WO2014061714A1 - ケイ素含有カルボン酸誘導体 - Google Patents
ケイ素含有カルボン酸誘導体 Download PDFInfo
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- WO2014061714A1 WO2014061714A1 PCT/JP2013/078121 JP2013078121W WO2014061714A1 WO 2014061714 A1 WO2014061714 A1 WO 2014061714A1 JP 2013078121 W JP2013078121 W JP 2013078121W WO 2014061714 A1 WO2014061714 A1 WO 2014061714A1
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- Prior art keywords
- group
- alkyl group
- hydrogen atom
- atom
- salt
- Prior art date
Links
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 title description 8
- 229910052710 silicon Inorganic materials 0.000 title description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 5
- 239000010703 silicon Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 125000003277 amino group Chemical group 0.000 claims abstract description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 125000006165 cyclic alkyl group Chemical group 0.000 claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 229910052805 deuterium Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004431 deuterium atom Chemical group 0.000 claims description 3
- -1 monoalkylamino group Chemical group 0.000 description 51
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 229960002870 gabapentin Drugs 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 150000001975 deuterium Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 4
- 229960001233 pregabalin Drugs 0.000 description 4
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- DQUVMKCUQHAVMC-UHFFFAOYSA-N chloromethyl-cyclopropyl-dimethylsilane Chemical compound ClC[Si](C)(C)C1CC1 DQUVMKCUQHAVMC-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- AEAVJUJZAMOSKN-UHFFFAOYSA-N silyl 3-cyanobutanoate Chemical compound [SiH3]OC(CC(C)C#N)=O AEAVJUJZAMOSKN-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OPLAASJHTPWAMS-UHFFFAOYSA-N CC(C#N)C(=O)O[SiH3] Chemical compound CC(C#N)C(=O)O[SiH3] OPLAASJHTPWAMS-UHFFFAOYSA-N 0.000 description 2
- 0 C[Si+](C)CC(*)C#N Chemical compound C[Si+](C)CC(*)C#N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000003709 fluoroalkyl group Chemical group 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000037323 metabolic rate Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- LJJDWRASITYPSP-UHFFFAOYSA-N 3-cyano-2-silylbutanoic acid Chemical compound [SiH3]C(C(=O)O)C(C)C#N LJJDWRASITYPSP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- KIVAFKYEPAGQAR-UHFFFAOYSA-N CC(C(OC(C)[SiH3])=O)C#N Chemical compound CC(C(OC(C)[SiH3])=O)C#N KIVAFKYEPAGQAR-UHFFFAOYSA-N 0.000 description 1
- KJFRKVOVDYCDLB-UHFFFAOYSA-N C[SiH](C)CC(CC(OCc1ccccc1)=O)C#N Chemical compound C[SiH](C)CC(CC(OCc1ccccc1)=O)C#N KJFRKVOVDYCDLB-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- VGJWNINOOOAJIV-UHFFFAOYSA-N benzyl 3-cyano-4-cyclopropyl-2-dimethylsilylbutanoate Chemical compound C1(CC1)CC(C(C(=O)OCC1=CC=CC=C1)[SiH](C)C)C#N VGJWNINOOOAJIV-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- ITKVLPYNJQOCPW-UHFFFAOYSA-N chloro-(chloromethyl)-dimethylsilane Chemical compound C[Si](C)(Cl)CCl ITKVLPYNJQOCPW-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IPLONMMJNGTUAI-UHFFFAOYSA-M lithium;bromide;hydrate Chemical compound [Li+].O.[Br-] IPLONMMJNGTUAI-UHFFFAOYSA-M 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
Definitions
- the carboxyl group is one of important functional groups in pharmaceutical compounds and is widely used in combination with various functional groups such as amino group, hydroxyl group and halogen atom.
- various functional groups such as amino group, hydroxyl group and halogen atom.
- gabapentin (2- [1- (aminomethyl) cyclohexyl] acetic acid) used as an antiepileptic drug and pregabalin ((S) -3- (amino) used for peripheral neuropathic pain (such as postherpetic neuralgia) Methyl) -5-methylhexanoic acid) is an example of a medicine having a combination with an amino group.
- An object of the present invention is to provide a novel silicon-containing carboxylic acid derivative useful as an active ingredient of a medicine.
- R 1 , R 2 , and R 3 represents a cyclic alkyl group, the remaining group represents a linear or branched alkyl group; n represents 0 or 1; R 4 represents an amino group (the amino group may have a substituent) or-(CX 2 ) m -COOH (m represents an integer of 0 to 3, and X represents a hydrogen atom or a deuterium atom; R 5 represents-(CY 2 ) p -COOR 6 (p represents an integer of 0 to 3, Y represents a hydrogen atom or a deuterium atom, R 6 represents a hydrogen atom or an alkyl group (the alkyl The group may have a substituent), or a salt thereof.
- R 1 is a cyclopropyl group
- R 2 and R 3 are methyl groups
- n is 0 or 1
- R 4 is an amino group, monoalkylamino group, or acylamino Or a salt thereof
- R 5 is — (CH 2 ) p —COOR 6 (p represents an integer of 0 to 3, R 6 is a hydrogen atom or an alkyl group); and R 1 Is a cyclopropyl group, R 2 and R 3 are methyl groups, n is 1, R 4 is an amino group, and R 5 is-(CH 2 ) p -COOR 6 (p is 0 to 3
- R 6 is a hydrogen atom or an alkyl group, or a salt thereof.
- the present invention provides a medicament comprising the compound represented by the above general formula (I) or a physiologically acceptable salt thereof as an active ingredient.
- the compound represented by the above general formula (I) or a salt thereof provided by the present invention can be used, for example, as an active ingredient of a medicine, has excellent in vivo stability, and delays the metabolic rate. It is useful as an active ingredient of medicine.
- At least one group of R 1 , R 2 , and R 3 represents a cyclic alkyl group, and the remaining groups represent a linear or branched alkyl group.
- a cyclic alkyl group a 3- to 10-membered cyclic alkyl group, preferably a 3- to 6-membered cyclic alkyl group can be used, particularly preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group. A group or the like can be used.
- One or two or more linear or branched alkyl groups may be substituted on the ring of the cyclic alkyl group.
- an alkyl group having about 1 to 6 carbon atoms such as a methyl group or an ethyl group
- R 1 , R 2 , and R 3 is preferably a cyclic alkyl group
- the cyclic alkyl group is preferably a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.
- R 1 , R 2 , and R 3 other than the cyclic alkyl group each independently represent a linear or branched alkyl group.
- the number of carbon atoms of the alkyl group is not particularly limited, but is, for example, about 1 to 18, preferably 1 to 12, more preferably 1 to 6, and particularly preferably about 1 to 4.
- This alkyl group may have one or more substituents. When having two or more substituents, they may be the same or different.
- the position of the substituent is not particularly limited, and may have a substituent at an arbitrary position.
- substituents examples include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), a hydroxyl group, an oxo group, a carboxyl group, an alkoxycarbonyl group, an acyl group, an amino group, an alkyl group, an alkenyl group, and an alkynyl group. , An alkoxy group, an aryl group, or an aralkyl group, but is not limited thereto. These substituents may be further substituted with another substituent. Examples of such include, but are not limited to, a fluoroalkyl group, a fluoroacetyl group, a methoxybenzyl group, and the like.
- N indicates 0 or 1.
- n is 0, it means that there is no methylene group.
- n is preferably 1.
- R 4 represents an amino group or — (CX 2 ) m —COOH.
- the amino group represented by R 4 may have one or two substituents.
- substituents for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an acyl group (for example, an alkanoyl group such as an acetyl group or an aroyl group such as a benzoyl group) can be used. It will never be done.
- amino group substituted with an acyl group examples include an acylamino group that forms an amide bond with a carboxyl group of an amino acid (for example, International Publication WO 02/100344), or a carbamate (for example, (2-methyl-1- Oxopropyloxy) ethoxycarbonyl group bonded to an amino group, etc.), but is not limited thereto.
- These amino group modification means with acyl groups are useful as prodrugs or sustained release means.
- the amino group represented by R 4 is preferably unsubstituted or has one alkyl group or acyl group. In the case of having one alkyl group, the alkyl group has, for example, about 1 to 6 carbon atoms.
- m represents an integer of 0 to 3, preferably m is 1 or 2, and more preferably m is 1.
- X represents a hydrogen atom or a deuterium atom, but when X is a deuterium atom, the substitution rate of deuterium (ratio of hydrogen atoms replaced by deuterium atoms) is at least 50%, preferably 70% More preferably, it means 80%, particularly preferably 90%, most preferably 95% or more, but does not need to be completely substituted with deuterium. Therefore, when X is a deuterium atom, it is necessary to interpret it including that a part of X is a hydrogen atom.
- R 4 is preferably an amino group, and the amino group is preferably an unsubstituted amino group or a monoalkylamino group.
- p represents an integer of 0 to 3, but p is preferably 1 or 2, and p is more preferably 1.
- Y represents a hydrogen atom or a deuterium atom, and is the same as described for X.
- R 6 represents a hydrogen atom or an alkyl group
- the alkyl group represented by R 6 may have a substituent
- the substituent include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, or Iodine atom), hydroxyl group, oxo group, carboxyl group, alkoxycarbonyl group, acyl group, amino group, alkyl group, alkenyl group, alkynyl group, alkoxy group, aryl group, or aralkyl group, but are not limited thereto. None happen.
- These substituents may be further substituted with another substituent. Examples of such include, but are not limited to, a fluoroalkyl group, a methoxymethyl group, an ethoxymethyl group, and the like.
- ester formed when R 6 represents an optionally substituted alkyl group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, Benzyl group, acetoxymethyl group, 1- (acetoxy) ethyl group, propionyloxymethyl group, 1- (propionyloxy) ethyl group, butyryloxymethyl group, 1- (butyryloxy) ethyl group, isobutyryloxymethyl group, 1- (isobutyryloxy) ethyl group, valeryloxymethyl group, 1- (valeryloxy) ethyl group, isovaleryloxymethyl group, 1- (isovaleryloxy) ethyl group, pivaloyloxymethyl group, 1- (pivaloyloxy) ethyl group, methoxycarbonyloxymethyl group, 1- (methoxycarbonyloxy) e
- the compound represented by the general formula (I) may form an acid addition salt or a base addition salt.
- acid addition salts include mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as p-toluenesulfonate, oxalate, and malate.
- base addition salt include metal salts such as sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salts, and organic amine salts such as triethylamine salt or ethanolamine salt.
- physiologically acceptable salts are preferred when the compounds of the present invention are used as active pharmaceutical ingredients.
- the compound represented by the general formula (I) may have one or two or more asymmetric carbons depending on the type of substituent, and any optical isomer based on these asymmetric carbons. Any mixture of optical isomers, racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, and the like are all encompassed within the scope of the present invention.
- the compound represented by the general formula (I) contains a double bond, geometric isomers exist, but in addition to the pure form of Z-form or E-form, mixtures of any proportions of the present invention Included in the range.
- any hydrates or solvates of the free compounds or the compounds in the form of salts are also included in the scope of the present invention.
- the compound of the present invention represented by the general formula (I) can be synthesized by the method specifically shown in the examples of the present specification. Since a method for synthesizing ⁇ -carbonylsilanes in which a silicon atom is introduced instead of a carbon atom has been reported (for example, GB 2,397,576A and Journal of Organometallic Chemistry, 690, pp.678-684, 2005) Any compound included in the general formula (I) can be easily produced by referring to the synthesis methods specifically shown in the examples of the present specification with reference to the publications of Examples of a method for synthesizing a compound having an amino acid and a carboxyl group include, for example, a method for synthesizing pregabalin and its analogs (U.S. Pat. , And No. 5,563,175).
- the use of the compound of the present invention represented by the general formula (I) is not particularly limited, for example, it can be used as an active ingredient of a medicine.
- medical uses include, but are not limited to, prevention and / or treatment of epilepsy, pain, inflammation, gastrointestinal disorders, insomnia, psychiatric disorders, diabetic peripheral neuropathy, etc.
- a compound having an amino acid and a carboxyl group is expected to have the same pharmacological action as, for example, pregabalin and gabapentin, and is therefore described in, for example, paragraph [0003] of International Publication WO 2010/017498 Can be used for specific applications.
- the entire disclosure of the above patent document is included in the disclosure of this specification by reference.
- the binding to the gabapentin receptor can be carried out by preparing a gabapentin receptor from the brain of a Wister rat according to the method of Suman-Chauhan et al. (Eur. J. Pharmacol, 244 (3), pp.293-301, 1993).
- the binding of the compound (1 ⁇ M) to the gabapentin receptor can be examined by inhibition of gabapentin binding in the presence of [ 3 H] gabapentin 0.02 ⁇ M, and the analgesic action is administered orally to the test compound using the rat Chung model.
- it can measure using the pain threshold value by irritation
- the compound of the present invention represented by the general formula (I) or a physiologically acceptable salt thereof is used as a pharmaceutical
- the above compound as a pharmaceutical or a physiologically acceptable salt thereof, or a hydrate thereof Or a solvate may be directly administered to mammals including humans, but can be preferably administered as an oral or parenteral pharmaceutical composition that can be produced by methods well known to those skilled in the art.
- the pharmaceutical composition suitable for oral administration include tablets, capsules, powders, fine granules, granules, liquids, and syrups.
- the pharmaceutical composition suitable for parenteral administration includes Examples include injections, instillations, suppositories, inhalants, eye drops, nasal drops, ointments, creams, patches, transdermal absorbents, transmucosal absorbents, and the like.
- additives for preparation include excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, Examples thereof include pH adjusters, stabilizers, propellants, and pressure-sensitive adhesives, and these can be appropriately selected by those skilled in the art depending on the form of the pharmaceutical composition, and can be used in combination of two or more. Also good.
- the dose of the drug is not particularly limited, and can be appropriately increased or decreased according to various factors that should be normally considered, such as the weight and age of the patient, the type and symptoms of the disease, and the route of administration.
- the dose of the drug can be used in the range of about 0.001 to 10,000 mg per day for an adult.
- Example 1 Preparation of chloromethyl (cyclopropyl) dimethylsilane Add iodine (small pieces) to a suspension of metal magnesium (2.19 g, 91.3 mgatom) in tetrahydrofuran (THF, 60 ml) and occasionally ice-cool in an argon atmosphere. Bromocyclopropane (7.3 ml, 91.7 mmol) was added dropwise. After dissolution of magnesium, the reaction vessel is ice-cooled, and a solution of chloro (chloromethyl) dimethylsilane (10.0 ml, 75.9 mmol) in THF (15 ml) is added dropwise over about 10 minutes, and the addition vessel is further added with THF (5 ml). Washed.
- the reaction vessel was ice-cooled, aqueous hydrochloric acid (1N) was added, and the mixture was stirred for 5 minutes and further at room temperature for 30 minutes.
- the precipitated urea was filtered under reduced pressure, and the filtrate was extracted with chloroform.
- the organic layer was washed with a saturated aqueous sodium bicarbonate solution, treated with a regular method, and purified by silica gel column chromatography [hexane-ethyl acetate (24: 1-19: 1)], and represented by 4-cyclopropyl (dimethyl) silyl-3-cyanobutanoic acid. Benzyl (7.50 g, 93%) was obtained as a colorless oil.
- the compound represented by the above general formula (I) or a salt thereof provided by the present invention can be used, for example, as an active ingredient of a medicine, has excellent in vivo stability, and delays the metabolic rate. It is useful as an active ingredient of medicine.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
金属マグネシウム(2.19 g, 91.3 mgatom)のテトラヒドロフラン(THF, 60 ml)懸濁液にヨウ素(小片)をくわえ、アルゴン雰囲気下、時折氷冷しつつブロモシクロプロパン(7.3 ml, 91.7 mmol)を滴下した。マグネシウムの溶解後反応容器を氷冷し、クロロ(クロロメチル)ジメチルシラン(10.0 ml, 75.9 mmol)のTHF (15 ml)溶液を約10分間で滴下、さらにTHF (5 ml)にて滴下容器を洗浄した。氷冷下30分、さらに室温にて16時間撹拌を続けた後、反応液を塩化アンモニウム-氷にあけ、ジエチルエーテルにて抽出。有機層を飽和食塩水で洗浄後常圧蒸留に付し、表記クロロメチル(シクロプロピル)ジメチルシラン(7.69 g, 68%)を無色油状物として得た。
1H-NMR (CDCl3) δ: -0.34 (1H, dddd, J=9.5, 9.5, 7, 7 Hz), 0.03 (6H, s), 0.23-0.29 (2H, m), 0.57-0.66 (2H, s), 2.80 (2H, s).
1H-NMR (CDCl3) δ: -0.37 (1H, dddd, J=9.5, 9.5, 7, 7 Hz), 0.020 (3H, s), 0.023 (3H, s), 0.21-0.27 (2H, m), 0.57-0.68 (2H, m), 1.26 (1H, dd, J=14.5, 9 Hz), 1.32 (1H, dd, J=14.5, 7 Hz), 1.33 (3H, t, J=7 Hz), 3.55 (1H, dd, J=9, 7 Hz), 4.20-4.31 (2H, m).
1H-NMR (CDCl3) δ: -0.36 (1H, dddd, J=9.5, 9.5, 7, 7 Hz), 0.02 (6H, s), 0.18-0.29 (2H, m), 0.57-0.69 (2H, m), 0.90 (1H, dd, J=14.5, 5.5 Hz), 1.05 (1H, dd, J=14.5, 10.5 Hz), 1.29 (3H, t, J=7 Hz), 2.60 (1H, dd, J=16.5, 7 Hz), 2.75 (1H, dd, J=16.5, 7.5 Hz), 3.13 (1H, dddd, J=10.5, 7.5, 7, 5.5 Hz), 4.20 (2H, q, J=7 Hz).
1H-NMR (CD3OD) δ: -0.38 (1H, dddd, J=9.5, 9.5, 7, 7 Hz), -0.04 (6H, s), 0.20-0.27 (2H, m), 0.57-0.64 (2H, m), 0.66 (1H, dd, J=15, 6 Hz), 0.73 (1H, dd, J=15, 8 Hz), 2.18-2.30 (1H, m), 2.33 (1H, dd, J=15.5, 9 Hz), 2.54 (1H, dd, J=15.5, 3 Hz), 2.87 (1H, dd, J=12.5, 7.5 Hz), 2.98 (1H, dd, J=12.5, 3.5 Hz).
Claims (3)
- R1がシクロプロピル基であり、R2及びR3がメチル基であり、nが0又は1であり、R4がアミノ基、モノアルキルアミノ基、又はアシルアミノ基であり、R5が-(CH2)p-COOR6(pは0から3の整数を示し、R6は水素原子又はアルキル基である)である請求項1に記載の化合物又はその塩。
- R1がシクロプロピル基であり、R2及びR3がメチル基であり、nが1であり、R4がアミノ基であり、R5が-(CH2)p-COOR6(pは0から3の整数を示し、R6は水素原子又はアルキル基である)である請求項1に記載の化合物又はその塩。
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EP13847854.0A EP2910560B1 (en) | 2012-10-18 | 2013-10-17 | Silicon-containing carboxylic acid derivative |
JP2014514942A JP5572783B1 (ja) | 2012-10-18 | 2013-10-17 | ケイ素含有カルボン酸誘導体 |
US14/435,621 US9353134B2 (en) | 2012-10-18 | 2013-10-17 | Silicon-containing carboxylic acid derivative |
CN201380054365.6A CN104781264A (zh) | 2012-10-18 | 2013-10-17 | 含有硅的羧酸衍生物 |
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EP (1) | EP2910560B1 (ja) |
JP (1) | JP5572783B1 (ja) |
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WO (1) | WO2014061714A1 (ja) |
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WO2002100344A2 (en) | 2001-06-11 | 2002-12-19 | Xenoport, Inc. | Amino acid conjugates providing for sustained systemic concentrations of gaba analogues |
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WO2012144551A1 (ja) * | 2011-04-20 | 2012-10-26 | 財団法人乙卯研究所 | ケイ素含有カルボン酸誘導体 |
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2013
- 2013-10-17 US US14/435,621 patent/US9353134B2/en not_active Expired - Fee Related
- 2013-10-17 EP EP13847854.0A patent/EP2910560B1/en not_active Not-in-force
- 2013-10-17 CN CN201380054365.6A patent/CN104781264A/zh active Pending
- 2013-10-17 JP JP2014514942A patent/JP5572783B1/ja not_active Expired - Fee Related
- 2013-10-17 WO PCT/JP2013/078121 patent/WO2014061714A1/ja active Application Filing
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JP5572783B1 (ja) | 2014-08-13 |
US20150232487A1 (en) | 2015-08-20 |
CN104781264A (zh) | 2015-07-15 |
JPWO2014061714A1 (ja) | 2016-09-05 |
EP2910560A1 (en) | 2015-08-26 |
US9353134B2 (en) | 2016-05-31 |
EP2910560B1 (en) | 2017-09-06 |
EP2910560A4 (en) | 2016-06-15 |
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