新型6，7-二氢-5H-嘧啶并[4，5-e][1，4]二氮（艹卓）-8（9H）-酮的合成
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摘要
本论文阐述了新颖嘧啶并[4,5-e][1,4]二氮-8(9H)-酮衍生物的设计和合成工作,内容分为两章。
第一章主要是对嘧啶并[4,5-e][1,4]二氮酮类似物所具有的一些生物活性做了简单的介绍,据文献报道嘧啶并[4,5-e][1,4]二氮酮类似物兼具速激肽受体拮抗剂、半胱氨酸蛋白酶抑制剂、Raf蛋白酶抑制剂等生物活性。在文章中对其文献报道过的合成方法做了总结。
第二章中,开发了以分子内酰胺化为关键步骤构建新颖嘧啶并[4,5-e][1,4]二氮酮分子骨架的方法,合成了13个代表性化合物。
The dissertation deals with the preparation of 6,7-dihydro-5H-pyrimido [4,5-e][1,4]diazepin-8(9H)-one via intramolecular lactamization as the key reaction step. It is divided into two chapters.
In Chapter One, we summarized the biological activity and synthetic methods of pyrimidine fused diazepin-ones and their analogues. Pyrimidine and diazepin-ones are hybrided by two privileged structures, pyrimidine and diazepine. The bicyclic pyrimido[4,5-e][1,4]diazepines were reported to exhibit a variety of biological activities. For example, some derivatives are known as tachykinin receptor antagonists, anticonvulsant agents, cysteine protease inhibitors and raf kinase inhibitors.Despite interesting biological activities, the synthetic methods for pyrimido[4,5-e][1,4]diazepines are limited in the literature, we were only able to find one method for the synthesis of pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivative prepared by a intramolecular coupling reaction of 2-(((4-amino-6-(methoxy carbonyl)pyrimidin-5-yl)methyl)(methyl)amino)acetic acid.
In chapter two, practical methodology was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivatives. This synthetic strategy is based on intramolecular cyclization of amino acid ester substituted 4-aminopyrimidines to construct the pyrimido[4,5-e][1,4]diazepine core. However, under the ring closing conditions of sodium ethoxide, the desired results could not be achieved. In view of this, we modified the route, Finally, nucleophilic substitution of chloromethylpyrimidine by various racemic amino acid esters provided 13 cyclization precursors in high overall yields.
In the cyclization step, we explored sodium hydride/tetrahydrofuran and room temperature for the cyclization conditions and then achieved the desired cyclization product with moderate yield. The successful route is as follows: Reduction of the formyl group in compound 4-amino-6-chloropyrimidine-carbaldehyde with NaBH4 in MeOH furnished the corresponding alcohol derivatives (4-amino-6-Chloropyrimidin -5yl)methanol in 92% yields. Compound (4-amino-6-Chloropyrimidin-5yl)methanol was treated with SOCl2 to lead to chloromethylpyrimidine 6-chloro-5-(chloromethyl) pyrimidin-4-amine. Nucleophilic substitution of compound 6-chloro-5-(chloromethyl) pyrimidin-4-amine by various racemic amino acid esters provided the cyclization precursors in high overall yields. Treatment of cyclization precursors with NaH in THF resulted the ring closure product .With the current condition 13 pyrimido[4,5-e][1,4]diazepin-8(9H)-ones were produced in moderate to high yields. As expected, the ring closure reaction proceeded slower when the size of the R1 and R2 group was increased. The cyclization reaction tolerates various groups in the amino acid esters, such as alkyl, aromatic, hydrogen and hydroxyethyl groups.
第一章主要是对嘧啶并[4,5-e][1,4]二氮酮类似物所具有的一些生物活性做了简单的介绍,据文献报道嘧啶并[4,5-e][1,4]二氮酮类似物兼具速激肽受体拮抗剂、半胱氨酸蛋白酶抑制剂、Raf蛋白酶抑制剂等生物活性。在文章中对其文献报道过的合成方法做了总结。
第二章中,开发了以分子内酰胺化为关键步骤构建新颖嘧啶并[4,5-e][1,4]二氮酮分子骨架的方法,合成了13个代表性化合物。
The dissertation deals with the preparation of 6,7-dihydro-5H-pyrimido [4,5-e][1,4]diazepin-8(9H)-one via intramolecular lactamization as the key reaction step. It is divided into two chapters.
In Chapter One, we summarized the biological activity and synthetic methods of pyrimidine fused diazepin-ones and their analogues. Pyrimidine and diazepin-ones are hybrided by two privileged structures, pyrimidine and diazepine. The bicyclic pyrimido[4,5-e][1,4]diazepines were reported to exhibit a variety of biological activities. For example, some derivatives are known as tachykinin receptor antagonists, anticonvulsant agents, cysteine protease inhibitors and raf kinase inhibitors.Despite interesting biological activities, the synthetic methods for pyrimido[4,5-e][1,4]diazepines are limited in the literature, we were only able to find one method for the synthesis of pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivative prepared by a intramolecular coupling reaction of 2-(((4-amino-6-(methoxy carbonyl)pyrimidin-5-yl)methyl)(methyl)amino)acetic acid.
In chapter two, practical methodology was developed for the synthesis of 6,7-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-8(9H)-one derivatives. This synthetic strategy is based on intramolecular cyclization of amino acid ester substituted 4-aminopyrimidines to construct the pyrimido[4,5-e][1,4]diazepine core. However, under the ring closing conditions of sodium ethoxide, the desired results could not be achieved. In view of this, we modified the route, Finally, nucleophilic substitution of chloromethylpyrimidine by various racemic amino acid esters provided 13 cyclization precursors in high overall yields.
In the cyclization step, we explored sodium hydride/tetrahydrofuran and room temperature for the cyclization conditions and then achieved the desired cyclization product with moderate yield. The successful route is as follows: Reduction of the formyl group in compound 4-amino-6-chloropyrimidine-carbaldehyde with NaBH4 in MeOH furnished the corresponding alcohol derivatives (4-amino-6-Chloropyrimidin -5yl)methanol in 92% yields. Compound (4-amino-6-Chloropyrimidin-5yl)methanol was treated with SOCl2 to lead to chloromethylpyrimidine 6-chloro-5-(chloromethyl) pyrimidin-4-amine. Nucleophilic substitution of compound 6-chloro-5-(chloromethyl) pyrimidin-4-amine by various racemic amino acid esters provided the cyclization precursors in high overall yields. Treatment of cyclization precursors with NaH in THF resulted the ring closure product .With the current condition 13 pyrimido[4,5-e][1,4]diazepin-8(9H)-ones were produced in moderate to high yields. As expected, the ring closure reaction proceeded slower when the size of the R1 and R2 group was increased. The cyclization reaction tolerates various groups in the amino acid esters, such as alkyl, aromatic, hydrogen and hydroxyethyl groups.
引文
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[2] SETO S,TANIKA A,IKEDA M,IZAWA S. Design,synthesis and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,5]oxazocin-5-ones as NK1 antagonists [J]. Bioorganic & Medicinal Chemistry,2005,13:5717-5732.
[3] OHMOTO K, HISAICHI K,OKUMA M,TANAKA M,KAWADA N. Patent EP1724264A1, 2006.
[4] MAURER D, FIEBIGER E, REININGER B, EBNER C, PETZELBAUER P, SHI G P, CHAPMAN H A, STING G. Fc{epsilon} Receptor I on Dendritic Cells Delivers IgE-Bound Multivalent Antigens into a Cathepsin S-Dependent Pathway of MHC Class II Presentation [J]. The Journal of Immunology,1998, 161:2731-2739.
[5] TADEJA BEVEC, VERONIKA, GALINA PUNGERCIC, IZTOK DOLENC,VITO TURK.Major Histocompatibility Complex Class II-associated p41 Invariant Chain Fragment Is a Strong Inhibitor o f Lysosomal Cathepsin L [J].The Journal of Experimental Medicine,1996,183:1331-1338.
[6] GUO-PING SHI, REBECCA A R, BRYANT, RICHARD RIESE, STEVEN VERHELST, CHRISTOPH DRIESSEN, ZHENQIANG LI, DIETER BROMME, HIDDE L, PLOEGH, HAROLD A CHAPMAN. Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages [J]. The Journal of Experimental Medicine, 2000,191:1177-1185.
[7] RICHARD J RIESE, RICHARD N MITCHELL, JOSE A VILLADANGOS, GUO-PING SHI, JAMES T PALMER, ELENA R KARP, GEORGE T, DE SANCTIS, HIDDE L PLOEGH, HAROLD A CHAPMAN. Cathepsin S Activity Regulates Antigen Presentation and Immunity [J].The Journal of Clinical Investigation, 1998,101(11):2351–2363.
[8] YOICHI MAEKAWA, KUNISUKE HIMENO, HIROYUKI ISHIKAWA, HAJIME HISAEDA, TOHRU SAKAI, TERUKI DAINICHI, TETSUJI ASAO, ROBERT A GOOD, NOBUHIKO KATUNUMA. Switch of CD4+ T Cell Differentiation from Th2 to Th1 by Treatment with Cathepsin B Inhibitor in Experimental Leishmaniasis [J]. The Journal of immunology,1998, 161:2120-2127.
[9] CHARLES A DINARELLO, SHELDON M WOLFF. The Role of interleukin-1 in Disease [J]. The New England Journal of Medicine [J], 1993, 328:106-113.
[10] NORMAN J, YANG J, FINK G, et al. Severity and mortality of experimental pancreatitis are dependent on interleukin-1-converting enzyme. Journal of Interferon and CytokineResearch [J], 1997, 17:113–118.
[11] N FUJIOKA, A MUKAIDA, A HARADA, M AKIYAMA, T KASAHARA, K KUNO, A OOI, M MAI, K MATSUSIMA. Preparation of specific antibodies against murine 1L-Ira and the establishment of 1L-Ira as an endogenous regulator of bacteria-induced fuiminant hepatitis in mice [J]. Journal of Leukocyte Biology, 1995, 58(1):90-98.
[12]) HUI Y LAN, DAVID J NIKOLIC-PATERSON, WEI HUI, JAMES L VANNICE, ROBERT C ATKINS. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat [J]. Kidney International, 1995, 47:1303-1309.
[13] CAPO C, ZUGUN F, STEIN A, et al. Upregulation of tumor necrosis factor alpha and interleukin-1βin Q fever endocarditis [J]. Infection and Immunity, 1996, 64:1638-1642.
[14] MATSUMORI A, YAMADA T, SUZUKI H, MATOBA Y, SASAYAMA S, Increased circulating cytokines in patients with myocarditis and cardiomyopathy [J]. British Heart Journal, 1994, 72:561-566.
[15] S C HSIEH, C Y TSAI, K H SUN, Y Y TSAI, S T TSAI, S H HAN, H S YU, C L YU. Defective spontaneous and bacterial lipopolysaccharide-stimulated production of interleukin-1 receptor antagonist by polymorphonuclear neutrophils of patients with active systemic lupus erythematosus [J]. The British Journal of Rheumatology, 1995, 34:107-112.
[16] MIGNON A, ROUQUET N, FABRE M, MARTIN S, PAGES JC, DHAINAUT JF, KAHN A, BRIAND P, JOULIN V. LPS challenge in D-galactosamine-sensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock [J]. American Journal of Respiratory and Critical care Medicine, 1999, 159:1308-1315.
[17] JENNIFER C,BING G, ALEXEY I, JOHN HOWARD J, GNANSAMBANDAM K, ALRXEY L, HAIRUO P,NOEL P, BRIAN C R, HIROKO T, JEFFREY V, THOMAS W,ZHILI X. Patent US2009005359A1, 2009.
[18] ANNA DHGOSZ. A Novel Synthesis of Pyrimidobenzodiazepines [J]. Archiv der Pharmazie, 1990(Weinheim), 323:59-60.
[19] DLUGOSZ ANNA. Synthesis and biological activity of pyrimidobenzodiazepine derivatives. New ring systems: triazolo- and tetrazolo-pyrimidobenzodiazepines [J]. Pharmazie, 1995, 50(3):180–182.
[20] BRACCIO MARIO DI, GROSSI GIANCARLO, ROMA GIORGIO, VARGIU LAURA, MURA MASSIMO, MARONGIU MARIA ELENA. 1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues [J]. European Journal of Medicinal Chemistry, 2001, 36(11-12): 935–950.
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