CN104470894A - 新吡咯烷衍生物 - Google Patents
新吡咯烷衍生物 Download PDFInfo
- Publication number
- CN104470894A CN104470894A CN201380035570.8A CN201380035570A CN104470894A CN 104470894 A CN104470894 A CN 104470894A CN 201380035570 A CN201380035570 A CN 201380035570A CN 104470894 A CN104470894 A CN 104470894A
- Authority
- CN
- China
- Prior art keywords
- compound
- derivatives according
- pyrrolidin derivatives
- aforementioned
- disease
- 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
- 150000003235 pyrrolidines Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 230000003287 optical effect Effects 0.000 claims abstract description 14
- 206010015037 epilepsy Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 208000004454 Hyperalgesia Diseases 0.000 claims abstract description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 7
- 206010053552 allodynia Diseases 0.000 claims abstract description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 7
- 208000008795 neuromyelitis optica Diseases 0.000 claims abstract description 6
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 6
- 206010012335 Dependence Diseases 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 38
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 206010003497 Asphyxia Diseases 0.000 claims description 9
- 206010052804 Drug tolerance Diseases 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- 230000026781 habituation Effects 0.000 claims description 6
- 210000005036 nerve Anatomy 0.000 claims description 6
- 230000036407 pain Effects 0.000 claims description 6
- 230000002093 peripheral effect Effects 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 206010065952 Hyperpathia Diseases 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 235000013305 food Nutrition 0.000 claims description 5
- 230000037406 food intake Effects 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 208000023178 Musculoskeletal disease Diseases 0.000 claims description 4
- AKDJPHMBIITIRR-UHFFFAOYSA-N 4-(1,2-diaminoethyl)pyrrolidin-3-ol Chemical compound NCC(N)C1CNCC1O AKDJPHMBIITIRR-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical group C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 241000282414 Homo sapiens Species 0.000 abstract description 3
- 208000028867 ischemia Diseases 0.000 abstract description 2
- 208000035154 Hyperesthesia Diseases 0.000 abstract 1
- 150000004677 hydrates Chemical class 0.000 abstract 1
- 230000004770 neurodegeneration Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- VLSMHEGGTFMBBZ-OOZYFLPDSA-M Kainate Chemical compound CC(=C)[C@H]1C[NH2+][C@H](C([O-])=O)[C@H]1CC([O-])=O VLSMHEGGTFMBBZ-OOZYFLPDSA-M 0.000 description 24
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 18
- 239000000523 sample Substances 0.000 description 18
- 238000005259 measurement Methods 0.000 description 17
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- 239000000370 acceptor Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000006352 cycloaddition reaction Methods 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 229940009098 aspartate Drugs 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000004093 cyano group Chemical group *C#N 0.000 description 8
- 238000001437 electrospray ionisation time-of-flight quadrupole detection Methods 0.000 description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 230000009870 specific binding Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000012546 transfer Methods 0.000 description 8
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000003513 alkali Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000001690 micro-dialysis Methods 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- YSTPAHQEHQSRJD-UHFFFAOYSA-N 3-Carvomenthenone Chemical compound CC(C)C1CCC(C)=CC1=O YSTPAHQEHQSRJD-UHFFFAOYSA-N 0.000 description 5
- RPXVIAFEQBNEAX-UHFFFAOYSA-N 6-Cyano-7-nitroquinoxaline-2,3-dione Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+](=O)[O-])C(C#N)=C2 RPXVIAFEQBNEAX-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- -1 diacetyl oxide antacid Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000036592 analgesia Effects 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229940049906 glutamate Drugs 0.000 description 4
- 229930195712 glutamate Natural products 0.000 description 4
- 210000001577 neostriatum Anatomy 0.000 description 4
- 230000035479 physiological effects, processes and functions Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- COCONHAJXGRUOC-UHFFFAOYSA-N 2-(benzylamino)acetonitrile Chemical compound N#CCNCC1=CC=CC=C1 COCONHAJXGRUOC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 238000005251 capillar electrophoresis Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000013553 cell monolayer Substances 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000002858 neurotransmitter agent Substances 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 3
- HNJBEVLQSNELDL-YZRHJBSPSA-N pyrrolidin-2-one Chemical class O=C1CC[14CH2]N1 HNJBEVLQSNELDL-YZRHJBSPSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LRFHKHHUKGZIGE-UHFFFAOYSA-N 1-benzyl-2,5-dihydropyrrole Chemical compound C=1C=CC=CC=1CN1CC=CC1 LRFHKHHUKGZIGE-UHFFFAOYSA-N 0.000 description 2
- OUENRUZPZZFMCA-UHFFFAOYSA-N 2-pyrrolidin-1-ium-3-ylacetate Chemical compound OC(=O)CC1CCNC1 OUENRUZPZZFMCA-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 2
- QEFCFJFZZLNSPP-UHFFFAOYSA-N Penmacric acid Chemical compound OC(=O)C(N)C1CC(C(O)=O)NC1=O QEFCFJFZZLNSPP-UHFFFAOYSA-N 0.000 description 2
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 238000003556 assay Methods 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
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 210000003161 choroid Anatomy 0.000 description 2
- 210000002987 choroid plexus Anatomy 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000002621 endocannabinoid Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229960002767 ethosuximide Drugs 0.000 description 2
- HAPOVYFOVVWLRS-UHFFFAOYSA-N ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000005350 fused silica glass Substances 0.000 description 2
- 230000000848 glutamatergic effect Effects 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 2
- 229950006874 kainic acid Drugs 0.000 description 2
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 2
- 229960004002 levetiracetam Drugs 0.000 description 2
- 238000000622 liquid--liquid extraction Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- NGHTXZCKLWZPGK-UHFFFAOYSA-N nefiracetam Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1C(=O)CCC1 NGHTXZCKLWZPGK-UHFFFAOYSA-N 0.000 description 2
- 229950004663 nefiracetam Drugs 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229960001227 oxiracetam Drugs 0.000 description 2
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 229930006968 piperitone Natural products 0.000 description 2
- 229960004526 piracetam Drugs 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 229960003389 pramiracetam Drugs 0.000 description 2
- ZULJGOSFKWFVRX-UHFFFAOYSA-N pramiracetam Chemical compound CC(C)N(C(C)C)CCNC(=O)CN1CCCC1=O ZULJGOSFKWFVRX-UHFFFAOYSA-N 0.000 description 2
- 229960002393 primidone Drugs 0.000 description 2
- DQMZLTXERSFNPB-UHFFFAOYSA-N primidone Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NCNC1=O DQMZLTXERSFNPB-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229960003015 rimonabant Drugs 0.000 description 2
- 229960003014 rufinamide Drugs 0.000 description 2
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 229960002911 zonisamide Drugs 0.000 description 2
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 2
- YSTPAHQEHQSRJD-SECBINFHSA-N (-)-piperitone Chemical compound CC(C)[C@H]1CCC(C)=CC1=O YSTPAHQEHQSRJD-SECBINFHSA-N 0.000 description 1
- 229930006950 (-)-piperitone Natural products 0.000 description 1
- HOZBSSWDEKVXNO-BXRBKJIMSA-N (2s)-2-azanylbutanedioic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CC(O)=O HOZBSSWDEKVXNO-BXRBKJIMSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- LPHDUZQZGZACHZ-UHFFFAOYSA-N 1-(2,2-diphenylethenyl)piperidine;hydrochloride Chemical compound Cl.C1CCCCN1C=C(C=1C=CC=CC=1)C1=CC=CC=C1 LPHDUZQZGZACHZ-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-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
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- HNXNAHOPHOFSKM-UHFFFAOYSA-M C(C)CC(=O)[O-].[Si+](=O)=O Chemical compound C(C)CC(=O)[O-].[Si+](=O)=O HNXNAHOPHOFSKM-UHFFFAOYSA-M 0.000 description 1
- 229940124802 CB1 antagonist Drugs 0.000 description 1
- 241000375384 Cannaboides Species 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241001343006 Pentaclethra macrophylla Species 0.000 description 1
- 235000017319 Pentaclethra macrophylla Nutrition 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 241000287531 Psittacidae Species 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- HQVHOQAKMCMIIM-HXUWFJFHSA-N WIN 55212-2 Chemical compound C([C@@H]1COC=2C=CC=C3C(C(=O)C=4C5=CC=CC=C5C=CC=4)=C(N1C3=2)C)N1CCOCC1 HQVHOQAKMCMIIM-HXUWFJFHSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229960000793 aniracetam Drugs 0.000 description 1
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical compound C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 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
- 239000006227 byproduct Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000036992 cognitive tasks Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- CEAZRRDELHUEMR-UHFFFAOYSA-N gentamicin Chemical class O1C(C(C)NC)CCC(N)C1OC1C(O)C(OC2C(C(NC)C(C)(O)CO2)O)C(N)CC1N CEAZRRDELHUEMR-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical compound Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- ZRKSVHFXTRFQFL-UHFFFAOYSA-N isocyanomethane Chemical compound C[N+]#[C-] ZRKSVHFXTRFQFL-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000013016 learning Effects 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- BMQVDVJKPMGHDO-UHFFFAOYSA-K magnesium;potassium;chloride;sulfate;trihydrate Chemical compound O.O.O.[Mg+2].[Cl-].[K+].[O-]S([O-])(=O)=O BMQVDVJKPMGHDO-UHFFFAOYSA-K 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 102000006239 metabotropic receptors Human genes 0.000 description 1
- 108020004083 metabotropic receptors Proteins 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical class [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000007659 motor function Effects 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
- ZIPLKLQPLOWLTM-UHFFFAOYSA-N naphthalene-2,3-dicarbaldehyde Chemical compound C1=CC=C2C=C(C=O)C(C=O)=CC2=C1 ZIPLKLQPLOWLTM-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 230000036403 neuro physiology Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 229940054441 o-phthalaldehyde Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical class [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及式(I)的新吡咯烷衍生物,其中R1、R2、R3、R4、R5和X如权利要求1中所定义,该式(I)的吡咯烷衍生物任选地为两性离子的形式,该式(I)的吡咯烷衍生物为纯光学异构体的形式,或为以任何比例的光学异构体的混合物的形式,或为富含一种光学异构体的形式,以及还涉及它们的药学上可接受的盐、溶剂化物或水合物,以及涉及含有所述化合物的药物组合物。所述化合物尤其可用于治疗特别是人类的癫痫、局部缺血、神经退行性疾病如帕金森病或亨廷顿舞蹈病、多发性硬化症、德维克病和阿尔茨海默病以及精神疾病如精神分裂症、抑郁、成瘾、异常性疼痛、痛觉过敏。
Description
本发明涉及用于治疗中枢神经系统疾病的技术领域。更具体地,本发明的目的是新吡咯烷衍生物、含有这些化合物的药物组合物,以及这些化合物作为药物以及特别是用于治疗特别是人类的癫痫(epilepsy)、局部缺血(ischemia)、神经退行性疾病如帕金森病(Parkinson’s disease)或亨廷顿舞蹈病(Huntington’s chorea)、多发性硬化症(multiple sclerosis)、德维克病(Devic’sdisease,NMO)、阿尔茨海默病(Alzheimer’s disease)、精神疾病如精神分裂症(schizophrenia)、抑郁(depression)、成瘾(addiction)、异常性疼痛(allodynia)、痛觉过敏(hyperalgia)、疼痛(痛觉缺失(analgesia))、器官或外周组织的癌症、肥胖症(obesity)、肌肉骨骼病症、心血管疾病或消化道疾病或者用于控制食物摄取的用途。
谷氨酸(Glu)和较小程度上的天冬氨酸(Asp)是中枢神经系统的主要神经递质[1-2]。这两种神经递质氨基酸存在于所有的神经网络,在大脑中的解剖学分布无处不在。它们在神经生理学过程中发挥作用,例如像自主系统控制、运动功能、疼痛控制、认知任务、学习和记忆……。在人类疾病的动物模型上进行的实验以及在人类中获得的数据已经揭示这种类型的神经递质在诸如癫痫、局部缺血、神经退行性疾病(帕金森病、亨廷顿舞蹈病)或精神疾病如精神分裂症的病理状况中发生改变[2-6]。这四个主要的研究主题是常规的研究酸-胺能神经元的控制的课题。其它涉及谷氨酸盐(glutamate)的病理状况也是已知的:可以特别提及的是多发性硬化症、德维克病、阿尔茨海默病、抑郁以及成瘾、异常性疼痛和痛觉过敏[7]。
存在天冬氨酸和谷氨酸的两个大的受体家族(离子型和代谢型)。这些受体已被分为5种类型(红藻氨酸盐(kainite)和NMDA为离子型受体,组I、组II和组III为代谢型受体),它们各自的亚型已根据它们的亲和性、细胞内耦合和/或解剖学定位得到确定(谷氨酸盐作用于所有亚型,而天冬氨酸盐(aspartate)只作用于NMDA受体)。在寻找选择性地旨在于其受体之一或亚型的药理学靶中,兴奋性氨基酸仍然是基本的难题。例如,开发了靶向氨基酸的兴奋性递质的药理活性物质用于治疗癫痫或用于防止由局部缺血引起的毒副反应。许多商业抗癫痫物质具有氨基酸结构。作为例子,可以提及的是较早开发的药剂中的苯巴比妥(Phenobarbital)、扑米酮(Primidone)、苯妥英(Phenytoin)以及最近开发的药剂中的乙酰唑胺(Acetazolamide)、唑尼沙胺(Zonisamide)和卢非酰胺(Rufinamide)。类似于Gaba的抗癫痫药和吡咯烷-2-酮衍生物也是用于治疗癫痫的商品药物的活性成分。可以提及乙琥胺(Ethosuximide)、吡拉西坦(Piracetam)、奥拉西坦(Oxiracetam)、左乙拉西坦(Levetiracetam)、普拉西坦(Pramiracetam)、阿尼西坦(Aniracetam)和萘非西坦(Nefiracetam)。
吡咯烷-2-酮的其它衍生物也因其它活性而是已知的。已报道的来自大叶五山柳苏木(Pentachlethra macrophylla)种子的Penmacric acid的食用及药用用途[8],Alahopsin是用于对抗多种革兰氏阳性和阴性菌的抗生素,也是丙基胶原羟化酶的抑制剂[9],就像dealanylalahopsin[9,10]。
然而,始终存在对具有用于治疗中枢神经系统疾病的益处的新化合物,特别是对于具有对细胞外谷氨酸盐和天冬氨酸盐的速率的调节活性的新化合物的需求。
本专利申请发明人的兴趣在于除吡咯烷-2-酮的衍生物以外的其它吡咯烷衍生物。
在本文中,本发明涉及式(I)的吡咯烷衍生物:
其中:
-R1表示氢原子、(C1-C6)烷基或C(O)(C1-C6)烷基基团,
-R2和R3,相同或不同,各自彼此独立地表示氢原子或(C1-C6)烷基基团;或R2=H且R3=C(O)(C1-C6)烷基,
-R4表示-COOH、-CN、-COORa、-C(=NOH)NH2、-CH2NH2、-CH2OH、-C(O)NH2、-C(O)NHRa、-COSRa,其中Ra表示(C1-C6)烷基基团,或R4表示四唑或1,2,4-噁二唑基团,
-R5表示氢原子或(C1-C6)烷基基团,
-X表示–C(O)-或–CHRb-,其中Rb表示–ORc或–OC(O)Rc,Rc表示氢原子或(C1-C6)烷基基团,
所述式(I)的吡咯烷衍生物任选地为两性离子的形式,
所述式(I)的吡咯烷衍生物为纯光学异构体的形式或为以任何比例的光学异构体的混合物的形式,或为富含一种光学异构体的形式,以及它们的药学上可接受的盐、溶剂化物或水合物。
在本发明的化合物的定义中,“烷基基团”表示直链或支链的饱和烃链。作为包含1至6个碳原子的烷基基团(表示为(C1-C6)烷基)的例子,可以特别提及甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、正戊基、正己基基团。
根据优选的实施方案,X表示–CHRb,其中特别是Rb=OH。在此情况下,本发明的吡咯烷酮衍生物可特别符合式(Ia):
其中R1、R2、R3、R4、R5和Rb如对式(I)的化合物所定义的,任选地为药学上可接受的盐、溶剂化物或水合物,或者符合式(Ib):
其中R1、R2、R3、R4、R5和Rb如对式(I)的化合物所定义的,任选地为药学上可接受的盐、溶剂化物或水合物。
根据具体实施方案,式(I)、式(Ia)或式(Ib)的化合物具有以下特征之一或以下特征的组合,或具有以下全部特征:
-R1为氢原子;
-R2=H且R3表示氢原子或甲基或-C(O)CH3基团;
-R4表示–COOH、-C(O)NHCH3或-CH2NH2;
-R5为氢原子,
-其表现为成盐的形式或两性离子的形式,包括季铵。
在本发明范围内使用的化合物根据常规技术来制备。它们尤其可以根据类似于实施例中使用的那些方法来获得。
可以使用如下说明的所谓的手性方法或所谓的非手性合成。
下面的反应式1,其中R’1表示如对(I)所定义的R1,或表示苄基类型的保护基,举例说明了手性方法。
反应式1
在第一步中,实现环加成,特别是在接近110℃的温度下,任选地在微波的活化下,将硝酮(III)和烯烃(IV)用于产生环加成物(II),其在以下反应之后产生化合物(I’a)或(I’b):在催化剂(例如碳负载钯)存在下在氢作用下引起N-O键断裂的氢解步骤,以及酸性水解(优选采用经H2SO4酸化的乙酸酐抗酸剂的混合物)然后碱性水解,引起如上面反应式1所示的在硝酮上的三个键断裂。化合物(I’a)和(I’b)直接对应于式(Ia)或(Ib)的化合物,或者根据本领域技术人员公知的技术在氨基基团或在羧酸基团上对其进行官能化。可将官能团NR’1自身去保护或烷基化,以便根据常规方法得到期望的化合物,也可以将OH官能团烷基化,以便得到–O(C1-C6)烷基基团。
另一策略可以是改变(如实施例中所述)裂解条件,以便直接获得期望的基团–NR2R3和/或R4。
可以根据下面的反应式2由手性薄荷酮(IV)获得硝酮(III)。
反应式2
稍后可以完成不同于氢的R5基团的引入。
在间-氯-过苯甲酸m-CPBA(优选2当量)和3-氯苯甲酸(它是氧化反应的副产物)的存在下,硝酮(III)可由化合物(V)来获得。初始试剂可商购获得(特别是3-吡咯啉和N-苄基-3-吡咯啉是商业产品)或可容易地得到。化合物(VI)尤其可以通过在0至78℃的温度范围下,特别是在室温下由相应的酯在甘氨酸甲酯盐酸盐上与甲胺反应来获得。
在获得非手性的方法中,可以使用没有任何手性的硝酮或腈氧化物。许多等同的非手性甘氨酸硝酮可从文献中获得。它们的合成尤其基于从卤代乙腈和取代的胺形成取代的氰基甲胺,随后氧化成硝酮[11]。
用于得到合适的硝酮的其它路线采用羟胺与乙醛酸(商业乙醛酸,或是纯一水合物,或是水溶液)或者其商业酯(乙酯)或易于制备(异丙基酯)的羰基官能团反应[12、13、14、15、16、17、18、19、20、21、22]。
在非手性途径中还可以不用硝酮而用腈氧化物来实现环加成。这样的腈氧化物可从相应的醛来获得,且可以随后用于在烯烃上偶极环加成产生异噁唑啉。根据下面的反应式3,其中R’1表示如对(I)所定义的R1,或者苄基型或叔丁氧基羰(boc)型的保护基,通过还原引起N–O键的断裂,同时还原双键[23]。
反应式3
本发明的化合物可特别地具有二或三个不对称碳原子。它们不同的光学异构体是本发明整体的一部分。因此,除非特别说明,本发明的各种化合物可以为所有可能的异构体形式,尤其是作为以所有比例的混合物。根据具体实施方案,本发明的化合物经测定为外消旋形式,两种对映异构体经测定为基本上相同的比例。根据另一实施方案,本发明的式(I)的化合物经测定可以为富含一种非对映异构体或对映异构体的形式,其中该非对映异构体或对映异构体过量为超过80%,或甚至超过95%,或甚至为纯异构体形式,即,其中该非对映异构体或对映异构体过量为超过99%,或甚至等于100%。
可将化合物(I)通过常规分离技术分离为异构体或为富含一种非对映异构体或对映异构体的形式:例如,可以使用原理已公知的采用光学活性的酸或碱分级重结晶外消旋盐,或者,最常见的,采用手性或非手性相的常规色谱技术。还可以如下所述直接使用所谓的手性合成得到期望的光学异构体。
上述式(I)的化合物还包括以下这些:其中一个或几个氢、碳或氮原子已被替换为卤素,特别是氯或氟,包括被替换为它们的放射性同位素例如氚、碳-14、或氟-18。这样标记的化合物可用于科研、代谢或药物动力学研究中和生化试验中。
在合成期间可用确保明确合成期望化合物的保护基团将任选地存在于式(I)的化合物的分子中以及反应中间体中的官能团永久性或临时性地保护起来。保护和脱保护反应根据本领域技术人员公知的技术进行。胺、醇或羧酸的临时保护基团意指保护基团,如在以下文献中描述的那些保护基团:Protective Groups in Organic Synthesis,Greene T.W.和Wuts P.G.M.,ed.JohnWiley and Sons,2006,以及Protecting Groups,Kocienski P J,1994,GeorgThieme Verlag。
本发明的化合物的盐根据本领域技术人员公知的技术进行制备。本发明的式(I)的化合物的盐包括与酸或碱形成的那些,取决于存在的取代基。这些酸或碱可选自无机或有机酸和碱,所述酸或碱允许式(I)的化合物以及药学上可接受的盐的分离或适当的结晶。作为合适的酸,可以提及草酸或光学活性酸,例如酒石酸、二苯甲酰酒石酸、扁桃酸或樟脑磺酸,以及那些形成生理学上可接受的盐的酸,所述生理学上可接受的盐如盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、磷酸二氢盐、马来酸盐、富马酸盐、2-萘磺酸盐、对-甲苯磺酸盐、甲磺酸盐、苯磺酸盐、异硫代硫酸盐。作为合适的碱,可以提及:赖氨酸、精氨酸、葡甲胺、苯乙苄胺、苄星青霉素(benzathine)和那些形成生理学上可接受的盐的碱,所述生理学上可接受的盐如钠盐、钾盐、钙盐。
作为水合物形式的化合物,可以提及例如半水合物、一水合物以及多水合物。
溶剂化物表示尤其是与在其合成期间或纯化期间使用的一种或几种溶剂分子缔合的化合物的形式,而不表示溶解于后者中。
在本发明范围内,已显示为以任何比例的光学异构体的混合物的形式、或为富含一种光学异构体的形式的式(I)化合物及其药学上可接受的盐、溶剂化物或水合物对细胞外谷氨酸盐和天冬氨酸盐水平具有直接和显著的影响。本发明的化合物的活性对应于谷氨酸盐和天冬氨酸盐水平的增加或降低,取决于所述化合物。此外,这些作用高度依赖于内源性谷氨酸盐水平,正如红藻氨酸盐所显示的。特别地,当初始谷氨酸盐水平高时,特别是大于10μmol/L时,大多数本发明的化合物以及在实施例中明确给出的式(I.1)至(I.4)的化合物,引起大鼠脑中细胞外谷氨酸盐水平的降低。因此,它们可以用于治疗对应于谷氨酸能活动过度(glutamatergic hyperactivity)的病理状况。通过外推法,根据通过反向透析引入化合物(1.1)至(I.4)的过程中使用的浓度,在动物中在外周给药后的活性范围估计在5至100mg/kg之间。
本发明的目的还有前述定义的化合物,其用作药物,特别是其用作治疗以下疾病的药物:癫痫、局部缺血、神经退行性疾病如帕金森病或亨廷顿舞蹈病、阿尔茨海默病、多发性硬化症、德维克病、精神疾病如精神分裂症、抑郁、成瘾、异常性疼痛、痛觉过敏、疼痛(痛觉缺失)、器官或外周组织的癌症、肥胖症、肌肉骨骼病症、心血管疾病或者消化道疾病或者用于控制食物摄取。
在本发明范围内,一个目标是本发明的化合物用于人类治疗的用途。
包括前述定义的化合物以及至少一种药学上可接受的赋形剂的药物组合物也是本发明整体的一部分。
术语“治疗”是指对一种疾病或病症导致所期望的临床效果或任何有益效果特别是包括抑制或减少一种或几种症状,消退、减缓或停止疾病或与之相关的症状的进展的任何预防或抑制治疗措施。
“治疗有效量”是指改善所治疗疾病的一个或几个特征参数的组合物的任何量。
由于其活性,本发明的化合物(无论其异构体形式如何)可用于制造意欲治疗如下疾病的药物:癫痫、局部缺血、神经退行性疾病如帕金森病或亨廷顿舞蹈病、阿尔茨海默病、多发性硬化症、德维克病、精神疾病如精神分裂症、抑郁、成瘾、异常性疼痛、痛觉过敏、疼痛(痛觉缺失)、器官或外周组织的癌症、肥胖症、肌肉骨骼病症、心血管疾病或者消化道疾病或用于控制食物摄取。
特别地,发现本发明的化合物在用于治疗以下疾病时是特别有益的:帕金森病,癫痫,成瘾性疾病或局部缺血。
本发明的目的还包括可被给药至动物特别是人类的药物组合物,该药物组合物含有有效剂量的本发明的化合物,以及特别是根据欧洲药典第7版的适当赋形剂。因此,本发明涉及药物组合物,该药物组合物包括本发明化合物以及至少一种药学上可接受的赋形剂。
存在于本发明的药物组合物中的赋形剂依据药物的形式以及所期望的给药方法进行选择。在用于口服、舌下、皮下、肌内、静脉内、软骨内、局部、气管内、鼻内、透皮、直肠或眼内给药的本发明的药物组合物中,可以以给药单位剂型的形式、作为与传统药学载体的混合物,将本发明的化合物给药至动物和/或人类用于预防性治疗上述疾病。合适的给药单位剂型包括口服形式(诸如片剂、明胶胶囊剂、粉剂、颗粒剂和口服溶液或悬浮液),舌下、面颊、气管内、鼻内给药形式,皮下、肌内、软骨内或静脉内给药形式以及直肠给药形式。对于局部应用,本发明的化合物可以以乳膏剂、软膏剂、贴剂或洗剂使用。
为了得到期望的效果,本发明的化合物将以治疗有效剂量,特别是用于治疗人类的治疗有效剂量,存在于组合物中。例如,活性成分剂量在每天每千克治疗患者的体重1至50mg之间变化。
当将固体组合物制备成片剂时,将主要的活性成分与药学载体混合,所述药物载体如明胶、淀粉、乳糖、硬脂酸镁、滑石、阿拉伯树胶或类似物。可将片剂用蔗糖、纤维素衍生物、或其它合适的材料包衣,或将它们进一步处理以使它们具有延长或延迟的活性,且使它们连续释放预定量的活性成分。
明胶胶囊的制备是通过如下步骤获得:混合有效成分与稀释剂,并将得到的混合物填入软或硬明胶胶囊中。
含有本发明的化合物的药物组合物也可以表现为液体,例如溶液、乳剂、混悬剂或糖浆剂。合适的液体载体可以是例如水,有机溶剂如甘油或二醇,以及它们以不同的比例在水中的混合物。
作为糖浆或酏剂,或用于作为滴剂给药的制剂可含有活性成分与无卡路里的甜味剂、防腐剂、以及给出味道的试剂和适宜的着色剂。可分散在水中的粉末或颗粒可含有与以下成分混合的活性成分:分散剂或润湿剂,或悬浮剂如聚乙烯吡咯烷酮,以及甜味剂或味道矫正剂。
通常,与前面对化合物(I)描述的那些相同的替代物,加上必要的变更,可适用于应用这些化合物的药物、组合物和用途。
以下实施例给出举例说明本发明的可能性,但没有任何限制的性质。
I.化学合成:
NMR信号的归属[58:18]遵循下文对分子3、4、8和11所示的编号方式。
化合物(I.1)至(I.4)的制备示于下文的反应式4中。
反应式4
化合物I.1的制备:(αS,3R,4S)4-羟基α-氨基乙酸-3-吡咯烷或(αS,3R,4S)α-氨基-(4-羟基-吡咯烷-3-基)乙酸
硝酮1(对应于式(III)的化合物)在商购N-Bn-3-吡咯啉2(对应于式(IV)的化合物)上环加成:合成3(对应于式(II)的化合物):
将硝酮1(392mg,1.64mmol)[24,25]和过量的商购N-Bn-3-吡咯啉2(314mg,1.97mmol,1.2当量)引入到适于Biotage Initiator微波反应器的烧瓶中。在用氩气将烧瓶充满后,将2.5ml无水甲苯倒入其中。将该烧瓶用隔膜密封并安装在微波装置中,根据指令照射,保持140℃的温度2小时,以便完全转化硝酮1。一旦烧瓶冷却,将反应粗产物浓缩,然后通过在硅胶柱(乙酸乙酯)上的快速色谱法纯化,得到环加成产物3(625mg,1.57mmol),收率为96%,并且完全是立体选择性的(在5克规模进行该反应,得到相似的结果)。
从置于冰冷环境(冷冻器)中的3的饱和乙醚溶液中获得化合物3的单晶。
Rf=0.48(EtOAc)。[α]D=+40.4(c 1.1,CH2Cl2)。1H NMR(400MHz,CDCl3):δ7.37–7.20(m,5H,CH-ar),4.59(td,J=7.0Hz,J=3.0Hz,1H,H-4),3.71–3.49(m,3H,NCH2Ph,H-6),3.42(dd,J=10.3Hz,J=6.6Hz,1H,H-3),2.78(dd,J=10.3Hz,J=3.0Hz,1H,H-5),2.75–2.69(m,4H,NCH3,H-2),2.65(dd,J=9.4Hz,J=3.7Hz,1H,H-2’),2.58(dd,J=9.9Hz,J=6.6Hz,1H,H-5’),2.14–2.08(m,1H,H-9),2.00(dtt,J=12.9Hz,J=6.5Hz,J=3.3Hz,1H,H-10),1.90–1.78(m,2H,H-11,H-12),1.68–1.59(m,1H,H-12’),1.48(dt,J=13.5Hz,J=6.7Hz,1H,H-15),1.38(dd,J=12.1Hz,J=3.2Hz,1H,H-13),1.18(t,J=12.3Hz,1H,H-9’),0.95–0.85(m,10H,H-11’,H-14,H-16)ppm。13C NMR(100MHz,CDCl3):δ172.8(C=O),138.9(CIV-ar),128.6(CH-ar),128.3(CH-ar),127.1(CH-ar),88.0(C-8),79.6(C-4),71.9(C-6),59.6(NCH2Ph),59.4(C-5),59.3(C-2),49.1(C-3),48.2(C-13),41.0(C-9),35.0(C-11),29.0(C-10),25.9(NCH3),24.5(C-15),24.2(CH3),22.6(C-12),22.4(CH3),18.7(CH3)ppm。HR-ESI-QToF MS(正离子模式):m/z经计算为C24H36N3O2[M+H]+398.2802,实测为398.2806。
化合物3经乙酰解形成杂二环4:
苏打溶液(缓慢加入以控制pH)中和。当pH约为8时,将所述介质倒入碳酸氢钠NaHCO3饱和溶液(300ml),然后进行液-液萃取(二氯甲烷,5×50ml)。在浓缩和干燥之后,将粗产物通过在二氧化硅(乙酸乙酯)上的快速色谱法纯化,以获得分子4(148mg,0.49mmol),产率为86%(对于对映异构体ent-4为90%)。在前头洗脱的馏分中,可回收和再利用手性助剂(-)-薄荷酮1(对于3水解成4加上薄荷酮,回收率为80%)。
Rf=0.28(EtOAc)。[α]D=-14.2(c 1,CH2Cl2)。1H NMR(400MHz,CDCl3):δ7.34–7.20(m,5H,CH-ar),6.44(bs,1H,NHCH3),4.97(bs 1H,H-6),4.71(dd,J=7.1Hz,J=4.8Hz,1H,H-4),3.62(t,J=7.1Hz,1H,H-3),3.57(d,J=12.7Hz,1H,1/2NCH2Ph),3.33(d,J=12.7Hz,1H,1/2NCH2Ph),3.10–2.99(m,2H,H-2,H-5),2.79(d,J=4.9Hz,3H,NCH3),2.34(dd,J=10.0Hz,J=7.1Hz,1H,H-2’),2.19(dd,J=11.6Hz,J=4.8Hz,1H,H-5’),2.09(s,3H,NC(O)CH3)ppm。13C NMR(100MHz,CDCl3):δ175.7(MeNC=O),169.8(C(O)NHCH3),138.1(CIV-ar),128.9(CH-ar),128.5(CH-ar),127.5(CH-ar),85.0(C-4),66.2(C-6),60.7(C-5),60.4(C-2),59.9(NCH2Ph),48.4(C-3),26.4(NCH3),21.2(C(O)CH3)ppm。HR-ESI-QToF MS(正离子模式):m/z经计算为C16H22N3O3[M+H]+304.1656,实测为304.1667。
4经N-脱乙酰化形成5:
液,所述溶液已预先在0℃搅拌10分钟(释放无水盐酸)。在0℃下15分钟后,放置所述介质以返回室温,然后通过加热回流1小时。冷却并加入5%碳酸钠Na2CO3溶液(4ml)后,将水相用乙酸乙酯(2×30ml)萃取。将有机相再次用5%碳酸钠溶液(2×40ml)洗涤,用二氯甲烷(2×20ml)再萃取水相。将溶剂蒸发并冷冻干燥,得到化合物5(104mg,0.4mmol,99%),即定量。
Rf=0.74(CH2Cl2/IPA,1/1)。[α]D=+10.9(c 1.3,CH2Cl2)。1H NMR(400MHz,CDCl3):δ7.37–7.23(m,5H,CH-ar),7.13(bs,1H,NHCH3),6.22(d,J=3.9Hz,1H,ONHR),4.62(dd,J=6.6Hz,J=4.8Hz,1H,H-4),3.66(bs 1H,H-6),3.62(t,J=6.7Hz,1H,H-3),3.48(d,J=6.1Hz,2H,NCH2Ph),3.07(d,J=10.9Hz,1H,H-5),3.00(d,J=9.9Hz,1H,H-2),2.79(d,J=5.0Hz,3H,NCH3),2.37(dd,J=9.9Hz,J=6.7Hz,1H,H-2’),2.21(dd,J=10.9Hz,J=4.9Hz,1H,H-5’)ppm。13C NMR(100MHz,CDCl3):δ171.2(C=O),138.4(CIV-ar),128.6(CH-ar),128.5(CH-ar),127.4(CH-ar),83.7(C-4),71.0(C-6),61.8(C-5),60.8(C-2),59.9(NCH2Ph),50.2(C-3),26.0(NCH3)ppm。HR-ESI-QToF MS(正离子模式):m/z经计算为C14H20N3O2[M+H]+262.1550,实测为262.1553。
直接乙酰解化合物3得到杂二环5:
6小时30分。一旦其回到室温,将该反应混合物在0℃的冰浴中冷却,然后将该酸性物质用5M苏打溶液(在2小时30分内逐滴加入)中和。当pH约为8时,将所述介质倒入碳酸氢钠NaHCO3饱和溶液(700ml),然后进行液-液萃取(二氯甲烷,5×100ml)。在浓缩和干燥之后,将含痕量N-乙酰化的化合物4的粗产物通过在二氧化硅上的快速色谱法纯化,以获得5(320mg,90%)。
5经脱苄基化以及N-O键的还原开口,随后经碱性水解:获得化合物I.1:(αS,3R,4S)4-羟基,α-氨基,3-吡咯烷-乙酸或(αS,3R,4S)α-氨基-(4-羟基-吡咯烷-3-基)乙酸
的。加入100μl的大约4当量的乙酸AcOH,在氢气下继续搅拌24小时。通过在硅藻土上过滤除去催化剂。将反应粗产物浓缩之后,将中间体N-甲基酰胺衍生物在氢氧化锂(lithine)(180mg,4.3mmol,10当量)的存在下在四氢呋喃:H2O混合物(1/1,v/v,8ml)中进行碱性水解3小时。蒸发后,将粗锂盐在经预处理的C-18二氧化硅柱(适于自动化设备Combiflash)进行色谱法分离,用水洗脱,接着通过离子交换树脂(Dowex 50W X8),在产物沉积之后,将该树脂依次用水,然后用氨水(浓度为2.5%的约10ml,然后浓度为5%的约10ml)洗脱。将含铵盐的馏分(TLC正丁醇/乙酸/水,3/1/1,通过浸入茚三酮的正丁醇溶液中然后加热显示)的干蒸发,然后经过C-18柱(超纯水),给出得到两性离子物质I.1的可能性,2个步骤的产率为57%(对映异构体为50%)。Rf=0.18(n-BuOH/H2O/AcOH,3/1/1)。[α]D=+4.2(c 0.5,DMSO/H20,4/1)。1H NMR(400MHz,D2O):δ4.58(t,J=3.0Hz,1H,H-4),3.54(d 1H,J=9.5Hz,H-6),3.44(dd,J=8.6Hz,J=11.8Hz,1H,H-2),3.39–3.36(m,2H,H-5,H-5’),3.29(d,J=11.8Hz,1H,H-2’),2.46(ddd,J=3.8Hz,J=9.1Hz,J=12.4Hz,1H,H-3)ppm。13C NMR(100MHz,D2O):δ178.6(C=O),69.8(C-4),54.0(C-6),53.7(C-5),46.4(C-3),46.1(C-2)ppm。HR-ESI-QToF MS(正离子模式):m/z经计算为C6H13N2O3[M+H]+161.0921,实测为161.0924。
根据类似于前述针对对映异构体I.1的路线,制备化合物I.2((αR,3S,4R)4-羟基,α-氨基,3-吡咯烷-乙酸或(αR,3S,4R)α-氨基-(4-羟基-吡咯烷-3-基)乙酸。
在理论上除了旋光率[α]是相反的信号之外,与I.1的数据相同。Rf=0.18(nBuOH/H2O/AcOH,3/1/1)。[α]D=-4.1(c 0.9,DMSO/H2O,4/1)。1H NMR(400MHz,D2O):δ4.58(t,J=2.9Hz,1H,H-4),3.55(d 1H,J=9.5Hz,H-6),3.45(dd,J=8.7Hz,J=11.8Hz,1H,H-2),3.39–3.36(m,2H,H-5,H-5’),3.30(d,J=11.8Hz,1H,H-2’),2.46(ddd,J=3.8Hz,J=9.0Hz,J=12.2Hz,1H,H-3)ppm。13C NMR(100MHz,D2O):δ178.4(C=O),69.8(C-4),53.9(C-6),53.7(C-5),46.3(C-3),46.1(C-2)ppm。ESI-QToF MS(负离子模式):m/z[M–H]-:159.1,[2M–H]-:319.2HR-ESI-QToF MS(正离子模式):m/z经计算为C6H13N2O3[M+H]+161.0921,实测为161.0923。
制备化合物I.3:(αR,3S,4R)4-羟基,α-乙酰氨基,3-吡咯烷-N-甲基乙酰胺或(αR,3S,4R)α-乙酰氨基-(4-羟基-吡咯烷-3-基)-N-甲基乙酰胺
在六羰基钼存在下还原开口对映异构体4的N-O键:获得化合物6TLC监测(CH2Cl2/IPA,8/2)后,将反应介质浓缩。将所得悬浮液稀释在二氯甲烷CH2Cl2(或四氢呋喃THF)中。将液体在硅藻土床(CH2Cl2/MeOH,9/1或THF/MeOH 9/1)上过滤,然后再次浓缩。将粗混合物通过色谱法在碱性氧化铝Al2O3(洗脱梯度为CH2Cl2,然后CH2Cl2/MeOH,8/2)上纯化,以获得67mg化合物6(57%)。Rf=0.18(Ace/IPA,1/1)。[α]D=-31.4(c 0.6,DMSO)。1HNMR(400MHz,CDCl3):δ7.34–7.23(m,5H,CH-ar),7.10(d,J=8.0Hz,1H,NHAc),6.86(d,J=4.4Hz,1H,NHCH3),4.53(dd,J=8.0Hz,J=5.5Hz,1H,H-6),4.45(td,J=5.5Hz,J=2.8Hz,1H,H-4),3.66(d,J=13.0Hz,1H,1/2NCH2Ph),3.54(d,J=13.0Hz,1H,1/2NCH2Ph),2.91(dd,J=10.3Hz,J=5.6Hz,1H,H-5),2.76(d,J=4.8Hz,3H,NCH3),2.64–2.48(m,4H,H-5’,H-3,H-2,H-2’),2.01(s,3H,NC(O)CH3)ppm。
HR-ESI-QToF MS(正离子模式):m/z经计算为C16H24N3O3[M+H]+306.1812,实测为306.1811。
6在H2和Pd(OH)2/C存在下进行脱苄基:获得化合物I.3
将含化合物6(40mg,0.13mmol)的25ml烧瓶进行下搅拌1小时,然后在硅藻土床上过滤(用CH2Cl2和EtOH洗涤)。浓缩后,将粗混合物通过色谱法在适于自动化设备(Combiflash系统,用水洗脱)的经预处理的C-18二氧化硅柱上纯化,以获得23mg化合物I.3(82%)。Rf=0.31(n-BuOH/H2O/AcOH,3/1/1)。[α]D=-35.1(c 0.6,DMSO)。1H NMR(400MHz,D2O):δ4.42(t,1H,J=4.0Hz;H-4),4.39–4.24(m,1H,H-6),3.31–3.17(m,2H,H-2,H-5),3.09–2.91(m,2H,H-2’,H-5’),2.77(br s,3H,NCH3),2.52–2.34(m,1H,H-3),2.06(br s,3H,NC(O)CH3)ppm。
HR-ESI-QToF MS(正离子模式):m/z经计算为C9H15N3NaO3[M+Na]+236.1006,实测为236.1005。
制备化合物I.4:(αS,3R,4S)4-羟基,α-氨基,3-吡咯烷N-甲基乙酰胺或(αS,3R,4S)α-氨基-(4-羟基-吡咯烷-3-基)-N-甲基乙酰胺
将含化合物5(100mg,0.38mmol)的50ml圆形烧Pd(OH)2/C(0.076mmol,0.2当量)。最后,将该烧瓶进行5次真空/氩气循环,然后进行5次真空/氢气循环。
在氢气(1atm)下搅拌,保持一夜,之后,TLC显示5的完全转化。催化剂通过在硅藻土层(EtOH/MeOH)上过滤来分离。浓缩后,将粗产物通过加入甲醇MeOH(2ml)和甲苯(5ml)处理,给出以沉淀物形式的化合物I.4,重36.7mg,即产率55%。
白色固体;Rf=0.19(n-BuOH,CH3CO2H,H2O,3:1:1);[α]22 D=+3.0(c 0.5,H2O)。
1H NMR(D2O,400MHz)δ2.40(m,1H,H-3),2.74(s,3H,Jgem=J2,3=11.8Hz,H-2),3.23(dd,1H,J2’,3=8.5Hz,Jgem=11.6Hz,H-2’),3.40(m,2H,H-5,H-5’),3.50(d,1H,J3,6=9.9Hz,H-6),4.61(m,1H,J3,4=3.7Hz,H-4);COSY实际上示出了H-6/H-3,以及H-3/H-2/H-2'和H-4的相关性;
13C NMR(D2O,100MHz)δ26.07(NCH3),45.37(C-2),47.29(C-3),53.07(C-6),53.70(C-5),69.31(C-4),175.9(CO);
MS:ESI(正离子模式):174.0[M+H]+,347.0[2M+H]+;HRMS经计算为C7H15N3O2Na1,m/z=196.1056;实测为:196.1051(还可见:174.1228[M+H]+;212.0788[2M+H]+)。
制备外消旋化合物I.5:(3,4-顺)4-羟基α-N-甲基氨基3-吡咯烷乙酸或(3,4-顺)α-N-甲基氨基-(4-羟基-吡咯烷-3-基)乙酸
制备硝酮7:
其是按照已经描述过的步骤[P.DeShong,C.M.Dicken,R.R.Staib,A.J.Freyer,S.W.Weinreb,J.Org.Chem.1982,47,4397-4403;P.DeShong,J.M.Leginus,J.Org.Chem.1984,49,3421-3423;Z.-Y.Hong,L.Liu,C.-C.Hsu,C.-H.Wong,Angew.Chem.Int.Ed.2006,45,7417-7421]。
将氧代乙基乙酸酯(也称为乙醛酸乙酯)(330mg,3.2mmol)溶解在甲苯(7ml)中,然后加入N-甲基羟胺盐酸盐(270mg,3.2mmol)和NaHCO3(543mg,6.4mmol),在室温下搅拌该混合物24小时。将反应混合物过滤并将溶剂蒸发。将硝酮7(363mg,87%,为Z/E 3:1的混合物)直接用于下一步骤而无需任何额外的纯化。外观:无色油。Rf=0.5(石油醚/乙酸乙酯4:1)。1H NMR(300MHz,CDCl3):异构体Z:δ7.23(q,1H,4J=0.7Hz,CH),4.24(q,2H,J=7.1Hz,O-CH2-CH3),4.17(d,3H,4J=0.7Hz,CH3-N),1.31(t,3H,J=7.1Hz,O-CH2-CH3)ppm;异构体E:δ7.11(br s,1H,CH),4.29(q,2H,J=7.1Hz,O-CH2-CH3),5.32(br s,3H,CH3-N),1.32(t,3H,J=7.1Hz,O-CH2-CH3)ppm。
硝酮7在苄基-3-吡咯啉2上环加成以获得杂二环8:
该二氧化硅柱除去另外形成的极性更大的化合物。外观:无色油。Rf=0.4(EtOAc/甲苯1/4)。1H NMR(500MHz,CDCl3):δ7.35-7.2(m,5H,H-Ar),4.60(dd,1H,3J=4.9Hz,J=7.4Hz,H-4),4.20(q,2H,3J=7.1Hz,H-8,H-8’),3.7(d,1H,2J=13.2Hz,H-11),3.58(d,1H,2J=13.2Hz,H-11’),3.24(q,1H,3J=7.1Hz,H-3),3.16(br s,1H,H-6),3.00(d,1H,3J=11Hz,H-5),2.94(d,1H,3J=9.8Hz,H-2),2.78(s,3H,NCH3),2.28(br s,1H,H-2’),2.19(br s,1H,H-5’),1.27(t,3H,3J=7.1Hz,H-9)ppm。13C NMR(126MHz,CDCl3):δ170.03(C-7),138.58,128.73,128.41,127.17(C-Ar),81.03(C-4),75.48(C-6),61.26(C-8),59.08(C-11),58.77(C-5),56.79(C-2),52.54(C-3),43.85(NCH3),14.24(C-9)ppm。HRMS ESI:m/z经计算为C16H23N2O3[M+H]+:291.1703;实测为:291.1702。
二环8经还原形成(3,4-顺)α-N-甲基氨基-(4-羟基-吡咯烷-3-基)乙酸I.5:将该环加成物8(150mg,517μmol)溶解于THF/中重结晶给出获得化合物I.5(80mg,85%)的可能性。外观:白色晶体;mp192℃(MeOH)。1H NMR(400MHz,D2O):δ4.54(t,1H,3J=3.2Hz,H-4),3.36(dd,1H,3J=3.3Hz,2J=12.8Hz,H-5),3.31(dd,1H,3J=0.9Hz,2J=12.7Hz,H-5’),3.26(dd,1H,3J=8.5Hz,2J=11.6Hz,H-2),3.17(t,1H,2J=3J=11.7Hz,H-2’),3.17(d,1H,J=10Hz,H-6),2.34(s,3H,NCH3),2.32(m,1H,H-3)ppm。13C NMR(101MHz,D2O):δ178.99(C-7),69.41(C-4),62.78(C-6),53.87(C-5),46.04(C-3),45.79(C-2),33.47(NCH3)ppm。HRMS CI:m/z经计算为C7H15N2O3[M+H]+:175.1078;实测为:175.1077。
制备外消旋化合物I.6:3,4-顺3-(1,2-二氨基乙基)-4-羟基-吡咯烷)
如H.Tokuyama,T.Kuboyama,A.Amano,T.Yamashita,T.Fukuyama,Synthesis 2000,1299-1304中所述,由N-氰基甲基苄胺9制备硝酮。
获得N-氰基甲基苄胺9:
在氩气气氛下加入苄胺(1ml,9.15mmol)的乙腈(50ml)溶液、氯乙腈(870μl,13.7mmol)和K2CO3(2.53g,18.3mmol)。在60℃下搅拌15小时后,将混合物在硅藻土上过滤,然后将滤液浓缩。通过色谱柱在硅胶上纯化(洗脱液:石油醚/乙酸乙酯3:1)N-氰基甲基苄胺9(1.03g,77%)。
外观:无色油。Rf=0.25(石油醚/乙酸乙酯2:1)。1H NMR(300MHz,CDCl3):δ7.4-7.25(m,5H,H-Ar),3.94(s,2H,CH2-CN),3.57(s,2H,CH2-Ph)ppm。13C NMR(75MHz,CDCl3):δ138.0,128.5,128.3,127.5,117.8,52.2,36.1ppm。
的Na2S2O3溶液(10ml),然后加入K2CO3饱和溶液(10ml)。
将混合物再搅拌30分钟,然后用二氯甲烷萃取三次。将有机相用盐水洗涤并用MgSO4干燥。在二氧化硅上纯化(洗脱剂:石油醚/乙酸乙酯4:1)允许获得为两种异构体形式Z和E(Z/E比例为3:1)的氰基硝酮10(550mg,95%)。外观:白色晶体。Rf(E)=0.7(石油醚/乙酸乙酯3:1);Rf(Z)=0.4(石油醚/乙酸乙酯3:1)。1H NMR(300MHz,CDCl3):δ7.6-7.3(m,5H,H-Ar),6.67(s,1H,CH-CN E),6.57(s,1H,CH-CN Z),5.32(s,2H,Ph-CH2E),5.01(s,2H,Ph-CH2Z)ppm。13C NMR(75MHz,CDCl3):δ132-129(C-Ar),113.2(CN,E),112.4(CN,Z),107.5(CH,E和Z),71.7(CH2,Z),70.1(CH2,E)ppm。
氰基硝酮10在2上环加成以获得杂二环11:
将氰基硝酮10(550mg,3.44mmol)和苄基-3-吡咯Rf=0.4(EtOAc/甲苯1/4)。1H NMR(400MHz,60℃,甲苯-D8):δ7.3-7.0(m,10H),4.28(ddd,1H,J=3.4Hz,J=6.0Hz,J=7.5Hz,H-4),4.17(d,1H,J=13.4Hz,H-9),3.81(d,1H,J=13.4Hz,H-9’),3.30(d,1H,J=13.1Hz,H-8),3.23(d,1H,J=13.1Hz,H-8’),3.06(d,1H,J=3.6Hz,H-6),2.79(ddd,1H,J=3.8Hz,J=7.9Hz,J=11.6Hz,H-3),2.47(ddd,1H,J=3.0Hz,J=10.0Hz,H-5),2.24(br m,1H,H-5’),2.16(br m,1H,H-2),2.07(br m,1H,H-2’)ppm。13CNMR(100MHz,60℃,甲苯-D8):δ139.3,136.7,129.7,129.7,129.0,129.0,128.8,128.8,128.8,128.8,128.1,127.6,116.5(C-7),81.4C-4),59.5(C-8),59.3(3C,C-5,C-6,C-9),57.0(C-2),53.0(C-3)ppm。HRMS:m/z经计算为C20H22N3O[M+H]+:320.1757;实测为:320.1767。
二环11经还原形成3,4-顺3-(1,2-二氨基乙基)-4-羟基-吡咯烷I.6:
将该环加成物11(40mg,125μmol)溶解于四氢呋喃硅藻土上过滤,然后蒸发溶剂(23mg)。质谱分析示出了绝大多数对应于期望的多元胺I.6的离子和为仍带苄基的次要产物的另一离子。13C NMR证实这两种产物以1:3至1:4的比例存在。13C NMR(75MHz,D2O):δ69.20(C-4),53.73(C-5),48.14(C-6),45.72(C-3),45.09(C-2),42.52(C-7)ppm。HRMS(ESI,正离子模式;注入溶剂:水/MeOH 1:1):m/z经计算为C6H16N3O[M+H]+146.1288;实测为:146.1281。
II.生物学活性
II.1对细胞外谷氨酸盐和天冬氨酸盐水平的调节活性的评价
无论是在学术实验室还是在工业实验室中,在给药靶向其受体的药理活性物质之前、期间以及之后跟踪谷氨酸盐(Glu)和天冬氨酸盐(Asp)的细胞外浓度而广泛使用的一种方法是脑内微透析技术[7]。因此使用这类试验以便与红藻氨酸(合成的分子是结构类似物(取代的吡咯烷))的体内作用相比,追踪本发明的分子在体内的作用。
微透析探针
根据已经公布的设计制造带有再生纤维素膜(Spectra/Por中空纤维;截留分子量为6000Da,外直径为225μm,长度为3mm,Spectrum MedicalIndustries,Los Angeles,CA,USA)和熔融二氧化硅管道(40μm i.d×105μmo.d.,Polymicro Technology,Phoenix,AZ,USA)的同心微透析探针(Bert等人,1996,[26])。借助Harvard泵(型号:22,South Natick,MA,USA),以1μl/min的流速对所述同心微透析探针灌注人工脑脊液或CSF(145.0mM NaCl;2.7mM KCl;1.0mM MgCl2;1.2mM CaCl2;0.45mM NaH2PO4;1.55mMNa2HPO4;pH 7.4)。
微透析探针的植入
在用尿烷(剂量:1.4g/kg,经由腹腔注射途径,供应商:Sigma-Aldrich,St.Louis,MO,USA)麻醉的平均体重为约300g的Wistar系雄性大鼠(供应商:Charles River,L’Arbresle,法国)上进行体内微透析实验。根据以下相对于前囟的立体坐标将所述探针植入背外侧纹状体:前-后0mm,侧偏+3.5mm,皮质表面下深度+6.5mm。从植入探针后的第4个小时开始时收集透析液(样品)。每5分钟将样品收集在200μl的PCR管(Axygene,Union City,CA,USA)中,并立即冷冻于-20℃。依次分析样品以确定谷氨酸盐和天冬氨酸盐的浓度。通过在探针的入口将灌注没有任何药理活性物质的CSF改为灌注含有药理活性物质的CSF而在原位通过反向微透析给药药理活性物质和本发明的化合物(Bert等人,2002[27];Parrot等人,2003[28])。
毛细管电泳(CE)
用配备有外部检测器LIF ZETALIF(Picometrics,Toulouse,法国)的P/ACE MDQ系统(Beckman-Coulter,Fullerton,CA,USA)进行CE分析。检测通过用He-Cd激光器Omnichrome(Chino,CA,USA)产生的波长442nm的荧光来实现。在490nm收集发射强度。分析前,将样品用萘-2,3-二甲醛衍生化,采用氰根离子作为亲核试剂(pH为8.7;硼酸盐缓冲液500mM)。通过使用早先完整详述并验证过的步骤(Sauvinet等人,2003[29];Bert等人,2002[27]),在熔融二氧化硅毛细管(Polymicro Technology)中进行分离,所述毛细管内径为50cm,外径为375μm,长度为63cm,有效长度为52cm。在纹状体样品中测得的Glu和Asp的浓度高于检测限,并借助于标准范围通过内推法来确定。
试剂
神经化学研究的所有试剂(除本发明的化合物之外)购自Sigma-Aldrich(St Louis,MO,USA)。将合成分子红藻氨酸盐(KA,为谷氨酸盐KA受体的激动剂)、CNQX、6-氰基-7-硝基喹喔啉-2,3-(1H,4H)-二酮(CAS-No.115066-14-3,KA受体拮抗剂)、Glu和Asp的母液等分为1或0.1mM,并储存在-30℃。在将其给药后,将所测试的药理活性物质在人工CSF中稀释。
数据分析
最终数据用百分比表示,为KA给药前的四个值的平均值。
结果和讨论
在体内在经完全麻醉的动物的脑(脑结构:纹状体)上对本发明的4个分子进行了测试。将它们的影响与红藻氨酸盐(KA)的影响进行了比较,所述红藻氨酸盐是KA型谷氨酸盐受体的激动剂。结果在随附的图1A、图1B、图2A、图2B和图3中示出。
所得的结果表明,对于KA的响应从一个对象到另一个对象是可变的。谷氨酸盐和天冬氨酸盐的水平受到1mmol/L KA的给药的影响。由此,该系统性控制使我们能够检查纹状体神经元对KA受体的反应性。图1A和图1B分别比较在具有和不具有红藻氨酸盐(KA)的情况下分子I.1和I.2的影响。图2A和图2B分别比较在具有和不具有红藻氨酸盐(KA)的情况下I.3和I.4的影响,以及图3示出相对于初始内源性谷氨酸盐浓度红藻氨酸盐(KA)的影响。
1mmol/L的化合物I.1(n=2):化合物I.1引起类似于KA的作用,该作用可被衰减,因为Glu和Asp的水平趋于回到基础水平。
1mmol/L的化合物I.2(n=2):化合物I.2引起Glu和Asp水平的降低(类似于红藻氨酸盐的作用),CNQX好像显著地部分衰减其作用,因为继其与化合物I.2共同给药后Asp的水平增加了。
1mmol/L的化合物I.3(n=2):化合物I.3引起类似于KA的作用,CNQX好像显著地部分衰减其作用,因为继其与化合物I.3(n=1)共同给药后Asp的水平增加了。
1mmol/L的化合物I.4(n=1):化合物I.4引起Glu和Asp水平的降低(类似于红藻氨酸盐的作用),CNQX好像显著地部分衰减其作用,因为继其与化合物I.4(n=1)共同给药后Asp的水平增加了。
表1 总结了初步结果
结果显示本发明的化合物(它们是红藻氨酸的结构类似物)对细胞外谷氨酸盐和天冬氨酸盐的水平起作用。
本发明的化合物,特别是化合物I.1、I.2、I.3和I.4在谷氨酸盐水平高时对谷氨酸盐有抑制作用,因此是用于治疗(特别是用于治疗人类)病理状况的良好候选物,所述病理状况如帕金森病、癫痫、成瘾性病症或局部缺血[2-5;7]。
II.2靶受体的确定
为了确定本发明的化合物的靶受体,在体外进行特异性结合抑制实验。体外药理学:特异性结合试验。
在研究中对六十个受体进行试验,根据标准化的方法通过使用如之前报道的它们的特异性放射性配体进行[30-88]。
该结果可以用在两种被测试化合物(I.2和I.4)之一的存在下获得的特异性对照结合的百分比[(测量的特异性结合/对照特异性结合)×100]和特异性对照结合的抑制的百分比[100-(测量的特异性结合/对照特异性结合)×100]表示。
这些实验(下文表2)表明,化合物I.2和I.4改变1型受体的对照激动剂与内源性大麻素(endocannabinoids)(CB-1)的特异性结合(根据在参考文献[83]中记载的试验)。
表2:被测试化合物在10μM(n=2)时对对照特异性结合的抑制百分比
采用对每个化合物进行的箱形图(box and whisker)型表示法,根据对60个靶受体(n=2)的分析,抑制百分比对应于显著的作用。
这些结果,以及神经化学结果,与神经药理学文献一致,所述神经化学结果显示化合物I.2和I.4引起脑细胞外谷氨酸盐水平的减少。事实上,CB-1受体的激动剂,如WIN55,212-2,也诱导离体和体内制备的纹状体中的谷氨酸盐水平的降低[89-90],而CB-1拮抗剂,如利莫那班(rimonabant)或SR-141716A,导致细胞外谷氨酸盐水平增加或不影响细胞外谷氨酸盐水平[91-92]。化合物I.2和I.4诱导类似于用大麻素能剂(cannabinoidergic agent)观察到的那些作用。
CB-1受体参与成瘾[93]和精神分裂症[94]、抑郁和疼痛[95]、神经退行性疾病[96],还参与控制食物摄取[97]以及心脏和消化功能[98]。因此,本发明的化合物,特别是化合物I.2和I.4,是用于治疗这些病理状况的良好候选物。
II.3通过血脑屏障
使用BIP平台(Centre de Recherche en Neurosciences de Lyon,Lyons,法国)进行比较四种感兴趣化合物通过脑脊髓液/血液屏障的流入的研究。用重建该界面的脉络丛上皮细胞(choroidal epithelium)的体外模型进行该研究。将脉络丛细胞通过将它们的基底外侧极点(pole)暴露于浓度为150μm的化合物60分钟。就这些转移而言,对蔗糖对细胞单层的渗透性进行了分析,以检测所述化合物的可能的毒性。
方法
脉络丛上皮细胞的初步培养
如早先公开的,从取自新生大鼠侧脑室的脉络膜丛上分离上皮细胞[99-100]。将细胞播种于多微孔支持体(Transwell PC,孔径为0.4μm,比表面积为0.33cm2,直径为6.5mm)上,并培养在DMEM-F12(1:1)中,其中补充有10%FCS,2mM谷氨酰胺和50μg/ml庆大霉素,以及各种生长因子[99]。每两天更新所述培养基直至实验当天。
渗透性的测量
在Ringer-Hepes缓冲液(RH)中,在37℃下,在搅拌(200rpm)下,在动力学条件(3相)下进行转移测量。对转移过程中两个隔室中使用的体积进行调整,以便使任何静水压力效应最小化。在开始渗透性研究之前,将插入物在RH中漂洗。对于每种化合物,所述转移在三个层粘连蛋白插入物(无任何细胞)以及三个具有细胞单层的插入物上平行地进行。
化合物I.1、I.2、I.3和I.4的流入
在动力学研究[101]期间(20分钟的时间)对四个感兴趣的化合物进行流入测量(从血液到脑脊髓液)。简言之,将在RH中稀释至150μm的感兴趣化合物放置在多孔培养板的下隔室中,其复制血液隔室。通过将含有RH的培养插入物放入上隔室开始转移,所述上隔室对应于脑脊液。定期地,去除上部培养基的等分试样并用在37℃下预热的等体积RH代替。在转移结束时,也对下部的培养基取样用于分析残余化合物。通过高效液相色谱法(HPLC)在装配有分光光度检测器的LC10Shimadzu系统链(Duisburg,德国)上对所取样品进行分析。
蔗糖的渗透性
在感兴趣化合物的转移结束时,将[14C]-蔗糖以等份加入插入物的上隔室。定期地,将所述插入物转移到含有在37℃预热的RH的相邻孔中。在蔗糖的转移结束时,将在孔中和在插入物中取样的培养基,通过液体闪烁计数法在βCanberra Packard TRI-CARB 1600TR计数器中进行分析。
渗透系数的计算
在[101]中详细描述了计算方法。简言之,在转移动力学期间来自接受隔室中的连续样品给出绘制清除曲线的可能性。这些曲线的斜率表示清除率,其可以等同于化合物的渗透性×表面积的乘积(PS,单位为μl.min-1/过滤器)。
在考虑交换表面积的情况下,由在粘连蛋白过滤器和带有细胞的过滤器上测定的PS来计算细胞单层的渗透系数Pe(cm.min-1)。
含量测定化合物I.1和I.2的方法
对于化合物I.1和I.2,应用来自现有方法[102]的HPLC含量测定技术,在测定之前先进行对伯胺衍生化的步骤。衍生化反应是用以下物质来进行的:OPA(邻苯二甲醛,10mg)、200μl甲醇、1.8ml的200mM pH9.5的硼酸盐缓冲液和10μl的2-β-巯基乙醇。在室温下,进行样品体积对体积反应2分钟。该衍生物稳定30到40分钟。
分析条件:RP-18柱,15cm,5μm。流动相:A:90/10(磷酸钾缓冲液50mM,pH 6/甲醇);B:100%甲醇。检测:340nm。流速:1ml/min。进样量:20μl。使用的梯度min(A:B):0-5(83:17);6-11(35:65);12-17(83:17)。
含量测定化合物I.3和I.4的方法
对于化合物I.3和I.4两者,开发了HPLC含量测定技术,在测定之前先进行用Fmoc(芴甲氧羰酰氯,5g/l在乙腈中)对仲胺衍生化的步骤。在室温下在200mM pH 9.5的硼酸盐缓冲液(25μl样品+20μl硼酸盐缓冲液+5μl的5g/LFmoc溶液)进行衍生化反应30分钟。形成的衍生物稳定2小时。
分析条件:RP-18柱,15cm,5μm。流动相:A:90/10(50mM pH值为4.2的乙酸钠缓冲液/乙腈);B:100%乙腈。检测:230nm。流速:1ml/min。进样量:20μl。用于分子I.3的梯度min(A:B):0(75:25);8.5(67:33);9.5-20(20:80);21-26(75:25)。用于分子I.4的梯度min(A:B):0(65:35);18(40:60);19-29(20:80);30-35(35:35)。
已进行的实验显示在体外本发明的化合物能够通过血脑屏障。
此外,对于所测试的四种化合物(I.1、I.2、I.3和I.4),给出外周血隔室朝向脑隔室的低渗透率(≤0.3×10-3cm/min),本发明的化合物能够诱导外周效应,而具有极少的中央次级效应。
这有力地表明了这些化合物由于作用于不同的器官和外周组织在除了前面提及的治疗之外还在治疗癌症[103]、肥胖[104]、肌肉-骨骼病症[105]、心血管疾病和消化道疾病[98]中的潜在的药理学用途。
引用文献
1.Fonnum F,(1984).Glutamate:a neurotransmitter in mammalian brain.JNeurochem,42,1-11.
2.Farber NB,Newcomer JW,Olney JW,(1998).The glutamate synapse inneuropsychiatric disorders.Focus on schizophrenia and Alzheimer's disease.ProgBrain Res,116,421-437.
3.Avoli M,Louvel J,Pumain R,Kohling R,(2005).Cellular and molecularmechanisms of epilepsy in the human brain.Prog Neurobiol,77,166-200.
4.Javitt DC,(2004).Glutamate as a therapeutic target in psychiatricdisorders.Mol Psychiatry,9,984-997,979.
5.Gubellini P,Pisani A,Centonze D,Bernardi G,Calabresi P,(2004).Metabotropic glutamate receptors and striatal synaptic plasticity:implications forneurological diseases.Prog Neurobiol,74,271-300.
6.Bevan MD,Atherton JF,Baufreton J,(2006).Cellular principlesunderlying normal and pathological activity in the subthalamic nucleus.CurrOpin Neurobiol,16,621-628.
7.Parrot S,Renaud B,Zimmer L,Denoroy L,(2011)Monitoringneurotransmitter amino acids by microdialysis:pharmacodynamics applications.In:“Applications of Microdialysis in Pharmaceutical Science”(Ed:T-H Tsai).Wiley.
8.C.Berini,N.Pelloux-Léon,F.Minassian,J.-N.Denis Org.Biomol.Chem.2009,7,4512-16
9.J.E.Baldwin,R.M.Adlington,D.W.Collins,C.J.Schofield Tetrahedron1990,46,4733-4748
10.S.Horii,H.Fukase,E.Higashide,M.Yoneda,H.Nishida,H.Sakai,A.Hirota,I.Isogai J.Antibiot.1985,38,302
11.Zanobini,A.;Gensini,M.;Magull,J.;Vidovic,D.;Kozhushkov,S.I.;Brandi,A.;de Meijere,A.Eur.J.Org.Chem.2004,4158-66
12.Thèse de J.A.Stanko,Duke University,USA,2009
13.U.Chiacchio,A.Corsaro,D.Iannazzo,A.Piperno,V.Pistarà,A.Rescifina,R.Romeo,G.Sindona,G.Romeo,Tetrahedron Asymm.2003,14,2717-2723.
14.L.Weselinski,E.Slyk,J.Jurczak Tetrahedron Lett.2011,25,381-384.
15.U.Chiacchio,A.Corsaro,V.Pistarà,A.Rescifina,D.Iannazzo,A.Piperno,G.Romeo,R.Romeo,G.Grassi Eur.J.Org.Chem.2002,1206-1212.
16.U.Chiacchio,F.Genovese,D.Iannazzo,V.Librando,P.Merino,A.Rescifina,R.Romeo,A.Procopio,G.Romeo,Tetrahedron 2004,60,441-448.
17.D.Iannazzo,C.Carnovale,S.V.Giofrè,R.Ettari,G.Romeo,R.Romeo,G.Lanza,U.Chiacchio Synlett 2011,245-248.
18.U.Chiacchio,A.Corsaro,G.Gumina,A.Rescifina,D.Iannazzo,A.Piperno,G.Romeo,R.Romeo J.Org.Chem.1999,64,9321-9327.
19.K.Kasahara,H.Iida,C.Kibayashi J.Org.Chem.1989,54,2225-2233.
20.V.Ondrus,M.Orsag,L.Fisera,N.Pronayova,Tetrahedron 1999,55,10425-10436.
21.N.Morita,K.Fukui,J.Irikuchi,H.Sato,Y.Takano,I.Okamoto,H.Ishibashi,O.Tamura J.Org.Chem.2008,73,7164–7174
22.O.Tamura,N.Morita,Y.Takano,K.Fukui,I.Okamoto,X.Huang,Y.Tsutsumi,H.Ishibashi,Synlett 2007,658-660.
23.M.Benltifa,S.Vidal,D.Gueyrard,P.G.Goekjian,M.Msaddek,J.-P.Praly,Tetrahedron Lett.2006,47,6143-6147
24.Altenbach,H.-J.;Kottenhahn,M.;Vogt,A.;M.;Grundler,A.;Hahn,M.a)DE 19533617A1,1997和b)USP6018050,2000
25.Vogt,A.;Altenbach,H.-J.;Kirschbaum,M.;Hahn,M.G.;M.S.P.;Hermann,A.R.a)EP 976721,2000;b)Chem.Abstr.2000,132,108296j.
26.Bert L,Robert F,Denoroy L,Stoppini L,Renaud B.J Chromatogr.A,1996,755,99-111.
27.Bert L,Parrot S,Robert F,Desvignes C,Denoroy L,Suaud-Chagny MF,Renaud B.Neuropharmacology,2002,43,825-835.
28.Parrot S,Bert L,Mouly-Badina L,Sauvinet V,Colussi-Mas J,Lambás-L,Robert F,Bouilloux JP,Suaud-Chagny MF,Denoroy L,RenaudB.Cell Mol Neurobiol. 2003,23,793-804.
29.Sauvinet V,Parrot S,Benturquia N,Bravo-Moratón E,Renaud B,Denoroy L.Electrophoresis 2003,24,3187-3196.
30.Aharony,D.et al.(1993),Mol.Pharmacol.,44:356-363.
31.Ardati,A.et al.(1997),Mol.Pharmacol.,51:816-824.
32.Bloomquist,B.T.et al.(1998),Biochem.Biophys.Res.Commun.,243:474-479.
33.Bonhaus,D.W.et al.(1995),Brit.J.Pharmacol.,115:622-628.
34.Brown,G.B.(1986),J.Neurosci.,6:2064-2070.
35.Brown,P.J.et al.(1990),J.Biol.Chem.,265:17995-18004.
36.Buchan,K.W.et al.(1994),Brit.J.Pharmacol.,112:1251-1257.
37.Couvineau,A.et al.(1985),Biochem.J.,231:139-143.
38.Dorje,F.et al.(1991),J.Pharmacol.Exp.Ther.,256:727-733.
39.Fuhlendorff,J.et al.(1990),Proc.Natl.Acad.Sci.U.S.A.,87:182-186.
40.Grandy,D.K.et al.(1989),Proc.Natl.Acad.Sci.U.S.A.,86:9762-9766.
41.Greengrass,P.and Bremner,R.(1979),Eur.J.Pharmacol.,55:323-326.
42.Hope,A.G.et al.(1996), Brit.J.Pharmacol.,118:1237-1245.
43.Hoyer,D.et al.(1985), Eur.J.Pharmacol.,118:1-12.
44.Hugues,M.et al.(1982),J.Biol.Chem.,257:2762-2769.
45.Lewin,A.H.et al.(1989),Mol.Pharmacol.,35:189-194.
46.Luthin,D.R.et al.(1995),Mol.Pharmacol.,47:307-313.
47.Monaghan,D.T.and Cotman,C.W.(1982),Brain Res.,252:91-100.
48.Monsma,F.J.et al.(1993),Mol.Pharmacol.,43:320-327.
49.Mulheron,J.G.et al.(1994),J.Biol.Chem.,269:12954-12962.
50.Murphy,D.E.et al.(1987),Neurochem.Res.,12:775-781.
51.Neote,K.et al.(1993),Cell,72:415-425.
52.Pacholczyk,T.et al.(1991),Nature,350:350-354.
53.Pristupa,Z.B.et al.(1994),Mol.Pharmacol.,45:125-135.
54.Rees,S.et al.(1994),FEBS Lett.,355:242-246.
55.Reynolds,I.J.et al.(1986),J.Pharmacol.Exp.Ther.,237:731-738.
56.Salvatore,C.A.et al.(1993),Proc.Natl.Acad.Sci.U.S.A.,90:10365-10369.
57.Schioth,H.B.et al.(1997),Neuropeptides,31:565-571.
58.Shen,Y.et al.(1993),J.Biol.Chem.,268:18200-18204.
59.Baron,B.M.et al.(1996),J.Pharmacol.Exp.Ther.,279:62-68.
60.Sills,M.A.et al.(1991),Eur.J.Pharmacol.,192:19-24.
61.Sorensen,R.G.and Blaustein,M.P.(1989),Mol.Pharmacol.,36:689-698.
62.Speth,R.C.et al.(1979),Life Sci.,24:351-358.
63.Townsend-Nicholson,A.and Schofield,P.R.(1994),J.Biol.Chem.,269:2373-2376.
64.Tsuji,A.et al.(1988),Antimicrob.Agents Chemother.,32:190-194.
65.Uhlen,S.and Wikberg,J.E.(1991),Pharmacol.Toxicol.,69:341-350;257.
66.Vignon,J.et al.(1986),Brain Res.,378:133-141.
67.Vita,N.et al.(1993),FEBS Lett.,317:139-142.
68.Wang,J.B.et al.(1994),FEBS Lett.,338:217-222.
69.White,J.R.et al.(1998),J.Biol.Chem.,273:10095-10098.
70.Zhou,Q.Y.et al.(1990),Nature,347:76-80.
71.Tahara,A.et al.(1998),Brit.J.Pharmacol.,125:1463-1470.
72.Pruneau,D.et al.(1998),Brit.J.Pharmacol.,125:365-372.
73.Wieland,H.A.et al.(1995),J.Pharmacol.Exp.Ther.,275:143-149.
74.Smit,M.J.et al.(1996),Brit.J.Pharmacol.,117:1071-1080.
75.Simonin,F.et al.(1994),Mol.Pharmacol.,46:1015-1021.
76.Leurs,R.et al.(1994),Brit.J.Pharmacol.,112:847-854.
77.Peralta,E.G.et al.(1987),Embo.J.,6:3923-3929.
78.Levin,M.C.et al.(2002),J.Biol.Chem.,277:30429-30435.
79.Bignon,E.et al.(1999),J.Pharmacol.Exp.Ther.289:742-751.
80.Tatsumi,M.et al.(1999),Eur.J.Pharmacol.,368:277-283.
81.Choi,D.S.et al.(1994),FEBS Lett.,352:393-399.
82.Witt-Enderby,P.A.and Dubocovich,M.L.(1996),Mol.Pharmacol.,50:166-174.
83.Rinaldi-Carmona,M.et al.(1996),J.Pharmacol.Exp.Ther.,278:871-878.
84.Sarau,H.M.et al.(1997),J.Pharmacol.Exp.Ther.,281:1303-1311.
85.Meng,F.et al.(1993),Proc.Natl.Acad.Sci.U.S.A..,90:9954-9958.
86.Le,M.T.et al.(2005),Eur.J.Pharmacol.,513:35-45.
87.Abramovitz,M.et al.(2000),Biochem.Biophys.Acta.,1483:285-293.
88.Joseph,S.S.et al.(2004),Naun.-Sch.Arch.Pharm.,369:525-532.
89.Morgese MG et al.(2009)Neurochemical changes in the striatum ofdyskinetic rats after administration of the cannabinoid agonist WIN55,212-2.Neurochem Int.,54(1):56-64.
90.Polissidis A.et al.(2013)Int J Neuropsychopharmacol.,16(2):393-403.
91.García-Arencibia M et al.,(2008)Neurosci Lett.438(1):10-3.
92.Berger C et al.,(2004)J Neurochem.88(5):1159-67.
93.Leweke et al(2012)Translational Psychiatry,2,e94.
94.Lacrosse and Olive(2013)Neuropeptide Systems and Schizophrenia.CNS NeurolDisord Drug Targets,[印刷前的电子出版物]
95.Adam et al.,(2012)Bioorganic&Medicinal Chemistry Letters.22:2932–2937.
96.Pintor A et al.,(2006)Neuropharmacology.51(5):1004-12.
97.Kirilly et al(2012)Acta Physiol.,1-20.
98.Thakur et al(2009)Expert Opin.Ther Patents,19(12):1647-1673.
99.Strazielle N,et al.J Neurosci.1999 Aug 1;19(15):6275-89.
100.Strazielle N,et al.AIDS.2003 Jul 4;17(10):1473-85.
101.Strazielle N,et al.Methods Mol Med.2003;89:291-304.
102.Teerlink T,et al.Anal Biochem.2002Apr15;303(2):131-7.
103.Hermanson and Marnett(2011)Cancer Metastasis Rev.,30:599-612.
104.Alen et al(2012)Vitam.Horm.,92:165-96.
105.Robert W.Cowan,et al.Frontiers in Endocrinology(2012),July,Vol.3Article89, doi:10.3389/fendo.2012.00089.
Claims (16)
1.式(I)的吡咯烷衍生物:
其中:
- R1表示氢原子、(C1-C6)烷基或C(O)(C1-C6)烷基基团,
- R2和R3,相同或不同,各自彼此独立地表示氢原子或(C1-C6)烷基基团;或者R2=H且R3=C(O)(C1-C6)烷基,
- R4表示-COOH、-CN、-COORa、-C(=NOH)NH2、-CH2NH2、-CH2OH、-C(O)NH2、-C(O)NHRa或-COSRa,其中Ra表示(C1-C6)烷基基团,或者R4表示四唑或1,2,4-噁二唑基团,
- R5表示氢原子或(C1-C6)烷基基团,
- X表示-C(O)-或-CHRb-,其中Rb表示-ORc或-OC(O)Rc,Rc表示氢原子或(C1-C6)烷基基团,
所述衍生物任选地为两性离子的形式,
所述衍生物作为纯光学异构体,或作为以任何比例的光学异构体的混合物,或为富含一种光学异构体的形式,以及它们的药学上可接受的盐、溶剂化物或水合物。
2.根据权利要求1或2所述的吡咯烷衍生物,特征在于X表示-CHRb,其中Rb如权利要求1中所定义。
3.根据权利要求1或2所述的吡咯烷衍生物,特征在于其符合式(Ia):
其中R1、R2、R3、R4、R5和Rb如权利要求1中所定义,以及它们的药学上可接受的盐、溶剂化物或水合物。
4.根据权利要求1或2所述的吡咯烷衍生物,特征在于其符合式(Ib):
其中R1、R2、R3、R4、R5和Rb如权利要求1中所定义,以及它们的药学上可接受的盐、溶剂化物或水合物。
5.根据权利要求2至4中任一项所述的吡咯烷衍生物,特征在于Rb=OH。
6.根据前述任一项权利要求所述的吡咯烷衍生物,特征在于R1为氢原子。
7.根据前述任一项权利要求所述的吡咯烷衍生物,特征在于R2=H且R3表示氢原子或甲基或-C(O)CH3基团。
8.根据前述任一项权利要求所述的吡咯烷衍生物,特征在于R4表示-COOH、-C(O)NHCH3或-CH2NH2。
9.根据前述任一项权利要求所述的吡咯烷衍生物,特征在于R5为氢原子。
10.根据前述任一项权利要求所述的吡咯烷衍生物,特征在于:其表现为成盐的形式或两性离子的形式,包括季铵。
11.根据权利要求1所述的吡咯烷衍生物,其选自:
- (αS,3R,4S)α-氨基-(4-羟基-吡咯烷-3-基)乙酸,化合物(I.1)
- (αR,3S,4R)α-氨基-(4-羟基-吡咯烷-3-基)乙酸,化合物(I.2)
- (αR,3S,4R)α-乙酰氨基-(4-羟基-吡咯烷-3-基)-N-甲基乙酰胺,化合物(I.3)
- (αS,3R,4S)α-氨基-(4-羟基-吡咯烷-3-基)-N-甲基乙酰胺,化合物(I.4)
- 3,4-顺α-N-甲基氨基-(4-羟基-吡咯烷-3-基)乙酸,化合物(I.5)
- 3,4-顺3-(1,2-二氨基乙基)-4-羟基-吡咯烷,化合物(I.6)
以及它们的药学上可接受的盐、溶剂化物或水合物。
12.根据前述任一项权利要求所述的吡咯烷衍生物,其用作药物。
13.根据前述任一项权利要求所述的吡咯烷衍生物,其用于治疗癫痫、局部缺血、神经退行性疾病如帕金森病或亨廷顿舞蹈病、多发性硬化症、德维克病、阿尔茨海默病、精神疾病如精神分裂症、抑郁、成瘾、异常性疼痛或痛觉过敏。
14.根据前述任一项权利要求所述的吡咯烷衍生物,其用于治疗帕金森病、癫痫、成瘾性病症或局部缺血。
15.根据前述任一项权利要求所述的吡咯烷衍生物,其用于治疗疼痛、器官或外周组织的癌症、肥胖症、肌肉骨骼病症、心血管疾病或消化道疾病或者用于控制食物摄取。
16.药物组合物,含有前述任一项权利要求所述的吡咯烷衍生物,以及至少一种药学上可接受的赋形剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1256322 | 2012-07-02 | ||
FR1256322A FR2992645B1 (fr) | 2012-07-02 | 2012-07-02 | Nouveaux derives de pyrrolidine |
PCT/FR2013/051524 WO2014006307A1 (fr) | 2012-07-02 | 2013-06-28 | Nouveaux derives de pyrrolidine |
Publications (1)
Publication Number | Publication Date |
---|---|
CN104470894A true CN104470894A (zh) | 2015-03-25 |
Family
ID=48914336
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380035570.8A Pending CN104470894A (zh) | 2012-07-02 | 2013-06-28 | 新吡咯烷衍生物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US9199931B2 (zh) |
EP (1) | EP2867204B1 (zh) |
CN (1) | CN104470894A (zh) |
FR (1) | FR2992645B1 (zh) |
WO (1) | WO2014006307A1 (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997003677A1 (en) * | 1995-07-24 | 1997-02-06 | Trustees Of Boston University | Inhibition of nmda receptor activity by pregnenolone sulfate derivatives |
US20040259917A1 (en) * | 2001-12-19 | 2004-12-23 | Cosford Nicholas D.P. | Heteroaryl substituted imidazole modulators of metabotropic glutamate receptor-5 |
CN101677546A (zh) * | 2007-06-22 | 2010-03-24 | 纽约州州立大学研究基金会 | 具有中枢神经系统活性的取代的吡咯烷化合物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5888996A (en) * | 1995-07-26 | 1999-03-30 | Trustees Of Boston University | Inhibition of NMDA receptor activity and modulation of glutamate-mediated synaptic activity |
DE19533617A1 (de) | 1995-09-11 | 1997-03-13 | Degussa | Neues Verfahren zur Herstellung von optisch aktiven alpha-Aminosäuren und alpha-Aminosäure-Derivaten |
DE19833853A1 (de) | 1998-07-28 | 2000-02-03 | Degussa | Verfahren zur Herstellung von Aminosäuren und Aminosäurederivaten |
US7667049B2 (en) * | 2006-03-09 | 2010-02-23 | Kyorin Pharmaceutical Co., Ltd. | Process for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof |
-
2012
- 2012-07-02 FR FR1256322A patent/FR2992645B1/fr not_active Expired - Fee Related
-
2013
- 2013-06-28 WO PCT/FR2013/051524 patent/WO2014006307A1/fr active Application Filing
- 2013-06-28 EP EP13744661.3A patent/EP2867204B1/fr not_active Not-in-force
- 2013-06-28 CN CN201380035570.8A patent/CN104470894A/zh active Pending
- 2013-06-28 US US14/412,050 patent/US9199931B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997003677A1 (en) * | 1995-07-24 | 1997-02-06 | Trustees Of Boston University | Inhibition of nmda receptor activity by pregnenolone sulfate derivatives |
US20040259917A1 (en) * | 2001-12-19 | 2004-12-23 | Cosford Nicholas D.P. | Heteroaryl substituted imidazole modulators of metabotropic glutamate receptor-5 |
CN101677546A (zh) * | 2007-06-22 | 2010-03-24 | 纽约州州立大学研究基金会 | 具有中枢神经系统活性的取代的吡咯烷化合物 |
Also Published As
Publication number | Publication date |
---|---|
WO2014006307A1 (fr) | 2014-01-09 |
US9199931B2 (en) | 2015-12-01 |
EP2867204A1 (fr) | 2015-05-06 |
EP2867204B1 (fr) | 2016-09-14 |
FR2992645B1 (fr) | 2014-08-01 |
US20150175537A1 (en) | 2015-06-25 |
FR2992645A1 (fr) | 2014-01-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111484477B (zh) | 一种苯并吡啶酮杂环化合物及其用途 | |
EP3676297B1 (en) | Compounds, compositions and methods | |
CN104540826B (zh) | 用作肾外髓钾通道的抑制剂的螺稠合的哌啶衍生物 | |
CN104797555B (zh) | N‑取代的苯甲酰胺及其使用方法 | |
CN105939997B (zh) | 作为dlk抑制剂的吡唑衍生物及其用途 | |
CN100549004C (zh) | 螺环杂环衍生物及其应用方法 | |
CN102753522B (zh) | 取代的吡咯烷-2-甲酰胺类 | |
ES2387405T3 (es) | Derivados de prolinamida como moduladores del canal de sodio | |
TWI586666B (zh) | Tetrahydrocarboline Derivatives (2) | |
JP6966425B2 (ja) | 抗がん剤としての複素環式の限定された三環系スルホンアミド | |
TW201103535A (en) | Carboxylic acid compounds | |
CN104718188A (zh) | N-取代的苯甲酰胺类及其在治疗疼痛中的用途 | |
CN101842369A (zh) | 用于治疗周围和中枢神经系统疾病的作为α2C拮抗剂的2,3-二氢苯并[1,4]二*英-2-基甲基衍生物 | |
EA031262B1 (ru) | Гетероциклические соединения и их применение в качестве ингибиторов орфанного рецептора гамма-t, родственного рецепторам ретиноидов (ror) | |
EP3409658B1 (en) | Tetrahydronaphthalene derivative | |
CN100418525C (zh) | 对钙通道α-2-δ亚基具有亲合力的脯氨酸衍生物 | |
CN101142180A (zh) | 作为组胺h3受体拮抗剂的吡咯烷衍生物 | |
EP3228615B1 (en) | Dihydronaphthalene derivatives useful in the treatment of s1p5-mediated diseases | |
EP0826684B1 (en) | Piperidine derivatives | |
ES2600133T3 (es) | Derivados de ariletinilo | |
CN103492366B (zh) | 伯胺二醇二氮烯鎓杂环衍生物 | |
MX2007000182A (es) | Metabolitos de indolilalquilamina como ligandos 5-hidroxitriptamina-6. | |
CN104470894A (zh) | 新吡咯烷衍生物 | |
CN114621135A (zh) | 一种lpa1小分子拮抗剂 | |
BR112021001853A2 (pt) | derivado de benzeno |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned | ||
AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20171208 |