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N-아실-α-아미노숙신이미드와 N-아실-α-아미노글루탈이미드의 합성

Synthesis of N-acyl-α-aminosuccinimides and N-acyl-α-aminoglutarimides

  • 발행 : 2004.02.01

초록

앞선 연구의 구조적 특성을 근거로 하여, 한 분자내에 MES 유발경련에 작용하는 cyclicimide의 구조를 포함하면, 그들의 구조가 경련 유발 수용체들에 상호 보완적으로 작용, MES및 PTZ유발 경련에 모두 작용할 수 있는 적용 범위가 넓은 항경련성 화합물이 될 수 있을 것으로 생각하여 N-acyl-$\alpha$-aminosuccinimide 1과 N-acyl-$\alpha$-aminoglutar- imide 2 유도체를 합성하였다. 먼저 (R)-2-benzyloxy carbonylamino-succinic acid 3을 출발 물질로 하여 N-acyl-a-aminosuccinimide 1 유도체인 (R)-Benzoic acid 4-benzyloxycarbonyl-amino-2-oxo-pyrrolidin-l-yl ester 6a, (R)4-nitro-benzoic acid 4-benzyloxycarbon-ylamino-2-oxo-pyrrolidin-1-yl ester 6b, (R)-4-nitro-benzoic acid 4-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl ester 6c, 그리고 (R)-propionic acid 4-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl ester 64를 합성하였다 또한 (R)-3-car-bobenzyloxy-aminoglutarrnic acid 7를 출발물질로 하여 N-acyl-$\alpha$-aminoglutarimide 2유도체인 (R)-(3-Benzyloxycarbonyl-amino-2,6-dioxo-piperidin-1-yloxy)-acetic acid methyl ester 10a, (R)-(3-benzyloxyarbonylamino-2,6-dioxo-piperidin-1-yloxy)-acetic acid ethyl ester l0b, 그리고 (R)-2-(3-benzylox-ycarbonylanino-2,6-dioxo-piperidin-1-yloxy)-propionic acid methyl ester l0c를 합성하였다. 합성된 화합물 6a, 6b, 6c, 6d, 10a, lOb, l0c에 대한 활성평가는 각 단계별 MES test와 PTZ test의 항경련 활성 시험 방법을 가지고 실험할 예정이다.

As a part of our study on the improvement of anticonvulsant, here we report the synthesis of N-acyl-$\alpha$-aminosuc-cinimides 1 and N-acyl-$\alpha$-aminoglutarimides 2. (R)-Benzoic acid 4-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylester 6a, (R)-4-nifro-benzoic acid 4-benzyloxycarbonylamino-2- oxo-pyrrolidin-1-yl ester 6b, (R) -4-nitro-benzoic acid 4-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl ester 6c, and (R)-propionic acid 4-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl ester 6d were synthesized from (R)-2-benzyloxy carbonylamino-succinic acid 3 as a starting meterial. (R)-(3- Benzyloxycarbonylamino-2,6-dioxo-piperidin-1-yloxy)-acetic acid methyl ester 10a, (R)-(3-benzyloxycarbonylamino-2,6-dioxo-piperidin-1-yloxy)-acetic acid ethy1 ester 10b, an d (R)-2-(3-benzyloxycarbonylamino-2,6- diox o-piperidin-1-yl oxy)-propionic acid methyl ester l0c were synthesized from (R)- 3-carbobenzyloxy-amino-glutarmic acid 7 as a starting meterial. The yield, mp, IR, $^1H-NMR,\; and^{13}C$- NMR spectra of the products 6a, 6b, 6c, 6d, 10a, l0b, l0c are summarized in footnote. The biological studies of these compounds are in progress and will be reported in future.

키워드

참고문헌

  1. J. Med. Chem. v.36 Synthesis and Metabotropic Receptor Activity of the Novel Rigidfied Glutamate Analogues (+) and (-) trans-Azetidine-2,4-dicarboxylic acid and Their N-Methyl Derivates A.P.Kozikiwski;W.Tuckmantel;Y.Liao;H.Manev;S.Ikonomovic;J.T.Wrobleski https://doi.org/10.1021/jm00070a016
  2. General principle Experimental selection, quantification and evaluation of Anticonvulsants in Antiepilpic Drugs(3rd Ed.) E.A.Swintard;J.H.Woodhead;H.S.White;M.R.Franklin
  3. J. Med. Chem. v.33 Preparation and Anticonvulsant Acivities of a Series of Functionalized α-Aromatic and α-heteroaromatic Amino acids H.Kohn;K.N.Sawhney;P.LeGall;J.D.Conley;D.W.Robertson;J.D.Leander https://doi.org/10.1021/jm00165a006
  4. J. Med. Chem. v.34 Synthesis and Anticon-vulsant Acivity of Imidoxy Derivatives Ivan O. Edafiogho;Scoot;Jascqueline A. Moore;Vida. Farrar;Jesses M. Nicholson https://doi.org/10.1021/jm00105a059
  5. Priciple of Medidicinal chemistry(4th edit.) Anticonvulsant J.A.Vida;W.O.Foye;T.Lemke;D.A.Williamseds
  6. Lippincott's illustrated Review: Pharmacology Harvey,R.A.;Champe,PC.
  7. J. Med. Chem. v.30 Functionalized D. L.-aminoacid Derivatives. Potent New Agents for the Treatment of Epilepsy J.D.Conley;H.Kokn
  8. Epilepsy, diagnosis Management Oualty of Life J.K.Penry
  9. NINCD Monography no.12 J.J.Costsworth
  10. Seizure disorder-A Pharmacological Approach to Treatment B.J.Wilder
  11. Annu. Rep. Med. Chem. v.20 J.M.LiebMann;J.A.Schenider https://doi.org/10.1016/S0065-7743(08)61028-3
  12. J. Med. Chem. v.36 3-Acyl-4-hydro- quinoline-2 (1H)-one. Systematically Active Anticonvulsants Acting by Antagonism at the Glycine site of the N-Methyl-D-Aspartate Receptor complex M.Rowley;P.D.Leeson;G.I.Stevenson;A.M.Moseley;I.Stansfield;I.Sanderson;L.Robinson;R.Baker;J.A.Kemp;G.R.Marshell;A.C.Foster;S.Gimwood;M.D.Tricklebank;K.L.Saywell https://doi.org/10.1021/jm00074a020
  13. J. Med. Chem. v.33 Role of Hydrogen binding in Ligand interraction with the N-Methyl-D-Aspartate Receptor ion Channel P.D.Leeson;R.W.Carling;K.James;J.D.Smith;K.W.Moor;E.H.Wong;R.Baker https://doi.org/10.1021/jm00167a005
  14. J. Med. Chem. v.36 Synthesis and Binding Properties of 2-amino-5-phosphono-3- pentenoic acid. Photoaffinity Ligands as Probes for the Glutamate Recognition site of the NMDA Receptor R.Heckendorn;H.AllGeier;JBaud;W.Gunzenhauser;C.Angst https://doi.org/10.1021/jm00075a029
  15. Epilepsia v.19 Antipilepic Drug Development Ⅱ Anticon-vulsant Drug Screening R.L.Krall;J.K.Penry;B.G.White;Kupferberg;E.A.Swinyard
  16. DHEW Publ(NIH)(U.S.) NIH. 78-1093 for standard method: Anticonvulsant Screening Project, Antiepilepti Drug Development Program NIH
  17. J. Med. Chem. v.36 Synthesis and Pharmacological Evaluation of Hexahydrofluoreamines as Noncompe titive Antagonists at the N-Methyl- D- Aspartate Receptors S.J.Hay;P.M.;Nonak;D.F.Ortwin;C.F.Bigge;N.L.Corbry;G.Johnson;L.J.Lescosky;J.C.MaloneA.Michael;M.D.Reily;L.L.Coughenour;L.J.Brahce;J.L.Shillis;A.Probert,Jr https://doi.org/10.1021/jm00058a002