IL102665A - History of benzimidazolone, their preparation and pharmaceutical preparations containing them - Google Patents
History of benzimidazolone, their preparation and pharmaceutical preparations containing themInfo
- Publication number
- IL102665A IL102665A IL10266592A IL10266592A IL102665A IL 102665 A IL102665 A IL 102665A IL 10266592 A IL10266592 A IL 10266592A IL 10266592 A IL10266592 A IL 10266592A IL 102665 A IL102665 A IL 102665A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- alkyl
- benzimidazol
- formula
- dihydro
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 150000008641 benzimidazolones Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- -1 hydroxy, nitro, amino Chemical group 0.000 claims abstract description 62
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000002253 acid Substances 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 230000008569 process Effects 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 4
- 125000004442 acylamino group Chemical group 0.000 claims abstract description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims abstract description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 4
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract 2
- 125000002252 acyl group Chemical group 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 20
- 239000004480 active ingredient Substances 0.000 claims description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 13
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052727 yttrium Inorganic materials 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 208000028017 Psychotic disease Diseases 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 230000007958 sleep Effects 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 208000019022 Mood disease Diseases 0.000 claims description 2
- 208000027626 Neurocognitive disease Diseases 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 206010027175 memory impairment Diseases 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 claims description 2
- 208000022821 personality disease Diseases 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 201000000980 schizophrenia Diseases 0.000 claims description 2
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 2
- 208000015891 sexual disease Diseases 0.000 claims description 2
- 208000019116 sleep disease Diseases 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 108091005479 5-HT2 receptors Proteins 0.000 abstract description 13
- 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 abstract description 12
- 102000017911 HTR1A Human genes 0.000 abstract description 11
- 101150015707 HTR1A gene Proteins 0.000 abstract description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 4
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 abstract description 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract description 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000004475 heteroaralkyl group Chemical group 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 description 94
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 51
- 238000004458 analytical method Methods 0.000 description 46
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 44
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000007792 addition Methods 0.000 description 13
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 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 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 101150041968 CDC13 gene Proteins 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 229960001866 silicon dioxide Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000011118 potassium hydroxide Nutrition 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 208000011580 syndromic disease Diseases 0.000 description 6
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 5
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 5
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 230000003542 behavioural effect Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 229960004132 diethyl ether Drugs 0.000 description 5
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229950002315 quipazine Drugs 0.000 description 4
- 239000002287 radioligand Substances 0.000 description 4
- 230000000862 serotonergic effect Effects 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- 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 3
- KKIMDKMETPPURN-UHFFFAOYSA-N 1-(3-(trifluoromethyl)phenyl)piperazine Chemical compound FC(F)(F)C1=CC=CC(N2CCNCC2)=C1 KKIMDKMETPPURN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 3
- 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 3
- 206010028347 Muscle twitching Diseases 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 230000036461 convulsion Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008020 evaporation Effects 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
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000003444 phase transfer catalyst Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- XRXDAJYKGWNHTQ-UHFFFAOYSA-N quipazine Chemical compound C1CNCCN1C1=CC=C(C=CC=C2)C2=N1 XRXDAJYKGWNHTQ-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- HLJJJPMNIFNKCI-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCCl)C2=C1 HLJJJPMNIFNKCI-UHFFFAOYSA-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
- IDTLKMNKJYQAMF-UHFFFAOYSA-N 3-hexyl-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCCC)C2=C1 IDTLKMNKJYQAMF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000005741 alkyl alkenyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 125000005018 aryl alkenyl group Chemical group 0.000 description 2
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 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
- CJYQQUPRURWLOW-YDLUHMIOSA-M dmsc Chemical compound [Na+].OP(=O)=O.OP(=O)=O.OP(=O)=O.[O-]P(=O)=O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O CJYQQUPRURWLOW-YDLUHMIOSA-M 0.000 description 2
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- WTIBKFFJLHLMKQ-UHFFFAOYSA-N n-(2-nitrophenyl)-3-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]propanamide Chemical compound [O-][N+](=O)C1=CC=CC=C1NC(=O)CCN1CCN(C=2C=C(C=CC=2)C(F)(F)F)CC1 WTIBKFFJLHLMKQ-UHFFFAOYSA-N 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-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
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-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
- 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 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- KPJZHOPZRAFDTN-ZRGWGRIASA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CN(C)C3=C1 KPJZHOPZRAFDTN-ZRGWGRIASA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 description 1
- DDMVHGULHRJOEC-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazin-1-ium;chloride Chemical compound Cl.COC1=CC=CC=C1N1CCNCC1 DDMVHGULHRJOEC-UHFFFAOYSA-N 0.000 description 1
- BENCLFCNPNTFBE-UHFFFAOYSA-N 1-(4-chlorobutyl)-3-hexylbenzimidazol-2-one Chemical compound C1=CC=C2N(CCCCCl)C(=O)N(CCCCCC)C2=C1 BENCLFCNPNTFBE-UHFFFAOYSA-N 0.000 description 1
- RENXQAJCFHGSQK-UHFFFAOYSA-N 1-(4-chlorobutyl)-4-[3-(trifluoromethyl)phenyl]piperazine Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCCCCl)CC2)=C1 RENXQAJCFHGSQK-UHFFFAOYSA-N 0.000 description 1
- BWKNRDTYLWSCHP-UHFFFAOYSA-N 1-(6-chlorohexyl)-3-ethylbenzimidazol-2-one Chemical compound C1=CC=C2N(CCCCCCCl)C(=O)N(CC)C2=C1 BWKNRDTYLWSCHP-UHFFFAOYSA-N 0.000 description 1
- IXQLYZNGLMLQMF-UHFFFAOYSA-N 1-(6-chlorohexyl)-4-[3-(trifluoromethyl)phenyl]piperazine Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCCCCCCl)CC2)=C1 IXQLYZNGLMLQMF-UHFFFAOYSA-N 0.000 description 1
- XDYRIGIBUWJCMR-UHFFFAOYSA-N 1-(7-methoxynaphthalen-1-yl)piperazine Chemical compound C12=CC(OC)=CC=C2C=CC=C1N1CCNCC1 XDYRIGIBUWJCMR-UHFFFAOYSA-N 0.000 description 1
- CXUCKELNYMZTRT-UHFFFAOYSA-N 1-Ethyl-2-benzimidazolinone Chemical compound C1=CC=C2NC(=O)N(CC)C2=C1 CXUCKELNYMZTRT-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- CUNQGKJRBAFZDG-UHFFFAOYSA-N 1-[1-chloro-4-(3-chlorophenyl)butyl]piperazine Chemical compound C1CNCCN1C(Cl)CCCC1=CC=CC(Cl)=C1 CUNQGKJRBAFZDG-UHFFFAOYSA-N 0.000 description 1
- YEDMDYKUSNYAOP-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]-1,4-diazepan-5-one Chemical compound FC(F)(F)C1=CC=CC(N2CCC(=O)NCC2)=C1 YEDMDYKUSNYAOP-UHFFFAOYSA-N 0.000 description 1
- GJNJTHXNDBRXOJ-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]-1,4-diazepan-5-one;1-[3-(trifluoromethyl)phenyl]piperidin-4-one Chemical compound FC(F)(F)C1=CC=CC(N2CCC(=O)CC2)=C1.FC(F)(F)C1=CC=CC(N2CCC(=O)NCC2)=C1 GJNJTHXNDBRXOJ-UHFFFAOYSA-N 0.000 description 1
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 1
- ONOBXDPYDHTSBQ-UHFFFAOYSA-N 2,3,4,7-tetrahydro-1h-diazepine Chemical compound C1CC=CCNN1 ONOBXDPYDHTSBQ-UHFFFAOYSA-N 0.000 description 1
- QUIMTLZDMCNYGY-UHFFFAOYSA-N 2,4-dichloro-1-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1Cl QUIMTLZDMCNYGY-UHFFFAOYSA-N 0.000 description 1
- IJCLNXZKUXGTRV-UHFFFAOYSA-N 2-(4-piperazin-1-ylbutyl)-1h-indole Chemical class C=1C2=CC=CC=C2NC=1CCCCN1CCNCC1 IJCLNXZKUXGTRV-UHFFFAOYSA-N 0.000 description 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 1
- YDJUKXZGPAOCSN-UHFFFAOYSA-N 2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethanamine Chemical compound C1CN(CCN)CCN1C1=CC=CC(C(F)(F)F)=C1 YDJUKXZGPAOCSN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 description 1
- 125000005999 2-bromoethyl group Chemical group 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- IDWYSAREIIUVTA-UHFFFAOYSA-N 2-n-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-4-methylbenzene-1,2-diamine Chemical compound COC1=CC=CC=C1N1CCN(CCCCNC=2C(=CC=C(C)C=2)N)CC1 IDWYSAREIIUVTA-UHFFFAOYSA-N 0.000 description 1
- CHXZHWFUIKBIMT-UHFFFAOYSA-N 2-n-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzene-1,2-diamine Chemical compound COC1=CC=CC=C1N1CCN(CCCCNC=2C(=CC=CC=2)N)CC1 CHXZHWFUIKBIMT-UHFFFAOYSA-N 0.000 description 1
- NVYNJPNJFJSQKA-UHFFFAOYSA-N 3-(2-bromoethyl)-5-methoxy-1h-benzimidazol-2-one;propanoic acid Chemical compound CCC(O)=O.COC1=CC=C2NC(=O)N(CCBr)C2=C1 NVYNJPNJFJSQKA-UHFFFAOYSA-N 0.000 description 1
- GUMPYDGUYXOYML-UHFFFAOYSA-N 3-(3-chloropropyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCl)C2=C1 GUMPYDGUYXOYML-UHFFFAOYSA-N 0.000 description 1
- YUEFDNLBCOAMOH-UHFFFAOYSA-N 3-(4-bromobutyl)-5-methoxy-1h-benzimidazol-2-one;propanoic acid Chemical compound CCC(O)=O.COC1=CC=C2NC(=O)N(CCCCBr)C2=C1 YUEFDNLBCOAMOH-UHFFFAOYSA-N 0.000 description 1
- ACPINKPMBDDALZ-UHFFFAOYSA-N 3-(6-chlorohexyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCCCCl)C2=C1 ACPINKPMBDDALZ-UHFFFAOYSA-N 0.000 description 1
- OTHMTHMLWGZJCQ-UHFFFAOYSA-N 3-amino-5-[4-(diethylamino)phenyl]-2-phenyl-5-(trifluoromethyl)-1h-pyrazole-4-carbonitrile Chemical compound C1=CC(N(CC)CC)=CC=C1C1(C(F)(F)F)C(C#N)=C(N)N(C=2C=CC=CC=2)N1 OTHMTHMLWGZJCQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XTWCBQJUPQCPEG-UHFFFAOYSA-N 3-bromo-n-(2-nitrophenyl)propanamide Chemical compound [O-][N+](=O)C1=CC=CC=C1NC(=O)CCBr XTWCBQJUPQCPEG-UHFFFAOYSA-N 0.000 description 1
- GHVRHFCPWGXLDQ-UHFFFAOYSA-N 3-methyl-2-oxobenzimidazole-1-carbonyl chloride Chemical compound C1=CC=C2N(C(Cl)=O)C(=O)N(C)C2=C1 GHVRHFCPWGXLDQ-UHFFFAOYSA-N 0.000 description 1
- VNOSSYFMRHFCMZ-UHFFFAOYSA-N 4,5-dichloro-2-n-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzene-1,2-diamine Chemical compound COC1=CC=CC=C1N1CCN(CCCCNC=2C(=CC(Cl)=C(Cl)C=2)N)CC1 VNOSSYFMRHFCMZ-UHFFFAOYSA-N 0.000 description 1
- UFJPFLDFMPVGRW-UHFFFAOYSA-N 4-[4-(2-methoxyphenyl)piperazin-1-yl]butan-1-amine Chemical compound COC1=CC=CC=C1N1CCN(CCCCN)CC1 UFJPFLDFMPVGRW-UHFFFAOYSA-N 0.000 description 1
- QFMJFXFXQAFGBO-UHFFFAOYSA-N 4-methoxy-2-nitroaniline Chemical compound COC1=CC=C(N)C([N+]([O-])=O)=C1 QFMJFXFXQAFGBO-UHFFFAOYSA-N 0.000 description 1
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- NQRKJSHTYJKKPE-UHFFFAOYSA-N 5-chloro-n-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-2-nitroaniline Chemical compound COC1=CC=CC=C1N1CCN(CCCCNC=2C(=CC=C(Cl)C=2)[N+]([O-])=O)CC1 NQRKJSHTYJKKPE-UHFFFAOYSA-N 0.000 description 1
- KAMRZHLJWBJZSE-UHFFFAOYSA-N 5-methoxy-1,3-dihydrobenzimidazol-2-one;propanoic acid Chemical compound CCC(O)=O.COC1=CC=C2NC(=O)NC2=C1 KAMRZHLJWBJZSE-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
- 101150067539 AMBP gene Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 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
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229960001186 methysergide Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- ZZTNOAYFPGTHOC-UHFFFAOYSA-N n-(2-aminophenyl)-3-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]propanamide Chemical compound NC1=CC=CC=C1NC(=O)CCN1CCN(C=2C=C(C=CC=2)C(F)(F)F)CC1 ZZTNOAYFPGTHOC-UHFFFAOYSA-N 0.000 description 1
- WHEYNZIWQZIXHP-UHFFFAOYSA-N n-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]-5-methyl-2-nitroaniline;hydrochloride Chemical compound Cl.COC1=CC=CC=C1N1CCN(CCCCNC=2C(=CC=C(C)C=2)[N+]([O-])=O)CC1 WHEYNZIWQZIXHP-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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical compound C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- NFXCUPVBISCOSF-UHFFFAOYSA-N propan-2-ol;dihydrochloride Chemical compound Cl.Cl.CC(C)O NFXCUPVBISCOSF-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229960001407 sodium bicarbonate Drugs 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ZOQXFEWZVKMARY-UHFFFAOYSA-N tris[3-(trifluoromethyl)phenyl]bismuthane Chemical compound FC(F)(F)C1=CC=CC([Bi](C=2C=C(C=CC=2)C(F)(F)F)C=2C=C(C=CC=2)C(F)(F)F)=C1 ZOQXFEWZVKMARY-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen atoms
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Compositions Of Macromolecular Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI912118A IT1251144B (it) | 1991-07-30 | 1991-07-30 | Derivati del benzimidazolone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL102665A true IL102665A (en) | 1996-10-31 |
Family
ID=11360463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10266592A IL102665A (en) | 1991-07-30 | 1992-07-28 | History of benzimidazolone, their preparation and pharmaceutical preparations containing them |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US5576318A (et) |
| EP (1) | EP0526434B1 (et) |
| JP (1) | JP2989667B2 (et) |
| KR (1) | KR100263495B1 (et) |
| AT (1) | ATE191910T1 (et) |
| AU (1) | AU665366B2 (et) |
| CA (1) | CA2114542C (et) |
| CZ (1) | CZ281511B6 (et) |
| DE (1) | DE69230926T2 (et) |
| DK (1) | DK0526434T3 (et) |
| EE (1) | EE03070B1 (et) |
| ES (1) | ES2144412T3 (et) |
| FI (1) | FI111460B (et) |
| GR (1) | GR3033947T3 (et) |
| HK (1) | HK1010725A1 (et) |
| HU (2) | HUT70195A (et) |
| IE (1) | IE922464A1 (et) |
| IL (1) | IL102665A (et) |
| IT (1) | IT1251144B (et) |
| MX (1) | MX9204139A (et) |
| NO (1) | NO304070B1 (et) |
| NZ (1) | NZ243777A (et) |
| PH (1) | PH30998A (et) |
| PL (1) | PL171329B1 (et) |
| PT (1) | PT526434E (et) |
| RU (1) | RU2096411C1 (et) |
| SG (1) | SG52407A1 (et) |
| SK (1) | SK279292B6 (et) |
| TW (1) | TW209862B (et) |
| UA (1) | UA42684C2 (et) |
| WO (1) | WO1993003016A1 (et) |
| ZA (1) | ZA925682B (et) |
Families Citing this family (80)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1251144B (it) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | Derivati del benzimidazolone |
| US5266571A (en) * | 1992-01-09 | 1993-11-30 | Amer Moh Samir | Treatment of hemorrhoids with 5-HT2 antagonists |
| SE9201138D0 (sv) * | 1992-04-09 | 1992-04-09 | Astra Ab | Novel phthalimidoalkylpiperazines |
| DK148392D0 (da) * | 1992-12-09 | 1992-12-09 | Lundbeck & Co As H | Heterocykliske forbindelser |
| AU6391894A (en) * | 1993-03-16 | 1994-10-11 | Pfizer Inc. | Naphthalene derivatives |
| JP3719612B2 (ja) * | 1993-06-14 | 2005-11-24 | 塩野義製薬株式会社 | ヘテロ環を含有する尿素誘導体 |
| ZA954688B (en) | 1994-06-08 | 1996-01-29 | Lundbeck & Co As H | Serotonin 5-HT1A and dopamin D2 receptor ligands |
| ATE206708T1 (de) * | 1994-06-14 | 2001-10-15 | Pfizer | Benzimidazolonderivate mit zentraler dopaminerger aktivität |
| DE69530988T2 (de) * | 1994-08-05 | 2003-12-04 | Pfizer | Benzimidazolderivate mit dopaminerger wirkung |
| US5883094A (en) * | 1995-04-24 | 1999-03-16 | Pfizer Inc. | Benzimidazolone derivatives with central dopaminergic activity |
| US5889010A (en) * | 1995-05-18 | 1999-03-30 | Pfizer Inc. | Benzimidazole derivatives having dopaminergic activity |
| WO1997016187A1 (en) * | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Muscarine antagonists |
| EP1087954A1 (en) * | 1998-06-15 | 2001-04-04 | American Home Products Corporation | Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents |
| US6376494B1 (en) | 1998-06-15 | 2002-04-23 | American Home Products Corporation | Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents |
| AR022303A1 (es) | 1999-01-22 | 2002-09-04 | Lundbeck & Co As H | Derivados de piperidina, tetrahidropiridina y piperazina, su preparacion y utilizacion |
| IT1313625B1 (it) * | 1999-09-22 | 2002-09-09 | Boehringer Ingelheim Italia | Derivati benzimidazolonici aventi affinita' mista per i recettori diserotonina e dopamina. |
| MXPA03002370A (es) * | 2000-09-19 | 2003-10-15 | Boehringer Ingelheim Pharma | Nuevos derivados bencimidazolona n,n'-disustituidos con afinidad en los receptores de serotonina y dopamina. |
| ATE341538T1 (de) * | 2000-09-19 | 2006-10-15 | Boehringer Ingelheim Pharma | Benzimidazolonderivate mit affinität zu serotonin-und dopaminrezeptoren |
| US6586435B2 (en) | 2000-09-19 | 2003-07-01 | Boehringer Ingelheim Pharma Kg | Benzimidazolone derivatives displaying affinity at the serotonin and dopamine receptors |
| US6521623B1 (en) | 2000-09-19 | 2003-02-18 | Boehringer Ingelheim Pharma Kg | N,N'-disubstituted benzimidazolone derivatives with affinity at the serotonin and dopamine receptors |
| EP1408976B3 (en) | 2001-07-20 | 2010-08-25 | Psychogenics Inc. | Treatment for attention-deficit hyperactivity disorder |
| US7183410B2 (en) * | 2001-08-02 | 2007-02-27 | Bidachem S.P.A. | Stable polymorph of flibanserin |
| CA2450093C (en) * | 2001-08-02 | 2008-09-23 | Bidachem S.P.A. | Stable polymorph of flibanserin, technical process for its preparation and the use thereof for preparing medicaments |
| DE10138273A1 (de) * | 2001-08-10 | 2003-02-27 | Boehringer Ingelheim Pharma | Arzneimittel mit neuroprotektiver Wirkung |
| US20030060475A1 (en) * | 2001-08-10 | 2003-03-27 | Boehringer Ingelheim Pharma Kg | Method of using flibanserin for neuroprotection |
| UA78974C2 (en) * | 2001-10-20 | 2007-05-10 | Boehringer Ingelheim Pharma | Use of flibanserin for treating disorders of sexual desire |
| US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
| MEP55308A (en) * | 2002-05-22 | 2011-05-10 | Boehringer Ingelheim Pharma | New pharmaceutical compositions containing flibanserin polymorph a |
| US20040048877A1 (en) * | 2002-05-22 | 2004-03-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions containing flibanserin |
| BR0314393A (pt) * | 2002-09-17 | 2005-07-19 | Warner Lambert Co | Piperazinas heterocìclicas substituìdas para o tratamento de esquizofrenia |
| ES2377484T3 (es) * | 2003-09-03 | 2012-03-28 | Pfizer, Inc. | Compuestos de bencimidazolona que tiene actividad agonista del receptor 5-HT |
| US20050239798A1 (en) * | 2004-04-22 | 2005-10-27 | Boehringer Ingelheim Pharmaceuticals, Inc. | Method for the treatment of premenstrual and other female sexual disorders |
| BRPI0510074A (pt) * | 2004-04-22 | 2007-10-16 | Boehringer Ingelheim Int | composições farmacêuticas para o tratamento de distúrbios sexuais ii |
| GEP20094638B (en) * | 2004-06-15 | 2009-03-10 | Pfizer | Benzimidazolone carboxylic acid derivatives |
| US7737163B2 (en) * | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
| US20060014757A1 (en) * | 2004-07-14 | 2006-01-19 | Boehringer Ingelheim Pharmaceuticals | Method for the treatment of anorexia nervosa |
| US20060025420A1 (en) * | 2004-07-30 | 2006-02-02 | Boehringer Ingelheimn International GmbH | Pharmaceutical compositions for the treatment of female sexual disorders |
| WO2006024471A1 (en) * | 2004-09-03 | 2006-03-09 | Boehringer Ingelheim International Gmbh | Method for the treatment of attention deficit hyperactivity disorder |
| EA012615B1 (ru) * | 2005-02-22 | 2009-10-30 | Пфайзер Инк. | Производные оксииндола в качестве агонистов 5-htрецептора |
| CA2599721A1 (en) * | 2005-03-04 | 2006-09-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for the treatment and/or prevention of depression |
| WO2006096434A2 (en) * | 2005-03-04 | 2006-09-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for the treatment and/or prevention of anxiety disorders |
| WO2006096439A2 (en) * | 2005-03-04 | 2006-09-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases |
| WO2006119884A2 (en) * | 2005-05-06 | 2006-11-16 | Boehringer Ingelheim International Gmbh | Method for the treatment of drug abuse with flibanserin |
| JP2008540673A (ja) * | 2005-05-19 | 2008-11-20 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 薬剤誘発性性機能不全の治療方法 |
| EP1888070A1 (en) * | 2005-05-19 | 2008-02-20 | Boehringer Ingelheim International GmbH | Method for the treatment of sexual dysfunctions due to medical conditions |
| ES2646326T3 (es) | 2005-08-03 | 2017-12-13 | Sprout Pharmaceuticals, Inc. | Uso de flibanserina en el tratamiento de la obesidad |
| US7790726B2 (en) * | 2005-08-16 | 2010-09-07 | Chemocentryx, Inc. | Monocyclic and bicyclic compounds and methods of use |
| US20070123540A1 (en) * | 2005-10-29 | 2007-05-31 | Angelo Ceci | Sexual desire enhancing medicaments comprising benzimidazolone derivatives |
| CA2626134C (en) * | 2005-10-29 | 2013-12-24 | Boehringer Ingelheim International Gmbh | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
| US20070105869A1 (en) * | 2005-11-08 | 2007-05-10 | Stephane Pollentier | Use of flibanserin for the treatment of pre-menopausal sexual desire disorders |
| US20090176698A1 (en) * | 2006-02-20 | 2009-07-09 | Boehringer Ingelheim International Gmbh | Benzimidazolone Derivatives for the Treatment of Urinary Incontinence |
| WO2007099828A1 (ja) * | 2006-02-23 | 2007-09-07 | Shionogi & Co., Ltd. | 環式基で置換された含窒素複素環誘導体 |
| US20090247546A1 (en) * | 2006-02-28 | 2009-10-01 | Boehringer Ingelheim International Gmbh | Treatment of Prevention of Valvular Heart Disease with Flibanserin |
| JP2009536176A (ja) * | 2006-05-09 | 2009-10-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 閉経後の性的欲求障害の治療のためのフリバンセリンの使用 |
| DE602007004615D1 (de) | 2006-06-30 | 2010-03-18 | Boehringer Ingelheim Pharma | Flibanserin zur behandlung von harninkontinenz und assoziierten erkrankungen |
| WO2008006838A1 (en) * | 2006-07-14 | 2008-01-17 | Boehringer Ingelheim International Gmbh | Use of flibanserin for the treatment of sexual disorders in females |
| AR062320A1 (es) | 2006-08-14 | 2008-10-29 | Boehringer Ingelheim Int | Formulaciones de flibanserina y metodo para fabricarlas |
| CL2007002214A1 (es) | 2006-08-14 | 2008-03-07 | Boehringer Ingelheim Int | Composicion farmaceutica en la forma de comprimido, donde al menos la longitud del comprimido en el estado anterior de la aplicacion es al menos 7/12 del diametro pilorico del paciente y despues de ingerirlo en estado alimentado, la longitud del comp |
| EA200900270A1 (ru) | 2006-08-25 | 2009-08-28 | Бёрингер Ингельхайм Интернациональ Гмбх | Системы регулируемого высвобождения и способ их приготовления |
| ATE524446T1 (de) | 2006-12-20 | 2011-09-15 | Boehringer Ingelheim Int | Sulfatierte benzimidazolon-derivate mit gemischter serotonin-rezeptor-affinität |
| JP5087011B2 (ja) * | 2007-01-23 | 2012-11-28 | 馨 井上 | 眼疾患モデル用非ヒト動物 |
| WO2008140239A1 (en) * | 2007-05-11 | 2008-11-20 | Korea Research Institute Of Chemical Technology | Imidazole derivatives having aryl piperidine substituent, method for preparation thereof and pharmaceutical compositions containing same |
| CL2008002693A1 (es) | 2007-09-12 | 2009-10-16 | Boehringer Ingelheim Int | Uso de flibanserina para el tratamiento de sintomas vasomotores seleccionados de sofocos, sudores nocturnos, cambios de estado de animo e irritabilidad |
| WO2009092720A1 (en) * | 2008-01-24 | 2009-07-30 | Neurosearch A/S | 4-phenyl-piperazin-1-yl-alkyl-benzoimidazol-2-one derivatives and their use as monoamine neurotransmitter re-uptake inhibitors |
| EP2090297A1 (en) | 2008-02-13 | 2009-08-19 | Boehringer Ingelheim International GmbH | Formulations of flibanserin |
| CA2686480A1 (en) * | 2008-12-15 | 2010-06-15 | Boehringer Ingelheim International Gmbh | New salts |
| WO2010146595A2 (en) * | 2009-06-16 | 2010-12-23 | Symed Labs Limited | Novel polymorphs of flibanserin hydrochloride |
| BRPI1003506B1 (pt) | 2010-09-24 | 2019-12-03 | Ache Int Bvi Ltd | composto alquil-piperazino-fenil-4(3h)quinazolinonas e uso do composto alquil-piperazino-fenil-4(3h)quinazolinonas associado aos receptores serotoninérgicos 5-ht1a e 5-ht2a |
| ES2734268T3 (es) * | 2012-10-11 | 2019-12-05 | Southern Res Inst | Derivados de urea y amida de aminoalquilpiperazinas y uso de los mismos |
| CN104926734B (zh) * | 2015-07-07 | 2017-04-05 | 苏州立新制药有限公司 | 氟班色林的制备方法 |
| WO2017076213A1 (zh) * | 2015-11-02 | 2017-05-11 | 苏州旺山旺水生物医药有限公司 | 苯并咪唑类化合物、其制备方法及用途 |
| WO2017076356A1 (zh) * | 2015-11-05 | 2017-05-11 | 苏州晶云药物科技有限公司 | 氟班色林的新晶型及其制备方法 |
| CN106749038A (zh) * | 2015-11-25 | 2017-05-31 | 山东诚创医药技术开发有限公司 | 一种氟班色林的制备方法 |
| CN106866546A (zh) * | 2015-12-10 | 2017-06-20 | 常州爱诺新睿医药技术有限公司 | 氟班色林或其药学上可接受的盐与药用辅料的固体分散体及其制备方法 |
| CN108699007A (zh) | 2016-01-31 | 2018-10-23 | 孟晓明 | 氟班色林的新晶型及其制备方法及其用途 |
| CN108349908B (zh) * | 2016-02-02 | 2021-07-20 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的苯并咪唑酮化合物及包含该化合物的组合物 |
| CN107235913B (zh) * | 2016-03-29 | 2020-07-10 | 苏州科伦药物研究有限公司 | 工业规模高效制造优质氟班色林的方法 |
| CN106866582A (zh) * | 2017-01-10 | 2017-06-20 | 广州隽沐生物科技有限公司 | 一种氟班色林中间体的制备方法 |
| HU231283B1 (hu) | 2018-08-01 | 2022-09-28 | Richter Gedeon Nyrt | Eljárás a flibanserin többlépéses folyamatos áramú előállítására |
| AU2022237901A1 (en) * | 2021-03-19 | 2023-09-28 | Centre National De La Recherche Scientifique | Applications of biased ligands of the serotonin 5-ht7 receptor for the treatment of pain, multiple sclerosis and the control of thermoregulation. |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3406178A (en) * | 1964-02-04 | 1968-10-15 | Monsanto Chem Australia Ltd | Preparation of 2-substituted benzimidazoles |
| US3362956A (en) * | 1965-08-19 | 1968-01-09 | Sterling Drug Inc | 1-[(heterocyclyl)-lower-alkyl]-4-substituted-piperazines |
| YU39992B (en) * | 1976-04-02 | 1985-06-30 | Janssen Pharmaceutica Nv | Process for obtaining new piperazine and piperidine derivatives |
| FI791926A (fi) * | 1978-06-20 | 1979-12-21 | Synthelabo | Fenylpiperazinderivat |
| IT1176613B (it) * | 1984-08-14 | 1987-08-18 | Ravizza Spa | Derivati piperazinici farmacologicamente attivi e processo per la loro preparazione |
| IE58370B1 (en) * | 1985-04-10 | 1993-09-08 | Lundbeck & Co As H | Indole derivatives |
| GB8607294D0 (en) * | 1985-04-17 | 1986-04-30 | Ici America Inc | Heterocyclic amide derivatives |
| HUT43600A (en) * | 1985-06-22 | 1987-11-30 | Sandoz Ag | Process for production of new thiazole derivatives and medical compound containing those |
| GB8601160D0 (en) * | 1986-01-17 | 1986-02-19 | Fujisawa Pharmaceutical Co | Heterocyclic compounds |
| US5036088A (en) * | 1986-06-09 | 1991-07-30 | Pfizer Inc. | Antiallergy and antiinflammatory agents, compositions and use |
| JPH0784462B2 (ja) * | 1986-07-25 | 1995-09-13 | 日清製粉株式会社 | ベンゾイミダゾ−ル誘導体 |
| US4954503A (en) * | 1989-09-11 | 1990-09-04 | Hoechst-Roussel Pharmaceuticals, Inc. | 3-(1-substituted-4-piperazinyl)-1H-indazoles |
| IT1251144B (it) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | Derivati del benzimidazolone |
-
1991
- 1991-07-30 IT ITMI912118A patent/IT1251144B/it active IP Right Grant
-
1992
- 1992-07-15 MX MX9204139A patent/MX9204139A/es unknown
- 1992-07-28 TW TW081105974A patent/TW209862B/zh not_active IP Right Cessation
- 1992-07-28 IL IL10266592A patent/IL102665A/en not_active IP Right Cessation
- 1992-07-29 PH PH44739A patent/PH30998A/en unknown
- 1992-07-29 IE IE246492A patent/IE922464A1/en not_active IP Right Cessation
- 1992-07-29 ZA ZA925682A patent/ZA925682B/xx unknown
- 1992-07-30 PL PL92302163A patent/PL171329B1/pl unknown
- 1992-07-30 CZ CZ94170A patent/CZ281511B6/cs not_active IP Right Cessation
- 1992-07-30 CA CA002114542A patent/CA2114542C/en not_active Expired - Lifetime
- 1992-07-30 DK DK92830427T patent/DK0526434T3/da active
- 1992-07-30 PT PT92830427T patent/PT526434E/pt unknown
- 1992-07-30 ES ES92830427T patent/ES2144412T3/es not_active Expired - Lifetime
- 1992-07-30 SK SK101-94A patent/SK279292B6/sk unknown
- 1992-07-30 WO PCT/IT1992/000088 patent/WO1993003016A1/en active IP Right Grant
- 1992-07-30 NZ NZ243777A patent/NZ243777A/en unknown
- 1992-07-30 HU HU9400255A patent/HUT70195A/hu unknown
- 1992-07-30 JP JP50345393A patent/JP2989667B2/ja not_active Expired - Lifetime
- 1992-07-30 SG SG1996004034A patent/SG52407A1/en unknown
- 1992-07-30 AT AT92830427T patent/ATE191910T1/de active
- 1992-07-30 RU RU9294015171A patent/RU2096411C1/ru active
- 1992-07-30 UA UA94005462A patent/UA42684C2/uk unknown
- 1992-07-30 AU AU24275/92A patent/AU665366B2/en not_active Expired
- 1992-07-30 DE DE69230926T patent/DE69230926T2/de not_active Expired - Lifetime
- 1992-07-30 EP EP92830427A patent/EP0526434B1/en not_active Expired - Lifetime
- 1992-07-30 KR KR1019940700293A patent/KR100263495B1/ko not_active IP Right Cessation
-
1994
- 1994-01-28 NO NO940306A patent/NO304070B1/no not_active IP Right Cessation
- 1994-01-28 FI FI940420A patent/FI111460B/fi not_active IP Right Cessation
- 1994-03-23 US US08/216,742 patent/US5576318A/en not_active Expired - Lifetime
- 1994-11-23 EE EE9400396A patent/EE03070B1/et unknown
-
1995
- 1995-06-20 HU HU95P/P00292P patent/HU211256A9/hu unknown
-
1998
- 1998-10-21 HK HK98111444A patent/HK1010725A1/xx not_active IP Right Cessation
-
2000
- 2000-07-12 GR GR20000401632T patent/GR3033947T3/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0526434B1 (en) | Benzimidazolone derivatives as 5-HT1A and 5-HT2 antagonists | |
| US6916804B2 (en) | Pyrimidine A2b selective antagonist compounds, their synthesis and use | |
| JP2941945B2 (ja) | 新規な４−アリールピペラジン類および４−アリールピペリジン類 | |
| EP1218352B1 (en) | Benzimidazolone derivatives having mixed serotonine and dopamine receptors affinity | |
| US5834493A (en) | Indole derivatives as 5-HT1A and/or 5-HT2 ligands | |
| DK168485B1 (da) | Carbostyrilderivater, fremgangsmåde til fremstilling deraf og farmaceutisk præparat indeholdende et sådant carbostyrilderivat | |
| US6284759B1 (en) | 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands | |
| US20130123270A1 (en) | Substituted piperazinyl-pyrrolidine compounds useful as chemokine receptor antagonists | |
| DE19952146A1 (de) | Arylalkane, Arylalkene und Aryl-azaalkane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung | |
| JPH0314563A (ja) | 新規４―フルオロ安息香酸誘導体 | |
| NO310236B1 (no) | Nye 2,3-diokso-1,2,3,4-tetrahydro-quinoksalinylderivater og farmasöytisk sammensetning omfattende samme | |
| JPH0568474B2 (et) | ||
| EP0444924B1 (en) | Fused 7-membered cyclic compound and antipsychotic preparation containing the same | |
| JPH01128970A (ja) | 新規複素環誘導体 | |
| JPH0573742B2 (et) | ||
| US6288230B1 (en) | 2-(2, 3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles: dopamine receptor subtype specific ligands | |
| US6432946B1 (en) | 3-aminoalkylamino-2H-1,4-benzoxazines and 3-aminoalkylamino-2H-1,4-benzothiazines: dopamine receptor subtype specific ligands | |
| JPH0688972B2 (ja) | 新規ピロリドン誘導体、その製造方法とこれを含む薬剤組成物 | |
| CA2364108A1 (en) | Acylamino cyclopropane derivatives | |
| US6313141B1 (en) | 2-aminoalkylaminoquinolines as dopamine D4 ligands | |
| JP2003277263A (ja) | 医薬組成物 | |
| CZ283499B6 (cs) | Deriváty 2-aminopyrazin-5-karboxamidu, způsob jejich přípravy a farmaceutická kompozice tyto deriváty obsahující | |
| WO2000018763A2 (en) | 2-(2,3-dihydrobenzofuran-5-yl)-4-aminomethylimidazoles: dopamine receptor subtype specific ligands | |
| MXPA99010869A (en) | 2-aminoalkylaminoquinolines as dopamine d4 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| NP | Permission for amending the patent specification granted (section 66, patents law 1967) | ||
| KB | Patent renewed | ||
| EXP | Patent expired |