JP5635914B2 - 置換インドール誘導体 - Google Patents
置換インドール誘導体 Download PDFInfo
- Publication number
- JP5635914B2 JP5635914B2 JP2010547116A JP2010547116A JP5635914B2 JP 5635914 B2 JP5635914 B2 JP 5635914B2 JP 2010547116 A JP2010547116 A JP 2010547116A JP 2010547116 A JP2010547116 A JP 2010547116A JP 5635914 B2 JP5635914 B2 JP 5635914B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- substituted indole
- group
- alkyl
- butyl
- 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.)
- Expired - Fee Related
Links
- 150000002475 indoles Chemical class 0.000 title claims description 50
- 229940054051 antipsychotic indole derivative Drugs 0.000 title description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 219
- 238000006243 chemical reaction Methods 0.000 claims description 103
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- 239000002904 solvent Substances 0.000 claims description 58
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 30
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 30
- -1 2-hexyl Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 15
- 208000002193 Pain Diseases 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 235000019253 formic acid Nutrition 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000001041 indolyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 230000036407 pain Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 150000001768 cations Chemical class 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 6
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 208000000094 Chronic Pain Diseases 0.000 claims description 4
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 206010027175 memory impairment Diseases 0.000 claims description 4
- 208000004296 neuralgia Diseases 0.000 claims description 4
- 208000021722 neuropathic pain Diseases 0.000 claims description 4
- 229940005483 opioid analgesics Drugs 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 claims description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010012735 Diarrhoea Diseases 0.000 claims description 3
- 208000026251 Opioid-Related disease Diseases 0.000 claims description 3
- 239000012317 TBTU Substances 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 3
- 208000005298 acute pain Diseases 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000001598 anti-natriuretic effect Effects 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 230000037406 food intake Effects 0.000 claims description 3
- 235000012631 food intake Nutrition 0.000 claims description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 206010006895 Cachexia Diseases 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000017228 Gastrointestinal motility disease Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 208000001953 Hypotension Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 208000023178 Musculoskeletal disease Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000004880 Polyuria Diseases 0.000 claims description 2
- 208000003251 Pruritus Diseases 0.000 claims description 2
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 2
- 208000009205 Tinnitus Diseases 0.000 claims description 2
- 230000003444 anaesthetic effect Effects 0.000 claims description 2
- 208000022531 anorexia Diseases 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 239000001961 anticonvulsive agent Substances 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 206010061428 decreased appetite Diseases 0.000 claims description 2
- 230000035619 diuresis Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003193 general anesthetic agent Substances 0.000 claims description 2
- 208000016354 hearing loss disease Diseases 0.000 claims description 2
- 230000036543 hypotension Effects 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 239000003158 myorelaxant agent Substances 0.000 claims description 2
- 230000003957 neurotransmitter release Effects 0.000 claims description 2
- 239000002664 nootropic agent Substances 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- 239000000014 opioid analgesic Substances 0.000 claims description 2
- 229940052318 opioid anesthetics Drugs 0.000 claims description 2
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 2
- 231100000886 tinnitus Toxicity 0.000 claims description 2
- 208000011117 substance-related disease Diseases 0.000 claims 2
- 206010012289 Dementia Diseases 0.000 claims 1
- 206010013654 Drug abuse Diseases 0.000 claims 1
- 238000011260 co-administration Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
- 239000011541 reaction mixture Substances 0.000 description 72
- 239000000047 product Substances 0.000 description 68
- 239000000243 solution Substances 0.000 description 68
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- 125000000217 alkyl group Chemical group 0.000 description 48
- 230000002829 reductive effect Effects 0.000 description 48
- 239000000203 mixture Substances 0.000 description 47
- 235000019439 ethyl acetate Nutrition 0.000 description 44
- 238000004809 thin layer chromatography Methods 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 239000011734 sodium Substances 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 17
- 108010020615 nociceptin receptor Proteins 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 235000011054 acetic acid Nutrition 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000003643 water by type Substances 0.000 description 13
- 239000007789 gas Substances 0.000 description 11
- 102000048266 Nociceptin Human genes 0.000 description 10
- 108090000622 Nociceptin Proteins 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 125000000753 cycloalkyl group Chemical group 0.000 description 10
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 8
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 6
- HQPVDHFPPVZXJG-UHFFFAOYSA-N 1-[4-(dimethylamino)-4-phenylpiperidin-1-yl]-3-methyl-2-(methylamino)butan-1-one;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(C(=O)C(C(C)C)NC)CCC1(N(C)C)C1=CC=CC=C1 HQPVDHFPPVZXJG-UHFFFAOYSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 150000001450 anions Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000007818 Grignard reagent Substances 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- KHGMAFLCMFOPIR-UHFFFAOYSA-N n,n-dimethyl-4-phenylpiperidin-4-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=1C=CC=CC=1C1(N(C)C)CCNCC1 KHGMAFLCMFOPIR-UHFFFAOYSA-N 0.000 description 5
- VYFGXPJVUSTGGP-UHFFFAOYSA-N n,n-dimethyl-4-thiophen-2-ylpiperidin-4-amine;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C=1C=CSC=1C1(N(C)C)CCNCC1 VYFGXPJVUSTGGP-UHFFFAOYSA-N 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
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- NDTQLQIKWHHMAF-UHFFFAOYSA-N piperidine-3-carbaldehyde trihydrochloride Chemical compound Cl.Cl.Cl.N1CC(CCC1)C=O NDTQLQIKWHHMAF-UHFFFAOYSA-N 0.000 description 1
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- XDJCYKMWJCYQJM-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCO XDJCYKMWJCYQJM-UHFFFAOYSA-N 0.000 description 1
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- VUIUAIFYQUYFQX-UHFFFAOYSA-N tert-butyl n-[3-[4-(dimethylamino)-4-phenylpiperidin-1-yl]propyl]-n-methylcarbamate Chemical compound C1CN(CCCN(C)C(=O)OC(C)(C)C)CCC1(N(C)C)C1=CC=CC=C1 VUIUAIFYQUYFQX-UHFFFAOYSA-N 0.000 description 1
- VZBXXQSJOQFMRO-UHFFFAOYSA-N tert-butyl n-[3-[4-(dimethylamino)-4-thiophen-2-ylpiperidin-1-yl]propyl]-n-methylcarbamate Chemical compound C=1C=CSC=1C1(N(C)C)CCN(CCCN(C)C(=O)OC(C)(C)C)CC1 VZBXXQSJOQFMRO-UHFFFAOYSA-N 0.000 description 1
- GBLIHCLLFDOPKL-UHFFFAOYSA-N tert-butyl n-methyl-n-[2-(4-phenyl-4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]carbamate;trihydrochloride Chemical compound Cl.Cl.Cl.C1CN(CCN(C)C(=O)OC(C)(C)C)CCC1(C=1C=CC=CC=1)N1CCCC1 GBLIHCLLFDOPKL-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Landscapes
- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
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- Diabetes (AREA)
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- Orthopedic Medicine & Surgery (AREA)
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- Dermatology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Nutrition Science (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08003238 | 2008-02-22 | ||
| EP08003238.6 | 2008-02-22 | ||
| PCT/EP2009/001232 WO2009103552A1 (en) | 2008-02-22 | 2009-02-20 | Substituted indole derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2011512374A JP2011512374A (ja) | 2011-04-21 |
| JP2011512374A5 JP2011512374A5 (enExample) | 2014-09-18 |
| JP5635914B2 true JP5635914B2 (ja) | 2014-12-03 |
Family
ID=39449548
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010547116A Expired - Fee Related JP5635914B2 (ja) | 2008-02-22 | 2009-02-20 | 置換インドール誘導体 |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US20090215828A1 (enExample) |
| EP (1) | EP2254883B1 (enExample) |
| JP (1) | JP5635914B2 (enExample) |
| CN (1) | CN102015683B (enExample) |
| AR (1) | AR070398A1 (enExample) |
| AU (1) | AU2009216920B2 (enExample) |
| CA (1) | CA2716270C (enExample) |
| CL (1) | CL2009000404A1 (enExample) |
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Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR070398A1 (es) | 2008-02-22 | 2010-03-31 | Gruenenthal Chemie | Derivados sustituidos de indol |
| US8580841B2 (en) | 2008-07-23 | 2013-11-12 | Arena Pharmaceuticals, Inc. | Substituted 1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
| CN105816453B (zh) | 2008-08-27 | 2021-03-05 | 艾尼纳制药公司 | 用于治疗自身免疫性病症和炎性病症的作为s1p1受体激动剂的经取代的三环酸衍生物 |
| TW201020247A (en) * | 2008-11-06 | 2010-06-01 | Gruenenthal Gmbh | Substituierte disulfonamide |
| SG182610A1 (en) | 2010-01-27 | 2012-08-30 | Arena Pharm Inc | Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
| CA2789480A1 (en) | 2010-03-03 | 2011-09-09 | Arena Pharmaceuticals, Inc. | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
| EP2566327B1 (en) | 2010-05-07 | 2017-03-29 | Glaxosmithkline LLC | Indoles |
| KR20140095073A (ko) | 2011-11-04 | 2014-07-31 | 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 | 치료 방법 |
| JO3425B1 (ar) | 2013-07-15 | 2019-10-20 | Novartis Ag | مشتقات البابيريدينيل-اندول واستخدامها كعامل متمم لمثبطات b |
| US11007175B2 (en) | 2015-01-06 | 2021-05-18 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
| BR112017027656B1 (pt) | 2015-06-22 | 2023-12-05 | Arena Pharmaceuticals, Inc. | Hábito cristalino de placa livre de sal de l-arginina de ácido (r)-2-(7-(4- ciclopentil-3-(trifluorometil)benzilóxi)- 1,2,3,4-tetra-hidrociclo-penta[b]indol-3- il)acético, composição farmacêutica que o compreende, seus usos e método de preparação do mesmo |
| MX2019005679A (es) | 2016-11-18 | 2019-08-14 | Merck Sharp & Dohme | Derivados de indol de utilidad como inhibidores de diacilglicerido o-aciltransferasa 2. |
| CA3053418A1 (en) | 2017-02-16 | 2018-08-23 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
| JP2020507610A (ja) | 2017-02-16 | 2020-03-12 | アリーナ ファーマシューティカルズ， インコーポレイテッド | 腸管外症状を伴う炎症性腸疾患の治療のための化合物および方法 |
| AU2018231120B2 (en) * | 2017-03-10 | 2022-06-23 | Rutgers, The State University Of New Jersey | Indole derivatives as efflux pump inhibitors |
| BR112020024762A2 (pt) | 2018-06-06 | 2021-03-23 | Arena Pharmaceuticals, Inc. | métodos de tratamento de condições relacionadas ao receptor s1p1 |
| CN119751336A (zh) | 2018-09-06 | 2025-04-04 | 艾尼纳制药公司 | 可用于治疗自身免疫性病症和炎性病症的化合物 |
| US20240408064A1 (en) * | 2021-10-15 | 2024-12-12 | Genetolead Inc. | Ras inhibitors, compositions and methods of use thereof |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1586817A (en) * | 1977-12-01 | 1981-03-25 | Wyeth John & Brother Ltd | Indole derivatives |
| JP3314938B2 (ja) * | 1995-06-06 | 2002-08-19 | ファイザー・インコーポレーテッド | グリコーゲンホスホリラーゼ抑制剤としての置換されたｎ−（インドール−２−カルボニル）−グリシンアミド類および誘導体 |
| DE60026581T2 (de) * | 1999-12-20 | 2006-12-28 | Eli Lilly And Co., Indianapolis | Indolderivate zur behandlung von depression und angstzuständen |
| DE10153346A1 (de) * | 2001-10-29 | 2004-04-22 | Grünenthal GmbH | Substituierte Indole |
| DE10252650A1 (de) | 2002-11-11 | 2004-05-27 | Grünenthal GmbH | Cyclohexyl-Harnstoff-Derivate |
| DE10252666A1 (de) | 2002-11-11 | 2004-08-05 | Grünenthal GmbH | N-Piperidyl-cyclohexan-Derivate |
| WO2005047253A1 (en) * | 2003-11-12 | 2005-05-26 | Lg Life Sciences Ltd. | Melanocortin receptor agonists |
| GB0510810D0 (en) * | 2005-05-26 | 2005-06-29 | Novartis Ag | Organic compounds |
| CA2641817A1 (en) * | 2006-02-01 | 2007-08-09 | Solvay Pharmaceuticals Gmbh | Novel dual nk2/nk3-antagonists, pharmaceutical compositions comprising them and processes for their preparation |
| US20070219214A1 (en) * | 2006-02-01 | 2007-09-20 | Solvay Pharmaceuticals Gmbh | Dual NK2/NK3-antagonists, pharmaceutical compositions comprising them, and processes for their preparation |
| CA2682483A1 (en) * | 2007-03-29 | 2008-10-09 | Novartis Ag | 3-imidazolyl-indoles for the treatment of proliferative diseases |
| AR070398A1 (es) | 2008-02-22 | 2010-03-31 | Gruenenthal Chemie | Derivados sustituidos de indol |
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2009
- 2009-02-16 AR ARP090100544A patent/AR070398A1/es not_active Application Discontinuation
- 2009-02-19 US US12/388,977 patent/US20090215828A1/en not_active Abandoned
- 2009-02-20 WO PCT/EP2009/001232 patent/WO2009103552A1/en not_active Ceased
- 2009-02-20 MX MX2010009045A patent/MX2010009045A/es active IP Right Grant
- 2009-02-20 RU RU2010138838/04A patent/RU2500677C2/ru not_active IP Right Cessation
- 2009-02-20 CN CN200980115064.3A patent/CN102015683B/zh not_active Expired - Fee Related
- 2009-02-20 JP JP2010547116A patent/JP5635914B2/ja not_active Expired - Fee Related
- 2009-02-20 AU AU2009216920A patent/AU2009216920B2/en not_active Ceased
- 2009-02-20 CL CL2009000404A patent/CL2009000404A1/es unknown
- 2009-02-20 EP EP09713555.2A patent/EP2254883B1/en not_active Not-in-force
- 2009-02-20 CA CA2716270A patent/CA2716270C/en not_active Expired - Fee Related
- 2009-02-20 PE PE2009000247A patent/PE20091490A1/es not_active Application Discontinuation
-
2010
- 2010-08-19 IL IL207684A patent/IL207684A/en not_active IP Right Cessation
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2012
- 2012-12-11 US US13/710,604 patent/US9206156B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20090215828A1 (en) | 2009-08-27 |
| AU2009216920A1 (en) | 2009-08-27 |
| PE20091490A1 (es) | 2009-09-26 |
| HK1149762A1 (en) | 2011-10-14 |
| AR070398A1 (es) | 2010-03-31 |
| EP2254883A1 (en) | 2010-12-01 |
| JP2011512374A (ja) | 2011-04-21 |
| AU2009216920B2 (en) | 2013-06-13 |
| US20130116283A1 (en) | 2013-05-09 |
| CA2716270C (en) | 2016-01-19 |
| CN102015683B (zh) | 2015-08-05 |
| EP2254883B1 (en) | 2014-11-26 |
| IL207684A (en) | 2015-08-31 |
| CN102015683A (zh) | 2011-04-13 |
| US9206156B2 (en) | 2015-12-08 |
| RU2010138838A (ru) | 2012-03-27 |
| MX2010009045A (es) | 2010-09-24 |
| CL2009000404A1 (es) | 2010-04-16 |
| CA2716270A1 (en) | 2009-08-27 |
| IL207684A0 (en) | 2010-12-30 |
| RU2500677C2 (ru) | 2013-12-10 |
| WO2009103552A1 (en) | 2009-08-27 |
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