JP2014513046A - ４−ヒドロキシ酪酸の重水素化類似体 - Google Patents
４−ヒドロキシ酪酸の重水素化類似体 Download PDFInfo
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- JP2014513046A JP2014513046A JP2013553647A JP2013553647A JP2014513046A JP 2014513046 A JP2014513046 A JP 2014513046A JP 2013553647 A JP2013553647 A JP 2013553647A JP 2013553647 A JP2013553647 A JP 2013553647A JP 2014513046 A JP2014513046 A JP 2014513046A
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- alkyl
- deuterium
- compound
- cycloalkyl
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- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 title abstract description 12
- 229940006015 4-hydroxybutyric acid Drugs 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
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- 238000000034 method Methods 0.000 claims abstract description 52
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 201000003631 narcolepsy Diseases 0.000 claims abstract description 16
- VWYANPOOORUCFJ-UHFFFAOYSA-N alpha-Fernenol Chemical compound CC1(C)C(O)CCC2(C)C3=CCC4(C)C5CCC(C(C)C)C5(C)CCC4(C)C3CCC21 VWYANPOOORUCFJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960003928 sodium oxybate Drugs 0.000 claims abstract description 14
- 208000001640 Fibromyalgia Diseases 0.000 claims abstract description 12
- 230000006872 improvement Effects 0.000 claims abstract description 6
- 230000000422 nocturnal effect Effects 0.000 claims abstract description 6
- 239000000651 prodrug Substances 0.000 claims abstract description 6
- 229940002612 prodrug Drugs 0.000 claims abstract description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 117
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 114
- 229910052739 hydrogen Inorganic materials 0.000 claims description 88
- 239000001257 hydrogen Substances 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 69
- 239000003814 drug Substances 0.000 claims description 56
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 55
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- 239000011734 sodium Substances 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 159000000000 sodium salts Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 23
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 10
- 230000000946 synaptic effect Effects 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
- 206010010904 Convulsion Diseases 0.000 claims description 8
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
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- 108090000312 Calcium Channels Proteins 0.000 claims description 6
- 102000003922 Calcium Channels Human genes 0.000 claims description 6
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 6
- 206010019468 Hemiplegia Diseases 0.000 claims description 6
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- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
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- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
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- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 208000001797 obstructive sleep apnea Diseases 0.000 claims description 5
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 claims description 4
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical group C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 claims description 4
- 208000019505 Deglutition disease Diseases 0.000 claims description 4
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 claims description 4
- 208000032140 Sleepiness Diseases 0.000 claims description 4
- 229960002866 duloxetine Drugs 0.000 claims description 4
- 229960002870 gabapentin Drugs 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 229960000600 milnacipran Drugs 0.000 claims description 4
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 4
- 229960001233 pregabalin Drugs 0.000 claims description 4
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 claims description 4
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004688 venlafaxine Drugs 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 206010013654 Drug abuse Diseases 0.000 claims 2
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- 239000002510 pyrogen Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
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- 230000002829 reductive effect Effects 0.000 description 23
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- 239000000243 solution Substances 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 19
- 239000002253 acid Substances 0.000 description 19
- 230000000155 isotopic effect Effects 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 16
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 15
- 229910052708 sodium Inorganic materials 0.000 description 15
- -1 pyrosulfate Chemical compound 0.000 description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
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- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 238000010348 incorporation Methods 0.000 description 11
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- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- YEJRWHAVMIAJKC-DICFDUPASA-N 4,4-dideuteriooxolan-2-one Chemical compound [2H]C1([2H])COC(=O)C1 YEJRWHAVMIAJKC-DICFDUPASA-N 0.000 description 6
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YEJRWHAVMIAJKC-RRVWJQJTSA-N [2H]C1([2H])CC([2H])([2H])C(=O)O1 Chemical compound [2H]C1([2H])CC([2H])([2H])C(=O)O1 YEJRWHAVMIAJKC-RRVWJQJTSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
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- WXXTUKMZIAPTCK-CQOLUAMGSA-N (2-methoxy-2-oxoethyl) 4-acetyloxy-2,2,4,4-tetradeuteriobutanoate Chemical compound CC(=O)OC([2H])([2H])CC([2H])([2H])C(=O)OCC(=O)OC WXXTUKMZIAPTCK-CQOLUAMGSA-N 0.000 description 4
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- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
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Landscapes
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| JP2018532771A (ja) * | 2015-09-23 | 2018-11-08 | エックスダブリュー ラボラトリーズ，インコーポレイテッド | γ−ヒドロキシ酪酸（ＧＨＢ）のプロドラッグ、その組成物および使用 |
| US11098007B2 (en) | 2016-06-24 | 2021-08-24 | Kyowa Hakko Bio Co., Ltd. | Crystal of amino acid salt of 3-hydroxyisovaleric acid and production method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2018532771A (ja) * | 2015-09-23 | 2018-11-08 | エックスダブリュー ラボラトリーズ，インコーポレイテッド | γ−ヒドロキシ酪酸（ＧＨＢ）のプロドラッグ、その組成物および使用 |
| WO2017086447A1 (ja) * | 2015-11-19 | 2017-05-26 | 協和発酵バイオ株式会社 | ３－ヒドロキシイソ吉草酸の一価カチオン塩の結晶および該結晶の製造方法 |
| JPWO2017086447A1 (ja) * | 2015-11-19 | 2018-09-06 | 協和発酵バイオ株式会社 | ３−ヒドロキシイソ吉草酸の一価カチオン塩の結晶および該結晶の製造方法 |
| US10647653B2 (en) | 2015-11-19 | 2020-05-12 | Kyowa Hakko Bio Co., Ltd. | Crystal of monovalent cation salt of 3-hydroxyisovaleric acid and process for producing the crystal |
| US11098007B2 (en) | 2016-06-24 | 2021-08-24 | Kyowa Hakko Bio Co., Ltd. | Crystal of amino acid salt of 3-hydroxyisovaleric acid and production method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20140008391A (ko) | 2014-01-21 |
| US20210403407A1 (en) | 2021-12-30 |
| US20140343119A1 (en) | 2014-11-20 |
| ES2804540T3 (es) | 2021-02-08 |
| MX2013009368A (es) | 2013-09-26 |
| US8759394B2 (en) | 2014-06-24 |
| US10040748B2 (en) | 2018-08-07 |
| IL227754B (en) | 2018-01-31 |
| US9309182B2 (en) | 2016-04-12 |
| BR112013020620A2 (pt) | 2016-10-04 |
| US20190100484A1 (en) | 2019-04-04 |
| WO2012112492A1 (en) | 2012-08-23 |
| JP6692319B2 (ja) | 2020-05-13 |
| MX355742B (es) | 2018-04-26 |
| CN103370289A (zh) | 2013-10-23 |
| US20160326086A1 (en) | 2016-11-10 |
| EP2675771A1 (en) | 2013-12-25 |
| KR101976218B1 (ko) | 2019-05-07 |
| CN103370289B (zh) | 2015-09-09 |
| IL227754A0 (en) | 2013-09-30 |
| JP2017165747A (ja) | 2017-09-21 |
| US20130012565A1 (en) | 2013-01-10 |
| EP2675771B1 (en) | 2020-04-08 |
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