CN115974799A - 氨基甲酸酯取代的醇衍生物及其在医药上的应用 - Google Patents
氨基甲酸酯取代的醇衍生物及其在医药上的应用 Download PDFInfo
- Publication number
- CN115974799A CN115974799A CN202211189615.4A CN202211189615A CN115974799A CN 115974799 A CN115974799 A CN 115974799A CN 202211189615 A CN202211189615 A CN 202211189615A CN 115974799 A CN115974799 A CN 115974799A
- Authority
- CN
- China
- Prior art keywords
- compound
- tetrazol
- chlorophenyl
- carbamate
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 10
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 title abstract description 10
- 150000001298 alcohols Chemical class 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 206010061334 Partial seizures Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 201000007186 focal epilepsy Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- -1 protium (H) Chemical compound 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000004698 Polyethylene Substances 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 235000006408 oxalic acid Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- HMTCTAFOMZTQMS-VIFPVBQESA-N (1r)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethanol Chemical compound C([C@H](O)C=1C(=CC=CC=1)Cl)N1N=CN=N1 HMTCTAFOMZTQMS-VIFPVBQESA-N 0.000 description 3
- SLILCNKDGFOZOJ-UHFFFAOYSA-N 1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethanone Chemical compound ClC1=CC=CC=C1C(=O)CN1N=NC=N1 SLILCNKDGFOZOJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010024642 Listless Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 229920002472 Starch Chemical class 0.000 description 1
- KJADKKWYZYXHBB-XBWDGYHZSA-N Topiramic acid Chemical compound C1O[C@@]2(COS(N)(=O)=O)OC(C)(C)O[C@H]2[C@@H]2OC(C)(C)O[C@@H]21 KJADKKWYZYXHBB-XBWDGYHZSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- GFHAXPJGXSQLPT-VIFPVBQESA-N [(1r)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl] carbamate Chemical compound C([C@H](OC(=O)N)C=1C(=CC=CC=1)Cl)N1N=CN=N1 GFHAXPJGXSQLPT-VIFPVBQESA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Chemical class 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Chemical class 0.000 description 1
- 229920002678 cellulose Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000028329 epileptic seizure Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 208000017971 listlessness Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension 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
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种氨基甲酸酯取代的醇衍生物、其立体异构体或者药学上可接受的盐,及其在医药上的应用。
Description
技术领域
本发明涉及一种氨基甲酸酯取代的醇衍生物、其立体异构体或者药学上可接受的盐,及其在医药上的应用。
背景技术
癫痫,是大脑神经元突发性异常放电,导致短暂的大脑功能障碍的一种慢性疾病,按发作类型,大致分为局灶性癫痫发作(约占60%)和全身性癫痫发作(约占40%)。目前抗局灶性癫痫一线用药主要为卡马西平、拉莫三嗪、左乙拉西坦、奥卡西平、托吡酯、丙戊酸钠,但都具有一定的副作用,包括头晕、头痛、精神紧张、精神萎靡、恶心等,并且约30%患者用药后仍然无法有效控制癫痫发作。因此,亟需开发更安全、更有效的抗局灶性癫痫药。
发明内容
本发明的目的是提供新的氨基甲酸酯取代的醇衍生物、其立体异构体或者药学上可接受的盐,及其在制备抗局灶性癫痫药物中的用途。
本发明的一个或多个实施方式提供通式(I)化合物或者其立体异构体:
其中:
R1选自H或者C1-6烷基;
R2选自H、OH、COOH、COOR2a或者C1-6烷基;
R2a选自C1-6烷基;
R3a选自H、C1-6烷基;
R3b、R3c、R3d、R3e各自独立地选自H或者C1-6烷基。
n选自0、1、2、3或4。
本发明的一个或多个实施方式提供的化合物选自,但不限于以下结构:
本申请的一个或多个实施方式提供药物组合物,所述药物组合物包含:
(1)上述的化合物或其立体异构体;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
本申请的一个或多个实施方式提供本申请的化合物或其立体异构体,或者本申请的药物组合物在制备抗局灶性癫痫药物中的用途。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8 元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如 10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
实施例1
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基(羟甲基)氨基甲酸酯(化合物1)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl(hydroxymethyl)carbamate
第一步:
1-(2-氯苯基)-2-(2H-四唑-2-基)乙烷-1-酮(1b)
1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-one
在1L的三口烧瓶中,加入1a(100g,429mmol)和乙腈(400mL),缓慢加入四氮唑(36g,514.8mmol),最后加入碳酸钾(72g,514.8mmol)。加料完毕后,升至45℃反应2h,TLC监测反应完全,冷却至室温。过滤除去碳酸钾,然后加入乙酸乙酯(300 mL x 3)萃取,无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析 (PE:EA=3:1)纯化得1b(32g,收率33.6%,淡黄色固体)。
1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.10(m,1H),7.67-7.63(m,2H),7.61-7.54(m,1H),6.58(m,2H).
第二步:
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙烷-1-醇(1c)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol
在500mL的三口烧瓶中,加入1b(32g,144.1mmol)和甲酸:三乙胺(5:2的加成物,100mL),缓慢加入手性催化剂(CAS:192139-90-5)(924mg,1.44mmol)。加料完毕后,反应24h,LC-MS监测反应完全。加入乙酸乙酯(200mL x 3)和200mL水萃取,无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(PE:EA=3:1)纯化得1c(32g,收率98.6%,淡黄色固体)。
1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.65(dd,J=7.6,1.9Hz,1H), 7.46(dd,J=7.7,1.5Hz,1H),7.44-7.33(m,2H),6.03(d,J=5.0Hz,1H),4.91-4. 67(m,2H).
第三步:
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)氨基甲酸乙酯(1d)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate
在1L的三口烧瓶中,加入1c(28g,124.4mmol)和四氢呋喃(300mL),冷却至零下10℃,缓慢加入磺酰氯异氰酸酯(21.3g,149mmol)。加料完毕后,反应1h,点板监测反应完全。加水(200mL)水解,室温搅拌2h,然后加入乙酸乙酯(200mL x 3) 水萃取,无水硫酸钠干燥、过滤、减压移除有机溶剂,粗产品通过柱层析(PE:EA=2:1) 纯化得1d(30.5g,收率91.48%,白色固体)。
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),7.52(dd,J=7.8,2.9Hz,1H), 7.49m,1H),7.44-7.39(m,2H),6.91(s,1H),6.63(s,1H),5.21-4.96(m,2H).
第四步:
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基(羟甲基)氨基甲酸酯(化合物1)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl(hydroxymethyl)carbamate
氮气保护下,在100mL三口瓶中,将化合物1d(300mg,1.12mmol),碳酸钾(19 mg,0.135mmol)和多聚甲醛(37mg,1.24mmol)溶于DMSO(3mL)中,室温反应过夜,反应结束,加水淬灭,乙酸乙酯萃取(10mL x 3),无水硫酸钠干燥,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:2-1:1.5)纯化得化合物1(288mg,收率86.2%, 无色油状物)。
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.14(t,J=6.5Hz,1H),7.52 (dd,J=5.7,3.5Hz,1H),7.49-7.34(m,2H),6.45(dd,J=8.4,3.7Hz,1H),5.57(t, J=6.8Hz,1H),5.09(ddd,J=18.2,14.4,6.2Hz,2H),4.42-4.18(m,2H).
LC-MS m/z(ESI)=298.70[M+1].
实施例2
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基((2-羟基乙氧基)甲基)氨基甲酸酯(化合物 2)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl((2-hydroxyethoxy)methyl)carbamate
在100mL圆底烧瓶中,依次加入化合物1(275mg,0.93mmol)、乙二醇(27 mg,0.42mmol)、草酸(4mg,0.04mmol)和甲苯(10mL)。加毕,反应于加热回流条件下,搅拌反应2h。LC-MS监测反应完全,加水(10mL)淬灭,饱和碳酸氢钠水溶液调节pH至弱碱性,乙酸乙酯萃取(20mL×3),减压除去有机溶剂,残留物经柱层析(EA:PE=1:10至1:2)纯化得化合物2(5mg,收率10.1%,无色油状物)。
1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.33(t,1H),7.53(dd,1H),7.48-7.44(m,1H),7.42(dd,2H),6.44(dd,1H),5.18-5.07(m,2H),4.55(t,1H),4.38(d,2H),3.41(q,2H),3.29(dd,2H).
LC-MS m/z(ESI)=342.1[M+1].
实施例3
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基((2-(2-(2-羟基乙氧基)乙氧基)乙氧基)甲基) 氨基甲酸酯(化合物3)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl((2-(2-(2-hydroxyethoxy)ethoxy) ethoxy)methyl)carbamate
在100mL圆底烧瓶中,依次加入化合物1(200mg,0.67mmol)、二缩乙二醇 (51mg,0.34mmol)、草酸(3mg,0.034mmol)和甲苯(10mL)。加毕,反应于加热回流条件下,搅拌反应2h。LC-MS监测反应完全,加水(10mL)淬灭,以饱和碳酸氢钠水溶液调节pH至弱碱性,乙酸乙酯萃取(20mL×3),减压除去有机溶剂,残留物经柱层析(EA:PE=1:10至1:1)纯化得化合物3(190mg,收率65.7%,无色油状物)。
化合物3:1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.34(t,1H),7.52(d d,1H),7.48-7.44(m,1H),7.41(dd,2H),6.45(dd,1H),5.15(dd,1H),5.09(dd,1H),4. 37(d,2H),3.48(d,1H),3.45-3.40(m,4H),3.38(dd,2H),3.34(s,5H).
LC-MS m/z(ESI)=430.1[M+1].
实施例4
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基((2-甲氧基乙氧基)甲基)氨基甲酸酯(化合物 4)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl((2-methoxyethoxy)methyl)carbamate
在100mL圆底烧瓶中,依次加入化合物1(550mg,1.85mmol)、乙二醇单甲醚(170mg,2.22mmol)、草酸(17mg,0.19mmol)和甲苯(10mL)。加毕,反应于加热回流条件下,搅拌反应2h。LC-MS监测反应完全,加水(10mL)淬灭,饱和碳酸氢钠水溶液调节pH至弱碱性,乙酸乙酯萃取(20mL×3),减压除去有机溶剂,残留物经柱层析(EA:PE=1:10至1:1)纯化得化合物4(290mg,收率44.1%,无色油状物)。
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.36(t,1H),7.58-7.50(m,1H),7.48-7.35(m,3H),6.45(dd,1H),5.22-5.04(m,2H),4.36(d,2H),3.40(dd,1H),3.38-3.34(m,3H),3.22-3.15(m,3H).
LC-MS m/z(ESI)=356.1[M+1].
实施例5
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基((2-(2-甲氧基乙氧基)乙氧基)甲基)氨基甲酸酯(化合物5)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl((2-(2-methoxyethoxy)ethoxy)methyl) carbamate
在100mL圆底烧瓶中,依次加入化合物1(500mg,1.68mmol)、聚乙二醇单甲醚(243mg,2.02mmol)、草酸(16mg,0.17mmol)和甲苯(10mL)。加毕,反应于加热回流条件下,搅拌反应2h。LC-MS监测反完全,加水淬灭(10mL),饱和碳酸氢钠水溶液调节pH至弱碱性,乙酸乙酯萃取(20mL×3),减压除去有机溶剂,残留物经柱层析(EA:PE=1:10至1:1)纯化得化合物5(213mg,收率31.6%,无色油状物)。
1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.34(t,1H),7.55-7.51(m,1 H),7.48-7.44(m,1H),7.44-7.38(m,2H),6.45(dd,1H),5.15(dd,1H),5.09(dd, 1H),4.37(d,2H),3.46(dd,2H),3.44-3.42(m,2H),3.41-3.36(m,4H),3.23(d, 3H).
LC-MS m/z(ESI)=400.1[M+1].
实施例6
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基(2,5,8,11-四氧十二烷基)氨基甲酸酯(化合物6)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl(2,5,8,11-tetraoxadodecyl)carbamate
在100mL圆底烧瓶中,依次加入化合物1(319mg,1.07mmol)、三甘醇单甲醚(212mg,1.29mmol)、草酸(12mg,0.107mmol)和甲苯(10mL)。加毕,反应于加热回流条件下,搅拌反应2h。LC-MS监测反应完全,加水(10mL)淬灭,饱和碳酸氢钠水溶液调节pH至弱碱性,乙酸乙酯萃取(20mL×3),减压除去有机溶剂,残留物经柱层析(EA:PE=1:10至1:1)纯化得化合物6(167mg,收率35.1%,无色油状物)。
1H NMR(600MHz,DMSO-d6)δ8.98(s,1H),8.34(t,1H),7.53(dd,1H),7.46(dd,1H),7.44-7.37(m,2H),6.45(dd,1H),5.15(dd,1H),5.09(dd,1H),4.38(d,2H),3.52-3.48(m,3H),3.47(d,3H),3.45-3.40(m,4H),3.38(dd,2H),3.23(s,3H).
LC-MS m/z(ESI)=444.2[M+1].
实施例7
(R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙基(1-羟乙基)氨基甲酸酯(化合物7)
(R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl(1-hydroxyethyl)carbamate
氮气保护下,向100mL三口瓶中,依次加入1d(200mg,0.75mmol)、碳酸钾 (14mg,0.09mmol)和多聚甲醛(52mg,0.90mmol),以二甲基亚砜(10mL)溶解。随后,反应于室温搅拌过夜。LC-MS监测完全,加水(10mL)淬灭,乙酸乙酯萃取(20mL×3),无水硫酸钠干燥,减压移除有机溶剂,粗产物通过柱层析(EA:PE =1:2至1:1.5)纯化得化合物7(110mg,收率47.4%,无色油状物)。
1H NMR(400MHz,DMSO-d6)δ9.05-8.93(m,1H),7.97(dd,1H),7.55-7.49 (m,1H),7.46-7.36(m,2H),6.49-6.34(m,1H),5.53(dd,1H),5.15-5.03(m,2H),5.0 2-4.88(m,1H),1.29-1.03(m,3H).
LC-MS m/z(ESI)=312.1[M+1].
实施例8
2-((((R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙氧基)羰基)氨基)-2-羟基乙酸甲酯(化合物 8)
methyl 2-((((R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethoxy)carbonyl)amino)-2-hydr oxyacetate
氮气保护下,向100mL圆底烧瓶中,依次加入1d(500mg,1.87mmol),乙醛酸甲酯(198mg,2.25mmol),以干燥甲苯(10mL)溶解。随后,混合物于110℃搅拌反应2h。LC-MS检测反应完全,加水(10mL)淬灭,乙酸乙酯萃取(20mL× 3),无水硫酸钠干燥,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:2至1:1. 5)纯化得化合物8,(88mg,收率13.3%,无色油状物)。
1H NMR(400MHz,DMSO-d6)δ8.99(d,1H),8.54(d,1H),7.57-7.45(m,2H), 7.45-7.37(m,2H),6.54(dd,1H),6.48-6.39(m,1H),5.20-5.03(m,3H),3.61(d,3 H).
LC-MS m/z(ESI)=356.1[M+1].
实施例9
2-((((R)-1-(2-氯苯基)-2-(2H-四唑-2-基)乙氧基)羰基)氨基)-2-羟基乙酸(化合物9)
2-((((R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethoxy)carbonyl)amino)-2-hydroxyaceti c acid
氮气保护下,向100mL圆底烧瓶中,依次加入1d(500mg,1.87mmol),乙醛酸甲酯(167mg,2.25mmol),以干燥甲苯(10mL)溶解。随后,混合物于110℃下搅拌反应2h。LC-MS检测反应完全,加水(10mL)淬灭,乙酸乙酯萃取(20mL ×3),无水硫酸钠干燥,减压移除有机溶剂,粗产物通过柱层析(EA:PE=1:2至1:1. 5)纯化得化合物9(54mg,收率8.5%,无色油状物)。
1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.98(d,1H),8.39(d,1H),7.5 8-7.45(m,2H),7.41(dd,2H),6.53-6.41(m,1H),6.30(s,1H),5.13(dd,1H),5.09-4. 98(m,2H).
LC-MS m/z(ESI)=342.1[M+1].
生物测试例
1、药代动力学测定
2.1试验材料
ICR小鼠(购自北京维通利华实验动物技术有限公司)
2.2实验步骤
(1)准备健康雄性ICR小鼠(18-22g),每个化合物用18只,分成2组(iv和po 组),每组9只,每个时间点选取3只进行采血。
(2)禁食过夜(自由饮水)后,以5%DMSO、95%的30%HP-β-CD(v:v)为溶剂对本发明化合物进行溶解(或形成混悬液)。分别经尾静脉(iv,1mg/kg)、灌胃 (po,10mg/kg)给药。
(3)iv组分别于给药后5min、15min、0.5h、1h、2h、4h、8h、12h、24h由颌下静脉采血0.1mL,由EDTA-K2抗凝,4℃离心5min分离血浆,于-20℃保存待测。
(4)po组分别于给药前及给药后15min、0.5h、1h、2h、4h、6h、8h、12h、24h 由颌下静脉采血0.1mL,处理方法同静脉组。
(5)采用LC/MS/MS法测定血浆的本发明化合物所释放森巴考特的浓度。
(6)使用AB公司的Analyst 1.6进行结果计算和拟合。结果如表1所示。
表1
结果表明,本发明专利化合物能够很好地释放森巴考特,且具有优异的药代参数。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (4)
3.一种药物组合物,所述药物组合物包括:
(1)权利要求1或2所述的化合物或其立体异构体;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
4.权利要求3所述的药物组合物或者权利要求1或2所述的化合物或其立体异构体在制备抗局灶性癫痫药物中的用途。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111196656 | 2021-10-14 | ||
CN2021111966561 | 2021-10-14 | ||
CN2022101050110 | 2022-01-28 | ||
CN202210105011 | 2022-01-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115974799A true CN115974799A (zh) | 2023-04-18 |
Family
ID=85956903
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211189615.4A Pending CN115974799A (zh) | 2021-10-14 | 2022-09-30 | 氨基甲酸酯取代的醇衍生物及其在医药上的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115974799A (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030153584A1 (en) * | 2001-04-11 | 2003-08-14 | Queen's University | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
CN101228138A (zh) * | 2005-04-22 | 2008-07-23 | Sk株式会社 | 神经治疗吡咯化合物 |
WO2016123533A1 (en) * | 2015-01-30 | 2016-08-04 | Neurocrine Biosciences, Inc. | Substituted triazoles and methods relating thereto |
WO2016190638A1 (ko) * | 2015-05-22 | 2016-12-01 | 에스케이바이오팜 주식회사 | 카리스바메이트를 포함하는 약제, 및 통증 또는 뇌전증을 예방, 경감 또는 치료하기 위한 그의 용도 |
US20210085646A1 (en) * | 2016-12-14 | 2021-03-25 | Sk Biopharmaceuticals Co., Ltd. | Orally Disintegrated Tablet Comprising Carbamate Compound |
-
2022
- 2022-09-30 CN CN202211189615.4A patent/CN115974799A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030153584A1 (en) * | 2001-04-11 | 2003-08-14 | Queen's University | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
CN101228138A (zh) * | 2005-04-22 | 2008-07-23 | Sk株式会社 | 神经治疗吡咯化合物 |
WO2016123533A1 (en) * | 2015-01-30 | 2016-08-04 | Neurocrine Biosciences, Inc. | Substituted triazoles and methods relating thereto |
WO2016190638A1 (ko) * | 2015-05-22 | 2016-12-01 | 에스케이바이오팜 주식회사 | 카리스바메이트를 포함하는 약제, 및 통증 또는 뇌전증을 예방, 경감 또는 치료하기 위한 그의 용도 |
US20210085646A1 (en) * | 2016-12-14 | 2021-03-25 | Sk Biopharmaceuticals Co., Ltd. | Orally Disintegrated Tablet Comprising Carbamate Compound |
Non-Patent Citations (2)
Title |
---|
SUSAN J. K.: "Cenobamate: First Approval", 《DRUGS》, vol. 80, no. 1, 13 January 2020 (2020-01-13), pages 73 - 78 * |
代玲玲等: "四唑类化合物的合成及应用研究新进展", 《有机化学》, vol. 33, 31 December 2013 (2013-12-31), pages 224 - 244 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106928206B (zh) | 醛基类化合物及其制法和用途 | |
SU820659A3 (ru) | Способ получени производных 4-амино- 5-АлКилСульфОНилОАНизАМидОВ, иХ СОлЕй,ОКиСЕй, лЕВО- и пРАВОВРАщАющиХизОМЕРОВ /иХ ВАРиАНТы/ | |
CN110461846A (zh) | 一类具有抑制并降解布鲁顿酪氨酸蛋白激酶Btk活性的化合物 | |
DD252375A5 (de) | Verfahren zur herstellung von benzimidazolderivaten | |
IL175512A (en) | A pure crystalline form of aripiprazole | |
EP3444247B1 (en) | Pyridone derivative comprising oxetane substituent, for treating fibrosis and inflammatory diseases | |
IE883248L (en) | Benzopyrans and intermediates | |
CA1308108C (en) | Antihypertensive benzopyran derivatives | |
CN115974799A (zh) | 氨基甲酸酯取代的醇衍生物及其在医药上的应用 | |
EP0148167A2 (fr) | Nouveaux dérivés de la quinoléine, leur procédé de préparation et les compositions pharmaceutiques les renfermant | |
NO311132B1 (no) | Nye diosmetinforbindelser, fremgangsmåte ved deres fremstilling og farmasöytiske preparater inneholdende dem | |
CN103288809A (zh) | 葛根素单磷酸盐或单磺酸盐衍生物及其制备方法 | |
CN114213285B (zh) | 福莫特罗有关物质及其制备方法和应用 | |
CN109280044B (zh) | 雷替曲塞杂质c及其制备和应用 | |
CN102381997A (zh) | 带有氨基酸酯末端的丙泊酚羟基酸酯类化合物及其制备方法和应用 | |
KR101919642B1 (ko) | 피페라진 유도체, 이를 제조하는 방법, 및 인슐린 저항성의 치료에서 이의 용도 | |
CN113698383B (zh) | 一种哌嗪类化合物及其应用 | |
CN105732613B (zh) | 一种9‑去甲基‑(+)‑α‑二氢丁苯那嗪的合成方法 | |
CN115141169B (zh) | 一种萜内酯衍生物及其在医药上的应用 | |
EP0336886B1 (de) | Thioverbindungen | |
KR20140047086A (ko) | 피페라진 유도체, 이를 제조하는 방법, 및 인슐린 저항성의 치료에서 이의 용도 | |
WO2022218382A1 (zh) | 氘代苯酚衍生物及其制备方法和用途 | |
DE3713872A1 (de) | Substituierte chinoxalyl-imidazolidin-2,4-dione, verfahren zu ihrer herstellung, ihre verwendung als arzneimittel sowie pharmazeutische praeparate | |
KR20000075918A (ko) | 도파민 수용체 서브타입 특이적 리간드로서의 1-(이소퀴놀린-1-일)-4-(1-페닐메틸)피페라진 | |
CA2397594C (en) | Ethanol solvate of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |