臺灣博碩士論文加值系統

本研究在探討arylpiperazine benzothiazinone 1,1-dioxide (A)與arylpiperazinylalkyl quinazolinone (B)兩系列衍生物對α1A接受器拮抗的選擇性潛力與藥理活性之評估。A系列採3,4-dimethoxyphenylacetic acid (25) 為起始物，加入催化量的濃硫酸在甲醇中加熱迴流進行酯化得3,4-dimethoxy-1-(carbomethoxy methyl)benzene (26)。化合物 26 與chlorosulfonic acid在0至-5℃下進行chlorosulfonation所得的4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonyl chloride (27)， 隨後與4-(2-methoxyphenyl)piperazinylalkylamines (23a-c)及4-(2-pyrimidinyl)- piperazinylalkylamines (24a-c)反應製得N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carbomethoxy- methylbenzenesulfonamides (28a-c)及N-((4-(2-pyrimidinyl)piperazinyl)- alkyl)-4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonamides (31a-c)。 化合物 28a-c及 31a-c經氫氧化鈉在甲醇中加熱迴流水解成N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxy-methylbenzenesulfonamides (29a-c) 及N-((4-(2-pyrimidinyl)- piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzenesulfonamides (32a-c)。 接著以 phosporus oxychloride 在室溫下苯中進行環化反應形成 N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (30a-c)及N-((4-(2-pyrimidinyl)-piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (33a-c)。
而B系列以2-aminobenzophenone (36) 為起始物，在195 ℃與尿素反應可得4-phenylquinazolin-2-one (37)。 而化合物 37 與p-methoxybenzyl chloride (38)在鹼中形成1-(p-methoxybenzyl)-4-phenylquinazolin-2-one (39)。 化合物 39 再以sodium cyanoborohydride還原1-(p-methoxybenzyl)-4-phenyl-3,4-dihydro-quinazolin-2-one (40) 得。
經由初步的藥理活性測試顯示已合成化合物 30a-c 與 33c 對於α1A、α1B、D1、D2L、D2S 與 5-HT1A 接受器皆有親和力，另外發現碳鏈長度的不同亦影響其對接受器的親和力與選擇性。而又以化合物 30b 對 α1A接受器具有相當高的活性，其IC50 到達 107.2 pM 。此外，化合物 30b 對 α1B/α1A、5-HT1A/α1A、D1/α1A、D2S/α1A 與 D2L /α1A的selectivity ratio分別為 118、12、6640、1538 與 6006 倍。
因此，化合物 30b值得我進一步研究探討其結構與活性間之關係。

This study is aimed to synthesize two series of compounds, namely, substituted arylpiperazinyl benzothiazinone 1,1-dioxide (A) and substituted arylpiperazinyl quinazolinone (B) derivatives for evaluation of α1A adrenoceptor selectivity and are considered to be potential for treatment of benign prostatic hyperplasia (BPH).
The synthesis of compounds in A series started from esterification of 3,4-dimethoxyphenyl acetic acid (25) in methanol with a catalytic amount of concentrated sulfuric acid to give 3,4-dimethoxy-1-(carbomethoxymethyl)benzene (26). Then 26 underwent chloro-sulfonation with chlorosulfonic acid to afford 4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonyl chloride (27). Compound 27 was treated with (2-methoxyphenyl)piperazinylalkyl amines (23a-c) and (2-pyrimidinyl)piperazinylalkyl amines (24a-c) to give N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carbomethoxymethyl benzenesulfonamides (28a-c) and N-((4-(2-pyrimidinyl)piperazinyl) alkyl)-4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonamides (31a-c), respectively. The hydrolysis of 28a-c and 31a-c with methanolic NaOH afforded N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzenesulfonamides (29a-c) and N-((4-(2-pyrimidinyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzene sulfonamides (32a-c), respectively. Compounds 29a-c and 32a-c were then treated with phosphorus oxychloride to provide N-((4-(2-methoxyphenyl)piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (30a-c) and N-((4-(2-pyrimidinyl)piperazinyl)-alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (33a-c), respectively.
For the synthesis of compounds in series B, 2-aminobenzophenone (36) and urea underwent condensation at 195 ℃ afford 4-phenyl quinazolin-2-one (37). The reaction of 37 reacted with p-methoxybenzyl chloride (38) gave 1-(p-methoxybenzyl)-4-phenyl- quinazolin-2-one (39) which was then treated with sodium cyanoborohydride to provide 1-(p-methoxy benzyl)-4-phenyl-3,4-dihydroquinazolin-2-one (40).
30a-c and 33c were subjected to different receptor binding assays. The preliminary results revealed that designed target compound 30a-c and 33c possess affinity toward α1A、α1B、 D1、 D2S、 D2L and 5-HT1A receptors. The different carbon chain length between the heterocycle moiety and arylpiperazine also affect the affinity and selectivity among different receptors. Among these compounds, compound 30b possess high affinity toward α1A receptors with IC50 = 107.2 pM and the selectivity ratio for α1B 、5-HT1A 、D1 、 D2S and D2L receptors is 118 、 12 、 6640 、 1538 and 6006, respectively.

目 錄
壹、緒論 1
(a) 2,4-Diaminoquinazoline類衍生物 2
(b) Piperidine類衍生物 3
(c) Piperazine類衍生物 4
(d) Phenethylamines and related compounds 5
貳、實驗動機與目的 7
一、設計構想 7
二、合成策略 11
(Ⅰ) Arylpiperazinylalkyl amines之合成 11
(Ⅱ) Sulfonamides 與 1, 2-benzothiazinone類標的化合物之合成 12
(Ⅲ) Quinazolinone類標的化合物之合成 13
參、結果與討論 15
一、合成部分： 15
(Ⅰ) Synthesis of arylpiperazinylalkyl amines 17
1. N-((4-(2-Methoxyphenyl)piperazinyl)alkyl)phthalimides (21a-c)與N-((4-(2-pyrimidinyl)piperazinyl)alkyl)- phthalimides (22a-c) 之合成 17
2. N-((4-(2-Methoxyphenyl)piperazinylalkylamines (23a-c) 與 N-((4-(2-pyrimidinyl)piperazinyl)alkylamines (24a-c) 之合成 18
(Ⅱ) Synthesis of sulfonamides and target compounds 20
1. 1-(carbomethoxymethyl)-3,4-dimethoxybenzene (26) 之合成 20
2. 2-Carbomethoxymethyl-4,5-dimethoxybenzenesulfonyl chloride (27) 之合成 21
3.N-((4-(2-Methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonamides (28a-c) 與N-((4-(2-pyrimidinyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carbomethoxymethylbenzenesulfonamides (31a-c) 之合成 23
4.N-((4-(2-Methoxyphenyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzenesulfonamides (29a-c) 與 N-((4-(2-pyrimidinyl)piperazinyl)alkyl)-4,5-dimethoxy-2-carboxymethylbenzenesulfonamides (32a-c) 之合成 25
5.N-((4-(2-Methoxyphenyl)piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (30a-c)與 N-((4-(2-pyrimidinyl)piperazinyl)alkyl)-6,7-dimethoxy-2H-1,2-benzothiazin-(4H)-3-one 1,1-dioxide (33a-c) 之合成 26
(Ⅲ) Quinazolinone 之合成 29
1. 4-Phenylquinazolin-2(1H)-one (37) 之合成 29
2. 1-(p-Methoxybenzyl)-4-phenylquinazolin-2-one (39) 之合成 30
3. 1-(p-Methoxybenzyl)-4-phenyl-3,4-dihydroquinazolin-2(1H)-one (40) 之合成 31
4. 3-(Bromoalkyl)-1-(p-methoxybenzyl)-4-phenyl-3,4-dihydroquinazolin-2-one (42a-c) 之合成 32
二、藥理活性部分 35
肆、結論 38
伍、實驗部分 40
陸、參考資料 59
圖 目 錄
Figure 1. 2,4-Diaminoquinazoline Derivatives 3
Figure 2. Piperidine Derivatives 4
Figure 3. Arylpiperazine Derivatives 5
Figure 4. Phenethylamines and related compounds 6
Figure 5. Isosterism of Ipsapirone (12) and Benzothiazinone Derivatives 9
Figure 6. Design of Quinazolinones 10
Figure 7. Retrosynthesis of Alkylamines 11
Figure 8. Retrosynthetic Route of Target Compounds in Series A 12
Figure 9. Retrosynthetic Route of Target Compounds in Series B 14
Figure 10. Synthesis of Target Compounds 15
Figure 11. Synthesis of Target Compounds 16
Figure 12. Formation of Side Product 34 during Deprotection of Phthalimides 20
Figure 13. Mechanism of Side Product 35 Formation 22
Figure 14. Formation of Side Products in Chlorosulfonation 23
Figure 15. Formation of Side Product 47 33
表 目 錄
Table 1. α1A-Antagonists and their activities 2
Table 2. Activity of Target Compounds in vitro 37
反 應 圖 示 目 錄
Scheme 1. Synthesis of 21a-c and 22a-c 18
Scheme 2. Synthesis of 23a-c and 24a-c 19
Scheme 3. Synthesis of 26 21
Scheme 4. Synthesis of 27 22
Scheme 5. Synthesis of 28a-c and 31a-c 24
Scheme 6. Synthesis of 29a-c and 32a-c 25
Scheme 7. Synthesis of 30a-c and 32a-c 27
Scheme 8. Synthesis of 37 29
Scheme 9. Synthesis of 39 30
Scheme 10. Synthesis of 40 32
Scheme 11. Synthesis of 42b 34

陸、參考資料
1. Kawabe, K. Current status of research on prostate-selective α1-antagonists. Bri. J. Urol. 1998, 81, Suppl. 1, 48 - 50.
2. Christmas, C. J. Risk/benefit issues in the different approaches to the therapy of benign prostatic hyperplasia. In the consensus meeting on new approaches in the pharmacotherapy of benign prostatic hyperplasia (BPH). Eur. Urol. 1996, 39, 381 - 382.
3. Hieble, J. P.; McCafferty, G. P.; Naselsky, D. P.; Bergsme, D. J.; Ruffolo, R. R. Jr.; Recent progress in the pharmacotherapy of disease of the lower urinary tract. Proc. 13th . Int. Symp. Med. Chem. Paris. 1995, 269s - 298s.
4. Lepor, H.; Shapiro, E.; This month in investigation urology: alpha adrenergic innervation of the prostate: insight into pharmacotherapy of benign prostatic hyperplasia. J. Urol. 1990, 143, 590 - 591.
5. Hieble, J. P.; Caine, M.; Zalaznik, E. In vitro characterization of the a-adrenoceptor in human prostate. Eur. J. Pharmacol. 107, 1985, 111 - 117.
6. Testa, R.; Guerner, L.; Ibba, M.; Struda, G.; Poggesi, E.; Toddei, C.; Simonazz, I.; Leonardi, A. Characterization of α1-adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit, dog and man. Eur. J. Pharmacol. 1993, 249, 307 - 315.
7. Rhodes, L.; Primika, RL.; Berman, C.; Vergult, G.; Gabriel, M.; Pierre-Malice, M.; Gibelin, B. Comparison of finasteride (Proscar) a 5-alpha reductase inhibitor with various commercial plant extracts and in vivo and in vitro 5-alpha reductase inhibitor. Prostate. 1993, 22, 43 - 51.
8. Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. Pharmacological options in the treatment of benign prostatic hyperplasia. J. Med. Chem. 1997, 40, 1293 - 1315.
9. Roehrborn, C. G.; Siegel, R. L. Safety and afficiency of doxazosin in benign prostatic hyperplasia: a pooled analysis of three double-blind, placebo-controlled studies. Urology 1996, 48, 406 - 415.
10. Elhilali, M.; Ramsey, E. W.; Berkin, J.; Casey, R. W. et al. A multicenter, randomized double-blind, placebo-controlled study to evaluate the safety and efficacy of tetrezosin in the treatment of benign prostatic hyperplasia. Urology 1996, 47, 335 - 342.
11. Lefervre-Borg, F.; O'Connor, S. E.; Schoemarker, H.; Hicks, P. E.; Lechaire, J.; Gautier, E.; Peeirre, F.; Pimoule, C.; Manoury, P.; Langer, S. Z. Alfuzosin, a selective α1 adrenoceptor antagonist in the lower urinary tract. Br. J. Pharmacol. 1993, 109, 1282 - 1289.
12. Shapiro, A.; Mazouz, B.; Caine, M. The alpha-adrenergic blocking effect of prazosin on the human prostate. Urol. Res. 1981, 9, 17 - 20.
13. Keetch, D. W.; Andriole, G. L. Medical therapy for benign prostatic hyperplasia. AJR. 1995, 164, 11 - 15.
14. Archibald, J. L.; Alps, B. J.; Cavalla, J. F.; Jackson, J. L. Synthesis and hypotensive activity of benzamidopiperidylethylindoles. J. Med. Chem. 1971, 14, 1054 - 1059.
15. Wetzel, J. M.; Miao, S. W.; Forray, C.; Borden, L. A.; Branchek, T. A.; Gluchowski, C. Discovery of α1a-Adrenergic Receptor Antagonists Based on the L-Type Ca2+ Channel Antagonist Niguldipine. J. Med. Chem. 1995, 38, 1579 - 1581.
16. (a). Boer, R.; Grassegger, A.; Schudt, C.; Glossmann, H. (+)-Niguldipine Binds with very High Affinity to Ca2+ Channels and to a Subtype of α1-Adrenoceptors. Euro. J. Pharmacol. Mol. Pharmacol. Sec. 1989, 172, 131-145. (b). Fisher, G.; Krumpl, G.; Mayer, N.; Schneider, W.; Raberger, G. Antihypertensive Effects of Niguldipine-HCl (B 844-39), a New Calcium Antagonist in Dogs. J. Cardiovasc. Pharmacol. 1987, 10, 268 - 273.
17. Ngarathnam, D.; Miao, S. W.; Lagu, B.; Chiu, G.; Fang, J.; Murali Dhar, T. G.; Zhang, J.; Tyagarajan, S.; Marzabadi, M. R.; Zhang, F.; Wong, W. C.; Sun, W.; Tian, D.; Wetzel, J. M.; Forray, C.; Chang, R S. L.; Broten, T. P.; Ransom, R. W.; Schorn, T. W.; Chen, T. B.; O'Malley, S.; Kling, P.; Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas, K. P.; Gluchowski, C. Design and sythesis of novel α1a adrenoceptor selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J. Med. Chem. 1999, 42, 4764 - 4777.
18. Lagu, B.; Tian, D.; Nagarathnam, D.; Marzabadi, M. R.; Wong, W. C.; Miao, S. W.; Zhang, F.; Sun, W.; Chiu, G.; Fang, J.; Forray, C.; Chang, R. S. L.; Ransom, R. W.; Chen, T. B.; O'Malley, S.; Zhang, K.; Vyas, K. P.; Gluchowski, K. Design and synthesis of novel α1a adrenoceptor selective antagonists. 3. Approaches to eliminate opioid agonist metabolites by using substituted phenylpiperazine side chian J. Med. Chem. 1999, 42, 4794 - 4803.
19. Murali Dhar, T. G.; Nagarathnam, D.; Marzabadi, M. R.; Lagu, B.; Wong, W. C.; Chiu, G.; Tyagarajan, S.; Miao, S. W.; Zhang, F.; Sun, W.; Tian, D.; Shen, Q.; Zhang, J.; Wetzel, J. M.; Forray, C.; Chang, R. S. L.; Broten, T. P.; Schorn, T. W.; Chen, T. B.; O'Malley, S.; Ransom, R.; Schneck, K.; Bendesky, R.; Harrell, C. M.; Vyas, K. P.; Zhang, K.; Gilbert, J.; Pettibone, D. J.; Patane, M. A.; Bock, M. G.; Freidinger, R. M.; Gluchowski, C. Design and synthesis of novel α1a adrenoceptor selective antagonists. 2. Approaches to eliminate opioid agonst metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J. Med. Chem. 1999, 42, 4778 - 4793.
20. Patane, M. A.; DiPardo, R. M.; Price, R. P.; Chang, R. S. L.; Ransom, R. W.; O'Malley, S. S.; Salvo, J. D.; Bock, M. G. Selective α-1A Adrenergic Receptor Antagonists. Effects of Pharmacophore Regio- and Stereochemistry on Potency and Selectivity. Bioorg. Med. Chem. Lett. 1998, 8, 2459 - 2500.
21. Leornardi, A.; Motta, G.; Riva, C.; Testa, R. Piperazine derivatives as alpha-1A-antagonists. International Patent Application No. WO 95/04049. Feb 9, 1995.
22. George, P. Uroselective α1-adrenoceptor antagonists for the treatment of benign prostatic hypertrophy. 13th International Symposium on Medicinal Chemistry, Paris, France, Sept. 19-23, 1994.
23. Blue, D. R.; Ford, A. P. D. W.; Morgans, D. J.; Padilla, F.; Clarke, D. E. Preclinical pharmacology of a novel α1A/L adrenoceptor antagonist, RS-100975. Neurourol. Urodyn. 1996, 14, 345 - 346.
24. Traber, J.; Davies, M. A.; Dompert, W. U.; Glaser, T.; Schuurman, T.; Seidel, P. R. Brain serotonin receptor as a target the putative anxiolytic TVXQ 7821. Brain. Res. Bull. 1984, 12, 741 - 744.
25. Raghupathi, R. K.; Rydelek-Fitzgerald, L.; Teitler, M.; Glennon, R. A. Analogues of the 5-HT1A serotonin antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine with reduced α1 adrenergic affinity. J. Med. Chem. 1991, 34, 2633 - 2638.
26. Glennon, R. A.; Naiman, N. A.; Pierson, M. E.; Titeler, M.; Lyon, R. A.; Weisberg, E. NAN-190: An arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur. J. Pharmacol. 1988, 154, 339 - 342.
27. Glennon, R. A.; Naiman, N. A.; Pierson, M. E.; Titeler, M.; Lyon, R. A.; Herndon, J. L.; Misenheimer, B. Stimulus properties of arylpiperazines: NAN-190, a potential 5-HT1A serotonin antagonist. Drug Dev. Res. 1989, 16, 335 - 339.
28. Castillo, C.; Ibarra, M.; Marquez, A. J.; Villalobos-Molina, R.; Hong, E. Vascular effect of ipsapirone are related with subtype of α1-adrenergic receptors. Arch. Med. Res. 1993, 24, 161 - 168.
29. Shibata, K.; Foglar, R.; Horie, K.; Obika, K.; Sakamoto, A.; Ogawa, S.; Tsujimoto, G. KMD-3213, a novel potent, α1a-adrenoceptor selectiveantagonist: characterisation using recombinant human α1 adrenoceptors and native tissues. Mol. Pharmacol. 1995, 48, 250 - 258.
30. Muramatsu, I.; Takita, M.; Suzuki, F.; Miyamoto, S.; Sakamoto, S.; Ohmura, T. Eur. J. Pharmacol. 1996, 300, 155 - 157.
31. Ford, A. P. D. W.; Arredondo, N. F.; Blue, D. R.; Bonhaus, D. W.; Jasper, J.; Kava, S.; Lesnick, J.; Pfister, J. R.; Shieh, I. A.; Vimont, R. L.; Williams, T. J.; McNeal, J. E.; Stamey, T. A.; Clarke, D. E. RS-17053 (N-[(cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective α1A-adrenoceptor antagonist, displays low affinity for functional α1 adrenoceptors in human prostate: implications for classification. Mol. Pharmacol. 1996, 49, 209 - 215.
32. Kenny, B. A.; Miller, A. M.; Williamson, I. J. R.; O'Connell, J.; Chalmers, D. H.; Naylor, A. M. Evaluation of the pharmacological selectivity profile of α1 adrenoceptor antagonists at prostatic α1 adrenoceptors: binding, functional and in vivo studies. Br. J. Pharmacol. 1996, 118, 871 - 878.
33. Basse-Tomusk, A.; Rebec, G. V. Ipsapirone depresses neuronal activity in the dorsal raphe nucleus and the hippocampal formation. Eur. J. Pharmacol. 1986, 130, 141 - 143
34. Nerenberg, J. B.; Erb, J. M.; Thompson, W. J.; Lee, H. Y.; Guare, J. P.; Munson, P. M.; Bergman, J. M.; Huff, J. R.; Broten, T. P.; Chang, R. S. L.; Chen, T. B.; O'Malley, S.; Schorn, T. W.; Scott, A. L. Design and Synthesis of N-Alkylated Saccharins as Selective α-1A Adrenergic Receptor Antagonists. Bioorg. Med. Chem. Lett 1998, 8, 2467 - 2472.
35. Glennon, R. A.; Naiman, N. A.; Lyon, R. A.; Titeler, M. Arylpiperazine Derivatives as High-Affinity 5-HT1A Serotonin Ligands. J. Med. Chem. 1988, 31, 1968 - 1971.
36. Peroutka, S. J. Selective interaction of novel anxiolytics with 5-hydroxytryptamine1A receptors. Biol. Psych. 1985, 20, 971 - 979.
37. Glennon, R. A.; Slusher, R. M.; Lyon, R. A.; Titeler, M.; McKenney, J. D. 5-HT1 and 5-HT2 binding characteristics of some quipazine analogues. J. Med. Chem. 1986, 29, 2375 - 2380.
38. Huff, J. R.; King, S. W.; Saari, W. S.; Springer, J. P.; Martin, G. E.; Williams, M. Bioactive conformation of 1-arylpiperazines at central seroyonin receptors. J. Med. Chem. 1985, 28, 945 - 948.
39. Glennon, R. A. Central serotonin receptors as targets for drug research. J. Med. Chem. 1987, 30, 1 - 12.
40. Wong, W. C.; Sun, W.; Lagu, B.; Tian, D.; Marzabadi, M. R.; Zhang, F.; Nagarathnam, D.; Miao, S. W.; Wetzel, J. M.; Peng, J.; Forray, C.; Chang, R. S. L.; Chen, T. B.; Ransom,R.; O'Malley, S.; Broten, T. P,; Kling, P.; Vyas, K. P.; Zhang, K.; Gluchowski, C. Design and synthesis of novel α1a adrenoceptor selective antagonists. 4. Structure activity relationship in the dihydropyrimidine series. J. Med. Chem. 1999, 42, 4804 - 4813.
41. Lagu, B.; Tian, D.; Chiu, G.; Nagrathnam, D.; Fang, J.; Shen, Q.; Forray, C.; Ransom, R. W.; Chang, R. S. L.; Vyas, K. P.; Zhang, K.; Gluchowski, C. Synthesis and evaluation of furo[3,4-d]pyrimidinones as selective α1a-adrenergic receptor antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 175 - 178.
42. Bremner, J. B.; Coban, B.; Griffith, R.; Groenewoud, K. M.; Yates, B. F. Ligand design for α1 adrenoreceptor subtype selective antagonists. Bioorg. Med. Chem. 2000, 8, 201 - 214.
43. Gardiner, J. M.; Bryce, M. R.; Bates, P. A.; Hursthouse, M. B. Cephalotaxine Analogues: Stereospecific Synthesis of Spiro-Fused 3-Benzazepine and 1,3-Benzodiazepine Derivatives. J. Org. Chem. 1990, 55, 1261 - 1266.
44. Huntress, E. H.; Carten, F. H. Identification of Organic Compounda. I. Chlorosulfonic Acid as a Reagent for the Identification of Aryl Halides. J. Amer. Chem. Soc. 1940, 62, 511 - 514.
45. Ludwig, M.; Pytela, O.; Kalfus, K.; Vecera, M. Dissociation of substituted benzenesulphonamides in water, methanol and ethanol. Collec. Czechoslovak Chem. Commun. 1984, 49, 1182 - 1192.
46. Catsoulacos, Panayotis. Synthesis of Some N-Substituted 6,7-Dimethoxy-1,2-benzothiazin(4H)-3-one 1,1-Dioxides. J. Heterocyclic Chem. 1971, 8, 947 - 950.
47. Catsoulacos, P.; Camoutsis, C. Benzothiazinone Dioxides and Their Derivatives. J. Heterocyclic Chem. 1979, 16, 1503 - 1524.
48. Camoutsis, Charalambos.; Catsoulacos, Panayotis. On the Synthesis of 3,4-Dimethoxy-2H-1,2-benzothiazine 1,1-dioxides. J. Heterocyclic Chem. 1992, 29, 569 - 570.
49. New, J. S.; Yevich, J. P.; Eison, M. S.; Taylor, D. P.; Eison, A. S.; Riblet, L. A.; VanderMaelen, C. P.; Temple, D. L. Buspirone analogues. 2. Structure activity relationships of aromatic imide derivatives. J. Med. Chem. 1986, 29, 1476 - 1482.
50. Nielsen, J.; Rasmussen, P. H. Implementation of a combinatorial cleavage and deprotection scheme. 1. Sythesis of phthalhydrazide libraries. Tetrahedron letters 1996, 37, 3351 - 3354
51. Hovius, K.; Wagenaar, A.; Engberts, J. B. F. N. Intramolecular sulfonamide-carboxamide rearrangement. Tetrahedron Letters. 1983, 24, 3137 - 3140.
52. Albada, M. P. van; Cerfontain, H. Aromatic sulphonation. Part 60. Siphonation in the reactions of aromatic compounds with chlorosulphuric acid in nitromethane and in dichloromethane. J. Chem. Soc. Perk. Trans. 2. 1977, 1548 - 1559.
53. Ishiwaka, T.; Sano, M.; Isagawa, K.; Fushizaki, Y.; Synthesis of ben[e]-1,3,4-triazepine derivatives from 2-aminobenzophenone. Bull. Chem. Soc. Jpn. 1970, 43, 135 - 138.
54. Borch, R. F.; Bernstien, M. D.; Durst, H. D. The cyanohydridoborate anion as aselective reducting agent. J. Am. Chem. Soc. 1971, 93, 2879 - 2904.