ME01192B - Metod pripreme i upotreba farmakološki aktivnog n-karbamoilmetil-4(r)-fenil-2-pirolidinona - Google Patents
Metod pripreme i upotreba farmakološki aktivnog n-karbamoilmetil-4(r)-fenil-2-pirolidinonaInfo
- Publication number
- ME01192B ME01192B MEP-2009-293A MEP29309A ME01192B ME 01192 B ME01192 B ME 01192B ME P29309 A MEP29309 A ME P29309A ME 01192 B ME01192 B ME 01192B
- Authority
- ME
- Montenegro
- Prior art keywords
- compound
- pyrrolidinone
- phenyl
- carbamoylmethyl
- carphedone
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- HOJZEMQCQRPLQQ-VIFPVBQESA-N (4r)-4-phenylpyrrolidin-2-one Chemical compound C1NC(=O)C[C@@H]1C1=CC=CC=C1 HOJZEMQCQRPLQQ-VIFPVBQESA-N 0.000 claims abstract description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 7
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000007126 N-alkylation reaction Methods 0.000 claims abstract description 3
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 3
- 230000021235 carbamoylation Effects 0.000 claims abstract 2
- LYONXVJRBWWGQO-JTQLQIEISA-N 2-[(4r)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide Chemical compound C1C(=O)N(CC(=O)N)C[C@H]1C1=CC=CC=C1 LYONXVJRBWWGQO-JTQLQIEISA-N 0.000 claims description 6
- 230000000202 analgesic effect Effects 0.000 claims description 6
- 239000003158 myorelaxant agent Substances 0.000 claims description 6
- 230000001430 anti-depressive effect Effects 0.000 claims description 5
- 239000000935 antidepressant agent Substances 0.000 claims description 5
- 229940005513 antidepressants Drugs 0.000 claims description 5
- 230000006742 locomotor activity Effects 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000002276 neurotropic effect Effects 0.000 claims 1
- 239000011814 protection agent Substances 0.000 claims 1
- 230000000144 pharmacologic effect Effects 0.000 abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- LYONXVJRBWWGQO-UHFFFAOYSA-N 2-(2-oxo-4-phenylpyrrolidin-1-yl)acetamide Chemical compound C1C(=O)N(CC(=O)N)CC1C1=CC=CC=C1 LYONXVJRBWWGQO-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- 238000012048 forced swim test Methods 0.000 description 5
- GLCIFTVZMWHJBE-LBPRGKRZSA-N ethyl 2-[(4r)-2-oxo-4-phenylpyrrolidin-1-yl]acetate Chemical compound C1C(=O)N(CC(=O)OCC)C[C@H]1C1=CC=CC=C1 GLCIFTVZMWHJBE-LBPRGKRZSA-N 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HOJZEMQCQRPLQQ-SECBINFHSA-N (4s)-4-phenylpyrrolidin-2-one Chemical compound C1NC(=O)C[C@H]1C1=CC=CC=C1 HOJZEMQCQRPLQQ-SECBINFHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- -1 analgesic Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical class NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 239000003368 psychostimulant agent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102220079670 rs759826252 Human genes 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JGONJCYCUZRGQF-UHFFFAOYSA-N 2-(3-phenylpyrrolidin-1-yl)acetamide Chemical compound C1N(CC(=O)N)CCC1C1=CC=CC=C1 JGONJCYCUZRGQF-UHFFFAOYSA-N 0.000 description 1
- LYONXVJRBWWGQO-SNVBAGLBSA-N 2-[(4s)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide Chemical compound C1C(=O)N(CC(=O)N)C[C@@H]1C1=CC=CC=C1 LYONXVJRBWWGQO-SNVBAGLBSA-N 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003923 mental ability Effects 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- 238000012346 open field test Methods 0.000 description 1
- DAFOCGYVTAOKAJ-UHFFFAOYSA-N phenibut Chemical compound OC(=O)CC(CN)C1=CC=CC=C1 DAFOCGYVTAOKAJ-UHFFFAOYSA-N 0.000 description 1
- 229960004122 phenibut Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 150000003953 γ-lactams Chemical class 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- 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
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- 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
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
Izum se odnosi na R -enantiomer N-karbamoilmetil-4-aril-2- pirolidinona (R-Karfedon) koji ima farmakološku vrednost. Metoda njegove pripreme uključuje jedinjenja (I) prema zahtjevu 1 pomoću N-alkilacije 4( R )-fenil-2-pirolidinona s etil bromacetatom koju sledi karbamoilacija intermedijarnog N-etoksikarbonilmetil-4( R )-aril-2-pirolidinon s amonijakom.
Description
Stanje tehnike
Pronalazak se odnosi na otkriće biološki aktivnog R-enantiomera N-karbamoilmetil-4-aril-2- pirolidinona i jednostavnu i efikasnu metodu njegove pripreme.
Poznato je da ljudi u stresnoj situaciji ili pod psihoemocionalnim naporom pokazuju iracionalne i neprimerene oblike ponašanja, poremećaje mentalne sposobnosti, smanjenu brzinu reakcije i povećan broj pogrešnih odluka, itd.
S toga, otkriće lekova koji ublažavaju i sprečavaju dejstvo stresnog faktora od značajne je važnosti. Za takvu se svrhu primenjuju nootropni GABA derivati: Fenibut i Baklofen, iako je njihova upotreba popraćena pospanošću, depresijom, vrtoglavicom, smanjenim psihomotornim reakcijama itd.
U poredjenju s GABA derivatima jedan drugi agens koji se široko upotrebljava za tu svrhu N-karbamoilmetil-4-aril-2- pirolidinon (karfedon (Caprhedon engl.), INN,) mogao bi se smatrati mnogo perspektivnijim psihostimulatorom zbog manje izraženih sporednih pojava.
Nisu poznati R- i S- enantiomerni oblici karfedona i njihova farmakološka svojstva. Do danas su objavljena jedino farmakološka svojstva racemičnog karfedona i nema podatka o mogućim razlikama farmakoloških svojstava za njegove odvojene R- i S-enantiomere. Nedostatak ove vrlo važne informacije takođe ne dozvoljava adekvatnu procenu stvarnog farmakološkog potencijala karfedona koji se već upotrebljava u medicini, jer je u stvarnosti predstavljen smesom R- i S- enantiomera, koji mogu pokazati različita farmakološka svojstva.
U predmetnom smo pronalasku razvili metode za pripremu čistog R- i S-karfedona i neočekivano otkrili da je R-karfedon kao antidepresiv, analgetik, mišićnog relaksansa i psihostimulativno jedinjenje efiksniji od racemičnog karfedona ili S-karfedona.
Abstrakt i detaljan opis
Pronalazak se odnosi na R-enantiomer amida 4-fenil-l-pirolidinacetatne kiseline. Naročito, izum se odnosi na N-karbamoilmetil-4(R)- fenil-2- pirolidinon formule:
novi hemijski spoj farmakološke vrednosti i metod njegove proizvodnje.
Detaljan opis pronlaska
Kao što smo otkrili, priprema R-karfedona 4 isto kao S-karfedona 4a se može lako postići pomoću N-alkilacije dostupnog 4(R)-fenil-2-pirolidinona (1) ili 4(S)-fenil-2-pirolidinona (1a) s etil bromacetatom (2) u prisutnosti jake baze i sledećom transformacijom etoksikarbonilne grupe u intermedijarnim 2-pirolidinonima 3 i 3a u karbamoilnu funkciju tretiranjem s amonijakom.
Sledeći primeri pokazuju sintetički deo pronalaska.
Primer 1
N-karbamoilmetil-4(R)-fenil-2-pirolidinon (4). Rastvor 4(R)-fenil-2-pirolidinona (1) (345 mg, 2.14 mM) u 1,4-dioksanu (30 ml) dodat je rastvoru natrijum hidrida (56 mg, 2.35 mM) u 1,4-dioksanu (30 ml). Smesa je zagrejana na 80-90°C tokom 30 minuta i zatim ohlađena na sobnoj temperaturi. Dodat je etil bromacetat (393 mg, 2.37 mM) i reakcijska smesa je refluksirana na 110-120°C tokom 6 sati. Dobijena smesa je koncentrisana pod smanjenim pritiskom. Ostatak je pročišćen kromatografijom u koloni na silikagelu sa smesom etilacetat-heksana 1:1, dajući N-etoksikarbonilmetil-4(R)-fenil-2-pirolidinon (3) (338 mg, 64%). [α]D20=+4.6°(c=3, MeOH). 1H NMR (CDCl3), δ: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, kvintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q, CH2CH3); 7.20-7.39 (5H, m, C6H5).
Rastvor N-etoksikarbonilmetil-4(R)-fenil-2-pirolidinona (3) (250 mg, 1.01 mM) u metanolu (30 ml) je zasićen strujom amonijaka u gasovitom stanju tokom 5 sati. Reakcijska smesa je koncentrisana pod smanjenim pritiskom i ostatak je pročišćen kromatografijom u koloni sa smesom etilacetat-heksana 1:1 silikagelom dajući N-karbamoilmetil-4(R)-fenil-2-pirolidinon (4a) (187 mg, 85%). T.t. 107.5-108°C. [α]D20=+8.5° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, kvintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 i 6.21 (1H i 1H, br.s i br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Primer 2
N-karbamoilmetil-4(S)-fenil-2-pirolidinon (4a). Supstitucijom pirolidinona 1 u Primeru 1 4(S)-fenil-2-pirolidinonom (1a) dobijen je S-enantiomerni N-karbonilmetil-4(S)-fenil-2-pirolidinon (4a). [α]D20=-8.3° (c=3, MeOH). 1H NMR (CDCl3), δ: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, kvintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 i 6.21 (1H i 1H, široki singlet (dalje u tekstu „br.s.“, broad singlet engl.) i br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Prema pronalasku, izvršili smo komparativno istraživanje aktivnosti antidepresiva, mišićnog relaksansa, lokomotorne i analgetske aktivnosti za R- i S-enantiomere N-karbamoilmetil-4-aril-2-pirolidinona i uporedili ih s onima racemičnog (karfedon) (Tablica 1-3). Neočekivano smo otkrili da R-karfedon ima izraženija poželjna farmakološka svojstva u pordjenju sa S-karfedonom.
Podaci iz Tablice 1 pokazuju izvrsnu antidepresivnu aktivnost R-enantiomera karfedona upotrebljavajući standardni Porsoltov test prisilnog plivanja (FST). Nakon početnog tretiranja s R-karfedonom, životinje nisu ni jedan trenutak provele nepokretne. Takođe, u slučaju životinja tretiranih s racemičnim karfedonom, vreme nepokretnosti je bilo značajno kraće. Suprotno navedenom, miševi u kontrolnim i S-karfedon grupama pokazali su karakteristično ponašanje za uslove FST testa registrovano kao nepokretnost kao odgovor na stresni faktor.
Slična prednost R-karfedona u poredjenju sa S-karfedonom i racematom primećena je u eksperimentima koji karakterišu motornu aktivnost miševa u standardnom testu otvorenog polja (Tablica 2). I.p. primena testiranih jedinjenja u jednakim dozama od 50 mg/kg izazvala je produženo i stabilno povećanje aktivnosti životinja kada se radilo o R-karfedonu, koja je na kraju perioda promatranja od 120 minuta bila otprilike dvostruko viša od aktivnosti izazvane S-karfedonom.
Podaci iz Tablice 3 pokazuju da je manjim dozama R-karfedona postignuta jednaka aktivnost mišićnog relaksansa i analgetski učinak testiranih spojeva u odnosu na jednake doze S-karfedona.
Tablica 1.
Antidepresivna svojstva testiranih spojeva u skladu s Porsoltovim* testom prisilnog plivanja (FST)**
Testna supstanca
Vreme nepokretnosti, sekunde*
Kontrola
215±10
karfedon
35±12##
R-karfedon
0##
S-karfedon
110±12#
*R.D.Porsolt, i dr., Arch. Intern. Pharmacodynamie, 1977., vol. 229, str. 327-336
**i.p. primena jedinjenja 1 sat pre testa kod mužjaka ICR miševa u dozi od 100 mg/kg
# P>0.05 vs kontrola
## P>0.001 vs kontrola
Tablica 2.
Karakteristike lokomotorne aktivnosti* nakon i.p. primene testiranih jedinjenja kod mužjaka ICR miševa u dozi od 50 mg/kg*
Testna supstanca
Zbirovi horizontalne aktivnosti (min.)
Zbirovi vertikalne aktivnosti (min.)
Zbirovi istraživačke aktivnosti (min.)
30
60
120
30
60
120
30
60
120
Kontrola
47.3±2.1
25.5±1.7
21.6±1.8
10.3±1.1
7.5±0.9
4.1±0.7
18.7±1.9
16.8±1.8
11.3±1.3
karfedon
72.3#±6.0
61.4#±6.7
49.4#±5.8
12.3±4.0
10.9±2.5
7.9±2.0
14.8±3.0
19.1±4.8
17.8±2.8
R-karfedon
77.9#±5.7
80.4#±6.5
78.4#±7.1
10.0±1.5
12.5±3.2
11.6±4.0
15.5±2.9
16.4±3.6
17.8±4.7
S-karfedon
56.3±5.7
43.3#±6.6
36.4±7.1
7.0±1.6
7.0±2.8
4.9±1.7
5.5#±1.5
7.8±4.2
11.5±2.8
* M.L. Weischer, Psycopharmacology 1976.; 50; 275
#P<0.05 ANOVA test sledi Studenov t-test.
Tablica 3.
Dejstvujce doze testiranih jedinjenja odgovorne za jednaku aktivnost mišićnog relaksansa1 i analgeticki učinak2 kod mužjaka IRC miševa.
Testna supstanca
ED50 (mg/kg)*
Aktivnost mišićnog relaksansa
Analgetski učinak
Dimnjak test (Chimney test)
Trakcija
Rotirajuća cev (Rota rod)
Topla ploča (Hot plate)
R-karfedon
199±38
456±122
193±26
10±42
S-karfedon
286±78
548±75
459±87
50±63
* i.p. primena u dozama od 50; 100; 250 i 500 mg/kg
1 N.W. Dunham, i dr., J.Am.Pharm.Assoc., 46:208, 1957.
2 N.B. Eddy, D. Leimbach, J. Pharmacol. Experimental Therapy, 1953., vol. 107, N 3, str. 358-393.
Dobijeni rezultati dokazuju visoku terapeutsku vrednost za R-karfedon koja prekoračuje jednaku terapeutsku vrednost za racemični karfedon, jer na farmaceutska svojstva ovog zadnjeg negativno utiče prisutnost S-karfedona karakterisana smanjenom i u nekim eksperimentima značajno slabijom aktivnosti.
Claims (7)
1. N-karbamoilmetil-4(R)-fenil-2-pirolidinon (I) s neurotropnom aktivnosti: gde * označava kiralni ugljenikov atom.
2. Upotreba jedinjenja (I) prema zahtevu 1, naznačena time da se navedeno jedinjenje upotrebljava kao antidepresiv.
3. Upotreba jedinjenja (I) prema zahtevu 1, naznačena time da se navedeno jedinjenje upotrebljava kao agens za zaštitu od stresa.
4. Upotreba jedinjenja (I) prema zahtevu 1, naznačena time da se navedeno jedinjenje upotreljava kao modulator lokomotorne aktivnosti.
5. Upotreba jedinjenja (I) prema zahtevu 1, naznačena time da se navedeno jedinjenje upotrebljava kao mišićni relaksans.
6. Upotreba jedinjenja (I) prema zahtevu 1, naznačena time da se navedeno jedinjenje upotrebljava kao analgetik.
7. Metoda pripreme jedinjenja (I) prema zahtevu 1, naznačena time da se provodi pomoću N-alkilacije 4(R)-fenil-2-pirolidinona s etil bromacetatom koju sledi karbamoilacija intermedijarnog N-etoksikarbonilmetil-4(R)-aril-2-pirolidinon s amonijakom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-06-45A LV13630B (en) | 2006-03-16 | 2006-03-16 | Method of preparation and use of pharmaceutically active n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone |
| PCT/EP2007/052424 WO2007104780A2 (en) | 2006-03-16 | 2007-03-15 | N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use |
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| ME01192B true ME01192B (me) | 2012-12-20 |
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| MEP-2009-293A ME01192B (me) | 2006-03-16 | 2007-03-15 | Metod pripreme i upotreba farmakološki aktivnog n-karbamoilmetil-4(r)-fenil-2-pirolidinona |
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| SI (1) | SI2013166T1 (me) |
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| RU2392915C1 (ru) * | 2009-04-14 | 2010-06-27 | Федеральное государственное учреждение "Новокузнецкий научно-практический центр медико-социальной экспертизы и реабилитации инвалидов Федерального агентства по здравоохранению и социальному развитию" (ФГУ ННПЦ МСЭ и РИ Росздрава) | Способ формирования двигательных функций у инвалидов с позвоночно-спинно-мозговой травмой |
| LV14346B (lv) * | 2009-11-05 | 2011-07-20 | Grindeks, A/S | 2-(4-Fenil-5-metil-2-oksopirolidin-1-il)-acetamīda 4R,5S-enantiomērs ar nootropo aktivitāti |
| RU2437659C1 (ru) * | 2010-11-12 | 2011-12-27 | Государственное образовательное учреждение высшего профессионального образования "Российский государственный педагогический университет им. А.И. Герцена" (РГПУ им. А.И. Герцена) | Средство, обладающее антидепрессивным, анксиолитическим и ноотропным действием |
| EP2694474A1 (en) * | 2011-03-11 | 2014-02-12 | Grindeks | 4r,5r-enantiomer of 2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide with nootropic activity |
| RU2480214C1 (ru) | 2011-09-22 | 2013-04-27 | Валентина Ивановна Ахапкина | Состав, обладающий модуляторной активностью с соразмерным влиянием, фармацевтическая субстанция (варианты), применение фармацевтической субстанции, фармацевтическая и парафармацевтическая композиция (варианты), способ получения фармацевтических составов |
| ES2727474T3 (es) | 2012-05-08 | 2019-10-16 | Nicox Ophthalmics Inc | Nanocristales de propionato de fluticasona |
| TW201408293A (zh) | 2012-07-05 | 2014-03-01 | Merz Pharma Gmbh & Co Kgaa | (r)-苯基披喇瑟盪於治療疾病相關疲勞之用途 |
| TW201408294A (zh) | 2012-07-05 | 2014-03-01 | Merz Pharma Gmbh & Co Kgaa | (r)-苯基披喇瑟盪於治療帕金森氏症之用除 |
| LV15003B (lv) * | 2013-10-22 | 2015-08-20 | Latvijas Organiskās Sintēzes Institūts | Farmaceitiska kompozīcija ķermeņa masas pieauguma kontrolei |
| LV15015B (lv) | 2013-12-13 | 2015-12-20 | Olainfarm, A/S | 3-karboksi-4-(R)-fenilpirolidin-2-ona sāls un tā pielietošana |
| LV15016B (lv) * | 2013-12-18 | 2016-01-20 | Olainfarm, A/S | N-karbamoilmetil-4(R)-fenil-2-pirolidinona polimorfās formas |
| EP2891491A1 (en) | 2014-01-03 | 2015-07-08 | Merz Pharma GmbH & Co. KGaA | Use of (r)-phenylpiracetam for the treatment of sleep disorders |
| LV15072B (lv) | 2014-05-14 | 2016-09-20 | Olainfarm, A/S | Farmaceitiska kompozīcija izmantošanai patoloģiska stāvokļa, kam raksturīga paaugstināta iNOS gēna ekspresija, profilaksei un ārstēšanai |
| EP3127539A1 (en) * | 2015-08-03 | 2017-02-08 | Latvian Institute Of Organic Synthesis | Use of 2-(5s-methyl-2-oxo-4r-phenyl-pyrrolidin-1-yl)-acetamide in the treatment of seizures |
| EP4582412A1 (en) * | 2022-08-31 | 2025-07-09 | Korea University Research and Business Foundation | Chiral gamma lactam derivative or pharmaceutically acceptable salt thereof, and preparation method therefor |
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| GB0004297D0 (en) * | 2000-02-23 | 2000-04-12 | Ucb Sa | 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses |
| RU2232578C1 (ru) * | 2003-04-10 | 2004-07-20 | Ахапкина Валентина Ивановна | Вещество, обладающее антидепрессивной активностью |
| RU2289404C1 (ru) * | 2005-04-06 | 2006-12-20 | ГОУ ВПО "Московский государственный медико-стоматологический университет Министерства здравоохранения РФ" | Способ премедикации у пациентов со средним уровнем психоэмоционального напряжения при амбулаторных стоматологических вмешательствах |
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| EA014668B1 (ru) | 2010-12-30 |
| US9382203B2 (en) | 2016-07-05 |
| US20100022784A1 (en) | 2010-01-28 |
| LT2008075A (en) | 2009-06-25 |
| LV13630B (en) | 2007-12-20 |
| PT2013166E (pt) | 2010-06-09 |
| EE05536B1 (et) | 2012-04-16 |
| CA2647206C (en) | 2011-09-27 |
| ATE460396T1 (de) | 2010-03-15 |
| US20150216846A1 (en) | 2015-08-06 |
| EE200800063A (et) | 2008-12-15 |
| HRP20090524A2 (hr) | 2009-12-31 |
| UA96440C2 (ru) | 2011-11-10 |
| WO2007104780A3 (en) | 2007-11-29 |
| DK2013166T3 (da) | 2010-07-05 |
| LT5589B (lt) | 2009-08-25 |
| ES2342024T3 (es) | 2010-06-30 |
| CN101448786A (zh) | 2009-06-03 |
| EP2013166A2 (en) | 2009-01-14 |
| PL2013166T3 (pl) | 2010-08-31 |
| HRP20090524C1 (hr) | 2017-03-10 |
| CA2647206A1 (en) | 2007-09-20 |
| DE602007005244D1 (de) | 2010-04-22 |
| SI2013166T1 (sl) | 2010-07-30 |
| CY1110170T1 (el) | 2015-01-14 |
| EA200801978A1 (ru) | 2009-04-28 |
| GEP20104915B (en) | 2010-03-10 |
| HRPK20090524B3 (hr) | 2012-12-31 |
| EP2013166B1 (en) | 2010-03-10 |
| US9102615B2 (en) | 2015-08-11 |
| WO2007104780A2 (en) | 2007-09-20 |
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