摘要
先导化合物的发现及优化是新药研究的重要基础。组合化学能够快速、高效合成大量具有分子多样性的化合物,在先导化合物的发现和优化过程中发挥着重要的作用。“优势结构”(privileged structure)是指一类能够与多种生物受体强烈结合或者作用的分子结构,它表现出“似先导化合物”、“似药”等性质。组合合成具有“优势结构”的化合物有助于提高发现先导化合物的概率。
苯并硫氮杂(艹卓)和苯并二氮杂(艹卓)都具有很广泛的生物活性,都属于优势结构。本论文以1,5-二氟-2,4-二硝基苯(DFDNB)为起始原料,探索并优化了液相平行合成1,5-苯并硫氮杂(艹卓)-4-酮和1,5-苯并二氮杂(艹卓)-2-酮化学库的方法。
1 1,5-苯并硫氮杂(艹卓)-4-酮
经定量亲核取代、硫醚氧化、芳香间二硝基还原、皂化和分子内关环等反应合成了重要基本分子骨架1,5-苯并硫氮杂(艹卓)-4-酮和1,1-二氧-1,5-苯并硫氮杂(艹卓)-4-酮母环,进而以它们为基础,衍生出一系列“取代多样性”的二环骨架。所得化合物具有三个或四个多样性位点。
苯并咪唑、苯并羰基咪唑和苯并硫代羰基咪唑都具有广泛的生物活性,将它们稠合到优势骨架1,5-苯并硫氮杂(艹卓)-4-酮中,有可能增加发现新先导化合物的机会。以中间体1,1-二氧-1,5-苯并硫氮杂(艹卓)-4-酮为原料,分别和醛、三光气、二硫化碳反应得到三类新的三环骨架。
本文中合成了1,5-苯并硫氮杂(艹卓)-4-酮类化合物109个。对所合成的化合物进行初步药理活性筛选,结果表明:化合物B28具有维甲酸受体拮抗作用,B13、B22和B36具有抗流感病毒活性。因此我们对这些化合物进行优化,制备了一个含有42个纯化合物的亚库。其活性评价正在进行中。
2 1,5-苯并二氮杂(艹卓)-2-酮
利用各种伯氨与丙烯酸甲酯进行共轭加成得到β-氨基酸酯,再经亲核取代、硫醚的氧化、硝基的还原、皂化、缩合等反应,合成了5,7,8-三取代的1,5-苯并二氮杂(艹卓)-2-酮类化合物。此外,用取代的β-氨基酸来进行亲核取代,可以得到具有四个或五个多样性位点的1,5-苯并二氮杂(艹卓)-2-酮类化合物。利用这两种方法我们合成了含有55个纯化合物的1,5-苯并二氮杂(艹卓)-2-酮化学库。这类化合物的活性评价正在进行中。
本论文中优化出的合成路线具有反应条件温和、反应速度快、收率高等特点,利用这些方法可以快速合成具有结构多样性的化合物库。
所有合成的化合物均经MS(LC-MS或HRMS)及NMR确证结构。并对其中一个化合物通过X-单晶衍射的方法确认了精确结构。
The number of lead compounds is the vital base for drug discovery. Combinatorial chemistry, which can rapidly provide large number of compounds, has been recognized as a powerful tool for both identification and optimization of lead compounds. Privileged structures, which have become a popular theme in medicinal chemistry recently, present a class of molecules capable of binding to or effect on multiple biological receptors with high affinity and demonstrate "drug-like" or "lead-like" properties. Therefore, the exploration of synthesis of privileged structures may provide more chances for discovery and optimization of novel lead compounds.
Benzothiazepine and benzodiazepine are both privileged structures eliciting broad spectrum of biological activities. Practical and efficient new solution-phase parallel methods have been developed in this thesis for the synthesis of 1,5-benzothiazepin-4-ones and 1,5-benzodiazepin-2-ones with a large variety of substituents starting from 1,5-difluoro-2,4-dinitrobenzene (DFDNB).
1. Solution-Phase Parallel Synthesis of 1,5-Benzothiazepin-4-ones
The synthetic route mainly includes quantitatively nucleophilic substitution, oxidation of sulfide, reduction of aromatic dinitro groups and cyclization, yielding two important scaffolds: 1,5-benzothiazepin-4-one and 1,1-dioxo-1,5-benzothiazepin-4-one. The benzothiazepine skeleton possesses three or four points of diversity and thus affords new opportunities for identification of hits in drug lead discovery and optimization.
Bnezimidazole, benzimidazolone and thio-benzimidazole are all privileged structures too, which also possess extensively biological activities. Therefore, integrating one of these privileged pharmacophores with 1,5-benzothiazepin-4-one would benefit for the more opportunities to discover new lead compounds. Treatment of 1,1-dioxo-1,5-benzothiazepin-4-one with aldehydes, triphosgene or carbon disulfide eventurely, three novel tricycles were developed respectively.
A library containing 109 single compounds were synthesized. Primary screening indicated that compound B28 elicit the retinoic acid receptor antagonist property and compounds B13, B22 and B36 exhibit anti flu property. A sub-library containing 42 pure compounds was then synthesized to optimize the activity. The data will be reported somewhere else soon.
2. Solution-Phase Parallel Synthesis of 1,5-Benzodiazepin-2-ones
The requisiteβ-amino esters were gained after reaction of various primary amines with methyl acrylate. They, together with several commercial availableβ-amino acids, were then used herein to successfully explore a solution-phase parallel synthetic method of 1,5-benzodiazepin-2-ones with four or five diversity points. A library containing 55 individual compounds was prepared.
These routes permit us to introduce a great molecular diversity at substitution level of 1,5-benzothiazepin-4-ones and 1,5-benzodiazepin-2-ones under mild reaction conditions. Large number of derivatives is able to be rapidly synthesized in excellent purity and high yield using these methods.
All the compounds synthesized in this thesis were fully characterized by MS (LC-MS or HRMS) and NMR. One of them is further determined by X-ray diffraction.
引文
1.刘刚,萧晓毅.《新药研究中的组合化学》,北京,科学出版社,2003.
2.Thompson,L.A.;Ellman,J.A.Chem.Rev.1996,96,555.
3.Golebiiowski,A.;Klopfenetein,S.R.Curr.Opin.Chem.Biol.2001,5,273.
4.Fruchtel,J.S.;Jung,G.Angew.Chem.Int.Ed.1996,35,17.
5.Evans,B.E.;Rittle,K.E.;Bock,M.G.J.Med.Chem.1988,31,2235.
6.Horton,D.A.;Bourne,G.T.;Smythe,M.L.Chem.Rev.2003,103,893.
7.Schwarz,M.;Tumelty,D.JOrg Chem.1999,64,2219o2231.
8.Floyd,D.M.;Kimball,D.S.;Krapcho,J.et al.JMed Chem.1992,35,756-772.
9.Hashimoto,K.;Watanabe,K.;Mochizuki,S.et al.Jpn J Pharmacol.1989,51,475-482.
10.Pelc,L.R.;Farber,N.E.;Warltier,D.C.et al.J Cardiovasc Pharmacol.1959,13,586-593.
11.Farber,N.E.;Gross,G.J.JPharmacol Exp Ther.1989,248,39-43.
12.Hester,R.K.;Shibata,S.Cardiovasc Drugs Ther.1990,4,1345-1354.
13.Inoue,H.;Konda,M.;Hashiyama,T.et al.J Med Chem.1991,34,675-687.
14.Skiles,J.W.;Sorcek,R.Jacober,S.et al.Bioorg Med Chem Lett.1993,3,773.
15.Julian,G.;David,J.L.;Livingston,D.J.et al.Inhibitors of interleukin-1 beta converting enzymepct.[P].WO9824804(1998)
16.Buhlmayer,P.;Furet,P.Benzazepinone derivatives[P].WO9413651-A1,(1994)
17.Freidinger,R.M.Med Res Rev,1989,9,271-290.
18.Liao,Y.;Venhuis,B.J.;Rodenhuis,N.J Med Chem,1999,42,2235-2244.
19.Garofalo,A.;Balconi,G.;Botta,M.;et al.J Med Chem.1993,28,213-220.
20.Santo,R.;Costi,R.Il Farmaco.2005,60,385-392.
21.Urbanski,M.J.;Chen,R.H.;Demarest,K.T.Bioorg.Med.Chem.Lett.2003,13,4031-4034.
22.Huang,P.;Loew,G.H.;Funamizu,H.;et al.J Med Chem.2001,44,4082-4091.
23.Yamamoto,H.;Asai,H.Chem Pharm Bull,1986,34,3844-3853.
24.Ambrogi,V.;Grandolini,G.Synthesis,1987,8,724.
25.Schwartz,A.;Madan,P.B.;Mohacsi,E.et al.J Org Chem.1992,57,851-856.
26.Kaye,P.T.;Mphahlele,M.J.Synth Commun,1995,25,1495-1509.
27.Supuran,C.T.;Scozzafava,A.;Casini,A.Med.Res.Rev.2003,23,146.
28.Boyd,A.E.Diabetes.1988,37,847.
29.Supuran,C.T.;Conroy,C.W.;Maren,T.H.Eur.J.Med.Chem.1996,31,843.
30.Supuran,C.T.;Scozzafava,A.;Clare,W.Med.Res.Rev.2002,23,329.
31.Supuran,C.T.;Scozzafava,A.;Casini,A.Med.Res.Rev.2003,23,535.
32.Roberts,P.J.;Castanr,J.Drugs Fut.1979,4,206.
33.DiJoseph,J.F.;Taylor,J.A.;Mir,G.N.Life Sci.1984,35,1031-1042.
34.Bach,P.;Steinbeck,G.J.Cardiovasc.Pharmacol.1988,12,637-642.
35.Muramoto,J.;Hotokebuchi,N.;Nishi,K.Arch.Int.Pharmacodyn.Ther.1991,312,27-38.
36.Helix,N.;Strobaek,D.;Dahl,B.H.;Christophersen,P.J.Membr.Biol.2003,196,83-94.
37.Bruce,L.J.;Robinson,H.C.;Guizouam,H.et al.Nat.Genet.2005,37,1258-1263.
38.Yamashita,K.;Minatoguchi,S.;Uno,Y.;Kariya,T.et al.Clin.Exp.Pharmacol.Physiol.2000,27,172-178.
39.Jordan,A.M.;Khan,T.H.;Malkin,H.et al.Bioorg.Med.Chem.2002,10,2625-2633.
40.Takenaga,T.;Isozaki,M.Drugs Fut.1993,18,909.
41.Bloom,J.D.;Ross,A.A.;O'Hara,B.M.et al.EP 1137632.
42.Nakamura,M.;Yamaguchi,M.;Sakai,O.Bioorg.Med.Chem.2003,11,1371.
43.Maden,P.;Knudsen,L.B.;Wiberg,F.C.et al.J.Med.Chem.1998,41,5150.
44.Palmer,B.D.;Kraker,A.J.;Hartl,B.G.;et al.J.Med.Chem.1999,42,2373.
45.Phillips,G..B.;Wei,G.P.Tetrahedron Lett.1996,37,4887.
46.Salluja,S.;Zou,R.;Drach,J.C.et al.J.Med.Chem.1996,39,881.
47.Jin,S.;Kim,J.S.;Sim,S.P.Bioorg.Med.Chem.Lett.2000,10,719.
48.周学良等编.《药物》,北京,化学工业出版社,2003.
49.L-Fmoc-Cys-OH是商业购买的L-Fmoc-Cys(Trt)-OH经三氟乙酸(TFA)脱除Trityl保护基得到的,见实验部分.
50.Johnson,C.R.Tetrahedron.1969,25,5649.
51.Brougham,P.;Cooper,M.S.;Cummerson,D.A.;et al.Sythesis 1987,1015.
52.Filby,W.G..;Guenther,K.;Penzhorn,R.D.J.Org.Chem.1973,38,4070.
53.王占国.博士学位论文.2005.
54.Fox,B.A.;Threfall,T.L.Org.Synth.,Coll.1973,5,346.
55.Ono,A.;Terasaki,S.;Tsuruoka,Y.Chem.Ind.(London).1983,477.
56.Petrini,M.;Ballini,R.;Rosini,G.Synthesis.1987,713.
57.He,Y.;Zhao,H.;Pan,X.;et al.Synth.Commun.1989,19,3047.
58.Hughes,I.;Tetrahedron Lett.1996,37,7595.
59.Gillespie,H.B.;Spano,F.;Graff,S.J.Org.Chem.1960,25,942.
60.Babler,J.H.;Sarussi,S.J.Synth.Commun.1981,11,925.
61.Mayer,J.P.;Zhang,J.W.;Bjergarde,K.;et al.Tetrahedron Lett.1996,37,8081.
62.Wei,G..P.;Phillips,G.B.Tetrahedron Lett.1998,39,179.
63.Terpko,M.O.;Heck,R.F.;J.Org.Chem.1980,45,4992.
64.Ayyangar,N.R.;Lugade,A.G.;Nikrad,P.V.;et al.Synthesis.1981,640.
65.Barrett,A.G..M.;Spilling,C.D.;Tetrahedron Lett.1988,29,5733.
66.Ram,S.;Ehrenkaufer,R.E.Tetrahedron Lett.1984,25,3415.
67.Inoue,H.;Konda,M.;Hashiyama,T.;et al.Chem.Pharm.Bull 1997,45,1008.
68.Carpino,L.A.;Williams,J.R.J.Chem.Soc.,Chem.Comm.1978,450-451.
69.Carpino,L.A.;Mansour,E.M.E.Cheng,C.H.et al.J.Org.Chem.1983,48,661-665.
70.Chi,Y.C.;Sun,C.M.Synlett.2000,591.
71.Vanden Eynde,J.J.;Delfosse,F.;Lor,P.;et al.Tetrahedron.1995,51,5813.
72.Beaulieu,P.L.;Hache,B.;Moos,E.Synthesis.2003,1683.
73.Li,L.;Liu,G.;Wang,Z.G.;et aI.J.Comb.Chem.2004,6,811.
74.Pan,P.C.;Sun,C.M.Tetrahedron Lett.1999,40,6443.
75.Raju,B.;Nguyen,N.;Holland,G.W.J.Comb.Chem.2002,4,320.
76.Eckert,H.;Forster,B.Angew.Chem.Int.Ed.Engl.1987,26,894.
77.Shingo,M.;Eiji,N.;Takashi,T.;Tetrahedron Lett.2001,42,1749.
78.Lee,J.;Gauthier,D.;Rivero,R.A.Tetrahedron Lett.1998,39,201.
1.郭宗儒.《药物分子设计》,北京,科学出版社,2005.
2.Hofmann,H.P.;Ereiskott,H.;Kretzschmar,R.et al.Arch.Pharmacol.1982,32(suppl),R44.
3.M(u|¨)ller,W.E.;Groh,B.;Bub,O.Pharmacopsychiatry.1986,10,314-315.
4.Nicholson,A.N.;Stone,B.M.;Clarke,C.H.Br J Clin Pharmacol.1977,4,567-572.
5.Kruse,H.Drug Dev.Res.1982,2(suppl 1),145-151.
6.Eltze,M.;G6nne,S.;Riedel,R.;Schlotke,B.et al.Eur.J.Pharmacol.1985,112,211-215.
7.Herpin,T.F.;Van Kirk,K.G.;Salvino,J.M.et al.J.Comb.Chem.2000,2,513-521.
8.Claremon,D.A.;Frieidinger,R.M.;Liverton,N.et al.PCT Int.Appl.WO 9640656.
9.Angelo,J.;Maddaluno,J.J.Am.Chem.SOC.1986,108,8 112-8114.
10.Mikovik,I.V.;Roglik,G.M.;Ivanovik,M.D.;et al.J.Chem.Soc.,Perkin Trans.I,1996,16,2041-2050.
[1]CAMPIANI G,NACCI V,BECHELLI S,et al.New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure[J].J Med Chem,1998,41(20):3763-3772.
[2] CAMPIANI G, BUTINI S, GEMMA S, et al. Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents, synthesis, structure-activity relationship, molecular modeling, and biological studies[J]. J Med Chem, 2002,45(2): 344-359.
[3] CAMPIANI G, BUTINI S, FATTORUSSO C, et al.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]. J Med Chem, 2004,47(1):143-157.
[4] LEHNART SE, TERRENOIRE C, REIKEN S, et al. Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias[J]. PNAS,2006, 103(20):7906-7910.
[5] LISY O, BURNETT JC Jr. New cardioprotective agent K201 is natriuretic and glomerular filtration rate enhancing[J]. Circulation, 2006, 113(2):246-251.
[6] CHE XF, NAKAJIMAA Y, SUMIZAWA T, et al. Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519[J]. Cancer Letters, 2002, 187(1): 111-119.
[7] GRUNEWALD GL, DAHANULKAR VH, CHING P, et al. Effect of Ring Size or an Additional Heteroatom on the Potency and Selectivity of Bicyclic Benzylamine-Type Inhibitors of Phenylethanolamine N-Methyltransferase[J]. J Med Chem, 1996, 39(18): 3539-3546.
[8] AXELROD J. Purification and Properties of Phenylethanolamine-N-methyl Transferase[J]. J Biol Chem, 1962, 237: 1657-1660.
[9] PERRY BD, STOLK JM, VANTINI G, et al. Strain difference in rat brain epinephrine synthesis regulation of a-adrenergic receptor number by epinephrine[J]. Science, 1983, 221(4617):1297-1299.
[10] CHOW SA, VINCENT KA, ELLISON V, et al. Reversal of integration and DNA splicing mediated by integrase of human immunodeficiency virus[J]. Science,1992, 255(5045): 723-6.
[11] NEAMATI N, TURPIN JA, WINSLOW HE, et al. Thiazolothiazepine Inhibitors of HIV-1 Integrase[J]. J Med Chem, 1999,42(17): 3334-3341.
[12] PEI YZ, LILLY MJ, OWEN D. Efficient Syntheses of Benzothiazepines as Antagonists for the Mitochondrial Sodium-Calcium Exchanger: Potential Therapeutics for Type II Diabetes [J]. J Org Chem, 2003, 68(1): 92-103.
[13] MIKI T, KORI M, FUJISHIMA A, et al. Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase[J]. Bioorganic & Medicinal Chemistry, 2002, 10(2): 385-400.
[14] EVANS BE, RITTLE KE, BOCK MG et al. Methods for drug discovery:development of potent, selective, orally effective cholecystokinin antagonists [J].J Med Chem, 1988, 31(12): 2235.
[15] SCHWARZ M, TUMELTY D. Solid-Phase Synthesis of 3,5-Disubstituted 2,3-Dihydro-1,5- benzothiazepin- 4(5H)-ones[J]. J Org Chem, 1999, 64(7):2219-2231.
[16] FLOYD DM, KIMBALL DS, KRAPCHO J, et al. Benzazepinone calcium channel blockers. 2. Structure activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones[J]. J Med Chem, 1992, 35(4): 756-772.
[17] SHIMIZU N, KISHIOKA S, MAEDA T, et al. Role of pharmacokinetic effects in the potentiation of morphine analgesia by L-type calcium channel blockers in mice[J]. J Pharmacol Sci, 2004, 94: 240-245
[18] SALADI RN, COHEN SR, PHELPS RG, et al. Diltiazem induces severe photodistributed hyperpigmentation[J]. Arch Dermatol, 2006, 142:206-210.
[19] HASHIMOTO K, WATANABE K, MOCHIZUKI S, et al. Effect of KT-362, a new Na and Ca influx and Ca release inhibitor, on canine ventricular arrhythmias[J]. Jpn J Pharmacol, 1989, 51(4): 475-482.
[20] HESTER RK, SHIBATA S. KT-362 related effects on intracellular calcium release and associated clinical potential: arrhythmias, myocardial ischemia and hypertension[J].Cardiovasc Drugs Ther, 1990,4(5): 1345-1354.
[21] INOUE H, KONDA M, HASHIYAMA T, et al. Synthesis of halogen-substituted 1,5-benzothiazepine derivatives and their vasodilating and hypotensive activities[J]. J Med Chem, 1991, 34(2): 675-687.
[22] SKILES JW, SORCEK R, JACOBER S, et al. Elastase inhibitors containing conformationally restricted lactams as P3-P2 dipeptide replacements[J]. Bioorg Med Chem Lett, 1993, 3(4): 773.
[23] JULIAN G, DAVID JL, LIVINGSTON DJ, et al. Inhibitors of interleukin-1 beta converting enzymepct. [P]. WO9824804 (1998)
[24] ONDETTI MA, RUBIN B, CUSHMAN DW, et al. Design of specific inhibitors of angiotensin converting enzyme: new class of orally active antihypertensive agents[J]. Science, 1977,196(4288): 441-443.
[25] PATCHETT AA, HARRIS E, TRISTRAM EW, et al. A new class of angiotensin-converting enzyme inhibitors [J]. Nature, 1980, 288(20): 280-282.
[26] PETRILLO EW, ONDETTI MA. Angiotensin-converting enzyme inhibitors: medicinal chemistry and biological actions[J]. Med. Res. Rev. 1982, 2(1): 1-41.
[27] WATTEY JWH. 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids [P].US4410520,1983.
[28] ITOH K, KORI M, INADA Y, et al. Synthesis and angiotensin converting enzyme inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives[J].Chem Pharm Bull, 1986,34(5): 2078-2089.
[29] BRAUNS T, PRINZ H, KIMBALL DS, et al. L-type calcium channels: binding domains for dihydropyridines and benzothiazepines are located in close proximity to each other[J]. Biochemistry, 1997, 36(12): 3625-3631.
[30] NAGEL A. Benzothiazepine and benzoxazepine derivatives as cholecystokinin receptor antagonists. [P].WO9401421-Al,1994.
[31] BUHLMAYER P, FURET P. Benzazepinone derivatives[P].WO9413651-A1,1994
[32] FREIDINGER RM. Cholecystokinin and gastrin antagonists[J]. Med Res Rev,1989, 9(3): 271-290.
[33] LIAO Y, VENHUIS BJ, RODENHUIS N, et al. New (Sulfonyloxy)piperazinyldibenzazepines as Potential Atypical Antipsychotics[J].J Med Chem, 1999, 42(12): 2235-2244.
[34] NAGAO T, SATO M, NAKAJIMA H, et al. Studies on a new 1,5-benzothiazepine derivative(CRD-401) [J]. Chem Pharm Bull, 1973, 21(1):92-97.
[35] NARITA M, GAINO M, SUZUKI T, et al. Synthesis and pharmacological properties of azido derivatives of 1,5-benzothiazepine Ca antagonist [J]. Chem Pharm Bull, 1990, 38(2): 407-410.
[36] AMBLARD M, DAFFIX I, BEDOS P, et al. Design and Synthesis of Potent Bradykinin Agonists Containing a Benzothiazepine Moiety[J]. J Med Chem,1999,42(20): 4185-4192.
[37] HESS JF, BORKOWSKI JA, YOUNG GS, et al. Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor[J]. Biochem Biophys Res Commun, 1992, 184(1): 260-268.
[38] REGOLI D, BARABE J. Pharmacology of bradykinin and related kinins[J].Pharmacol Rev 1980, 32(1): 1-46.
[39] GAROFALO A, BALCONI G, BOTTA M, et al. Thioanalogues of anti-tumor antibiotics. II. Synthesis and preliminary in vitro cytotoxicity evaluation of tricyclic [l,4]benzothiazepine derivatives[J]. J Med Chem, 1993, 28(3): 213-220.
[40] DISANTO R, COSTI, R. 2H-pyrrolo[3,4-b][1,5]benzothiazepine derivatives as potential inhibitors of HIV-1 reverse transcriptasw[J]. II Farmaco, 2005, 60(5):385-392.
[41] URBANSKI MJ, CHEN RH, DEMAREST KT. 2,5-Disubstituted 3,4-dihydro-2H-benzo[b][1,4] thiazepines as potent and selective V2 arginine vasopressin receptor antagonists[J]. Bioorganic & Medicinal Chemistry Letters,2003, 13(22): 4031-4034.
[42] MARCACCINI S, MIGUEL D,TORROBA T, et al. 1,4-Thiazepines,1,4-Benzothiazepin-5-ones, and 1,4-Benzothioxepin Orthoamides via Multicomponent Reactions of Isocyanides[J]. J Org Chem, 2003, 68(8):3315-3318.
[43] LARON Z. Growth hormone secretagogues. Clinical experience and therapeutic potential[J].Drugs, 1995, 50(4): 595-601.
[44] HUANG P, LOEW GH, FUNAMIZU H, et al. Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues[J].J Med Chem,2001,44(24):4082-4091.
[45]YAMAMOTO H,ASAI H.Effects of BTM-1086 on ulceration,gastric secretion and mucosal blood flow in experimental animals[J].Chem Pharm Bull,1986,34(9):3844-3853.
[46]YAMAMOTO H,NAKAMURA Y,KUNOH Y,et al.Antiulcer effect of BTM-1086 in experimental animals[J].Jpn J Pharmacol,1986,41(3):283-292.
[47]MICHELI F,DEGIORGIS F,FERIANI A,et al.A combinatorial approach to [1,5]benzothiazepine derivatives as potential antibacterial agents[J].J.Comb Chem,2001,3(2):224-228.
[48]TAKAYANAGI I,NAKAZO K,KIZAWA Y.Possible mechanisms of a new type of antispasmodic drug,BTM- 1042(cis-(-)-2,3-dihydro-3-(4-methyl-piperazinyl)methyl-2-phenyl-1,5-benzothiazepin-4(SH)-one dihydrochloride)[J].Jpn J Pharmacol,1980,30(5):647-654.
[49]KANTOCI D,MURRAY ED,QUIGGLE DD,et al.Endogenous natriuretic factors.5.synthesis and biological activity of a natriuretic metabolite of diltiazem and its derivatives[J].J Med Chem,1996,39(6):1196-1200.