EP2694474A1 - 4r,5r-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activity - Google Patents
4r,5r-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activityInfo
- Publication number
- EP2694474A1 EP2694474A1 EP12709308.6A EP12709308A EP2694474A1 EP 2694474 A1 EP2694474 A1 EP 2694474A1 EP 12709308 A EP12709308 A EP 12709308A EP 2694474 A1 EP2694474 A1 EP 2694474A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- phenyl
- oxo
- pyrrolidin
- acetamide
- 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.)
- Withdrawn
Links
- 230000001777 nootropic effect Effects 0.000 title claims description 7
- ZTGRWYMPQCQTHD-UHFFFAOYSA-N 2-(2-methyl-5-oxo-3-phenylpyrrolidin-1-yl)acetamide Chemical compound C1C(=O)N(CC(N)=O)C(C)C1C1=CC=CC=C1 ZTGRWYMPQCQTHD-UHFFFAOYSA-N 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 235000011054 acetic acid Nutrition 0.000 claims description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 4
- PPGRVWNKZPOCIU-UHFFFAOYSA-N 2-[1-(4,5-dihydro-1,3-oxazol-2-yl)cyclopropyl]-4,5-dihydro-1,3-oxazole Chemical compound C1CC1(C=1OCCN=1)C1=NCCO1 PPGRVWNKZPOCIU-UHFFFAOYSA-N 0.000 claims description 4
- WGSVFWFSJDAYBM-UHFFFAOYSA-N 2-nitroprop-1-enylbenzene Chemical compound [O-][N+](=O)C(C)=CC1=CC=CC=C1 WGSVFWFSJDAYBM-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 4
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- 125000003368 amide group Chemical group 0.000 claims 2
- -1 bromoacetic acid ester Chemical class 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- BYHDDXPKOZIZRV-UHFFFAOYSA-N 5-phenylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=CC=C1 BYHDDXPKOZIZRV-UHFFFAOYSA-N 0.000 claims 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 238000007126 N-alkylation reaction Methods 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims 1
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 229940106681 chloroacetic acid Drugs 0.000 claims 1
- 230000007278 cognition impairment Effects 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 229910021645 metal ion Inorganic materials 0.000 claims 1
- 239000002664 nootropic agent Substances 0.000 claims 1
- 229910001415 sodium ion Inorganic materials 0.000 claims 1
- 230000019771 cognition Effects 0.000 abstract description 4
- 230000002708 enhancing effect Effects 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- ZIZRQVWVGIHEIC-UHFFFAOYSA-N 5-methyl-4-phenylpyrrolidin-2-one Chemical compound CC1NC(=O)CC1C1=CC=CC=C1 ZIZRQVWVGIHEIC-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 150000003613 toluenes Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012549 training Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000006845 Michael addition reaction Methods 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 238000011302 passive avoidance test Methods 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 229920005372 Plexiglas® Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 1
- 230000007172 age related pathology Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- GSMPSKWDIFSIAR-UHFFFAOYSA-N n-cyclohexyl-1-(4-nitrophenyl)methanimine Chemical compound C1=CC([N+](=O)[O-])=CC=C1C=NC1CCCCC1 GSMPSKWDIFSIAR-UHFFFAOYSA-N 0.000 description 1
- 230000002276 neurotropic effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- This invention relates to preparation and medical use of 4/?,5/?-enantiomer of 2-(5- methyl-2-oxo-4-phenylpyrrolidin-1 -yl)-acetamide for use as nootropic medicament.
- cognition enhancing drugs facilitate attention abilities and acquisition, storage and retrieval of information and attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies.
- EP 2013166 B (AKCIJU SABIEDRIBA OLAINFARM) 10.03.2010 disclosed R- enantiomer of /V-carbamoylmethyl-4-phenyl-2-pyrrolidinone being different from the present one only in that 5-methyl group is lacking with neurotropic activity. Summary of invention
- the chemical scheme of 2-(5/?-methyl-2-oxo- 4 ?-phenyl-pyrrolidin-1 -yl)-acetamide (1) preparation includes the synthesis of 4/?,5/?-enantiomer of 5-methyl-4-phenylpyrrolidin-2-one (2) and the insertion of acetamide group in position 1 of the pyrrolidone ring:
- this problem was solved by asymmetric Michael addition of 2-nitroprop-1 -enylbenzene (3) to diethyl malonate (3) in the presence of complex catalyst consisting of chiral 2,2'-cyclopropylidene-bis-oxazoline 5, magnesium triflate and organic base leading to the formation of diethyl 2-[2( ?,5)- nitro-1 ?-phenylpropyl]-malonate diastereoisomeric mixture (6).
- 2,2'-cyclopropylidene-bis-oxazoline 5 magnesium triflate and organic base, which is selected from morpholine, N-methylmorpholine, 1 ,1 ,3,3- tetramethylguanidine and their mixtures, leading to the formation of diethyl 2-[2( ?,5)-nitro-1 ( )-phenylpropyl]-malonate erythro- and threo- diastereoisomeric mixture (6) in ratio 3:1 ;
- 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide may be used as a highly effective agent for a medicament with nootropic activity.
- Passive avoidance test was performed in a shuttle-box apparatus (Ugo Basile, Italy) with two communicating compartments of equal size (20x10 x16 cm) and a stainless steel grid floor (bars spaced 0.7 cm apart).
- the right-hand compartment (shock compartment) was painted black to obtain a dark chamber.
- the left-hand compartment was painted white and illuminated by a bulb (100 W) installed on the top of a plexiglass cover. These compartments were separated by a guillotine door (5x4 cm). On day 1 (training trial), mice were placed in the illuminated compartment and the door between the two compartments was opened 60 s later.
- mice entered the dark compartment with all four feet When mice entered the dark compartment with all four feet, the door automatically closed and an inescapable electrical foot shock (0.1 mA; 3 s) was delivered through the grid floor. Latency to cross into the dark compartment (training latency) was automatically measured. The retention test was performed 24 hours later (day 2). Mice were placed into the light (safe) compartment, with access to the dark one (within 15 s) for a period of 600 s (cut-off time). The latency to cross into the dark compartment with all four feet was automatically measured (retention latency).
- the compounds were administered intraperitoneally at the dose of 46 ⁇ /kg 60 min before the training trial (day 1 ).
- the saline control group was run concurrently with the drug-treated groups.
- the statistical analysis was performed by Student's t-test. Data represent means ⁇ S.E.M.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the 5R,4R-enantiomer of 2-(5-methyl-2-oxo-4-phenyl- pyrrolidin-1-yl)-acetamide with cognition enhancing activity of high pharmacological value and to its preparation method.
Description
Description
4 ?,5 ?-ENANTIOMER OF 2-(5-METHYL-2-OXO-4-PHENYL-PYRROLIDIN-1 -YL)- ACETAMIDE WITH NOOTROPIC ACTIVITY Technical Field
This invention relates to preparation and medical use of 4/?,5/?-enantiomer of 2-(5- methyl-2-oxo-4-phenylpyrrolidin-1 -yl)-acetamide for use as nootropic medicament. Background Art
It is known that cognition enhancing drugs facilitate attention abilities and acquisition, storage and retrieval of information and attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies.
Racemic molecule of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide, a piracetam structural derivative, was mentioned in 2001 (M. V. Berestovitskaya, M. M. Zobachova, B. M. Novikov, O. S. Vasileva, N. V. Usik, S. M. Aleksandrova, I. N. Turenkov. International Conference on the Synthesis of Nitrogen Heterocycles, Moscov, Oct. 9-12, 2001 , vol. 1 , pp. 229-233). However there is no data on the chemical structure and biological properties of this compound provided.
EP 2013166 B (AKCIJU SABIEDRIBA OLAINFARM) 10.03.2010 disclosed R- enantiomer of /V-carbamoylmethyl-4-phenyl-2-pyrrolidinone being different from the present one only in that 5-methyl group is lacking with neurotropic activity. Summary of invention
According to the current invention, the pharmacological studies of racemic 2-(5- methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide, containing two chiral centers in positions 4 and 5 of the pyrrolidone ring, unexpectedly revealed its rather promising cognition enhancing properties. However, when we have prepared separate 4/?,5/?-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)- acetamide and subjected it to nootropic investigation, it surprisingly and unexpectedly appeared to be much more pharmacologically active in comparison to the parent racemic compound.
According to the current invention, we describe a method of preparation of 4 ?,5 ?- enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide of Formula 1 with cognition enhancing properties of high pharmacological value:
which is a new chemical compound with nootropic activity.
According to the current invention, the chemical scheme of 2-(5/?-methyl-2-oxo- 4 ?-phenyl-pyrrolidin-1 -yl)-acetamide (1) preparation includes the synthesis of 4/?,5/?-enantiomer of 5-methyl-4-phenylpyrrolidin-2-one (2) and the insertion of acetamide group in position 1 of the pyrrolidone ring:
Methods of racemic 5-methyl-4-phenylpyrrolidin-2-one preparation and its separation into enantiomeric mixture of erythro- and / 7reo-isomers were documented in literature (Colonge J., Pouchol J.M., Bull. Soc. Chim., 1962, 598- 603; Langlois M.. et. al. Bull. Soc. Chim., 1971 , 2976-2982; Lesniak S., Pasternak B., Tetrahedron Lett, 2005, 46, 3093-3095). However, no written evidence about the resolution of racemic 5-methyl-4-phenylpyrrolidin-2-one into separate enantiomers or their direct synthesis from chiral or non-chiral chemical substances has been found.
According to the current invention, this problem was solved by asymmetric Michael addition of 2-nitroprop-1 -enylbenzene (3) to diethyl malonate (3) in the presence of complex catalyst consisting of chiral 2,2'-cyclopropylidene-bis-oxazoline 5, magnesium triflate and organic base leading to the formation of diethyl 2-[2( ?,5)- nitro-1 ?-phenylpropyl]-malonate diastereoisomeric mixture (6).
Chemical scheme of 5( )-methyl-4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2) preparation includes following steps:
a) asymmetric Michael addition of 2-nitroprop-1 -enylbenzene (3) to diethyl malonate (3) in the presence of complex catalyst consisting of chiral
2,2'-cyclopropylidene-bis-oxazoline 5, magnesium triflate and organic
base, which is selected from morpholine, N-methylmorpholine, 1 ,1 ,3,3- tetramethylguanidine and their mixtures, leading to the formation of diethyl 2-[2( ?,5)-nitro-1 ( )-phenylpropyl]-malonate erythro- and threo- diastereoisomeric mixture (6) in ratio 3:1 ;
b) hydrolysis and decarboxylation of diethyl ester 6 in acidic media, where acidic media is selected from the group, consisting of formic, acetic and hydrochloric acids and their mixtures, in temperature range between 70° and 1 10°C
c) conversion of 4-nitro-3( )-phenylpentanoic acid (10) by esterification with methanol into diasteroisomeric mixture of methyl 4( ?,5)-nitro-3( )- phenylpentanoate (11 );
d) separation of methyl 4( ?,5)-nitro-3( )-phenylpentanoate (11) to individual 4 ?-12 enantiomer by column chromatography;
e) hydrogenation of nitro group in methyl 4( )-nitro-3( )- phenylpentanoate (4 ?-12) in the presence of Ni Reney catalyst, under pressure between 3 and 60 atm, with the formation of 5( )-methyl- 4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2).
«yrt»:.*»0=3:l erythro.threo =3:1 «^.^=3:1
f) the conversion of 5( )-methyl-4( )-phenylpyrrolidin-2-one (4 ?,5 ?-2) into 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetamide (1 ) included the treatment of 4 ?,5 ?-2 with alkali metal ion,
g) alkylation of intermediate 13 with haloacetic acid ethyl ester, and h) amidation of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]- acetate (14) with ammonia in a suitable solvent, where suitable solvent is selected from the group consisting of methanol, ethanol, propanol, chloroform, methylene chloride, ethyl acetate and 1 ,4-dioxane.
According to the current invention, comparative pharmacological evaluation of 2- (4 ?-phenyl-2-oxopyrrolidin-1 -yl)acetamide), racemic 2-(5-methyl-2-oxo-4-phenyl- pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)- acetamide, employing standard passive avoidance test, proved the high effectiveness of the optically active 2-(5 ?-methyl-2-oxo-4 ?-phenylpyrrolidin-1 -yl)- acetamide (1 ) as an enhancer of learning and memory.
Therefore, 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide may be used as a highly effective agent for a medicament with nootropic activity.
Description of embodiments
The scope of the invention should not be limited to the working examples, which are for demonstration purposes. One skilled in the art can practice the invention based on the disclosures in the present patent application.
The following examples are illustrating but not restricting the present invention.
Examples
Example 1.
The solution of (3a ?,3'a ?,8a5,8'a5)-2,2'-cyclopropylidenebis-[3a,8a]-dihydro-8H- indeno-[1 ,2-d]-oxazole (420 mg, 1.18 mM) in chloroform (hydrocarbon stabilized) (5 ml), magnesium triflate (378 mg, 0. 1.18 mM) and water (25 μΙ_) were added in 250 ml reaction flask at room temperature and mixture was stirred under argon for 1 hour. Molecular sieves (1.0 g) and 1 ,4-dioxane (30 ml) were added to the obtained mixture, which was stirred for additional 30 min. Obtained suspension was diluted with 45 ml of chloroform solution containing diethylmalonate (1.67 g, 10.2 mM), 2-nitroprop-1 -enylbenzene (1.63 g, 10.0 mM) and morpholine (46 μΙ_). Reaction mixture was stirred at room temperature. Conversion and selectivity were determined by chiral HPLC analysis [Chiralpak IC, 4.6x250 mm, 1.0 ml/min, eluent
i-PrOH-Hexane (1 :9)] each 48 hours. After the completion of reaction, the reaction mixture was diluted with hexane (50 ml), stirred for 20 min. and the solid was filtered off. The filtrate was washed with 5% aqueous HCI (2x50 ml), brine (2x50 ml), dried over anhydrous Na2SO4. The drying reagent was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :10) collecting fractions with Rf 0.28. Yield 87% (2.8 g). Obtained low-melting yellow solid, according to chiral HPLS is a mixture of erythro- and / 7/ecHsomers of diethyl 2-(2- nitro-1 ( )-phenylpropyl)-malonate in ratio 3:1. Optical purity: 93% ee.
H NMR (CDC ), δ, ppm (J, Hz): 0.85 (2.25 H, t, J=7.0 eryt iro-CH2C ); 0.93 (0.75 H, t, J=7.0 / 7reo-CH2CH3); 1.15-1.27 (3H, m, CH2CH3); 1.29 (0.75 H, d, J=6.8, / 7reoCH3CNO2); 1.37 (2.25 H, d, J=6.8, e/y/ 7r^CH3CNO2); 3.63-3.93 (3H, m, CH2CH3, COCHCO); 4.07-4.29 (3H, m, CH2CH3, PhCH,); 4.29-5.06 (0.25H, m, threo-CHNOi); 5.07-5.16 (0.75H, m, erythro-CHNOi); 6.99-7.28 (5H, m, C6H5). Example 2.
The substitution of morpholine in example 1 by N-methylmorpholine resulted in the formation of diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate as a mixture of erythro- and / 7/ecHsomers 3:1. Optical purity: 94% ee. Yield 85%.
Example 3.
The substitution of morpholine in example 1 by the mixture of morpholine (46 μΙ_) and tetra-methylguanidine (46 μΙ_) resulted in the formation of diethyl 2-(2-nitro- 1 (/ )-phenylpropyl)-malonate as a mixture of erythro- and / 7/ecHsomers 3:1. Optical purity: 95% ee. Yield 87%.
Example 4.
Diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate (2.00 g, 6.21 mM) was refluxed in acetic acid (30 ml) for 18 hours. After the completion of reaction, the reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :5) collecting fractions with R 0.22. Obtained yellow solid was the mixture of erythro- and threo- isomers of 4-nitro-3( )-phenylpentanoic acid in ratio 3:1. Yield 42% (581 mg).
NMR (CDCb), δ, ppm (J, Hz): 1.27 (0.60 H, d, J=6.6 threo-5-CHz); 1.48 (2.40 H, d, J=6.6 erythro-5-CHz); 2.61 -2.91 (2H, m, 2-CH2); 3.54-3.70 (1 H, m, 3-H); 4.66- 4.70 (0.20 H, m, threo-A ); 4.77-4.87 (0.80 H, m, erythro-A ); 7.05-7.48 (5H, m, C6H5).
Example 5.
The substitution of acetic acid in example 4 by 36% hydrochloric acid resulted in the formation of the mixture of erythro- and / 7/ecHsomers of 4-nitro-3( )- phenylpentanoic acid in ratio 3:1 . Yield 44%.
Example 6.
The substitution of acetic acid in example 4 by the mixture of acetic and 36% hydrochloric acids in ratio 1 :3 resulted in the formation of the mixture of erythro- and / 7/ecHsomers of 4-nitro-3( )-phenylpentanoic acid in ratio 3:1 . Yield 48%. Example 7.
The mixture of erythro- and / 7reo-isomers of 4-nitro-3 ?-phenylpentanoic acid (500 mg, 2.24 mM) and thionyl chloride (61 μΙ_, 1.0 mM) in methanol (20 ml) was refluxed for 6 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography on silica ethylacetate/hexane (1 :10) collecting fractions with R 0.28. Obtained yellow solid was the mixture of erythro- and threoAsomers of methyl 4-nitro-3( )- phenylpentanoate in ratio 3:1 . Yield 89% (473 mg).
H NMR (CDC ), δ, ppm (J, Hz): 1.27 (0.60 H, d, J=6.6 threo-5-CHz); 1 .48 (2.40 H, d, J=6.6 erythro-5-CHz); 2.58-2.285 (2H, m, 2-CH2); 3.46 (0.60 H, s, threo-OCH ); 3.53 (2.40 H, s, erytro-OCH ); 3.56-3.71 (1 H, m, 3-H); 4.68-4.77 (0.20 H, m, threo- 4-H); 4.79-4.88 (0.80 H, m, erythro-A ); 7.07-7.31 (5H, m, C6H5).
Example 8.
The mixture of erythro- and / 7reo-isomers of methyl 4-nitro-3( )-phenylpentanoate in ratio 3:1 (4.5 g) was fractionated by column chromatography on silca ethylacetate/hexane (1 :15). Fractions with Rf 0.26 containing methyl 4( )-nitro- 3( )-phenylpentanoate were collected and evaporated under reduced pressure. Yield 810 mg (72%) of low melting yellow solid.
H NMR (CDCb), δ, ppm (J, Hz): 1 .27 (3 H, d, J=6.6 threo-5-CHz); 2.58-2.285 (2H, m, 2-CH2); 3.46 (3 H, s, threo-OCH ); 3.56-3.71 (1 H, m, 3-H); 4.68-4.77 (1 H, m, threo-A ); 7.07-7.31 (5H, m, C6H5).
Example 9.
The stirring suspension of methyl 4( )-nitro-3( )-phenylpentanoate (600 mg, 2.52 mM) in ethanol (40 ml) and 1 ml of 50% Ni Reney slurry in water was hydrogenated at 50 °C and 50 atm for 18 hours. After the completion of reaction, the reaction mixture was cooled, the catalyst was filtered off and washed with 30 ml of ethanol. The filtrate concentrated under reduced pressure. The purification of
residue by liquid column chromatorgaphy on silca gel ChhCb/EtOH (20:1) collecting fractions with Rf 0.40. Obtained white solid 375 mg according chiral HPLC is the 5( )-methyl-4( )-phenylpyrrolidin-2-one. Yield 85%.
NMR (CDC ), δ, ppm (J, Hz): 1.20 (3.00 H, d, J=6.5 5-CH3); 2.48-2.57 (1 H, m, 3-CH2); 2.65-2.74 (1 H, m, 3-CH2); 2.98-3.07 (1 H, m, 4-H) 3.65-3.75 (1 H, m, 5-H); 6.76 (1 H, br. s, NH); 7.07-7.33 (5H, m, C6H5).
Example 10.
The solution of 5( )-methyl-4( )-phenylpyrrolidin-2-one (351 mg, 2.00 mM) in toluene (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in toluene (30 ml). The stirred mixture was heated at 80 - 90°C during 30 min and then cooled to the room temperature. Ethyl bromoacetate (368 mg, 2.20mM) was added to the reaction mixture, which was heated at 1 10 -120°C for 6 hours and than concentrated under reduced pressure. The residue was dissolved in toluene (30 ml). Obtained solution was washed with 5% aqueous HCI (2x50 ml), brine (2x50 ml), dried over anhydrous Na2SO4. The drying reagent was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica Ch C /MeOH (20:1 ). Fractions with R 0.48 were collected and evaporated under reduced pressure, giving ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate (367 mg, 70%) as colorless oil.
1 H NMR (CDCb), δ, ppm (J, Hz): 1.16 (3.00 H, d, J=6.3 threo-5-CHz); 1.23 (3H, t, J=7.0, CH2CH3); 2.53-2.63 (1 H, m, CH2);2.76-2.86 (1 H, m, CH2); 2.92-3.01 (1 H, m, 4-H); 3.71 (1 H, d, J=17.7, NCH2COO); 3.74-3.83 (1 H, m, 5-H); 4.10-4.20 (3H, m, CH2CH3); 4.38 (1 H, d, J=17.8, NCH2COO); 7.18-7.33 (5H, m, C6H5).
Example 11.
The substitution of sodium hydride in example 10 by sodium ethoxide resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 69%.
Example 12.
The substitution of ethyl bromoacetate in example 10 by ethyl chloroacetate resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]- acetate with yield 71 %.
Example 13.
The substitution of toluene in example 10 by hexane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 70%.
Example 14.
The substitution of toluene in example 10 by benzene resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 70%.
Example 15.
The substitution of toluene in example 10 by 1 ,4-dioxane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 71 %. Example 16.
The substitution of toluene in example 10 by dichloromethane resulted in the formation of the 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate with yield 69%.
Example 17.
The solution of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetate (700 mg, 2.68 mM) in ethanol (30 ml) was saturated with gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and residue was purified by column chromatography with Ch C /EtOH (20:1 ). Fractions with Rf 0.32 were collected and evaporated under reduced pressure, giving 2-[5(R)- methyl-2-oxo-4( )-phenyl-pyrrolidin-1 -yl]-acetamide 498 mg, 80%) as white solid recrystallized from water. M.p. 1 17-118°C.
Calculated for C13H16N2O2 (232.28) C 67.22; H 6.94; N 12.06. Found: C 67.25; H 6.96; N 12.10.
NMR (CDC ), δ: 1.23 (3.00 H, d, J=6.2 5-CH3); 2.52-2.62 (1 H, m, 3-CH2); 2.77- 2.86 (1 H, m, 3-CH2); 3.95-3.05 (1 H, m, 4-H); 3.67-3.85 (1 H, m, 5-H); 3.85 (1 H, d, J=16, NCH2COO); 3.97 (1 H, d, J=16, NCH2COO); 5.54 and 6.25 (2H, br.s, br.s, NH2); 7.16-7.33 (5H, m, C6H5).
Biological tests
Learning and memory
Passive avoidance test was performed in a shuttle-box apparatus (Ugo Basile, Italy) with two communicating compartments of equal size (20x10 x16 cm) and a stainless steel grid floor (bars spaced 0.7 cm apart). The right-hand compartment (shock compartment) was painted black to obtain a dark chamber. The left-hand compartment was painted white and illuminated by a bulb (100 W) installed on the top of a plexiglass cover. These compartments were separated by a guillotine door (5x4 cm). On day 1 (training trial), mice were placed in the illuminated compartment and the door between the two compartments was opened 60 s later. When mice entered the dark compartment with all four feet, the door automatically
closed and an inescapable electrical foot shock (0.1 mA; 3 s) was delivered through the grid floor. Latency to cross into the dark compartment (training latency) was automatically measured. The retention test was performed 24 hours later (day 2). Mice were placed into the light (safe) compartment, with access to the dark one (within 15 s) for a period of 600 s (cut-off time). The latency to cross into the dark compartment with all four feet was automatically measured (retention latency).
Effects of 2-(4 ?-phenyl-2-oxopyrrolidin-1 -yl)acetamide), racemic 2-(5-methyl-2- oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl- pyrrolidin-1 -yl)-acetamide on retention of passive avoidance response (memory) in ICR male mice.
Data presented in Table 1 demonstrate effects of, 2-(4 ?-phenyl-2-oxopyrrolidin-1 - yl)acetamide, racemic 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1 -yl)-acetamide and 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide on memory in the passive avoidance task in mice.
Table 1
Effects of administrated compounds on memory in the passive avoidance task in
*p< 0.05, # 7<0.05, $ p< 0.05 versus saline control group, 2-(4 ?-phenyl-2- oxopyrrolidin-1 -yl)acetamide-treated group and racemic 2-(5-methyl-2-oxo-4- phenyl-pyrrolidin-1 -yl)-acetamide-treated group, respectively; /7 >10
The compounds were administered intraperitoneally at the dose of 46 μΐτιοΙ/kg 60 min before the training trial (day 1 ). The saline control group was run concurrently with the drug-treated groups. The statistical analysis was performed by Student's t-test. Data represent means ± S.E.M.
As it is presented in Table 1, 2-(5 ?-methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)- acetamide treatment at the dose of 46 μΐτιοΙ/kg induced a statistically significant enhancement of memory.
Claims
1. 2-(5 ?-Methyl-2-oxo-4 -phenyl-pyrrolidin-1 -yl)-acetamide (I)
wherein * marks chiral carbon atoms.
2. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as a
medicament.
3. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as a nootropic medicament.
4. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use as cognition enhancer.
5. 2-(5 ?-Methyl-2-oxo-4 ?-phenyl-pyrrolidin-1 -yl)-acetamide for use in treating of cognitive deficits.
6. A process of preparation of a compound (I) according to the claim 1 , which includes following steps:
a) the addition of 2-nitroprop-1 -enylbenzene to diethyl malonate in the presence of complex catalysts consisting of chiral 2,2'- cyclopropylidene-bis-oxazoline, magnesium triflate and organic base with the formation of diethyl 2-(2-nitro-1 ( )-phenylpropyl)-malonate. b) hydrolysis and decarboxylation of diethyl 2-(2-nitro-1 ( )- phenylpropyl)-malonate in acidic media with the formation of 4-nitro- 3( )-phenylpentanoic acid.
c) esterification of 4-nitro-3( )phenylpentanoic acid with methanol with the formation of methyl 4-nitro-3( )-phenylpentanoate. d) chromatographic resolution of the diastereoisomeric mixture of methyl 4-nitro-3( )-phenylpentanoate into its separate 3 ?,4 ?- and 3/?,45-enantiomers by column chromatography.
e) hydrogenation of methyl 4( )-nitro-3( )-phenylpentanoate the presence of Ni Reney catalyst with the formation of 5(/ )-methyl- 4( )-phenylpyrrolidin-2-one. f) substitution of hydrogen in the amide group of 5( )-methyl-4( )- phenylpyrrolidin-2-one with metal ion in a suitable organic solvent. g) N-alkylation of N-metallated 5( )-methyl-4( )-phenylpyrrolidin-2-one with haloacetic acid esters in a suitable organic solvent; h) amidation of ethyl 2-[5( )-methyl-2-oxo-4( )-phenyl-pyrrolidin-1-yl]- acetate with ammonia in a suitable solvent.
7. A process according to claim 6 wherein in step a) chiral 2,2'-cyclopropylidene- bis(oxazoline) is (3a ?,3'a ?,8aS,8'aS)-2,2'-cyclopropylidenebis-[3a,8a]- dihydro-8H-indeno-[1 ,2-d]-oxazole.
8. A process according to claim 6 wherein in step a) organic base is selected from the group, consisting of morpholine, N-methylmorpholine, 1 ,1 ,3,3- tetramethylquanidine and their mixtures.
9. A process according to claim 6 wherein in step b) media for acidic hydrolysis is selected from the group, consisting of formic, acetic and hydrochloric acids and their mixtures.
10. A process according to claim 6 wherein in step b) temperature of
decarboxylation reaction is between 70° and 110°C.
11. A process according to claim 6 wherein in step e) hydrogen pressure is
between 3 and 60 atm.
12. A process according to claim 6 wherein in step f) sodium ion is introduced in the amide group of 5( )-methyl-4( )-phenylpyrrolidin-2-one by sodium hydride or sodium ethoxide.
13. A process according to claim 6 wherein in step g) haloacetic acid ester is
represented with bromoacetic acid ester or chloroacetic acid ester.
14. A process according to claim 6-15 wherein a suitable organic solvent for
reactions is selected from the group, consisting of hexane, benzene, toluene, chloroform, dichloromethane, dichloroethane, ethyl acetate, methyl acetate, diethyl ether, 1 ,4-dioxane, dimethylsulfoxide and mixtures of them.
15. A process according to claim 6 wherein in step h) a suitable organic solvent is selected from group consisting of methanol, ethanol, propanol; chloroform, methylene chloride; ethyl acetate and 1 ,4-dioxane.
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| EP12709308.6A EP2694474A1 (en) | 2011-03-11 | 2012-03-09 | 4r,5r-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activity |
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