WO2005021534A1 - 1,3−ジヒドロ−2h−インドール−2−オン誘導体 - Google Patents
1,3−ジヒドロ−2h−インドール−2−オン誘導体 Download PDFInfo
- Publication number
- WO2005021534A1 WO2005021534A1 PCT/JP2004/012398 JP2004012398W WO2005021534A1 WO 2005021534 A1 WO2005021534 A1 WO 2005021534A1 JP 2004012398 W JP2004012398 W JP 2004012398W WO 2005021534 A1 WO2005021534 A1 WO 2005021534A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- dihydro
- indole
- compound
- dimethoxyphenyl
- Prior art date
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- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 222
- -1 methylenedioxy Chemical group 0.000 claims abstract description 129
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 125000005843 halogen group Chemical group 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 229910052731 fluorine Chemical group 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 107
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 53
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 40
- MLLMAIJXIZOSFS-LURJTMIESA-N (2s)-n,n-dimethylpyrrolidine-2-carboxamide Chemical compound CN(C)C(=O)[C@@H]1CCCN1 MLLMAIJXIZOSFS-LURJTMIESA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 3
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 3
- 239000011737 fluorine Chemical group 0.000 abstract description 3
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical group C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 abstract description 3
- 229960003726 vasopressin Drugs 0.000 abstract description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 230000003042 antagnostic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 252
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 144
- 238000006243 chemical reaction Methods 0.000 description 129
- 239000000243 solution Substances 0.000 description 128
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 94
- 238000003786 synthesis reaction Methods 0.000 description 92
- 238000005160 1H NMR spectroscopy Methods 0.000 description 86
- 230000015572 biosynthetic process Effects 0.000 description 84
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 230000002829 reductive effect Effects 0.000 description 75
- 239000011734 sodium Substances 0.000 description 75
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 73
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- 238000001816 cooling Methods 0.000 description 57
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
- 239000012044 organic layer Substances 0.000 description 51
- 238000004440 column chromatography Methods 0.000 description 50
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 48
- 238000003756 stirring Methods 0.000 description 47
- 239000002274 desiccant Substances 0.000 description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- 238000000034 method Methods 0.000 description 40
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- 239000010410 layer Substances 0.000 description 39
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- 235000019341 magnesium sulphate Nutrition 0.000 description 36
- 239000007787 solid Substances 0.000 description 33
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000012299 nitrogen atmosphere Substances 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 23
- 239000012046 mixed solvent Substances 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 239000002585 base Substances 0.000 description 21
- 108020003175 receptors Proteins 0.000 description 21
- 102000005962 receptors Human genes 0.000 description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 238000007429 general method Methods 0.000 description 16
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- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 16
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
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- 210000004556 brain Anatomy 0.000 description 13
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- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 12
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 10
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229940070891 pyridium Drugs 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- GZGWEDQFRVOWFA-UHFFFAOYSA-N sulfo methanesulfonate Chemical compound CS(=O)(=O)OS(O)(=O)=O GZGWEDQFRVOWFA-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JMORIDAQGDQESW-MLWJPKLSSA-N tert-butyl (2s)-4-fluoropyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CC(F)CN1 JMORIDAQGDQESW-MLWJPKLSSA-N 0.000 description 1
- OULCDZRGONPVMZ-BDAKNGLRSA-N tert-butyl (2s,4r)-2-(dimethylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C OULCDZRGONPVMZ-BDAKNGLRSA-N 0.000 description 1
- UYDCRNHLCFHHFR-BDAKNGLRSA-N tert-butyl (2s,4r)-2-(dimethylcarbamoyl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C UYDCRNHLCFHHFR-BDAKNGLRSA-N 0.000 description 1
- OULCDZRGONPVMZ-IUCAKERBSA-N tert-butyl (2s,4s)-2-(dimethylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C OULCDZRGONPVMZ-IUCAKERBSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-IUYQGCFVSA-N trans-4-hydroxy-D-proline Chemical compound O[C@@H]1CN[C@@H](C(O)=O)C1 PMMYEEVYMWASQN-IUYQGCFVSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport 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
- 230000025033 vasoconstriction Effects 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions
- the present invention relates to a 1,3-dihydro-2H-indole-2-one derivative, a production method thereof, and an intermediate thereof. More specifically, it has arginine-vasopleucine Vlb receptor antagonism, depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, hypertension, gastrointestinal diseases, drug dependence, epilepsy, brain 1,3-Dihydro-2H-indole-2-one derivatives useful for treating or preventing diseases such as infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related disease, and alopecia, and a method for producing the same And its intermediates.
- Arginine-vasopressin is a peptide consisting of 9 amino acids, which is mainly biosynthesized in the hypothalamus and is deeply involved as a posterior pituitary hormone in regulating plasma osmotic pressure, blood pressure and body fluid volume.
- the AVP receptor has been cloned into three subtypes of Vla, Vlb and V2 receptors, and is known to be a seven-transmembrane receptor.
- the V2 receptor is coupled to Gs and increases cAMP levels.
- Vla receptor is coupled to Gq / ll, promotes PI response, increases intracellular Ca, is expressed in brain, liver, adrenal glands, vascular smooth muscle, etc., and is involved in vasoconstriction.
- the Vlb receptor like the Via receptor, is conjugated to GqZll and promotes PI response (Non-Patent Documents 1 and 2).
- Vlb receptor is most abundant in the pituitary gland (expressed in more than 90% of ACTH-secreting cells in the anterior lobe), and is estimated to be involved in AVP secretion of ACTH from the anterior pituitary by the AVP.
- Vlb receptors are present not only in the pituitary gland but also in a wide area of the brain, in the hippocampus, amygdala, entorhinal cortex and other limbic systems, in the cerebral cortex, in the olfactory bulb, and in the raphe nucleus, the nucleus of the serotonin nervous system ( Non-patent document 3 ⁇ Non-patent document 4).
- Vlb receptor is associated with depression and anxiety, and the usefulness of the Vlb receptor antagonist has been studied. It has been shown that aggresive behavior is reduced in Vlb receptor KO mice (Non-Patent Document 5). Also, Vlb receptor antagonist It has been reported that injection of septum into the septum increased the time spent on open roads (anxiolytic effect) in an elevated plus maze test (Non-Patent Document 6). Recently, a Vlb receptor-specific antagonist, which is a 1,3-dihydro-2H_indole-2-one derivative that can be administered peripherally, has been created (Patent Documents 16). In addition, antidepressant and anxiolytic effects of 1,3-dihydro_2H_indoleno_2_one derivatives in various animal models have been reported (Non-Patent Document 7 and Non-Patent Document 8).
- the compound disclosed in Patent Document 1 has a high affinity (114 ⁇ 10-olZL) for the Vlb receptor and is a compound that selectively acts on both AVP, AVP + CRF and binding stress-induced increase in ACTH. Antagonize.
- Patent Documents 1 to 16 do not disclose a compound in which a fluorine atom is introduced into a pyrrolidine ring portion bonded to the 3-position of 1,3-dihydro_2H_indolin-2-one.
- Non-patent document 1 Sugimoto T, Kawashima G, J. Biol. Chem., 269, 27088-27092, 1994.
- Non-patent document 2 Lolait S, Brownstein M, PNAS, 92, 6783-6787, 1995.
- Non-patent document 3 Vaccari C, Ostrowski N, Endocrinology, 139, 5015-5033, 1998.
- Non-patent document 4 Hernando F, Burbach J, Endocrinology, 142, 1659-1668, 2001.
- Non-patent document 5 Wersinger SR, Toung WS, Mol, Psychiatry, 7, 975-984, 2002.
- Non-patent document 6 Liebsch G, Engelmann M, Neurosci, Lett. 217, 101-104, 1996.
- Non-patent document 7 Gal CS, Le Fur G, 300, 1122-1130, 2002.
- Non-Patent Document 8 Griebel G, Soubrie P, 99, 6370a-6375, 2002.
- Patent document 1 WO 01/55130
- Patent Document 2 W ⁇ 01 / 55134
- Patent Document 3 WO01 / 64668
- Patent Document 4 WO01Z98295
- Patent Document 5 WO03Z008407
- Patent Document 6 W: 2004Z009585
- An object of the present invention is to provide a drug which is effective for a pathological condition relating to arginine-vasopressin Vlb receptor.
- a pathological condition relating to arginine-vasopressin Vlb receptor.
- Depression Anxiety, Alzheimer's Disease, For Kinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related diseases, alopecia, etc.
- the present inventors have conducted intensive studies, and as a result, a novel 1 that selectively antagonizes the arginine-vasopressin Vlb receptor, has excellent metabolic stability, shows good brain transport and high plasma concentration. , 3-Dihydro-2H-indole-2-one derivatives were found, and the present invention was completed.
- R is a halogen atom, carbon atom number 1 number 1
- R represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms,
- R is a halogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms,
- R is a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, or R is in the 3-position of phenyl, and R and R are Represents a methylenedioxy group,
- R represents a hydrogen atom or a fluorine atom
- R represents an ethylamino group, a dimethylamino group, an azetidine-11-yl group or a carbon atom number 11-
- R represents an alkoxy group having 1 to 4 carbon atoms
- R represents an alkoxy group having 1 to 4 carbon atoms.
- a preferred compound of the formula (1) is
- R represents a chlorine atom, a methyl group, a methoxy group, a trifluoromethyl group or a trifluoromethoxy group
- R represents a hydrogen atom, a chlorine atom, a methyl group or a methoxy group
- R represents a fluorine atom or a methoxy group
- R represents a hydrogen atom, a chlorine atom, a methyl group, a methoxy group, or R is at the 3-position of the fuel, and R and R together form a methylenedioxy group;
- R represents a hydrogen atom or a fluorine atom
- R represents a dimethylamino group, an azetidine-11-yl group or a methoxy group
- R is at the 2-position of the phenyl and represents a methoxy group
- R is a 1,3-dihydro-2H-indolin-1-one derivative represented by a methoxy group, or a pharmaceutically acceptable salt thereof.
- a more preferred compound of the formula (1) is a compound of the formula (la) wherein the substituent at the 2-position of pyrrolidine is in the (S) configuration.
- R 1, R 2, R 3, R 4, R 5, R 6, R and R are the same as defined in the above formula (1).
- Hal is a halogen atom
- Another embodiment of the present invention is a pharmaceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- the invention's effect is a pharmaceutical composition containing a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- the compound of the present invention is a selective vasopressin Vlb receptor antagonist having excellent metabolic stability, good brain transportability and high plasma concentration, and is used for depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, hypertension, gastrointestinal disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related diseases, alopecia, etc. Useful for treatment and prevention.
- the halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- it is a chlorine atom or a fluorine atom.
- the alkyl group having 1 to 4 carbon atoms means a linear or branched alkyl group having 1 to 4 carbon atoms, and is a methynole group, an ethyl group, a propyl group, an isopropyl group, a butyl group. Group, isobutyl group or tert-butyl group. Preferably, it is a methyl group.
- the alkoxy group having 1 to 4 carbon atoms means a linear or branched alkoxy group having 1 to 4 carbon atoms, and is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a buto group.
- the group forming an alkylene group having 3 to 6 carbon atoms is a trimethylene group, a tetramethylene group, a pentamethylene group, or a hexamethylene group. Preferably it is a trimethylene group.
- Pharmaceutically acceptable salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, succinic acid, trifluoroacetic acid Examples thereof include salts with organic acids such as acetic acid, dichloroacetic acid, methanesulfonic acid, p-tonolenesulfonic acid, naphthalenesulfonic acid, dalconic acid, benzenesulfonic acid, and citric acid.
- the compound of the present invention may exist as various solvates. In some cases, it is a hydrate from the viewpoint of applicability as a medicine.
- the salt of the compound represented by the formula (2) which is useful as an intermediate, is a mineral acid salt or an organic acid salt without particular limitation as long as it can be used for the synthesis of the compound.
- Examples of the mineral salts include hydrochloride, hydrobromide, sulfate, phosphate, nitrate, hydrogen sulfate, and dihydrogen phosphate.
- Organic acid salts include, for example, acetate, oxalate, lactate, tartrate, fumarate, and malate. Includes oleate, succinate, trifluoroacetate, dichloroacetate, methanesulfonate, p-toluenesulfonate, naphthalenesulfonate, dalconate, benzenesulfonate, citrate, etc. it can.
- the compounds of the present invention also include compounds in which one or more hydrogen, carbon, nitrogen, oxygen, and sulfur atoms have been replaced with radioisotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, or for biological analysis as receptor ligands.
- the compound of the present invention can be formulated into a pharmaceutical preparation by combining it with one or more pharmaceutically acceptable carriers, excipients, or diluents.
- the carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sonorebitone, mannitol, polyethylene glycolone, propylene glycolone, starch, gum, gelatin, gelatin, anoreginate, calcium silicate.
- Calcium phosphate cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, various oils such as soybean oil, etc. .
- additives such as a bulking agent, a binder, a disintegrant, a pH adjuster, and a dissolving agent are mixed with the above-mentioned carriers, excipients or diluents as needed, to prepare a common preparation.
- a common preparation e.g., a tablet, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, and skin patches.
- the compound of the present invention can be administered orally or parenterally to an adult patient at 0.001-500 mg once or several times a day. This dose can be appropriately increased or decreased depending on the type of the disease to be treated, the age, weight, and symptoms of the patient.
- the compound of the present invention can be produced, for example, according to the method shown below.
- the compound of the present invention has the formula (2) [0041]
- R and R are the above formulas
- the reaction is carried out in the presence of a base, for example, a metal hydride such as sodium hydride, or an alkali metal alkoxide such as potassium tert-butoxide, in an anhydrous solvent such as N, N-dimethylformamide or tetrahydrofuran, or a mixed solvent thereof, at a temperature of 70 ° Perform at a temperature of C— + 60 ° C.
- a base for example, a metal hydride such as sodium hydride, or an alkali metal alkoxide such as potassium tert-butoxide
- the compound of the present invention can be obtained by removing the reaction system power and purifying the compound by a general method, for example, crystallization, chromatography or the like.
- the compound of the present invention can be obtained as a free form or by isolation as a salt by a general method.
- a salt can be formed by treating the compound with an acid in an organic solvent.
- the free form is dissolved together with an acid in ethers such as Jethyl ether, alcohols such as isopropyl alcohol, or acetone, dichloromethane, ethyl acetate, or acetonitrile, and the above-mentioned salt is obtained by using a general method.
- ethers such as Jethyl ether
- alcohols such as isopropyl alcohol, or acetone, dichloromethane, ethyl acetate, or acetonitrile
- Examples of the acid used include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, and lactic acid. , Tartaric acid, fumaric acid, maleic acid, succinic acid, trifluoroacetic acid, dichloroacetic acid, methanesulfonic acid, p-tonoleenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, gluconic acid, and citric acid.
- the compound of the present invention may be isolated, for example, as a hydrochloride, oxalate, or the like. If necessary, the free form can be obtained by converting the obtained salt to, for example, hydroxyl. It can be obtained by neutralization using sodium chloride, triethylamine, an alkali metal carbonate such as sodium carbonate or sodium hydrogen carbonate, or an alkali metal hydrogen carbonate.
- the compound represented by the formula (2) is represented by the formula (5)
- the reaction can be carried out in an inert solvent such as dichloromethane, tetrahydrofuran, or the like, or a mixed solvent thereof in the presence of a base such as a solvent, under a temperature condition from room temperature to near the boiling point of the solvent.
- a base such as a solvent
- the compound represented by the formula (3) is a known compound described in EP0469984 and WO95 / 18105 and the like, and can be produced by the methods described therein.
- the compound represented by the formula (3) can be produced by halogenating a benzenesulfonic acid derivative or a salt thereof, for example, a sodium salt or a potassium salt.
- the reaction is carried out in the presence of a halogenating agent, such as, for example, chloridion thionyl or phosphorus oxychloride, in a non-solvent or an inert solvent, for example, in a solvent such as a halogenated hydrocarbon, N, N-dimethylformamide, at -10 ° C—Proceeds under temperature conditions between 200 ° C.
- a halogenating agent such as, for example, chloridion thionyl or phosphorus oxychloride
- a non-solvent or an inert solvent for example, in a solvent such as a halogenated hydrocarbon, N, N-dimethylformamide
- 2,4-Dimethoxybenzenesulfo-lucouric chloride is commercially available or can be produced according to the method described in the literature (Journal of American Chemical Society, 1952, 74, 2006.).
- the compound represented by the formula (5) is described in, for example, WO95Z18105, WO01Z74775, WO01 / 55130, WO01 / 55134, WO01 / 64668, WO01 / 98295, W003 / 008407 and the like. It can be manufactured according to the method described above.
- Another method for producing the compound represented by the compound (5) includes a compound (6b) [0058]
- the compound can be converted according to the method described in the literature (Farm. Zh. (K-iev), 1976, 5, 30-33.) Using a halogenating agent such as bromine or N-chlorosuccinimide. it can.
- a halogenating agent such as bromine or N-chlorosuccinimide. it can.
- the compound represented by the formula (6a) can be prepared, for example, by the methods described in WO95Z18105, WOOl / 74775 ⁇ W001 / 55130, WO01 / 55134, WO01 / 64668, WO01 / 98295, WO03 / 008407 and the like. It can be manufactured according to
- the compound represented by the formula (4) can be generally produced by a synthetic route shown in Scheme 1.
- Pr represents a protecting group for a nitrogen atom, particularly a benzyloxycarbonyl group or a tert-butoxycarbonyl group.
- step 1-la in step 1-la, compound (7): (4R)-or (4S) -4-hydroxy_L_proline, or (4R)-or (4S) _4-hydroxy-D-proline
- compound (8) can be produced by introducing a protecting group according to a general method.
- compound (8) can be subjected to esterification or amidation according to a general method to produce compound (10).
- the carboxylic acid of the compound (7) can be produced according to a general method in the step l_lb, by esterification or amidation to produce the compound (9).
- the compound (10) can be produced by introducing a protecting group into the nitrogen atom according to a general method (Steps 1-2b).
- Dehydration condensing agents include, for example, 1-ethyl-3_ (3-dimethylaminopropyl) force norlevodiimide 'hydrochloride, dicyclohexinolecanolevodiimide, dipheninolephosphoninoleazide, Examples thereof include carbonyldiimidazole and the like. If necessary, an activator such as 1-hydroxybenzotriazolone or hydroxysuccinimide can be used.
- reaction solvent examples include dichloromethane, chlorophonolem, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like, and a mixed solvent thereof.
- the reaction can be carried out using a base.
- the base include organic amines such as triethylamine and diisopropylethylamine, and organic amines such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate.
- Inorganic bases such as acid salts and potassium carbonate
- the reaction can be carried out at ⁇ 50 ° C. to around the boiling point of the reaction solvent.
- amidation can be performed using a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate.
- the solvent for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, and ethyl acetate, or a mixed solvent thereof.
- the reaction can be performed using a base.
- the base examples include organic amines such as triethylamine and diisopropylethylamine, organic acid salts such as sodium 2-ethylhexanoate and potassium 2-ethylhexanoate, And inorganic bases such as potassium carbonate.
- the reaction can be carried out at a temperature of from 150 ° C. to a temperature near the boiling point of the reaction solvent.
- esterification reactions of carboxylic acids include the following.
- methyl esterification can be performed with a diazo compound such as diazomethane.
- a solvent such as dichloromethane, chloroform, methanol, ethanol, or a mixed solvent thereof can be used.
- esterification can be carried out by deriving a carboxylic acid into an acid halide and allowing the alcoholic conjugate to act.
- the acid halogenation can be carried out using thionyl chloride, thionyl bromide, phosphorus oxychloride or the like.
- the reaction can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, N, N-dimethylformamide, toluene, tetrahydrofuran, or a mixed solvent thereof.
- Esterification can be performed by reacting an alcohol, such as methanol or ethanol, on the acid halide thus prepared.
- This reaction can be achieved by adding an alcohol to the acid halide reaction system, or by reacting the isolated acid halide with an alcohol.
- a method using a dehydration condensing agent is exemplified.
- Examples of the dehydrating condensing agent include 1-ethyl-3_ (3-dimethylaminopropyl) carbodiimide 'hydrochloride, dicyclohexylcanolevodiimide, diphenylphosphonyl azide, carberdiimidazole and the like.
- Examples of the reaction solvent include dichloromethane, chlorophonolem, 1,2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, dioxane, toluene, ethyl acetate and the like, and a mixed solvent thereof. In this case, the reaction can be carried out using a base.
- Examples of the base include amines such as triethylamine, diisopropylethylamine and 4- (dimethylamino) pyridin; sodium 2-ethylhexanoate; Organic acid salts such as potassium 2-ethylhexanoate; and inorganic bases such as potassium carbonate.
- the reaction can be carried out under a temperature condition of ⁇ 50 ° C. to around the boiling point of the reaction solvent.
- esterification can be performed using, for example, a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate, di-tert-butyl dicarbonate, or the like.
- Solvents for these reactions include, for example, solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylinolenolemamide, toluene, and ethyl acetate, or a mixed solvent thereof.
- the reaction can be carried out using a base.
- Examples of the base include organic amines such as triethylamine, diisopropylethylamine, 4_ (dimethylamino) pyridine, sodium 2-ethylhexanoate and 2-ethyl.
- Examples thereof include organic acid salts such as potassium xanate and inorganic bases such as potassium carbonate.
- the reaction can be carried out at a temperature of from 150 ° C. to around the boiling point of the reaction solvent.
- the protection of the amino group can be carried out, for example, using di-tert-butyl dicarbonate, benzylchloroformate or the like, in the presence of a suitable base.
- the base include, for example, amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
- solvents for these reactions include solvents that do not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, toluene, ethyl acetate, and water, or a mixed solvent thereof. These reactions can be performed at -50 ° C-50 ° C.
- a 4-hydroxy form can also be obtained in a 4-fluoro form, and a 4,4-difluoro form can be obtained from a 4-keto form.
- Examples of monofluorination include a method in which a hydroxyl group is converted into a leaving group and then converted into a fluoro group.
- Examples of the conversion to a leaving group include chlorination, bromination, iodination, methanesulfonyl sulfate, ⁇ -tonoleene sulfonylation, and the like.
- Examples of the chloridani reaction include, for example, tetrachloroanicarbon and triphenylphosphine. If you use Methods, a method using thionyl oxyphosphorus chloride, a method in which a leaving group is formed using tosyl chloride and the like, followed by replacement with lithium chloride or the like. In these reactions, a solvent that does not participate in the reaction such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or a mixed solvent thereof can be used. These reactions can be performed at -50-100 ° C.
- Examples of the bromination reaction include, for example, a method using carbon tetrabromide and triphenylphosphine. This reaction can be carried out at ⁇ 50 ° C. in a solvent that does not participate in the reaction such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, or a mixed solvent thereof.
- Examples of the iodination reaction include, for example, a method using iodine, triphenylphosphine and imidazole.
- a solvent that does not participate in the reaction such as tetrahydrofuran, dioxane, dichloromethane, clonor honolem, N, N-dimethylformamide, or a mixed solvent thereof can be used. These reactions can be carried out at a temperature of -50 to 100 ° C.
- Methanesulfonylation and p-toluenesulfonylation can be performed using methanesulfonyl chloride, P-toluenesulfonyl chloride, and the like, respectively.
- a suitable base may be added.
- the base to be added include organic amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate.
- the reaction solvent may be N, N-dimethylformamide, tetrahydrofuran, dioxane, dichloromethane, chlorophoronem, 1,2-dichloroethane, or other solvents that do not participate in the reaction, or a mixture of them at -50 to 50 ° C. Temperature conditions.
- Examples of a method of converting to a leaving group after converting to a fluoro group include a method of reacting, for example, tetrabutylammonium fluoride, cesium fluoride, potassium fluoride, sodium fluoride, or the like. These reactions should be carried out in a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, N, N-dimethylformamide, water, etc., or in a mixed solvent thereof at a temperature of -50 to 100 ° C. Can be.
- the difluorination is performed after oxidizing a hydroxyl group to a ketone group.
- the oxidation method (step l_3b) can be performed using, for example, chromic acid such as pyridinium dichromate and pyridinium dichromate.
- Reaction solvents include dichloromethane and chloroform. The reaction can be carried out at a temperature around o ° c—the boiling point of the reaction solvent.
- the reaction can be performed using, for example, a Dess-Martin reagent (1,1,1_triacetoxy-11,1-dihydro-1,2_benzoyl doxol-3- (lH) _one).
- a Dess-Martin reagent (1,1,1_triacetoxy-11,1-dihydro-1,2_benzoyl doxol-3- (lH) _one).
- the reaction solvent include dichloromethane, chloroform, and the like, and the reaction can be carried out at a temperature of 40 ° C.
- the reaction can also be carried out using IBX (1-hydroxy-1,2_benzodoxoxanore-3 (1H) one-one-oxide).
- Dimethyl sulfoxide is used as a reaction solvent, and the reaction can be further diluted with a solvent that does not participate in the reaction, such as tetrahydrofuran, dichloromethane, and chloroform.
- the reaction temperature can be from 0 to 40 ° C.
- the oxidation reaction is not particularly limited as long as it is a method capable of oxidizing an alcohol to a ketone other than the above.
- a reaction between dimethyl sulfoxide and an activator eg, oxalyl chloride, N-chlorosuccinimide, dicyclohexylcarposimide
- a reaction using perruthenate (VII) tetra-n-propylammonium and N-methylmorpholine oxide Oxidation method and the like for a comprehensive overview of the oxidation reaction, see Richard C. Larock,
- the difluorination in step 1-4b includes, for example, a method using a fluorinating agent such as dimethylsulfur trifluoride and [bis (2-methoxyethyl) amino] sulfur trifluoride.
- a fluorinating agent such as dimethylsulfur trifluoride and [bis (2-methoxyethyl) amino] sulfur trifluoride.
- These reactions are initiated in a solvent that does not participate in the reaction, such as tetrahydrofuran, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, toluene, etc., or a mixed solvent thereof at _78 ° C to room temperature, It is achieved by performing the reaction continuously near the boiling point of the solvent.
- the protecting group for the nitrogen atom is deprotected by a general method (steps 14a and 15b) to produce compounds (14) and (15) or salts thereof.
- an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or the like is used.
- an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, or the like is used.
- deprotection can be carried out by diluting or dissolving the acid with an organic solvent or water, and the reaction can be carried out at a temperature of -50 ° C to 50 ° C.
- organic solvent examples include ethanol, methanol, tetrahydrofuran, N, N-dimethyl honoleamide, dichloromethane, chlorohonolem, 1,2-dichloroethane and the like, or a mixed solvent thereof.
- the deprotection force can be obtained by a hydrogenolysis reaction using a metal catalyst such as palladium.
- a solvent that does not participate in the reaction such as ethanol, methanol, tetrahydrofuran, and ethyl acetate, or a mixed solvent thereof can be used.
- the reaction can be performed at 0 ° C 100 ° C.
- hydrogen gas can be used in this reaction, and the reaction can also be performed using, for example, a combination of formic acid and ammonium formate.
- a base such as getylamine, piperidine, ammonia, sodium hydroxide, or hydroxide hydroxide is used. Can be deprotected. These bases can be used alone or after being diluted, dissolved or suspended in a solvent. At this time, water, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chloroform, 1,2-dichloroethane and the like, or a mixed solvent thereof can be used as the solvent. The reaction can be performed at 0 ° C.—about the boiling point of the solvent.
- the ability to deprotect by using tetrakis (triphenylphosphine) palladium or the like as a catalyst or a reagent is high.
- S can.
- the reaction can be carried out in a solvent which does not participate in the reaction, such as dichloromethane, chloroform, tetrahydrofuran and the like.
- the reaction can be carried out at 0 ° C.—about the boiling point of the solvent.
- (4R)-or (4S) _4-hydroxy_L_proline or (4R)-or (4S) _4-hydroxy D-proline is commercially available.
- the compounds shown in (16) and (18), that is, (4R) -N-protected-1-hydroxyl-proline (16) or (4S) -N-protected_4-hydroxy-L— Proline (18) is used to perform N, N-dimethylamidation in steps 2-la and 2-lb according to the general method of amide bond formation, and then in steps 2_2a and 2_2b, a fluorinating agent, particularly Fluorination using a mixture of 1,2,3,3,3_hexafluoro mouth—1_ (getylamino) propane and 1,2,3,3,3_pentafluoro mouth—1_ (getylamino) _2_propene I do.
- a fluorinating agent particularly Fluorination using a mixture of 1,2,3,3,3_hexafluoro mouth—1_ (getylamino) propane and 1,2,3,3,3_pentafluoro mouth—1_ (getylamino) _2_propene I do.
- the configuration at the 4-position of compounds (16) and (18), which are synthesis raw materials is (R) configuration
- (S) Either configuration can result in a (4R) configuration of the monofluorinated compound (20).
- the obtained compound (20) can be deprotected by a general method to obtain a compound (21) or a salt thereof.
- the compound can be produced by the synthetic route shown in Scheme 3.
- Methyl or ethyl (2S, 4R) -N-protected-1-hydroxy-2-pyrrolidine carboxylate shown in compound (22) is used as a raw material for synthesis, and a general hydroxyl group is fluorinated (step 3-1).
- a general hydroxyl group is fluorinated (step 3-1).
- the obtained compound (23) can be deprotected by a general method (Step 3-5) to give methyl or ethyl (4R) -4_fluoro-L-prolinate (27) or a salt thereof.
- compound (23) can hydrolyze the ester (step 3_2) by a general method to produce carboxylic acid compound (24).
- carboxylic acid compound (24) After amidation (Step 3-3) of the obtained carboxylic acid compound (24) according to a general method of peptide bond formation, the protecting group for the nitrogen atom is deprotected by a general method (Step 3-4).
- the hydrolysis of the ester can be carried out using a base such as a metal hydroxide such as sodium hydroxide or a metal carbonate such as potassium carbonate.
- a base such as a metal hydroxide such as sodium hydroxide or a metal carbonate such as potassium carbonate.
- the solvent for this reaction include alcohols such as methanol and ethanol, solvents such as tetrahydrofuran, dioxane, N, N-dimethylformamide, water, and the like, or a mixed solvent thereof.
- the reaction can be carried out under a temperature condition of -20 ° C to around the boiling point of the reaction solvent.
- the carboxylic acid is protected with a group that can be deprotected with another ester such as an acid such as tert-butyl ester, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, etc. Can be used and deprotected.
- the deprotection can be carried out by diluting or dissolving the acid with an organic solvent or water, and the reaction can be carried out under a temperature condition of ⁇ 50 ° C. and 50 ° C.
- organic solvent examples include ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, dichloromethane, chlorophonolem, 1,2-dichloroethane and the like, or a mixed solvent thereof.
- deprotection can be performed by a hydrogenolysis reaction using a metal catalyst such as palladium.
- Solvents such as ethanol, methanol, tetrahydrofuran and ethyl acetate A solvent that does not participate in the reaction or a mixed solvent thereof can be used. The reaction is o ° c—
- reaction can be performed at 100 ° C.
- hydrogen gas can be used for this reaction, and for example, the reaction can also be performed using a combination of formic acid and ammonium formate.
- deprotection when protected with a group that can be deprotected by a metal catalyst such as aryl ester, deprotection can be achieved by using tetrakis (triphenylphosphine) palladium or the like as a catalyst or a reagent.
- the reaction can be carried out in a solvent that does not participate in the reaction, such as dichloromethane, chloroform, tetrahydrofuran and the like.
- the reaction can be performed at a temperature of 0 ° C near the boiling point of the solvent.
- R is a fluorine atom, and R is a dimethylamino group or
- silica gel 60 and silica gel 60N are silica gels marketed by Kanto Chemical Co., Ltd.
- Chromatorex NH is a silica gel marketed by Fuji Silicia Corporation.
- the progress of the reaction was monitored by thin layer chromatography (TLC) using a 0.25 mm silica gel 60 F plate (manufactured by Menorex).
- the TLC plate was observed by UV (254 nm) or coloration using a 20% sodium phosphomolybdate / ethanol solution.
- Step l_la Synthesis of tert-butyl (2S, 4R) _2_ [(dimethylamino) carbonyl] _4-hydroxypyrrolidine_1_carboxylate
- Step l_2a tert-butyl (2S, 4R) _2_ [(dimethylamino) carbonyl] —4_fluor Synthesis of oral pyrrolidine-1-carboxylate.
- Step 1 To a suspension of 25.7 g of the compound obtained in la and 500 g of sodium fluoride in 260 ml of dichloromethane was added 1,1,2,3,3,3-hexafluoro-11- (ethylamino) under ice-cooling. ) 26.6 g of a mixture of propane and 1,2,3,3,3_pentafluorol 1_ (getylamino) -2_propene (about 3: 1) was added dropwise over 10 minutes, and then stirred at room temperature for 16 hours. 100 ml of a 5% aqueous potassium carbonate solution was added to the reaction solution under ice-cooling, followed by stirring at the same temperature for 30 minutes.
- Step l_lb Synthesis of tert-butyl (2S, 4S) _2 _ [(dimethylamino) carbonyl] _4-hydroxyhydroxypyrrolidine_1_carboxylate
- Step l_2b Synthesis of tert_butyl (2S, 4R) _2 _ [(dimethylamino) carbonyl] _4_fluoropyrrolidine_1_carboxylate
- Step 1 To a suspension of the compound obtained in l_lb 8.54 g and sodium fluoride 1.67 g in dichloromethane (90 ml) was added 1,1,2,3,3,3_hexafluoro-1_ (ethylamino) propane under ice-cooling. 8.85 g of a mixture of 1,2,3,3,3_pentafluorol 1_ (getylamino) -2_propene (about 3: 1) was added dropwise over 2 minutes, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added dropwise to 200 ml of a saturated aqueous solution of sodium hydrogen carbonate over 3 minutes and stirred for 1 hour.
- Step 1-3 Synthesis of (4R) _4_fluoro_N, N-dimethyl-L-prolinamide trifluoroacetate
- Step l-2b To a solution of the compound obtained in Step l-2b (3.50 g) in chloroform (25 ml) was added trifluoroacetic acid (10.5 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was distilled off under reduced pressure to obtain 7.27 g (yellow oil) of a residue. This compound was used for the next reaction without purification.
- Step 1-4 (4R) —1— [5—black mouth—3— (2-methoxyphenyl) —2-oxo—2,3-dihydric mouth—1H—indole—3_yl] — Synthesis of 4-fluoro-N, N-dimethyl-L-prolinamide
- Step 1—5 (4R) —1— [5—Mouth—1 — [(2,4-Dimethoxyphenyl) sulfonyl] —3- (2-Methoxyphenyl) 1-2-oxo Synthesis of 1,2,3-dihydro-1H-indole-1-inole] —4-funoleol N, N_dimethyl-L-prolinamide (levorotatory isomer)
- Step 2-1 Synthesis of l_tert_butyl 2_methyl (2S, 4S) _4_fluoropyrrolidine-1, 2-dicarboxylate
- the reaction solution was poured into 200 ml of an aqueous saturated sodium bicarbonate solution with stirring under ice-cooling, and then stirred for 15 minutes. After allowing to stand, liquid separation was performed, and the obtained organic layer was evaporated under reduced pressure to obtain a residue.
- the aqueous layer was extracted with 60 ml of ethyl acetate and combined with the previous residue.
- the organic layer was washed with 40 ml of a 10% aqueous solution of potassium hydrogen sulfate and saturated brine, dried over sodium sulfate, and the desiccant was filtered off. The medium was distilled off under reduced pressure.
- Step 2-2 Synthesis of (4S) _l_ (tert_butoxycarbonyl) _4_fluoro_L-proline Under ice-cooling, a solution of 30.2 g of the compound obtained in step 2-1 in a 181 ml methanol solution in 2 mol ZL water was added. After dropping over 86 minutes while stirring to 86 ml of an aqueous sodium solution, the mixture was stirred at room temperature for 16 hours. After methanol was distilled off under reduced pressure, 136 ml of toluene was added and stirred, and then the aqueous layer was separated and stirred under ice cooling.
- Step 2_3 Synthesis of tert_butyl (2S, 4S) _2 _ [(dimethylamino) carbonyl] _4_fluoropyrrolidine-1-carboxylate
- Step 2-4 Synthesis of (4S) _4_fluoro_N, N-dimethyl_L-prolinamide trifluoroacetate
- Trifluoroacetic acid (18 ml) was added to a solution of the compound obtained in step 2_3 (5.98 g) in chloroform (60 ml) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. Thereafter, the solvent was distilled off under reduced pressure to obtain 12.lg (colorless oil) of the residue. This compound was used for the next reaction without purification.
- Step 2-5 (4S) _1_ [5_chloro mouth _3_ (2-methoxyphenyl) _2_oxo_2,3-dihydro mouth-1H-indole-3_yl] —4-fluoro-N Of N, N-dimethyl-L-prolinamide
- step 2-4 3,5-dichloro-3- (2-methoxyphenyl) -1,3, -dihydro-2H_indone-2-one 6.44 g and the compound obtained in step 2-4 (23 Ommol, crude) was mixed with 12.7 g of triethylamine under ice-cooling, and the mixture was stirred at room temperature for 24.5 hours.
- the reaction solution was poured into a 5% aqueous potassium carbonate solution (200 ml) while stirring, and extracted with a black hole form.
- the combined organic layer was washed with saturated saline, dried over magnesium sulfate, and dried.
- Step 2-6 (4S) _1_ [5_chloro- 1 _ [(2,4-dimethoxyphenyl) sulfonyl] _3_ (2-methoxyphenyl) -l-oxo-2,3-dihydro-l Synthesis of 1H-indole-3-inole] —4-funoleol N, N_dimethyl-L-prolinamide (levorotatory isomer)
- Step 3_1 Synthesis of l_tert-butynole 2-methinole (2S) _4-oxopyrrolidine_1,2-dicanoleboxylate
- Step 3-2 Synthesis of l_tert_butyl 2_methyl (2S) _4,4-difluoropyrrolidine-1,2-dicarboxylate
- Step 3-4 Synthesis of tert-butyl (2S) _2 _ [(dimethylamino) carbonyl] —4,4-difluoropyrrolidine-1-carboxylate
- Step 3-5 Synthesis of 4,4-difluoro_N, N-dimethyl_L-prolinamide trifluoroacetate
- reaction solution was poured into a 5% aqueous solution of potassium carbonate (50 ml) with stirring, and extracted with chloroform (30 ml ⁇ 2).
- chloroform (30 ml ⁇ 2).
- the combined organic layer was washed with saturated saline, dried over magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain 5.82 g of a residue (brown solid).
- Step 4-1 Methyl (4S) _4_Fluoro mouth—Synthesis of L_prolinate trifluoroacetate
- 1.5 g of the compound obtained in Step 2-1 was used as a starting material to give the title compound. 2.56 g (yellow oil) were obtained.
- Step 4-2 Methyl (4S) _1_ [5_cloth_3_ (2-methoxypheninole) -l_2-oxo_2,3-dihydro_1H-indone-nor-3-inole] -4_fluoro_L-prolinate Synthesis of
- Step 5-1 Synthesis of 1-benzyl 2-methyl (2S) -4_fluoropyrrolidine-1-1,2-dicarboxylate
- llg was added dropwise over 10 minutes and stirred at room temperature for 16 hours Thereafter, a 5% aqueous solution of potassium carbonate (100 ml) was stirred in the reaction solution at the same temperature for 30 minutes under ice cooling. After liquid separation, the obtained aqueous layer was extracted with chloroform (30 ml ⁇ 2), and the combined organic layers were washed with saturated saline (50 ml), dried over magnesium sulfate, and the desiccant was filtered off. The lower solvent was distilled off.
- Step 5-2 Synthesis of l-[(benzyloxy) carbonyl] _4_fluoro-L-proline Compound obtained in Step 5-1 under ice-cooling 1.
- 45 g of methanol in 15 ml of 2 mol ZL aqueous sodium hydroxide solution 3.6 ml The mixture was stirred at room temperature for 4 hours.
- Step 5-3 Synthesis of 1-benzyl 2_tert_butyl (2S) _4_fluoropyrrolidine- 1, 2-dicanolevoxylate
- Step 5-4 Synthesis of tert-butyl 4-fluoro-L-prolinate
- Step 5-5 tert- Synthesis of butyl 1- [5-chloro-2--3- (2-methoxypheninole) -2-oxo-2,3-dihydro-1H-indone-1-3-inole] -4_fluoro-1-L-prolinate
- Step 5_6 tert_butyl 1_ [5_ (2,4-dimethoxyphenyl) sulfonyl
- Step 6_l Synthesis of tert_butyl (2R, 4R) _2 _ [(dimethylamino) carbonyl] -14-hydroxypyrrolidine-1-carboxylate
- (4S) _l_ (tert_butoxycarbonyl) _4-hydroxy-D-proline 2 ⁇ 50 g and 1-hydroxybenzotriazole monohydrate 2.19 g of a N, N-dimethylformamide 25 ml solution was stirred for 5 minutes. Thereafter, 2.49 g of 1-ethyl-3_ (3-dimethylaminopropyl) carposimid 'hydrochloride was added and stirred at the same temperature for 30 minutes. Thereafter, 1.95 g of a 50% aqueous solution of dimethylamine was added to the reaction solution, followed by stirring at room temperature for 16 hours.
- Step 6_2 Synthesis of tert_butyl (2R) _2 _ [(dimethylamino) carbonyl] —4_fluoropyrrolidine-11-carboxylate
- Step 6-3 Synthesis of 4-fluoro-N, N-dimethinole D-prolinamide trifluoroacetate
- Step 6_4 1_ [5_black mouth_3_ (2-methoxypheninole) -l_2-oxo_2,3-dihydro-lH_indolin- 3_yl] -4-fluoro-N, N-dimethyl-D —Synthesis of prolinamide Under a nitrogen atmosphere, 3,5-dichloro-3- (2-methoxyphenyl) —1,3-dihydro—2H_indonolone 2_one 2.36 g and obtained in step 6-3 Compound 3. 30g of chlorophonolem (20m
- Step 7_l Synthesis of tert_butyl (2S, 4S) _2- (azetidine-11-ylcarbonyl)-4-hydroxypyrrolidine-1_carboxylate
- Step 7_2 Synthesis of tert-butyl (2S) _2— (azetidine-1-ylcarbonyl) _4-fluoropyrrolidine-1-carboxylate
- Step 7-3 Synthesis of (2S) _2- (azetidine-1-ylcarbonyl) _4_fluoropyrrolidine trifluoroacetate
- Step 7-4 3 _ [(2S) _2- (azetidine-1-ylcarbonyl) _4_fluoropyrrolidine_1-inole] -5_clo mouth_3_ (2-methoxypheninole) _1,3-dihydro-1 Synthesis of 2H—Indone 2 1
- step 7-3 3,5-dichloro-3- (2-methoxyphenyl) -1,3-dihydro-2H_indonore_2_one 2.37 g and the compound obtained in step 7-3 (crude product) ) was added to a solution of (20 ml) in black hole under ice-cooling, and the mixture was heated to room temperature and stirred at the same temperature for 13 hours. A 5% aqueous solution of potassium carbonate (10 ml) was added to the reaction solution while stirring, and the mixture was stirred for 15 minutes.
- Step 7_5 3 _ [(2S) _2- (azetidine 1-ylcarbonyl) _4_fluoropyrrolidine- 1-yl] 5-cloclonal 1-[(2,4-dimethoxyphenyl) sulfonate ] — 3- (2-methoxyphenyl) _1,3-dihydro-2H Synthesis of indole-2-one (levorotatory isomer)
- Step 8-1 Synthesis of benzyl (2S) _2 _ [(ethylamino) carbonyl] _4_fluoropyrrolidin-1-carboxylate
- Step 8-2 Synthesis of N-ethynole_4-fluoro-L-prolinamide
- Step 8_1 The compound obtained in Step 8_1 in a stream of hydrogen 1.80 g, 10.
- a suspension of 360 mg / o palladium-carbon in methanol (36 ml) was stirred at room temperature for 3 hours.
- the insoluble material was separated by filtration and concentrated under reduced pressure to obtain 1.07 g of the title compound. This compound was used for the next reaction without purification.
- Step 8_3 Synthesis of 1_ [5_black mouth_3_ (2-methoxypheninole) -l_2-oxo_2,3-dihydro-lH_indoleno_3_inole] _N-ethyl-4_fluoro_L-prolinamide
- Step 8 4: 1— [5—black—1 — [(2,4-dimethoxyphenyl) sulfonyl] —3— (2-methoxy Synthesis of 1-oxo-2,3-dihydro-1H-indole-1-yl] -N-ethyl-14-fluoro-L-prolinamide (levorotatory isomer)
- Step 9-2 Synthesis of (4R) _4_fluoro_N, N-dimethyl_L-prolinamide
- Step 9-3 (4R) -l- [3- (2,4-dimethoxyphenyl) -1,5,6-dimethoxy-2-oxo-1,2,3-dihydro-1H-indolinore-3-yl ] —Synthesis of 4-fluoro-N, N-dimethyl-L-prolinamide (mixture of diastereoisomers)
- Step 9-4 (4R) -l- ⁇ 3- (2,4-dimethoxyphenyl) —1 _ [(2,4-dimethoxyphenyl) sulfonyl] —5,6-dimethoxy Synthesis of _2_oxo_2,3-dihydro-1H-indoneno _3-inoren ⁇ _4-Fluoro_N, N-dimethyl-L-prolinamide (Levorotatory isomer, dextrorotatory isomer)
- step 9-3 Under a nitrogen atmosphere, 200 mg of the diastereoisomer mixture obtained in step 9-3 was added to a suspension of 18 mg of sodium hydride in a suspension of N, N-dimethylformamide (2 ml) under ice cooling, and the same temperature was maintained for 1 hour. Stirred. Under ice-cooling, 107 mg of 2,4-dimethoxybenzenesulfuryl chloride was stirred at the same temperature for 30 minutes, then ethyl acetate (30 ml) and a 5% aqueous potassium carbonate solution (20 ml) were added, and the mixture was added at room temperature for 15 minutes.
- Step 10-1 Synthesis of 5-chloro-1-hydroxy-3- (2-isopropylphenyl) 1-1,3-dihydro-2H-indole-2-one
- Step 10_2 (4R) _1_ [5_black_mouth_3_ (2-isopropylphenyl) -l_2-oxo_2,3-dihydro-lH-indole-3-yl] -l4-fluoro-N, N —Dimethyl L-prolinamide Composition
- Step 10-3 (4R) _1_ [5_chloro mouth_1 _ [(2,4-dimethoxyphenyl) sulfonyl] _3_
- Step 11—1 Synthesis of 3 -— [2- (benzyloxy) phenyl] —3-hydroxy-3,5,6,7-tetrahydrocyclopenta [f] indoleux-2 (1H) -one
- Step 1 1-3 (4R) -l- ⁇ 3- [2- (benzyloxy) phenyl] -l-[(2,4_dimethoxyphenyl) sulfonyl]-2-oxo1-1,2 Of 1,3,5,6,7-Hexahydrocyclopenta [f] indole-1-yl ⁇ _4-fluoro-N, N-dimethinole L-prolinamide (Levorotatory isomer)
- Step 11-4 (4R) _1_ [1 _ [(2,4-dimethoxyphenyl) sulfonyl] _3_ (2-hydroxyphenyl) -1-2-oxo-1,2,3,5,6 Synthesis of 7-hexahydrocyclopenta [f] indole-1-yl] -4-fluoro-N, N-dimethyl-L-prolinamide (levorotatory isomer) In a nitrogen atmosphere, in step 11-3 To a solution of the obtained compound (42 mg) in methanol (1 ml) was added 20% palladium hydroxide (50% water) (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 75 minutes.
- 20% palladium hydroxide 50% water
- Step 12-1 Synthesis of 3_ (2_fluorophenyl) _3-hydroxy_5_ (trifluoromethyl) _1,3—dihydro-2H_india
- Step 12-2 (4R ) _4_Fluoro mouth — 1_ [3_ (2_fluorophenyl) _2_oxo _5_ (Trifluoromethyl) -1,2,3-dihydro-1H—indole-1-3-inole] —N, N-dimethyl-1-L-prolinamide Synthesis of (Diastereoisomer mixture)
- Step 12-3 (4R) -l- [l-[(2,4-dimethoxyphenyl) sulfonyl] _3_ (2_fluoromethyl) -2-oxo-5- (trifluoromethyl ) —Synthesis of 2,3-dihydro-1H-indole-3-yl] -14_fluoro_N, N-dimethyl-L-prolinamide (Levorotatory isomer) Using 100 mg of the compound obtained in 12-2 as a starting material, 32 mg (colorless amorphous) of the title compound was obtained.
- Step 13 1: 5-chloro—3-hydroxy—3 -— [2- (trifluoromethoxy) phenyl] —6- (trifluoromethyl) 1-1,3-dihydro-2H-indole-2-one Synthesis
- Step 13-2 (4R) _1_ [5_black_mouth
- 0.12 ml of pyridine is added to a solution of the compound obtained in step 13-1 in 500 mg of chloroform (3 ml), and a solution of 0.10 ml of thionyl chloride in 0.1 ml of chloroform (1 ml) is added dropwise under ice-cooling. And stirred for 1 hour. After the completion of the reaction, water was extracted with porcine form. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
- Step 13 3: (4R) —1— [5—black mouth—1 — [(2,4-dimethoxyphenyl) sulfonyl] —2-oxo _3_ [2_ (trifluoromethoxy) phenyl ] _6_ (trifluoromethylinole) _2,3-dihydro-1H-indole_3_yl] —4-fluoro-N, N-dimethyl_L-prolinamide (left (Rotatory isomer)
- Step 14 1: (4R) —4-Fluoro—1— [3- (2-Methoxyphenyl) —2-oxo-5— (Trifluoromethoxy) -1,2,3-dihydro-1H-indole-1-inole ] —Synthesis of N, N-Dimethyl-L-Peptide Linamide
- Step 14-2 (4R) _1_ [1_ [(2,4-dimethoxyphenyl) sulfonyl] —3_ ( 2-Methoxy phenyl-1-2-oxo-5- (trifluoromethoxy) -1,2,3-dihydro-1-H-indoleno-3-yl] _4_fluoro_N, N-dimethyl-L-prolinamide ( Synthesis of levorot
- Step 15-1 (4R) —4-Fluoro—1— [3- (2-Methoxyphenyl) —5-Methyl-2-oxo-1,2,3-dihydro-1H—indole-3-yl] — Synthesis of N, N-dimethyl-L-prolinamide
- Step 15-2 (4R) _1_ [1 _ [(2,4-dimethoxyphenyl) sulfonyl] -3_ (2-methoxyphenyl) 1-5-methyl-12-oxo-2,3 Synthesis of —Dihydro-1H—indole-3-yl] -4-—Fluoro-N, N-dimethyl-L-prolinamide (Levorotatory isomer, dextrorotatory isomer)
- 620 mg of the compound obtained in step 15-1 (mixture of diastereoisomers) was added to a solution of 67 mg of sodium hydride in a solution of N, N-dimethylformamide (10 ml) in an ice bath, and the mixture was stirred for 40 minutes.
- Step 16—2 (4R) — 1— [4,5-Dichloro-1- (2-methoxy-15-methylphenyl) -1-2-oxo-1,2,3-dihydro-1H—Indonele_3 -Yl] -4-Fluoro-N, N-Dimethyl L-Pop
- Step 16-3 (4R) _1_ [4,5-dichloro (2,4-dimethoxyphenyl) sulfonyl] _3_ (2-methoxy-15-methinolepheninole) -1_oxo_2,3 —Dihydro-1H—indolinole-3-yl] -14-fluoro-N, N-dimethyl-L-prolinamide (levorotatory isomer, dextrorotatory isomer)
- Step 16-2 Under a nitrogen atmosphere, 301 mg of the compound (mixture of diastereoisomers) obtained in Step 16-2 was added to a solution of 26 mg of sodium hydride in a solution of 26 mg of tetrahydrofuran (3 ml) in an ice bath, followed by stirring for 20 minutes. Thereafter, a solution of 170 mg of 2,4-dimethoxybenzenesulfonyl chloride in furan (2 ml) with tetrahydrid was added dropwise. After stirring at the same temperature for 2 hours, ethyl acetate (5 ml) and a 5% aqueous potassium carbonate solution (10 ml) were added and stirred at room temperature for 30 minutes.
- Step 17—1 Synthesis of 5-chloro-3- (5-methoxy-2-methoxyphenyl) -1-hydroxy_4-methyl-1, 3-dihydro-1 2H-indole-2-one
- Step 17—2 (4R) —1— [5—Black Mouth 3— (5—Black Mouth 2-Methoxypheninole) -1-4-Methinole Synthesis of 2-, 3-oxo-2,3-dihydro-1H-indonele_3-3-inole] _4-funolere N, N-dimethinole L-prolinamide
- Step 17 3: (4R) —1— ⁇ 5—black mouth—3— (5—black mouth—2-methoxyphenyl) — 1 — [(2,4-dimethoxyphenyl) sulfonyl] — 4_methyl_2-oxo-2,3-dihydro-1H_indole Synthesis of 3-yl ⁇ _4_fluoro_N, N_dimethyl-L-prolinamide (levorotatory isomer)
- Step 19-2 Synthesis of potassium 2,4_dibutoxybenzenesulfonate
- phosphoryl chloride (30.7 g) was added to 3.90 g of the compound obtained in Step 19_2 under an ice bath, followed by stirring at 130 ° C for 5.5 hours. After cooling to room temperature, the mixture was poured into ice (200 ml) and stirred for 20 minutes. Subsequently, getyl ether (50 ml) was added, and the mixture was further stirred for 30 minutes. After extraction with getyl ether (50 ml ⁇ 2), the organic layer was washed with saturated saline and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure.
- Step 19-4 (4R) _1_ [5_black mouth_1 _ [(2,4_dibutoxyphenyl) sulfonyl] —3_
- step 1-4 Under a nitrogen atmosphere, 200 mg of the compound (isomer B) obtained in step 1-4 was added to a suspension of 20 mg of sodium hydride in tetrahydrofuran (3 ml) under an ice bath, and the mixture was stirred for 20 minutes. Thereafter, a solution of 2,4-dibutoxybenzenesulfuryl chloride (160 mg) in tetrahydrofuran (2 ml) was added dropwise. After stirring at the same temperature for 2 hours, ethyl acetate (5 ml) and a 5% aqueous potassium carbonate solution (10 ml) were added and stirred at room temperature for 30 minutes.
- Vlb and Via receptor binding experiments Preparation of crude membrane preparations from organ tissues and Vlb and Via receptor binding experiments were performed according to the methods described in J. Clin. Invest. 98, 2729-2738 (1996). Membrane preparations were prepared from rat pituitary gland for Vlb receptor binding experiments and from rat liver tissue for Via receptor binding experiments. As the test drug, the compounds of Examples 1, 2, and 3 were used.
- the obtained precipitate was suspended in a 50 mmol / L Tris-HCl buffer (pH 7.4) containing 0.1% serum albumin and 10 mmol / L magnesium chloride to a protein concentration of 600 ⁇ g / ml. , And used as a crude membrane sample in binding experiments.
- the crude membrane preparation (0.5 ml, 300 protein / Assy) was reacted with [] Arg-vasopressin (final concentration 0.4 nmol / L) at 25 ° C for 60 minutes.
- the reaction solution was suction-filtered on a GF / C glass fiber filter paper immersed in 0.3% polyethyleneimine for 2 hours using a cell harvester for receptor binding experiments.
- the amount of binding in the presence of 5 ⁇ mol / L Arg-vasopressin is defined as non-specific binding, and the total binding force, which is the binding in the absence of 5 ⁇ mol / L Arg-vasopressin, is determined by subtracting the non-specific binding. It was decided to be a joint.
- the test drug was dissolved in a 100% DMSO solution and added to the membrane sample simultaneously with [ 3 H] Arg-vasopressin. 0.
- the IC50 value of the test drug was calculated based on the inhibition curve force at the concentration of InmolZL lx molZL. 50% inhibitory concentration of Example 1, 2, 3 wherein compound is to Vlb receptors is 1 one 1 OOx 10- 9 molZL, while for VI a receptor 10- 8 10- 6 mol / L.
- Example 1 Using Sprague-Dawley rats (male, 8 weeks old), the compound of Example 1 and compound A (WO 01/55130, the compound described in Example 1) (dissolved using 0.03 mol / L HC1 containing 5% Cremophor EL to prepare a 2 mg / mL solution) at 5 mL / kg (10 mg / kg). It was administered orally.
- the plasma concentrations of the compound of Example 1 and Compound A were measured by liquid chromatography tandem mass spectrometry (LC / MS / MS). That is, acetonitrile 200 was added to 50 zL of plasma or brain homogenate, stirred, centrifuged, and the supernatant was injected into a liquid chromatograph.
- the column used was an Agilent ZORBAX SB-C18 (length 50 mm, diameter 2.1 mm). The eluent is 0.1. /. Acetonitrile containing 0.1% acetic acid and acetic acid was used.
- Sciex API3000 LC / MS / MS System was used for MS / MS conditions, ESI was used for ionization, and positive ion and MRM mode were used for monitoring.
- the compound of Example 1 used m / z 632 ⁇ 472 as an index, and the compound A used m / z 630 ⁇ 472 as an index.
- Table 2 shows the plasma and brain concentrations at each blood sampling time after oral administration, and Table 3 shows the average plasma concentrations.
- Example 1 The compound of Example 1 in which fluorine was introduced into the pyrrolidine ring had a higher brain concentration than compound A at 1 and 2 hours after administration and a higher plasma concentration than compound A even after 2 hours. was confirmed.
- the compound of the present invention has an arginine-pasopressin Vlb receptor antagonism, and has depression, anxiety, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, hypertension, gastrointestinal disorders, It is useful for treating and preventing diseases such as drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related diseases, and alopecia.
Description
Claims
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JP2005513484A JP4618127B2 (ja) | 2003-08-28 | 2004-08-27 | 1,3−ジヒドロ−2h−インドール−2−オン誘導体 |
US10/569,833 US7528124B2 (en) | 2003-08-28 | 2004-08-27 | 1,3-dihydro-2H-indol-2-one derivative |
EP04772354A EP1659121A4 (en) | 2003-08-28 | 2004-08-27 | D RIV OF 1,3-DIHYDRO-2H-INDOL-2-ONE |
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WO2005021534A1 true WO2005021534A1 (ja) | 2005-03-10 |
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PCT/JP2004/012398 WO2005021534A1 (ja) | 2003-08-28 | 2004-08-27 | 1,3−ジヒドロ−2h−インドール−2−オン誘導体 |
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US (1) | US7528124B2 (ja) |
EP (1) | EP1659121A4 (ja) |
JP (1) | JP4618127B2 (ja) |
WO (1) | WO2005021534A1 (ja) |
Cited By (7)
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WO2006103986A1 (ja) * | 2005-03-28 | 2006-10-05 | Tosoh F-Tech, Inc. | 光学活性なフルオロプロリン誘導体の製造方法 |
DE102005015957A1 (de) * | 2005-03-31 | 2006-10-05 | Abbott Gmbh & Co. Kg | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung |
US8044079B2 (en) | 2005-12-02 | 2011-10-25 | Abbott Gmbh & Co. Kg | Substituted oxindole derivatives, medicaments containing said derivatives and use thereof |
US8119676B2 (en) | 2006-08-26 | 2012-02-21 | Abbott GmbH & Co. HG | Substituted benzimidazolone derivatives, medicaments comprising them and their use |
WO2012043791A1 (ja) | 2010-10-01 | 2012-04-05 | 大正製薬株式会社 | 1,2,4-トリアゾロン誘導体 |
WO2013062027A1 (ja) | 2011-10-27 | 2013-05-02 | 大正製薬株式会社 | アゾール誘導体 |
WO2013147117A1 (ja) | 2012-03-30 | 2013-10-03 | 大正製薬株式会社 | 縮環アゾール誘導体 |
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JP5125501B2 (ja) * | 2005-01-28 | 2013-01-23 | 大正製薬株式会社 | 1,3−ジヒドロ−2h−インドール−2−オン化合物、及び芳香族複素環が縮合したピロリジン−2−オン化合物 |
JP2008534461A (ja) * | 2005-03-24 | 2008-08-28 | アボット ゲーエムベーハー ウント カンパニー カーゲー | 置換オキシインドール誘導体、前記誘導体を含む医薬およびそれの使用 |
WO2008107399A1 (en) * | 2007-03-02 | 2008-09-12 | Abbott Gmbh & Co. Kg | Substituted oxindole compounds |
EP2195286A2 (en) * | 2007-09-10 | 2010-06-16 | Cipla Limited | Process for the preparation of a raf kinase inhibitor and intermediates for use in the process |
GB201210686D0 (en) | 2012-06-15 | 2012-08-01 | Holsboermaschmeyer Neurochemie Gmbh | V1B receptor antagonist for use in the treatment of patients having an elevated AVP level and/or an elevated copeptin level |
GB201310782D0 (en) | 2013-06-17 | 2013-07-31 | Max Planck Innovation Gmbh | Method for predicting a treatment response to a CRHR1 antagonist and/or V1B antagonist in a patient with depressive and/or anxiety symptoms |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001098295A1 (fr) * | 2000-06-19 | 2001-12-27 | Sanofi-Synthelabo | Derives de 1,3-dihydro-2h-indol-2-one et leur utilisation en tant que ligands des recepteurs v1b et v1a de l'arginine-vasopressine |
JP2003523351A (ja) * | 2000-01-25 | 2003-08-05 | サノフィ−サンテラボ | 新規1,3−ジヒドロ−2h−インドール−2−オン誘導体、それらの製造法およびそれらを含む医薬組成物 |
JP2003523354A (ja) * | 2000-01-25 | 2003-08-05 | サノフィ−サンテラボ | 新規な1,3−ジヒドロ−2h−インドール−2−オン誘導体、それらの製法およびそれらを含有する医薬組成物 |
JP2003525287A (ja) * | 2000-02-25 | 2003-08-26 | サノフィ−サンテラボ | 新規な1,3−ジヒドロ−2h−インドール−2−オン、その製造方法およびそれらを含む医薬組成物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2827604B1 (fr) | 2001-07-17 | 2003-09-19 | Sanofi Synthelabo | Nouveaux derives de 1-phenylsulfonyl-1,3-dihydro-2h-indol-2- one, un procede pour leur preparation et les compositions pharmaceutiques en contenant |
FR2842527B1 (fr) | 2002-07-19 | 2005-01-28 | Sanofi Synthelabo | Derives d'acyloxypyrolidine, leur preparation et leur application en therapeutique |
ITTV20020127A1 (it) | 2002-10-29 | 2004-04-30 | Siet Soc It Elettronica T Rasformatori S | Dispositivo di protezione per trasformatori, particolarmente per la alimentazione di lampade |
US7334582B2 (en) | 2003-10-31 | 2008-02-26 | Medtronic, Inc. | Electronic valve reader |
-
2004
- 2004-08-27 EP EP04772354A patent/EP1659121A4/en not_active Withdrawn
- 2004-08-27 US US10/569,833 patent/US7528124B2/en not_active Expired - Fee Related
- 2004-08-27 JP JP2005513484A patent/JP4618127B2/ja not_active Expired - Fee Related
- 2004-08-27 WO PCT/JP2004/012398 patent/WO2005021534A1/ja active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003523351A (ja) * | 2000-01-25 | 2003-08-05 | サノフィ−サンテラボ | 新規1,3−ジヒドロ−2h−インドール−2−オン誘導体、それらの製造法およびそれらを含む医薬組成物 |
JP2003523354A (ja) * | 2000-01-25 | 2003-08-05 | サノフィ−サンテラボ | 新規な1,3−ジヒドロ−2h−インドール−2−オン誘導体、それらの製法およびそれらを含有する医薬組成物 |
JP2003525287A (ja) * | 2000-02-25 | 2003-08-26 | サノフィ−サンテラボ | 新規な1,3−ジヒドロ−2h−インドール−2−オン、その製造方法およびそれらを含む医薬組成物 |
WO2001098295A1 (fr) * | 2000-06-19 | 2001-12-27 | Sanofi-Synthelabo | Derives de 1,3-dihydro-2h-indol-2-one et leur utilisation en tant que ligands des recepteurs v1b et v1a de l'arginine-vasopressine |
Non-Patent Citations (1)
Title |
---|
See also references of EP1659121A4 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006103986A1 (ja) * | 2005-03-28 | 2006-10-05 | Tosoh F-Tech, Inc. | 光学活性なフルオロプロリン誘導体の製造方法 |
JP5117185B2 (ja) * | 2005-03-28 | 2013-01-09 | 東ソ−・エフテック株式会社 | 光学活性なフルオロプロリン誘導体の製造方法 |
DE102005015957A1 (de) * | 2005-03-31 | 2006-10-05 | Abbott Gmbh & Co. Kg | Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung |
US8044079B2 (en) | 2005-12-02 | 2011-10-25 | Abbott Gmbh & Co. Kg | Substituted oxindole derivatives, medicaments containing said derivatives and use thereof |
US9006276B2 (en) | 2005-12-02 | 2015-04-14 | AbbVie Deutschland GmbH & Co. KG | Substituted oxindole derivatives, medicaments containing said derivatives and use thereof |
US8119676B2 (en) | 2006-08-26 | 2012-02-21 | Abbott GmbH & Co. HG | Substituted benzimidazolone derivatives, medicaments comprising them and their use |
WO2012043791A1 (ja) | 2010-10-01 | 2012-04-05 | 大正製薬株式会社 | 1,2,4-トリアゾロン誘導体 |
US9193695B2 (en) | 2010-10-01 | 2015-11-24 | Taisho Pharmaceutical Co., Ltd. | 1, 2, 4-triazolone derivative and use thereof as an antagonist on the arginine-vasopressin 1B receptor |
WO2013062027A1 (ja) | 2011-10-27 | 2013-05-02 | 大正製薬株式会社 | アゾール誘導体 |
KR20140081824A (ko) | 2011-10-27 | 2014-07-01 | 다이쇼 세이야꾸 가부시끼가이샤 | 아졸 유도체 |
US9522914B2 (en) | 2011-10-27 | 2016-12-20 | Taisho Pharmaceutical Co., Ltd | Azole derivative |
WO2013147117A1 (ja) | 2012-03-30 | 2013-10-03 | 大正製薬株式会社 | 縮環アゾール誘導体 |
Also Published As
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US20060276449A1 (en) | 2006-12-07 |
EP1659121A1 (en) | 2006-05-24 |
JPWO2005021534A1 (ja) | 2007-11-01 |
US7528124B2 (en) | 2009-05-05 |
JP4618127B2 (ja) | 2011-01-26 |
EP1659121A4 (en) | 2008-11-26 |
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