JP5159317B2 - インダゾール−カルボキサミド化合物 - Google Patents
インダゾール−カルボキサミド化合物 Download PDFInfo
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- JP5159317B2 JP5159317B2 JP2007548417A JP2007548417A JP5159317B2 JP 5159317 B2 JP5159317 B2 JP 5159317B2 JP 2007548417 A JP2007548417 A JP 2007548417A JP 2007548417 A JP2007548417 A JP 2007548417A JP 5159317 B2 JP5159317 B2 JP 5159317B2
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- Prior art keywords
- alkyl
- compound
- formula
- hydroxy
- hydrogen
- Prior art date
- Legal status (The legal status 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 status listed.)
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- DITBWPUMEUDVLU-UHFFFAOYSA-N 1h-indazole-3-carboxamide Chemical class C1=CC=C2C(C(=O)N)=NNC2=C1 DITBWPUMEUDVLU-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 241
- 238000000034 method Methods 0.000 claims abstract description 88
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 139
- -1 1,1-dioxo isothiazolidinyl Chemical group 0.000 claims description 134
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 128
- 229910052739 hydrogen Inorganic materials 0.000 claims description 122
- 239000001257 hydrogen Substances 0.000 claims description 111
- FHUPHXAYPNYFIU-UHFFFAOYSA-N 1-propan-2-ylindazole-3-carboxylic acid Chemical compound C1=CC=C2N(C(C)C)N=C(C(O)=O)C2=C1 FHUPHXAYPNYFIU-UHFFFAOYSA-N 0.000 claims description 85
- 238000006243 chemical reaction Methods 0.000 claims description 81
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 66
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 53
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 50
- 150000002431 hydrogen Chemical class 0.000 claims description 46
- 102000005962 receptors Human genes 0.000 claims description 46
- 108020003175 receptors Proteins 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 28
- 150000001408 amides Chemical class 0.000 claims description 26
- 125000005466 alkylenyl group Chemical group 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 239000012453 solvate Substances 0.000 claims description 15
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 12
- 230000002496 gastric effect Effects 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 206010010774 Constipation Diseases 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 7
- 201000006549 dyspepsia Diseases 0.000 claims description 7
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 6
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 claims description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 5
- 230000005176 gastrointestinal motility Effects 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 4
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 206010021518 Impaired gastric emptying Diseases 0.000 claims description 3
- 206010033799 Paralysis Diseases 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 208000003243 intestinal obstruction Diseases 0.000 claims description 3
- 230000002980 postoperative effect Effects 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 206010052105 Gastrointestinal hypomotility Diseases 0.000 claims 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 135
- 239000000018 receptor agonist Substances 0.000 abstract description 16
- 229940044601 receptor agonist Drugs 0.000 abstract description 16
- 201000010099 disease Diseases 0.000 abstract description 15
- 230000008569 process Effects 0.000 abstract description 11
- DDMSOGRHSPMSLW-UHFFFAOYSA-N indazole-1-carboxamide Chemical compound C1=CC=C2N(C(=O)N)N=CC2=C1 DDMSOGRHSPMSLW-UHFFFAOYSA-N 0.000 abstract description 2
- 108091005482 5-HT4 receptors Proteins 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000000243 solution Substances 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 41
- 239000000047 product Substances 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 33
- CKQVRZJOMJRTOY-UHFFFAOYSA-N octadecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCC(O)=O CKQVRZJOMJRTOY-UHFFFAOYSA-N 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000003556 assay Methods 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 230000014759 maintenance of location Effects 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000002585 base Substances 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 16
- 239000003701 inert diluent Substances 0.000 description 15
- 239000012528 membrane Substances 0.000 description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
- 239000002775 capsule Substances 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 238000009739 binding Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 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 10
- 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 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000007995 HEPES buffer Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 238000001990 intravenous administration Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000003653 radioligand binding assay Methods 0.000 description 9
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000012472 biological sample Substances 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 7
- 239000007903 gelatin capsule Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
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- 239000012044 organic layer Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- FHPZUVVXVRYZAS-SFYZADRCSA-N (1r,5s)-8-methyl-8-azabicyclo[3.2.1]octan-5-amine Chemical compound C1CC[C@@]2(N)CC[C@]1([H])N2C FHPZUVVXVRYZAS-SFYZADRCSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
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- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
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- MOZPSIXKYJUTKI-RLXJOQACSA-N [1-[2-(methanesulfonamido)ethyl]piperidin-4-yl]methyl 1-(tritritiomethyl)indole-3-carboxylate Chemical compound C12=CC=CC=C2N(C([3H])([3H])[3H])C=C1C(=O)OCC1CCN(CCNS(C)(=O)=O)CC1 MOZPSIXKYJUTKI-RLXJOQACSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
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- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 4
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- OVRJVKCZJCNSOW-UHFFFAOYSA-N thian-4-one Chemical compound O=C1CCSCC1 OVRJVKCZJCNSOW-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- 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
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Developing Agents For Electrophotography (AREA)
Applications Claiming Priority (3)
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| US63880004P | 2004-12-22 | 2004-12-22 | |
| US60/638,800 | 2004-12-22 | ||
| PCT/US2005/046295 WO2006069125A1 (en) | 2004-12-22 | 2005-12-21 | Indazole-carboxamide compounds |
Publications (3)
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| JP2008525466A JP2008525466A (ja) | 2008-07-17 |
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| US20070060606A1 (en) * | 1999-10-07 | 2007-03-15 | Robertson Harold A | Compounds and methods for modulating phosphodiesterase 10A |
| TWI351282B (en) | 2004-04-07 | 2011-11-01 | Theravance Inc | Quinolinone-carboxamide compounds as 5-ht4 recepto |
| US7396933B2 (en) * | 2004-11-05 | 2008-07-08 | Theravance, Inc. | Quinolinone-carboxamide compounds |
| ES2332808T3 (es) * | 2004-11-05 | 2010-02-12 | Theravance, Inc. | Compuestos agonistas del receptor 5-ht4. |
| WO2006088988A1 (en) * | 2005-02-17 | 2006-08-24 | Theravance, Inc. | Crystalline form of an indazole-carboxamide compound |
| BRPI0608392A2 (pt) * | 2005-03-02 | 2009-12-29 | Theravance Inc | compostos de quinolinona como agonistas do receptor 5-ht4 |
| US7317022B2 (en) * | 2005-06-07 | 2008-01-08 | Theravance, Inc. | Benzoimidazolone-carboxamide compounds as 5-HT4 receptors agonists |
| MY143574A (en) * | 2005-11-22 | 2011-05-31 | Theravance Inc | Carbamate compounds as 5-ht4 receptor agonists |
| GB0525068D0 (en) | 2005-12-08 | 2006-01-18 | Novartis Ag | Organic compounds |
| CN101384588B (zh) * | 2006-02-16 | 2011-08-31 | 施万制药 | 制备5-ht4受体激动剂化合物的中间体的方法 |
| AU2009213488A1 (en) * | 2008-02-13 | 2009-08-20 | Eisai R & D Management Co., Ltd. | Bicycloamine derivative |
| US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
| CN102639526B (zh) | 2009-09-14 | 2014-06-04 | 苏文生命科学有限公司 | 作为5-ht4受体配体的1,2-二氢-2-氧代喹啉化合物 |
| AR080056A1 (es) | 2010-02-01 | 2012-03-07 | Novartis Ag | Derivados de ciclohexil-amida como antagonistas de los receptores de crf |
| JP2013518085A (ja) | 2010-02-01 | 2013-05-20 | ノバルティス アーゲー | ＣＲＦ−１受容体アンタゴニストとしてのピラゾロ［５，１ｂ］オキサゾール誘導体 |
| US8835444B2 (en) | 2010-02-02 | 2014-09-16 | Novartis Ag | Cyclohexyl amide derivatives as CRF receptor antagonists |
| AR086554A1 (es) | 2011-05-27 | 2014-01-08 | Novartis Ag | Derivados de la piperidina 3-espirociclica como agonistas de receptores de la ghrelina |
| JP2014510708A (ja) * | 2011-06-07 | 2014-05-01 | 大日本住友製薬株式会社 | インダゾール誘導体およびピロロピリジン誘導体ならびにその医薬用途 |
| CA2867043A1 (en) | 2012-05-03 | 2013-11-07 | Novartis Ag | L-malate salt of 2,7-diaza-spiro[4.5]dec-7-yle derivatives and crystalline forms thereof as ghrelin receptor agonists |
| JP2014133739A (ja) * | 2012-12-12 | 2014-07-24 | Dainippon Sumitomo Pharma Co Ltd | インダゾール誘導体またはピロロピリジン誘導体からなる医薬 |
| WO2015092804A1 (en) * | 2013-12-16 | 2015-06-25 | Suven Life Sciences Limited | Indazole compounds as 5-ht4 receptor agonists |
| US9884847B2 (en) * | 2014-07-25 | 2018-02-06 | Innov17 Llc | Indazole retinoic acid receptor-related orphan receptor modulators and uses thereof |
| MX366033B (es) * | 2014-08-16 | 2019-06-25 | Suven Life Sciences Ltd | Proceso para produccion a gran escala de oxalato de 1-isopropil-3-{5-[1-(3-metoxipropil) piperidin-4-il]-[1,3,4]oxadia zol-2-il}-1h-indazol. |
| GB201511382D0 (en) | 2015-06-29 | 2015-08-12 | Imp Innovations Ltd | Novel compounds and their use in therapy |
| DK3684767T3 (da) | 2017-09-22 | 2024-07-15 | Jubilant Epipad LLC | Heterocykliske forbindelser som pad-inhibitorer |
| AU2018352142B2 (en) | 2017-10-18 | 2022-08-25 | Jubilant Epipad LLC | Imidazo-pyridine compounds as PAD inhibitors |
| CN111386265A (zh) | 2017-11-06 | 2020-07-07 | 朱比连特普罗德尔有限责任公司 | 作为pd1/pd-l1活化的抑制剂的嘧啶衍生物 |
| SMT202400203T1 (it) | 2017-11-24 | 2024-07-09 | Jubilant Episcribe Llc | Composti eterociclici come inibitori di prmt5 |
| CA3093527A1 (en) | 2018-03-13 | 2019-09-19 | Jubilant Prodel LLC | Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation |
| JP2020199139A (ja) | 2019-06-12 | 2020-12-17 | コニカミノルタ株式会社 | 制御装置、放射線撮影システム、制御方法及びプログラム |
| WO2021046789A1 (zh) * | 2019-09-12 | 2021-03-18 | 广东东阳光药业有限公司 | 吲唑-甲酰胺衍生物及其用途 |
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-
2005
- 2005-12-21 ES ES05854933T patent/ES2347265T3/es not_active Expired - Lifetime
- 2005-12-21 CN CNA2005800433844A patent/CN101080406A/zh active Pending
- 2005-12-21 AT AT05854933T patent/ATE469897T1/de not_active IP Right Cessation
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- 2005-12-21 MX MX2007007818A patent/MX2007007818A/es active IP Right Grant
- 2005-12-21 DE DE602005021696T patent/DE602005021696D1/de not_active Expired - Lifetime
- 2005-12-21 US US11/314,591 patent/US7419989B2/en not_active Expired - Lifetime
- 2005-12-21 WO PCT/US2005/046295 patent/WO2006069125A1/en not_active Ceased
- 2005-12-21 BR BRPI0519708-2A patent/BRPI0519708A2/pt not_active IP Right Cessation
- 2005-12-21 KR KR1020077016579A patent/KR20070091665A/ko not_active Ceased
- 2005-12-21 AU AU2005319190A patent/AU2005319190A1/en not_active Abandoned
- 2005-12-21 RU RU2007128061/04A patent/RU2404179C2/ru not_active IP Right Cessation
- 2005-12-21 CA CA002588037A patent/CA2588037A1/en not_active Abandoned
-
2007
- 2007-05-14 IL IL183160A patent/IL183160A0/en unknown
- 2007-06-08 MA MA29976A patent/MA29088B1/fr unknown
- 2007-06-18 ZA ZA200705115A patent/ZA200705115B/xx unknown
- 2007-06-21 NO NO20073182A patent/NO20073182L/no not_active Application Discontinuation
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2008
- 2008-01-15 US US12/008,840 patent/US7786136B2/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| MA29088B1 (fr) | 2007-12-03 |
| KR20070091665A (ko) | 2007-09-11 |
| BRPI0519708A2 (pt) | 2009-03-10 |
| US20100292223A1 (en) | 2010-11-18 |
| EP1831211B1 (en) | 2010-06-02 |
| AU2005319190A1 (en) | 2006-06-29 |
| ZA200705115B (en) | 2008-06-25 |
| RU2007128061A (ru) | 2009-01-27 |
| EP1831211A1 (en) | 2007-09-12 |
| US7786136B2 (en) | 2010-08-31 |
| NZ555180A (en) | 2010-09-30 |
| US8003664B2 (en) | 2011-08-23 |
| CN101080406A (zh) | 2007-11-28 |
| US20060135764A1 (en) | 2006-06-22 |
| RU2404179C2 (ru) | 2010-11-20 |
| ATE469897T1 (de) | 2010-06-15 |
| US7419989B2 (en) | 2008-09-02 |
| NO20073182L (no) | 2007-08-28 |
| CA2588037A1 (en) | 2006-06-29 |
| JP2008525466A (ja) | 2008-07-17 |
| MX2007007818A (es) | 2007-09-11 |
| US20080132491A1 (en) | 2008-06-05 |
| DE602005021696D1 (de) | 2010-07-15 |
| WO2006069125A1 (en) | 2006-06-29 |
| IL183160A0 (en) | 2007-09-20 |
| ES2347265T3 (es) | 2010-10-27 |
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