC([N+]([O-])=O)=C1CN1C(=O)C2=CC=CC=C2C1=O LRMCJMFUQDKEPJ-UHFFFAOYSA-N 0.000 description 1
ATNRWKCFZXAEBT-UHFFFAOYSA-N 2-[(2-methyl-3-nitrophenyl)methyl]isoindole-1,3-dione Chemical compound C1=CC=C([N+]([O-])=O)C(C)=C1CN1C(=O)C2=CC=CC=C2C1=O ATNRWKCFZXAEBT-UHFFFAOYSA-N 0.000 description 1
ABEMNKFDHQOBEC-UHFFFAOYSA-N 2-[(2-methyl-6-nitrophenyl)methyl]isoindole-1,3-dione Chemical compound CC1=CC=CC([N+]([O-])=O)=C1CN1C(=O)C2=CC=CC=C2C1=O ABEMNKFDHQOBEC-UHFFFAOYSA-N 0.000 description 1
FIRDKKXWYLTXLG-UHFFFAOYSA-N 2-[(4-fluoro-2-nitrophenyl)methyl]isoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC(F)=CC=C1CN1C(=O)C2=CC=CC=C2C1=O FIRDKKXWYLTXLG-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
WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
ZZTXGLBRQLEFLX-UHFFFAOYSA-N 2-nitrobenzoyl isocyanate Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)N=C=O ZZTXGLBRQLEFLX-UHFFFAOYSA-N 0.000 description 1
QULTWXIRPYWHGU-UHFFFAOYSA-N 2-oxo-3,4-dihydro-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)CC2=C1 QULTWXIRPYWHGU-UHFFFAOYSA-N 0.000 description 1
HCCVSBZTMBEYPT-UHFFFAOYSA-N 3-(aminomethyl)-4-nitrobenzamide 3-(aminomethyl)-4-nitrobenzonitrile Chemical compound C(N)(=O)C=1C=CC(=C(CN)C1)[N+](=O)[O-].C(#N)C=1C=CC(=C(CN)C1)[N+](=O)[O-] HCCVSBZTMBEYPT-UHFFFAOYSA-N 0.000 description 1
BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
HVLMWCBEAXEKAD-UHFFFAOYSA-N 4-diphenylacetoxy-N-methylpiperidine Chemical compound C1CN(C)CCC1OC(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 HVLMWCBEAXEKAD-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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 1
ATPGYYPVVKZFGR-UHFFFAOYSA-N 9-azabicyclo[3.3.1]nonane Chemical group C1CCC2CCCC1N2 ATPGYYPVVKZFGR-UHFFFAOYSA-N 0.000 description 1
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
206010006458 Bronchitis chronic Diseases 0.000 description 1
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
206010007645 Cardiospasm Diseases 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
206010008674 Cholinergic syndrome Diseases 0.000 description 1
101150012960 Chrm2 gene Proteins 0.000 description 1
206010010774 Constipation Diseases 0.000 description 1
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 1
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
206010014561 Emphysema Diseases 0.000 description 1
208000000289 Esophageal Achalasia Diseases 0.000 description 1
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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 1
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
241000243251 Hydra Species 0.000 description 1
229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
208000007101 Muscle Cramp Diseases 0.000 description 1
208000006550 Mydriasis Diseases 0.000 description 1
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
150000001204 N-oxides Chemical class 0.000 description 1
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
208000008469 Peptic Ulcer Diseases 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
239000007868 Raney catalyst Substances 0.000 description 1
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
229910000564 Raney nickel Inorganic materials 0.000 description 1
241000700159 Rattus Species 0.000 description 1
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
208000005392 Spasm Diseases 0.000 description 1
229930006000 Sucrose Natural products 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
208000001871 Tachycardia Diseases 0.000 description 1
206010046555 Urinary retention Diseases 0.000 description 1
JPKKQJKQTPNWTR-KQAYXBCTSA-N [(1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] (2r)-3-hydroxy-2-phenylpropanoate;sulfuric acid;hydrate Chemical compound O.OS(O)(=O)=O.C1([C@H](CO)C(=O)OC2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1.C1([C@H](CO)C(=O)OC2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 JPKKQJKQTPNWTR-KQAYXBCTSA-N 0.000 description 1
PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
VYWQTJWGWLKBQA-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;chloride Chemical compound Cl.NC(N)=O VYWQTJWGWLKBQA-UHFFFAOYSA-N 0.000 description 1
235000010489 acacia gum Nutrition 0.000 description 1
239000001785 acacia senegal l. willd gum Substances 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
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
229960004373 acetylcholine Drugs 0.000 description 1
201000000621 achalasia Diseases 0.000 description 1
239000012190 activator Substances 0.000 description 1
YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
230000001262 anti-secretory effect Effects 0.000 description 1
239000003699 antiulcer agent Substances 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
239000008135 aqueous vehicle Substances 0.000 description 1
230000004872 arterial blood pressure Effects 0.000 description 1
238000003556 assay Methods 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
NZUPCNDJBJXXRF-UHFFFAOYSA-O bethanechol Chemical compound C[N+](C)(C)CC(C)OC(N)=O NZUPCNDJBJXXRF-UHFFFAOYSA-O 0.000 description 1
229960000910 bethanechol Drugs 0.000 description 1
230000015572 biosynthetic process Effects 0.000 description 1
230000008499 blood brain barrier function Effects 0.000 description 1
210000001218 blood-brain barrier Anatomy 0.000 description 1
230000037396 body weight Effects 0.000 description 1
208000006218 bradycardia Diseases 0.000 description 1
230000036471 bradycardia Effects 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
210000000621 bronchi Anatomy 0.000 description 1
206010006451 bronchitis Diseases 0.000 description 1
230000007883 bronchodilation Effects 0.000 description 1
239000001110 calcium chloride Substances 0.000 description 1
235000011148 calcium chloride Nutrition 0.000 description 1
229910001628 calcium chloride Inorganic materials 0.000 description 1
IGWCIHCQFSETGG-UHFFFAOYSA-N carbonochloridic acid;hydron;chloride Chemical compound Cl.OC(Cl)=O IGWCIHCQFSETGG-UHFFFAOYSA-N 0.000 description 1
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
150000003857 carboxamides Chemical class 0.000 description 1
210000001168 carotid artery common Anatomy 0.000 description 1
239000000969 carrier Substances 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
238000005119 centrifugation Methods 0.000 description 1
238000007385 chemical modification Methods 0.000 description 1
FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
238000013375 chromatographic separation Methods 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
208000007451 chronic bronchitis Diseases 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
229940126543 compound 14 Drugs 0.000 description 1
229940126142 compound 16 Drugs 0.000 description 1
229940125810 compound 20 Drugs 0.000 description 1
229940125833 compound 23 Drugs 0.000 description 1
229940125878 compound 36 Drugs 0.000 description 1
229940126540 compound 41 Drugs 0.000 description 1
229940125936 compound 42 Drugs 0.000 description 1
229940126545 compound 53 Drugs 0.000 description 1
238000012937 correction Methods 0.000 description 1
239000013058 crude material Substances 0.000 description 1
125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
238000007405 data analysis Methods 0.000 description 1
238000011157 data evaluation Methods 0.000 description 1
230000018044 dehydration Effects 0.000 description 1
238000006297 dehydration reaction Methods 0.000 description 1
125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
230000008034 disappearance Effects 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
231100000673 dose–response relationship Toxicity 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003814 drug Substances 0.000 description 1
239000003937 drug carrier Substances 0.000 description 1
238000009509 drug development Methods 0.000 description 1
206010013781 dry mouth Diseases 0.000 description 1
239000012636 effector Substances 0.000 description 1
210000000105 enteric nervous system Anatomy 0.000 description 1
FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
JPUTTYRVDANTBN-UHFFFAOYSA-N ethyl methanimidate;hydrochloride Chemical compound Cl.CCOC=N JPUTTYRVDANTBN-UHFFFAOYSA-N 0.000 description 1
230000000763 evoking effect Effects 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
239000012530 fluid Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
239000012458 free base Substances 0.000 description 1
238000004108 freeze drying Methods 0.000 description 1
238000011990 functional testing Methods 0.000 description 1
210000000609 ganglia Anatomy 0.000 description 1
230000005176 gastrointestinal motility Effects 0.000 description 1
239000008103 glucose Substances 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
229920000669 heparin Polymers 0.000 description 1
238000000265 homogenisation Methods 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
238000007327 hydrogenolysis reaction Methods 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
150000003949 imides Chemical class 0.000 description 1
230000006872 improvement Effects 0.000 description 1
238000011065 in-situ storage Methods 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
239000002198 insoluble material Substances 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
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
208000002551 irritable bowel syndrome Diseases 0.000 description 1
QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-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
238000002372 labelling Methods 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
238000012417 linear regression Methods 0.000 description 1
RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
210000004072 lung Anatomy 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
150000002688 maleic acid derivatives Chemical class 0.000 description 1
239000003550 marker Substances 0.000 description 1
239000000463 material Substances 0.000 description 1
229940102396 methyl bromide Drugs 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
FLZZNZJENFNFOJ-UHFFFAOYSA-N methyl n'-nitrocarbamimidothioate Chemical compound CSC(N)=N[N+]([O-])=O FLZZNZJENFNFOJ-UHFFFAOYSA-N 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
230000004899 motility Effects 0.000 description 1
YCJZWBZJSYLMPB-UHFFFAOYSA-N n-(2-chloropyrimidin-4-yl)-2,5-dimethyl-1-phenylimidazole-4-carboxamide Chemical compound CC=1N(C=2C=CC=CC=2)C(C)=NC=1C(=O)NC1=CC=NC(Cl)=N1 YCJZWBZJSYLMPB-UHFFFAOYSA-N 0.000 description 1
LIEFJQMANXDSCN-UHFFFAOYSA-N n-[(2-aminophenyl)methyl]-1-methylpiperidine-4-carboxamide Chemical compound C1CN(C)CCC1C(=O)NCC1=CC=CC=C1N LIEFJQMANXDSCN-UHFFFAOYSA-N 0.000 description 1
ZNFTXGSQWZYIHY-UHFFFAOYSA-N n-[(2-aminophenyl)methyl]-2-(1-methylpiperidin-4-yl)acetamide Chemical compound C1CN(C)CCC1CC(=O)NCC1=CC=CC=C1N ZNFTXGSQWZYIHY-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
230000001537 neural effect Effects 0.000 description 1
239000002687 nonaqueous vehicle Substances 0.000 description 1
229940098462 oral drops Drugs 0.000 description 1
210000000056 organ Anatomy 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical class C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
230000035515 penetration Effects 0.000 description 1
208000011906 peptic ulcer disease Diseases 0.000 description 1
150000002978 peroxides Chemical class 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
239000012286 potassium permanganate Substances 0.000 description 1
FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
230000002265 prevention Effects 0.000 description 1
238000000746 purification Methods 0.000 description 1
206010037628 pylorospasm Diseases 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000012216 screening Methods 0.000 description 1
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
239000012453 solvate Substances 0.000 description 1
239000002731 stomach secretion inhibitor Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000005720 sucrose Substances 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
150000003512 tertiary amines Chemical group 0.000 description 1
125000001302 tertiary amino group Chemical group 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 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
125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
230000001960 triggered effect Effects 0.000 description 1
239000008215 water for injection Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- 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
- 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
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
- 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. cocaine
- 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
- C07D451/14—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 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Pulmonology (AREA)
Endocrinology (AREA)
Reproductive Health (AREA)
Epidemiology (AREA)
Urology & Nephrology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Plural Heterocyclic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Hydrogenated Pyridines (AREA)
Indole Compounds (AREA)
Quinoline Compounds (AREA)
Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Photoreceptors In Electrophotography (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Thiazole And Isothizaole Compounds (AREA)

IL9325790A 1989-02-06 1990-02-02 History of trotocycles containing nitrogen, their preparation and pharmaceutical preparations containing them IL93257A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
IT8919316A IT1228293B (it)	1989-02-06	1989-02-06	Benzoderivati di composti eterociclici contenenti azoto.

Publications (2)

Publication Number	Publication Date
IL93257A0 IL93257A0 (en)	1990-11-29
IL93257A true IL93257A (en)	1994-07-31

Family

ID=11156671

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9325790A IL93257A (en)	1989-02-06	1990-02-02	History of trotocycles containing nitrogen, their preparation and pharmaceutical preparations containing them

Country Status (23)

Country	Link
US (1)	US5106851A (pl)
EP (1)	EP0382687B1 (pl)
JP (1)	JPH03197462A (pl)
KR (1)	KR900012919A (pl)
AT (1)	ATE132140T1 (pl)
AU (1)	AU623733B2 (pl)
CA (1)	CA2009300A1 (pl)
CZ (1)	CZ277886B6 (pl)
DE (1)	DE69024381T2 (pl)
DK (1)	DK0382687T3 (pl)
ES (1)	ES2081966T3 (pl)
FI (1)	FI96686C (pl)
GR (1)	GR3018549T3 (pl)
HU (2)	HUT54118A (pl)
IL (1)	IL93257A (pl)
IT (1)	IT1228293B (pl)
MX (1)	MX19368A (pl)
NO (1)	NO173500C (pl)
PL (1)	PL162682B1 (pl)
PT (1)	PT93066B (pl)
RU (1)	RU2040524C1 (pl)
YU (1)	YU21590A (pl)
ZA (1)	ZA90825B (pl)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1226389B (it) *	1988-07-12	1991-01-15	Angeli Inst Spa	Nuovi derivati ammidinici e guanidinici
US5225419A (en) *	1989-10-14	1993-07-06	John Wyeth & Brother, Limited	Certain 1,8-ethano or propano-1,4-dihydro-4-oxo-quinoline-3-carboxamides and derivatives thereof
GB2236751B (en) *	1989-10-14	1993-04-28	Wyeth John & Brother Ltd	Heterocyclic compounds
HU211081B (en) *	1990-12-18	1995-10-30	Sandoz Ag	Process for producing indole derivatives as serotonin antagonists and pharmaceutical compositions containing the same
JPH0692948A (ja) *	1992-03-04	1994-04-05	Snow Brand Milk Prod Co Ltd	新規なアセタミド誘導体及びその用途
JPH05310732A (ja) *	1992-03-12	1993-11-22	Mitsubishi Kasei Corp	シンノリン−３−カルボン酸誘導体
JP2699794B2 (ja) *	1992-03-12	1998-01-19	三菱化学株式会社	チエノ〔３，２−ｂ〕ピリジン誘導体
WO1994012497A1 (fr) *	1992-11-20	1994-06-09	Taisho Pharmaceutical Co., Ltd.	Compose heterocyclique
US5340826A (en) *	1993-02-04	1994-08-23	Pfizer Inc.	Pharmaceutical agents for treatment of urinary incontinence
KR970701191A (ko) *	1994-02-28	1997-03-17	우에하라 아키라	복소환 화합물
JP3829879B2 (ja) *	1994-05-18	2006-10-04	大正製薬株式会社	キノリンカルボン酸誘導体
CA2196979A1 (en) *	1994-08-25	1996-02-29	T. Y. Shen	7-azabicyclo¬2.2.1\|-heptane and -heptene derivatives as cholinergic receptor ligands
NO2005012I1 (no) *	1994-12-28	2005-06-06	Debio Rech Pharma Sa	Triptorelin og farmasoytisk akseptable salter derav
EE9900034A (et) *	1996-07-29	1999-08-16	Pharmacia & Upjohn Ab	Arüültsükloalkaankarboksüülestrid, nende kasutamine, farmatseutilised kompositsioonid ja valmistamine
CA2391498A1 (en) *	1999-11-18	2001-05-25	Antexpharma, Inc.	Substituted 1-benzazepines and derivatives thereof
FR2801310B1 (fr) *	1999-11-24	2004-04-16	Adir	NOUVEAUX DERIVES DE DIHYDROFURO-[3,4-b]QUINOLEIN-1-ONES, LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT
US6451813B1 (en)	2001-01-26	2002-09-17	R. T. Alamo Ventures I, Llc	Treatment of gastroparesis in certain patient groups
MXPA03009894A (es) *	2001-06-19	2004-02-17	Warner Lambert Co	Agentes antibacterianos.
EP1500652A4 (en) *	2002-04-26	2006-05-03	Nippon Shinyaku Co Ltd	DERIVATIVE AND MEDICINAL PRODUCT OF QUINAZOLINE
DE10255040A1 (de) *	2002-11-26	2004-06-03	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Neue Carbaminsäureester mit anticholinerger Wirksamkeit
ES2338882T3 (es) *	2003-11-24	2010-05-13	Pfizer, Inc.	Compuestos de acido quinolona-carboxilico que tienen actividad agonista del receptor 5-ht4.
ATE531367T1 (de) *	2004-09-17	2011-11-15	Whitehead Biomedical Inst	Verbindungen, zusammensetzungen und verfahren zur verhinderung einer a-synuklein-vergiftung
DK2217597T3 (da) *	2007-10-01	2011-06-20	Comentis Inc	Quinuclidin-4-ylmethyl-1h-indol-3-carboxylatderivater som alpha-7-nicotin-acetylcholin-receptor-ligander til behandling af Alzheimers sygdom
US9145396B2 (en)	2008-12-01	2015-09-29	Targacept, Inc.	Synthesis and novel salt forms of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine
LT2685986T (lt) *	2011-03-18	2020-03-10	Genzyme Corporation	Gliukozilceramido sintazės slopiklis
MA37975B2 (fr)	2012-09-11	2021-03-31	Genzyme Corp	Inhibiteurs de synthase de glucosylcéramide
TW201617342A (zh)	2014-07-11	2016-05-16	阿法馬根公司	調節α７活性之啶類
US11377452B2 (en)	2017-01-16	2022-07-05	Drexel University	Glutamate transporter activators and methods using same
PT3920912T (pt)	2019-02-04	2025-09-09	Genzyme Corp	Tratamento de ciliopatias usando inibidores da glucosilceramida sintase (gcs)
IL295255A (en)	2020-02-03	2022-10-01	Genzyme Corp	Methods for treating neurological symptoms associated with lysosomal storage diseases
IL300090A (en)	2020-07-24	2023-03-01	Genzyme Corp	Pharmaceutical preparations containing VENGLUSTAT

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4284768A (en) *	1980-07-02	1981-08-18	American Home Products Corporation	1,2-Dihydro-4-amino-2-oxo-3-quinoline-carboxylic acid derivatives
IE52670B1 (en) *	1981-03-03	1988-01-20	Leo Ab	Heterocyclic carboxamides,compositions containing such compounds,and processes for their preparation
WO1984001151A1 (en) *	1982-09-24	1984-03-29	Beecham Group Plc	Amino-azabicycloalkyl derivatives as dopamine antagonists
US4599336A (en) *	1983-08-08	1986-07-08	Hoffmann-La Roche Inc.	Derivatives of (E)-3-(4-oxo-4H-quinazolin-3-yl)-2-propenamide
DE3429830A1 (de) *	1983-08-26	1985-03-07	Sandoz-Patent-GmbH, 7850 Lörrach	Automatische carbonsaeure- und sulfonsaeureester oder -amide
US4849513A (en) *	1983-12-20	1989-07-18	California Institute Of Technology	Deoxyribonucleoside phosphoramidites in which an aliphatic amino group is attached to the sugar ring and their use for the preparation of oligonucleotides containing aliphatic amino groups
GB8623142D0 (en) *	1986-09-26	1986-10-29	Beecham Group Plc	Compounds
DK623586A (da) *	1985-12-27	1987-06-28	Eisai Co Ltd	Piperidinderivater eller salte deraf og farmaceutiske kompositioner indeholdende forbindelserne

1989
- 1989-02-06 IT IT8919316A patent/IT1228293B/it active
1990
- 1990-01-24 CZ CS90335A patent/CZ277886B6/cs unknown
- 1990-02-02 MX MX1936890A patent/MX19368A/es unknown
- 1990-02-02 IL IL9325790A patent/IL93257A/en not_active IP Right Cessation
- 1990-02-02 US US07/474,187 patent/US5106851A/en not_active Expired - Fee Related
- 1990-02-05 FI FI900553A patent/FI96686C/fi not_active IP Right Cessation
- 1990-02-05 ZA ZA90825A patent/ZA90825B/xx unknown
- 1990-02-05 PL PL28364290A patent/PL162682B1/pl unknown
- 1990-02-05 JP JP2025889A patent/JPH03197462A/ja active Pending
- 1990-02-05 AT AT90830040T patent/ATE132140T1/de not_active IP Right Cessation
- 1990-02-05 NO NO900542A patent/NO173500C/no unknown
- 1990-02-05 DK DK90830040.3T patent/DK0382687T3/da active
- 1990-02-05 HU HU90671A patent/HUT54118A/hu unknown
- 1990-02-05 DE DE69024381T patent/DE69024381T2/de not_active Expired - Fee Related
- 1990-02-05 YU YU21590A patent/YU21590A/sh unknown
- 1990-02-05 ES ES90830040T patent/ES2081966T3/es not_active Expired - Lifetime
- 1990-02-05 CA CA002009300A patent/CA2009300A1/en not_active Abandoned
- 1990-02-05 AU AU49086/90A patent/AU623733B2/en not_active Ceased
- 1990-02-05 PT PT93066A patent/PT93066B/pt not_active IP Right Cessation
- 1990-02-05 EP EP90830040A patent/EP0382687B1/en not_active Expired - Lifetime
- 1990-02-05 KR KR1019900001319A patent/KR900012919A/ko not_active Ceased
1992
- 1992-05-08 RU SU925011529A patent/RU2040524C1/ru active
1994
- 1994-11-21 HU HU94P/P00048P patent/HU210348A9/hu unknown
1995
- 1995-12-28 GR GR950403474T patent/GR3018549T3/el unknown

Also Published As

Publication number	Publication date
HU900671D0 (en)	1990-04-28
AU623733B2 (en)	1992-05-21
GR3018549T3 (en)	1996-03-31
FI96686C (fi)	1996-08-12
HUT54118A (en)	1991-01-28
DE69024381T2 (de)	1996-05-15
AU4908690A (en)	1990-10-25
NO900542L (no)	1990-08-07
DE69024381D1 (de)	1996-02-08
NO173500B (no)	1993-09-13
PL162682B1 (pl)	1993-12-31
RU2040524C1 (ru)	1995-07-25
FI900553A0 (fi)	1990-02-05
HU210348A9 (en)	1995-03-28
CZ33590A3 (en)	1993-02-17
IT1228293B (it)	1991-06-07
CA2009300A1 (en)	1990-08-06
ES2081966T3 (es)	1996-03-16
KR900012919A (ko)	1990-09-03
ATE132140T1 (de)	1996-01-15
PL283642A1 (en)	1991-02-11
IL93257A0 (en)	1990-11-29
US5106851A (en)	1992-04-21
EP0382687A3 (en)	1991-12-04
MX19368A (es)	1993-09-01
JPH03197462A (ja)	1991-08-28
FI96686B (fi)	1996-04-30
YU21590A (sh)	1993-05-28
EP0382687A2 (en)	1990-08-16
NO173500C (no)	1993-12-22
EP0382687B1 (en)	1995-12-27
CZ277886B6 (en)	1993-06-16
NO900542D0 (no)	1990-02-05
ZA90825B (en)	1991-10-30
IT8919316A0 (it)	1989-02-06
DK0382687T3 (da)	1996-02-05
PT93066A (pt)	1990-08-31
PT93066B (pt)	1997-01-31

Legal Events

Date	Code	Title	Description
1996-05-14	KB	Patent renewed
2001-06-14	RH	Patent void

Publication	Publication Date	Title
EP0382687B1 (en)	1995-12-27	Benzofused-N-containing heterocycle derivatives
CA1337347C (en)	1995-10-17	Benzimidazoline-2-one-1-carboxylic acid derivatives useful as 5-ht receptor antagonists
EP0313393B1 (en)	1994-03-16	Benzoxazine compounds and pharmaceutical use thereof
US5358954A (en)	1994-10-25	Benzimidazoline-2-oxo-1-carboxylic acid derivatives useful as 5-HT receptor antagonists
HK1007143B (en)	1999-04-01	Benzoxazine compounds and pharmaceutical use thereof
EP0530353A1 (en)	1993-03-10	New imidazopyridines as serotonergic 5-ht 3? antagonists
ZA200208969B (en)	2003-10-07	Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists.
US5164386A (en)	1992-11-17	R(-)3-quinuclidinol derivatives
US5047410A (en)	1991-09-10	Indolyl derivatives and their use as 5-HT3, receptor antagonists
EP0493031B1 (en)	1995-08-30	Dihydrobenzofuran carboxamides and process for their preparation
MXPA98000620A (en)	1998-04-01	(r) -5-bromo-n- (1-ethyl-4-methylhexahidro-1h-1,4-diazepin-6-il) -2-metoxy-6-methylamin-3-pyridincarboxamide, process for preparation of the same and pharmaceutical composition containing such compue
EP0309424A2 (en)	1989-03-29	New amidino derivatives
US4973592A (en)	1990-11-27	1,3-diazocycloalkenes as muscarinic receptor blocking agents
US6413978B1 (en)	2002-07-02	Basic derivatives of benz[e] isoindol-1-ones and pyrrolo[3,4-c] quinolin-1-ones with 5-HT3-antagonistic activity, their preparation and their therapeutic use
US5552408A (en)	1996-09-03	Benzimidazoline-2-oxo-1-carboxylic acid derivatives useful as 5-ht receptor antagonists
US5252570A (en)	1993-10-12	Amidino and guanidino derivatives
JP2002509151A (ja)	2002-03-26	ニューロキニンアンタゴニストとしてのピペラジノ誘導体
DD297815A5 (de)	1992-05-07	Ir-prismenspektrometer
HU210353A9 (hu)	1995-03-28	Új triciklusos vegyületek és ezeket tartalmazó gyógyszerkészítmények Az átmeneti oltalom a(z) 1-43. és 48. igénypontokra vonatkozik.