新型嘧啶并[4，5-b]噻吩并[1，4]二氮的合成研究
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摘要
本论文包括以下内容:(1)介绍了嘧啶并噻吩并二氮七元环化合物的生物活性及合成方法。(2)简述了两种经典反应Bischler-Napieralski反应和Pictet-Spengler反应(3)研究了从4,6-二氯-5-硝基嘧啶出发,经胺基噻吩取代,硝基经还原后所得前体与羧酸及其衍生物发生Bischler-Napieralski-type反应以及Pictet-Spengler反应合成嘧啶并噻吩并二氮七元环化合物反应规律,最终合成了新颖的化合物库。
The development of privileged heterocyclic scaffolds isa rapidly emerging subject in medicinal chemistry. Benzodiazepine analogues are considered as privileged structures in medicinal chemistry and often possess a wide range of interesting pharmacological activities.
Pyrimidines and pyrimidine- fused compounds are widely studied because of their interesting pharmacolo-gicalactivities. For example, some pyrrolopyrimidines arereported to have antitumor activities, some aminopyridopyrimi-dinesare novel non-nucleoside adenosine kinaseinhibitors, certain furanopyrimidines are potent andselective inhibitors of human cytomegalovirus (HCMV), 4 and 5-substituted furo[2,3-d]pyrimidines exhibit potentinhibitory activity against the growth of tumor cells. Another class of heterocyclic scaffolds with celebrated biological activities in the central nervous system is the benzothienodiazepines. for example, Olanzapine.
Recently, we introduced a new methodology for the efficient synthesis of pyrimidine-fused thienodiazepines via Bischler- Napieralski-type and Pictet–Spengler reactions. To expand the scope of these methods and access to new heterocyclic scaffolds, we envisioned that Bischler-Napieralski-type and Pictet–Spengler-like cyclization of 5-Amino-6-chloro-4-N-methyl-thiophene-pyrimidine with an acyl chloride or aldehyde should lead to tricyclic 4-chloro-pyrimido[4,5-b][1,4]thienodiazepines or 4-chloro-5,6-dihy- dropyrimido[4,5-b][1,4]thienodiazepines. The 4-chloro group in 4-chloro-pyrimido[4,5-b][1,4]thienodiazepines can be easily converted to other groups by a substitution reaction with a nucleophile (such as an amine, alcohol, and phenol and so on) .the synthetic strategy provides an efficient way to access to libraries of novel heterocyclic compounds with potential pharmaceutical or biological activities.
The development of privileged heterocyclic scaffolds isa rapidly emerging subject in medicinal chemistry. Benzodiazepine analogues are considered as privileged structures in medicinal chemistry and often possess a wide range of interesting pharmacological activities.
Pyrimidines and pyrimidine- fused compounds are widely studied because of their interesting pharmacolo-gicalactivities. For example, some pyrrolopyrimidines arereported to have antitumor activities, some aminopyridopyrimi-dinesare novel non-nucleoside adenosine kinaseinhibitors, certain furanopyrimidines are potent andselective inhibitors of human cytomegalovirus (HCMV), 4 and 5-substituted furo[2,3-d]pyrimidines exhibit potentinhibitory activity against the growth of tumor cells. Another class of heterocyclic scaffolds with celebrated biological activities in the central nervous system is the benzothienodiazepines. for example, Olanzapine.
Recently, we introduced a new methodology for the efficient synthesis of pyrimidine-fused thienodiazepines via Bischler- Napieralski-type and Pictet–Spengler reactions. To expand the scope of these methods and access to new heterocyclic scaffolds, we envisioned that Bischler-Napieralski-type and Pictet–Spengler-like cyclization of 5-Amino-6-chloro-4-N-methyl-thiophene-pyrimidine with an acyl chloride or aldehyde should lead to tricyclic 4-chloro-pyrimido[4,5-b][1,4]thienodiazepines or 4-chloro-5,6-dihy- dropyrimido[4,5-b][1,4]thienodiazepines. The 4-chloro group in 4-chloro-pyrimido[4,5-b][1,4]thienodiazepines can be easily converted to other groups by a substitution reaction with a nucleophile (such as an amine, alcohol, and phenol and so on) .the synthetic strategy provides an efficient way to access to libraries of novel heterocyclic compounds with potential pharmaceutical or biological activities.
引文
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[10] Chakrabarti.J.; Hotten. T. ; Pullar. I.;Steggles. D. ; Heteroareno -benzodiazepines. Part 7. Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b] and [4,3-b] [1,5] benzodiazepines as potential anxiolytics J. Med. Chem. 1989,32, 2573-2582
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[21] Huang,C.Q.; Wilcoxen,K.M.; Grigoriadis,D.E.; McCarthy,J.R.; Chen.C. Design and synthesis of 3-(2-pyridyl) pyrazolo [1,5-a] pyrimidines as potent CRF1 receptor antagonists. Bioorg. Med. Chem. Lett. ,2004, 14, 3943-3947.
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[2] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical Function from a Few Good Reactions. Angew. Chem., Int. Ed. Engl. 2001, 40, 2004–2021.
[3] Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen,T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235–2246.
[4] Campiani, G.; Butini, S.; Gemma, S.; Nacci, V.; Fattorusso, C.; Catalanotti, B.; Giorgi, G.; Cagnotto, A.; Goegan, M.; Mennini, T.; Minetti, P.; Di Cesare, M. A.; Mastroianni, D.; Scafetta, N.; Galletti, B.; Stasi, M. A.; Castorina, M.; Pacifici, L.; Ghirardi, O.; Tinti, O.; Carminati, P. Pyrrolo[1,3]benzothiazepine-Based Atypical Antipsychotic Agents. Synthesis, Structure-Activity Relationship, Molecular Modeling, and Biological Studies J. Med. Chem. 2002, 45, 344.
[5] Campiani, G.; Butini, S.; Fattorusso, C.; Catalanotti, B.; Gemma, S.; Nacci, V.; Morelli, E.; Cagnotto, A.; Mereghetti, I.; Mennini, T.; Carli, M.; Minetti, P.; Di Cesare, M. A.; Mastroianni, D.; Scafetta, N.; Galletti, B.; Stasi, M. A.; Castorina, M.; Pacifici, L.; Vertechy, M.; Serio, S. D.; Ghirardi, O.; Tinti, O.; Carminati, P.; Pyrrolo [1,3]benzothiazepine- Based Serotonin and Dopamine Receptor Antagonists. Molecular Modeling, Further Structure-Activity Relationship Studies, and Identification of Novel Atypical Antipsychotic Agents J. Med. Chem. 2004, 47, 143.
[6] Mouithys-Mickalad, A.; Kauffmann, J.-M.; Petit, C.; Bruhwyler, J.; Liao, Y.; Wikstrom, H.; Damas, J.; Delarge, J.; Deby-Dupont, G.; Geczy, J.; Liegeois, J.-F. Electrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-like Analogues J. Med. Chem. 2001, 44, 769.
[7] Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein, F.; Kisliuk, R. L.; Synthesis of Classical, Three-Carbon-Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d]pyrimidine Analogues as Antifolates J. Med. Chem. 2004, 47, 6893.
[8] EP: 454436, 1991210230;U S: 5229382, 1993207220. (CA 1991, 116: 83703u)
[9] Chakrabarti.J.; Hotten. T. ; Pullar. I.;Steggles. D. ; Heteroareno- benzodiazepines. 6. Synthesis and pharmacological evaluation of CNS activities of [1,2,3] triazolo [4,5-b] [1,5]-, imidazolo[4,5,-b] [1,5]-, and pyrido [2,3-b] [1,5] benzodiazepines 10 – Piperazinyl -4H - 1,2,3 - triazolo [4,5-b] [1,5]benzodiazepines with neuroleptic activity J. Med. Chem. 1989, 32, 2375-2381
[10] Chakrabarti.J.; Hotten. T. ; Pullar. I.;Steggles. D. ; Heteroareno -benzodiazepines. Part 7. Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b] and [4,3-b] [1,5] benzodiazepines as potential anxiolytics J. Med. Chem. 1989,32, 2573-2582
[11] 仉文升,李安良.药物化学,北京:高等教育出版社,1999.
[12] McGuire,J.J.Curr.Pharm.Des.,2003,9,2593.
[13] Sanders, W.J.; Nienaber, V.L.; Lerner, C.G.; McCall, J. O. ; Merrick, S. M.; Swanson, S.J.; Harlan, J.E.; Stoll,V.S.; Stamper,G.F.; Betz,S.F.;Condroski,K.R.;Meadows,R.P.;Severin,J.M.;Walter,K.A.; Magdalinos, P.; Jakob, C.G.; Wagner, R.; Beutel, B.A. Discovery of Potent Inhibitors of Dihydroneopterin Aldolase Using CrystaLEAD High-Throughput X-ray Crystallographic Screening and Structure- Directed Lead Optimization. J. Med. Chem., 2004, 47, 1709-1718.
[14] Ridley, R. G. Nature , 2002, 415, 686
[15] Lee, C-H.; Daanen, J.F.; Jiang,M.; Yu,H.; Kohlhaas,K.L.; Alexander, K.; Jarvis,M.F.; Kowaluk,E.L.; Bhagwat,S.S. Synthesis and biological evaluation of Clitocine analogues as adenosine kinase inhibitors. Bioorg.Med.Chem.Lett., 2001, 11, 2419 - 2422.
[16] Perner,R.J.; Lee,C-H.; Jiang,M.; Gu,Y-G.; DiDomenico,S.; Bayburt, E. K.; Alexander, K.M.; Kohlhaas, K.L.; Jarvis, M.F.; Kowaluk, E.l.; Bhagwat, S. S. Synthesis and biological evaluation of 6,7-disubstituted 4-aminopyrido[2,3-d] pyridimines as adenosine kinase inhibitors. Bioorg. Med.Chem.Lett.,2005,15,2803-2807.
[17] Gomtsyan, A.; Didomenico, S.; Lee, C-H.; Stewart, A.O.; Bhagwat, S.S.; Kowaluk,E.A.; Jarvis,M.F. Synthesis and biological evaluation of pteridine and pyrazolopyrimidine based adenosine kinase inhibitors. Bioorg.Med.Chem.Lett., 2004, 14, 4165 - 4168.
[18] Gomtsyan,A.; Didomenico,S.; Lee,C-H.; Matulenko,M.A.; Elizabeth,K.K.; Kowaluk,E.A.Wismer,C.T.; Mikusa,J.; Yu,H.; Kohlhaas,K.; Matulenko,M.F.; Bhagwat,S.S. Design, Synthesis, and Structure -ActivityRelationship of 6-Alkynylpyrimidines as Potent Adenosine Kinase Inhibitors. J.Med.Chem.,2002,45,3639-3648.
[19] Sznaidman,M.L.; Meade,E.A.; Beauchamp,L.M.; Russell,S.; Tisdale,M.The antiinfluenza activity of pyrroo [2,3-d] pyrimidines. Bioorg. Med. Chem. Lett.,1996, 6(5), 565 - 568.
[20] Calderwood,D.J.; Johnston,D.N.; Munschauer,R.; Rafferty,P. Pyrrolo[2,3-d]pyrimidines Containing Diverse N-7 Substituents asPotentInhibitors of Lck. Bioorg. Med. Chem. Lett., 2002, 12, 1683 - 1686.
[21] Huang,C.Q.; Wilcoxen,K.M.; Grigoriadis,D.E.; McCarthy,J.R.; Chen.C. Design and synthesis of 3-(2-pyridyl) pyrazolo [1,5-a] pyrimidines as potent CRF1 receptor antagonists. Bioorg. Med. Chem. Lett. ,2004, 14, 3943-3947.
[22] Yuan, J.; Gulianello, M.Lombaert, S.D.; Brodbeck, R.; Kieltyka, A.; Hodgetts, K.J 3-Aryl pyrazolo [4,3-d] pyrimidine derivatives: nonpeptide CRF-1antagonists. Bioorg. Med. Chem. Lett., 2002, 12, 2133 - 2136.
[23] Connolly,C.J.C. Hamby,J. M.Schroeder,M.C.et al. Discovery and structure-activity studies of a novel series of pyrido [2,3-d] pyrimi -dinetyrosine kinase inhibitors. Bioorg. Med. Chem. Lett.,1997, 7 (18), 2415 - 2420.
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