EP1324987A1 - Indazoles a action analogue a l'hormone thyroidienne, leur procede de fabrication et leur utilisation dans des medicaments - Google Patents
Indazoles a action analogue a l'hormone thyroidienne, leur procede de fabrication et leur utilisation dans des medicamentsInfo
- Publication number
- EP1324987A1 EP1324987A1 EP01978337A EP01978337A EP1324987A1 EP 1324987 A1 EP1324987 A1 EP 1324987A1 EP 01978337 A EP01978337 A EP 01978337A EP 01978337 A EP01978337 A EP 01978337A EP 1324987 A1 EP1324987 A1 EP 1324987A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- hydrogen
- different
- hydroxy
- cycloalkyl
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 11
- 230000008569 process Effects 0.000 title claims description 7
- 230000000694 effects Effects 0.000 title description 15
- 150000002473 indoazoles Chemical class 0.000 title description 5
- 210000001685 thyroid gland Anatomy 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000005495 thyroid hormone Substances 0.000 claims abstract description 6
- 229940036555 thyroid hormone Drugs 0.000 claims abstract description 6
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 claims abstract description 5
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 claims abstract description 4
- -1 cyano, nitro , Amino Chemical group 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 150000002431 hydrogen Chemical class 0.000 claims description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 239000000543 intermediate Substances 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- ORTFAQDWJHRMNX-UHFFFAOYSA-M oxidooxomethyl Chemical compound [O-][C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-M 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 230000004962 physiological condition Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000009257 reactivity Effects 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 22
- 239000000126 substance Substances 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical class OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- CRWPUHBLAIVSDF-UHFFFAOYSA-N ethyl 2-[3,5-dimethyl-4-[(3-propyl-2h-indazol-5-yl)oxy]anilino]-2-oxoacetate Chemical compound C1=C2C(CCC)=NNC2=CC=C1OC1=C(C)C=C(NC(=O)C(=O)OCC)C=C1C CRWPUHBLAIVSDF-UHFFFAOYSA-N 0.000 description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- OVIUSOBGIUXZAX-UHFFFAOYSA-N 3,5-dimethyl-4-[(3-pentyl-2h-indazol-5-yl)oxy]aniline Chemical compound C1=C2C(CCCCC)=NNC2=CC=C1OC1=C(C)C=C(N)C=C1C OVIUSOBGIUXZAX-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- RHAGPMZPHJCDHK-UHFFFAOYSA-N ethyl 2-[3,5-dimethyl-4-[(3-pentyl-2h-indazol-5-yl)oxy]anilino]-2-oxoacetate Chemical compound C1=C2C(CCCCC)=NNC2=CC=C1OC1=C(C)C=C(NC(=O)C(=O)OCC)C=C1C RHAGPMZPHJCDHK-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- UYCUMNRCCJNSBR-UHFFFAOYSA-N 2-ethoxy-2-oxoacetic acid;hydrochloride Chemical compound Cl.CCOC(=O)C(O)=O UYCUMNRCCJNSBR-UHFFFAOYSA-N 0.000 description 5
- LILVVZJBGYMAKS-UHFFFAOYSA-N 2-nitro-5-phenylmethoxybenzaldehyde Chemical compound C1=C(C=O)C([N+](=O)[O-])=CC=C1OCC1=CC=CC=C1 LILVVZJBGYMAKS-UHFFFAOYSA-N 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- FUWQMMBMEUTHPL-UHFFFAOYSA-N tert-butyl 5-[4-[acetyloxy(ethyl)amino]-2,6-dimethylphenoxy]-3-pentylindazole-1-carboxylate Chemical compound C1=C2C(CCCCC)=NN(C(=O)OC(C)(C)C)C2=CC=C1OC1=C(C)C=C(N(CC)OC(C)=O)C=C1C FUWQMMBMEUTHPL-UHFFFAOYSA-N 0.000 description 5
- VJEBIHTVWPSCEM-UHFFFAOYSA-N 2-fluoro-1,3-dimethyl-5-nitrobenzene Chemical compound CC1=CC([N+]([O-])=O)=CC(C)=C1F VJEBIHTVWPSCEM-UHFFFAOYSA-N 0.000 description 4
- CYPUGLNLGLHICP-UHFFFAOYSA-N 5-(2,6-dimethyl-4-nitrophenoxy)-3-pentyl-2h-indazole Chemical compound C1=C2C(CCCCC)=NNC2=CC=C1OC1=C(C)C=C([N+]([O-])=O)C=C1C CYPUGLNLGLHICP-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
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- 239000012043 crude product Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ATYJOWFJEOTIAG-UHFFFAOYSA-N 3,5-dimethyl-4-[(3-propan-2-yl-2h-indazol-5-yl)oxy]aniline Chemical compound C1=C2C(C(C)C)=NNC2=CC=C1OC1=C(C)C=C(N)C=C1C ATYJOWFJEOTIAG-UHFFFAOYSA-N 0.000 description 3
- HNXITJMPNQRASS-UHFFFAOYSA-N 3,5-dimethyl-4-[(3-propyl-2h-indazol-5-yl)oxy]aniline Chemical compound C1=C2C(CCC)=NNC2=CC=C1OC1=C(C)C=C(N)C=C1C HNXITJMPNQRASS-UHFFFAOYSA-N 0.000 description 3
- KWYVEWHBDWKTHM-UHFFFAOYSA-N 3-(2-methylpropyl)-2h-indazol-5-ol Chemical compound C1=C(O)C=C2C(CC(C)C)=NNC2=C1 KWYVEWHBDWKTHM-UHFFFAOYSA-N 0.000 description 3
- SMTYELJXGSGPLG-UHFFFAOYSA-N 3-pentyl-2h-indazol-5-ol Chemical compound C1=C(O)C=C2C(CCCCC)=NNC2=C1 SMTYELJXGSGPLG-UHFFFAOYSA-N 0.000 description 3
- GHXOLVPEMVPYDF-UHFFFAOYSA-N 3-propan-2-yl-2h-indazol-5-ol Chemical compound C1=C(O)C=C2C(C(C)C)=NNC2=C1 GHXOLVPEMVPYDF-UHFFFAOYSA-N 0.000 description 3
- AXRNIDSDSQYRBR-UHFFFAOYSA-N 5-(2,6-dimethyl-4-nitrophenoxy)-3-(2-methylpropyl)-2h-indazole Chemical compound C1=C2C(CC(C)C)=NNC2=CC=C1OC1=C(C)C=C([N+]([O-])=O)C=C1C AXRNIDSDSQYRBR-UHFFFAOYSA-N 0.000 description 3
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
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- 230000002526 effect on cardiovascular system Effects 0.000 description 3
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- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 3
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- ORJKQRGABJETMK-UHFFFAOYSA-N 3,5-dimethyl-4-[[3-(2-methylpropyl)-2h-indazol-5-yl]oxy]aniline Chemical compound C1=C2C(CC(C)C)=NNC2=CC=C1OC1=C(C)C=C(N)C=C1C ORJKQRGABJETMK-UHFFFAOYSA-N 0.000 description 2
- RFEXBYWADSSOTN-UHFFFAOYSA-N 3-propyl-2h-indazol-5-ol Chemical compound C1=C(O)C=C2C(CCC)=NNC2=C1 RFEXBYWADSSOTN-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZKHRQRCQSXMUOP-UHFFFAOYSA-N 5-(2,6-dimethyl-4-nitrophenoxy)-3-propan-2-yl-2h-indazole Chemical compound C1=C2C(C(C)C)=NNC2=CC=C1OC1=C(C)C=C([N+]([O-])=O)C=C1C ZKHRQRCQSXMUOP-UHFFFAOYSA-N 0.000 description 2
- RMVRDYBATFXRLY-UHFFFAOYSA-N 5-(2,6-dimethyl-4-nitrophenoxy)-3-propyl-2h-indazole Chemical compound C1=C2C(CCC)=NNC2=CC=C1OC1=C(C)C=C([N+]([O-])=O)C=C1C RMVRDYBATFXRLY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
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- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- FFUIUNZKXBJVSC-UHFFFAOYSA-M magnesium;2-methylprop-1-ene;bromide Chemical compound [Mg+2].[Br-].CC(C)=[CH-] FFUIUNZKXBJVSC-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 description 1
- WQMNNHNWITXOAH-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].CC=[CH-] WQMNNHNWITXOAH-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
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- 239000002184 metal Substances 0.000 description 1
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- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
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- SOWBFZRMHSNYGE-UHFFFAOYSA-N oxamic acid Chemical class NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 239000006187 pill Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
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- 159000000001 potassium salts Chemical class 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 229930002330 retinoic acid Natural products 0.000 description 1
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- 239000008159 sesame oil Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- ABZLKHKQJHEPAX-UHFFFAOYSA-N tetramethylrhodamine Chemical compound C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C([O-])=O ABZLKHKQJHEPAX-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 239000012581 transferrin Substances 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Definitions
- R 20 and R 21 together represent oxygen, or are each the same or different and represent hydrogen, halogen, hydroxy, (Cj-Cg) alkyl, (C r C 6 ) alkoxy or the radical -NR 15 R 16 and
- aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms.
- Preferred aryl groups are phenyl and naphthyl.
- Cycloalkyl in the context of the invention represents a cycloalkyl group with preferably 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- the compounds according to the invention can exist in stereoisomeric forms which are either like image and mirror image (enantiomers) or which are not obtained like image and mirror image (diastereomers).
- the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
- the racemic forms can be uniformly standardized into the stereoisomers
- Z represents CH 2 or in particular oxygen
- Example 8 ⁇ [ethoxy (oxo) acetyl] amino ⁇ -2,6-dimethylphenoxy) -3- ⁇ ropyl-1H-indazol-1-yl] (oxo) - acetates (Example 8). In addition, 18 mg (40%) of the ethyl - ( ⁇ 3,5-dimethyl-4 - [(3-propyl-1H-indazol-5-yl) oxy] phenyl ⁇ amino) (oxo) acetate (Example 8 a) won.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne de nouveaux dérivés de l'indazole, de formule (I), dans laquelle, Z désigne O, S, CH2, CHF ou CF2, et où R1-R7 ont les significations spécifiées dans la revendication 1, ces dérivés ayant une action analogue à l'hormone thyroïdienne. L'invention concerne en outre leur procédé de fabrication et leur utilisation dans des médicaments.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10046029 | 2000-09-18 | ||
| DE10046029A DE10046029A1 (de) | 2000-09-18 | 2000-09-18 | Indazole |
| PCT/EP2001/010204 WO2002022586A1 (fr) | 2000-09-18 | 2001-09-05 | Indazoles a action analogue a l'hormone thyroidienne, leur procede de fabrication et leur utilisation dans des medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1324987A1 true EP1324987A1 (fr) | 2003-07-09 |
Family
ID=7656569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP01978337A Withdrawn EP1324987A1 (fr) | 2000-09-18 | 2001-09-05 | Indazoles a action analogue a l'hormone thyroidienne, leur procede de fabrication et leur utilisation dans des medicaments |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US6608049B2 (fr) |
| EP (1) | EP1324987A1 (fr) |
| AU (1) | AU2002210484A1 (fr) |
| CA (1) | CA2422353A1 (fr) |
| DE (1) | DE10046029A1 (fr) |
| WO (1) | WO2002022586A1 (fr) |
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| AU2004259738B2 (en) | 2003-07-17 | 2011-11-17 | Plexxikon, Inc. | PPAR active compounds |
| CA2546601A1 (fr) * | 2003-11-19 | 2005-06-09 | Metabasis Therapeutics, Inc. | Nouvelles substances thyromimetiques contenant du phosphore |
| JP2007523938A (ja) | 2004-02-27 | 2007-08-23 | エフ．ホフマン−ラ ロシュ アーゲー | ピラゾールの縮合誘導体 |
| WO2005085248A1 (fr) | 2004-02-27 | 2005-09-15 | F.Hoffmann-La Roche Ag | Derives pyrazolo heteroaryl-condenses |
| BRPI0508107A (pt) | 2004-02-27 | 2007-07-17 | Hoffmann La Roche | derivados de indazol e composições farmacêuticas contendo os mesmos |
| US7026846B1 (en) * | 2004-07-09 | 2006-04-11 | Analog Devices, Inc. | Synthesizer structures and methods that reduce spurious signals |
| PE20060417A1 (es) * | 2004-08-03 | 2006-06-13 | Wyeth Corp | Indazoles como moduladores de lxrs |
| EP1647549A1 (fr) | 2004-10-14 | 2006-04-19 | Laboratoire Theramex | Indazoles, benzisoxazoles et benzisothiazoles en tant qu'agents oestrogéniques |
| US7601847B2 (en) | 2004-10-26 | 2009-10-13 | Wyeth | Preparation and purification of 4-(indazol-3-yl)phenols |
| RU2007148927A (ru) * | 2005-05-26 | 2009-07-10 | Метабэйзис Терапьютикс, Инк. (Us) | Новые тиреомиметики, содержащие фосфиновую кислоту |
| US20090232879A1 (en) | 2005-05-26 | 2009-09-17 | Metabasis Therapeutics, Inc. | Thyromimetics for the Treatment of Fatty Liver Diseases |
| US20060292194A1 (en) * | 2005-06-24 | 2006-12-28 | Thomas Lavin | Treatment for burns and adipose deposits using thyroid hormone compound in a human |
| GB0513692D0 (en) * | 2005-07-04 | 2005-08-10 | Karobio Ab | Novel pharmaceutical compositions |
| AU2006283941A1 (en) | 2005-08-25 | 2007-03-01 | F. Hoffmann-La Roche Ag | P38 MAP kinase inhibitors and methods for using the same |
| EP2036887A1 (fr) * | 2006-06-28 | 2009-03-18 | Sanwa Kagaku Kenkyusho Co., Ltd | Nouveau dérivé hétérocyclique 6-5 bicyclique et utilisation médicale de celui-ci |
| TWI365185B (en) | 2008-07-24 | 2012-06-01 | Lilly Co Eli | Amidophenoxyindazoles useful as inhibitors of c-met |
| JOP20190024A1 (ar) | 2016-08-26 | 2019-02-19 | Gilead Sciences Inc | مركبات بيروليزين بها استبدال واستخداماتها |
| JP2020500199A (ja) | 2016-11-21 | 2020-01-09 | バイキング・セラピューティクス・インコーポレイテッド | グリコーゲン蓄積症の治療方法 |
| AU2018280118B2 (en) | 2017-06-05 | 2021-07-15 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| CA3091142C (fr) | 2018-02-26 | 2023-04-11 | Gilead Sciences, Inc. | Composes de pyrrolizine substitues et utilisations connexes |
| EA202091979A1 (ru) | 2018-03-22 | 2021-06-22 | Вайкинг Терапьютикс, Инк. | Кристаллические формы и способы получения кристаллических форм соединения |
| US12102646B2 (en) | 2018-12-05 | 2024-10-01 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis and inflammation |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2032171A1 (de) * | 1970-06-30 | 1972-01-13 | Agfa Gevaert AG, 5090 Leverkusen | Lichtempfindliches farbfotografisches Material |
| GB8501372D0 (en) | 1985-01-18 | 1985-02-20 | Smith Kline French Lab | Chemical compounds |
| DE69314718T2 (de) | 1992-07-21 | 1998-02-26 | Ciba Geigy Ag | Oxamidsäure-Derivate als hypocholesterämische Mittel |
| US6266622B1 (en) | 1995-12-13 | 2001-07-24 | Regents Of The University Of California | Nuclear receptor ligands and ligand binding domains |
| US5883294A (en) | 1997-06-18 | 1999-03-16 | The Regeants Of The University Of California | Selective thyroid hormone analogs |
| DE19830431A1 (de) * | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | Sulfonylamino-carbonsäure-N-arylamide als Guanylatcyclase-Aktivatoren |
| KR20010106415A (ko) * | 1998-07-23 | 2001-11-29 | 스튜어트 알. 수터, 스티븐 베네티아너, 피터 존 기딩스 | Ｉｌ-8 수용체 길항제 |
| CZ20013117A3 (cs) | 1999-03-01 | 2002-06-12 | Pfizer Products Inc. | Oxamové kyseliny a jejich deriváty jako ligandy thyreoidního receptoru |
| CO5160290A1 (es) | 1999-03-29 | 2002-05-30 | Novartis Ag | Derivados de acido fenoxifeniloxamico sustituido . |
| YU54202A (sh) * | 2000-01-18 | 2006-01-16 | Agouron Pharmaceuticals Inc. | Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije |
-
2000
- 2000-09-18 DE DE10046029A patent/DE10046029A1/de not_active Withdrawn
-
2001
- 2001-09-05 CA CA002422353A patent/CA2422353A1/fr not_active Abandoned
- 2001-09-05 WO PCT/EP2001/010204 patent/WO2002022586A1/fr not_active Ceased
- 2001-09-05 AU AU2002210484A patent/AU2002210484A1/en not_active Abandoned
- 2001-09-05 EP EP01978337A patent/EP1324987A1/fr not_active Withdrawn
- 2001-09-18 US US09/956,566 patent/US6608049B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0222586A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20020193610A1 (en) | 2002-12-19 |
| US6608049B2 (en) | 2003-08-19 |
| AU2002210484A1 (en) | 2002-03-26 |
| DE10046029A1 (de) | 2002-03-28 |
| CA2422353A1 (fr) | 2003-03-14 |
| WO2002022586A1 (fr) | 2002-03-21 |
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