臺灣博碩士論文加值系統

為了得到強力的抗血小板與抗血管增生之化合物，所以著者以3-(4-methylphenyl)-1H-indazole (6)為key intermediate，從事其衍生物的合成。
利用1-N-嗎福啉基環己烯與4-甲基苯甲醯氯在三乙基胺的存在下反應，接著以鹽酸水溶液水解即可得2-oxocyclohexyl 4- methylphenyl ketone (4)。將化合物4與聯胺進行反應，可以得到3-(4-methylphenyl)-4,5,6,7-tetrahydro-1H-indazole (5)。繼而以Pd/C之催化脫氫反應將化合物5氧化成3-(4-methylphenyl)-1H-indazole (6)。最後將化合物6與各種取代的芐基氯進行benzylation 後，形成兩類主要的衍生物；1-(substituted benzyl)-3-(4-methylphenyl)-1H-indazole (7、9、11、13、15、16、18)與2-(substituted benzyl)-3-(4-methylphenyl)-2H-indazole (8、10、12、14、17、19 - 21)。
將化合物6及其相關化合物進行生物活性之評估。結果發現大部份N2取代性衍生物(8、10、12、14、17、19 - 21)比N1取代性衍生物(9、11、13、15、16)具有較顯著的抗血小板活性。而在N2取代性衍生物中，2-(4-chlorobenzyl)-3-(4-methylphenyl)-2H-indazole (8), 2-(4-methylbenzyl)-3-(4-methylphenyl)-2H-indazole (14) 以及 2-(4-methoxybenzyl)-3-(4-methylphenyl)-2H-indazole (19)具有顯著的抗血管增生活性，值得進一步探討。

In order to search novel compounds with potent antiplatelet and antiangiogenesis activities, 3-(4-methylphenyl)-1H-indazole (6) was used as the key intermediate and its derivatives were synthesized.
In the presence of triethylamine, 1-(N-morpholino)cyclohexene was reacted with 4-methylbenzoyl chloride. Followed by hydrolysis using dil. hydrochloric acid, 2-oxocyclohexyl 4-methylphenyl ketone (4) was obtained. 3-(4-Methylphenyl)-4,5,6,7-tetrahydro-1H-indazole (5) was gained after reaction of compound 4 and hydrazine. The product, 3-(4-methyl phenyl)-1H-indazole (6), was obtained after compound 5 was oxygenated by catalytic dehydrogenation on Pd/C. Finally, benzylation of compound 6 with various substituted benzyl chloride produced the derivatives, 1-(substituted benzyl)-3-(4-methylphenyl)-1H-indazoles (7、9、11、13、15、16、18) and 2-(substituted benzyl)-3-(4-methyl phenyl)-2H-indazoles (8、10、12、14、17、19 - 21).
Compound 6 and its related compounds were evaluated for their biological activities. Most of N2-substituted derivatives (8、10、12、14、17、19、20、21) showed more prominent antiplatelet activity than N1-substituted derivatives (9、11、13、15、16). Among these N2-substituted derivatives, 2-(4-chlorobenzyl)-3-(4-methylphenyl)-2H-indazole (8), 2-(4-methylbenzyl)-3-(4-methylphenyl)-2H-indazole (14) and 2-(4-methoxybenzyl)-3-(4-methylphenyl)-2H-indazole (19) showed significant antiangiogenesis and worthy for further investigation.

中文摘要
英文摘要
第一章 緒論
第一節 血小板(platelet)之生理及病理角色……………… 1
第二節 癌症………………………………………………… 4
第三節 凝血酶(thrombin)之主要生理功能……………… 7
第四節 吲唑類(indazole)化合物之合成方法……………… 9
第五節 YD-3之研究概況………………………………… 11
第六節 研究動機與目的…………………………………… 13
第二章 結果與討論
第一節 化學合成
I、標的化合物的合成概述……………………………… 16
第二節 藥理活性試驗結果
I、抗血小板凝集活性…………………………………… 59
II、抑制血管增生之活性………………………………… 63
III、細胞致毒活性………………………………………… 68
第三章 結論…………………………………………………… 71
第四章 實驗部份
第一節 試藥………………………………………………… 73
第二節 重要儀器…………………………………………… 75
第三節 各化合物之製備…………………………………… 77
第四節 藥理試驗方法……………………………………… 91
參考文獻………………………………………………………… 94
圖譜………………………………………………………….… 99
圖譜目錄
圖4-1,圖4-2 化合物4之MS圖譜及IR光譜圖………………. 19
圖4-3 化合物4之1H-NMR (CDCl3, 200 MHz)圖譜…………. 20
圖4-4a 化合物4之1H-1H cosy (CDCl3, 200 MHz)圖譜……… 20
圖4-4b 化合物4之1H-1H cosy (CDCl3, 200 MHz)圖譜……… 21
圖4-5 化合物4之13C-NMR (CDCl3, 50 MHz)圖譜…………… 21
圖4-6a 化合物4之HMQC (CDCl3)圖譜……………………….. 22
圖4-6b 化合物4之HMQC (CDCl3)圖譜……………………….. 22
圖5-1,圖5-2 化合物5之MS圖譜及IR光譜圖………………. 24
圖5-3 化合物5之1H-NMR (CDCl3, 200 MHz)圖譜…………... 25
圖5-4 化合物5之13C-NMR (CDCl3, 50 MHz)圖譜…………… 25
圖5-5a 化合物5之13C-1H cosy (CDCl3)光譜………………… 26
圖5-5b 化合物5之13C-1H cosy (CDCl3)圖譜………………… 26
圖6-1,圖6-2 化合物6之MS圖譜及IR光譜圖………………. 29
圖6-3 化合物6之1H-NMR (CDCl3, 300 MHz)圖譜…………... 30
圖6-4 化合物6之1H-1H cosy (CDCl3, 300 MHz)圖譜………. 30
圖6-5 化合物6之13C-NMR (CDCl3, 75 MHz)圖譜…………… 31
圖6-6 化合物6之HMQC (CDCl3)圖譜………………………... 31
圖6-7 化合物6之HMBC (CDCl3)圖譜………………………... 32
圖18-1,圖18-2 化合物18之MS圖譜及IR光譜圖…………... 38
圖18-3 化合物18之1H-NMR (DMSO-d6, 400 MHz)圖譜……. 39
圖18-4 化合物18之1H-1H cosy (DMSO-d6, 400 MHz)圖譜… 39
圖18-5 化合物18之13C-NMR (DMSO-d6, 50 MHz)光譜…….. 40
圖18-6 化合物18之HMQC (DMSO-d6)圖譜…………………. 40
圖18-7 化合物18之HMBC (DMSO-d6)圖譜…………………. 41
圖19-1,圖19-2 化合物19之MS圖譜及IR光譜圖…………... 44
圖19-3 化合物19之1H-NMR (DMSO-d6, 400 MHz)圖譜……. 45
圖19-4 化合物19之1H-1H cosy (DMSO-d6, 400 MHz)圖譜… 45
圖19-5 化合物19之13C-NMR (DMSO-d6, 50 MHz)圖譜…….. 46
圖19-6 化合物19之HMQC (DMSO-d6)圖譜…………………. 46
圖19-7a 化合物19之HMBC (DMSO-d6)圖譜…………………. 47
圖19-7b 化合物19之HMBC (DMSO-d6)圖譜………………… 48
圖22-1,圖22-2 化合物22之MS圖譜及IR光譜圖…………... 53
圖22-3 化合物22之1H-NMR (CDCl3, 400 MHz)圖譜………... 54
圖22-4 化合物22之1H-1H cosy (CDCl3, 400 MHz)圖譜……. 54
圖22-5 化合物22之13C-NMR (CDCl3, 50 MHz)圖譜………… 55
圖22-6 化合物22之HMQC (CDCl3)圖譜……………………... 55
圖22-7a 化合物22之HMBC (CDCl3)圖譜…………………….. 56
圖22-7b 化合物22之HMBC (CDCl3)圖譜…………………….. 57
圖7-1,圖7-2 化合物7之MS圖譜及IR光譜圖………………. 99
圖7-3 化合物7之1H-NMR (CDCl3, 200 MHz)圖譜…………... 100
圖7-4 化合物7之13C-NMR (CDCl3, 50 MHz)圖譜…………… 100
圖8-1,圖8-2 化合物8之MS圖譜及IR光譜圖………………. 101
圖8-3 化合物8之1H-NMR (CDCl3, 200 MHz)圖譜…………... 102
圖8-4 化合物8之13C-NMR (CDCl3, 50 MHz)圖譜…………… 102
圖9-1,圖9-2 化合物9之MS圖譜及IR光譜圖………………. 103
圖9-3 化合物9之1H-NMR (CDCl3, 200 MHz)圖譜…………... 104
圖9-4 化合物9之13C-NMR (CDCl3, 50 MHz)圖譜…………… 104
圖10-1,圖10-2 化合物10之MS圖譜及IR光譜圖…………… 105
圖10-3 化合物10之1H-NMR (CDCl3, 200 MHz)圖譜……….. 106
圖10-4 化合物10之13C-NMR (CDCl3, 50 MHz)圖譜………… 106
圖11-1,圖11-2 化合物11之MS圖譜及IR光譜圖…………... 107
圖11-3 化合物11之1H-NMR (CDCl3, 200 MHz)圖譜……….. 108
圖11-4 化合物11之13C-NMR (CDCl3, 50 MHz)圖譜………… 108
圖12-1,圖12-2 化合物12之MS圖譜及IR光譜圖…………... 109
圖12-3 化合物12之1H-NMR (CDCl3, 200 MHz)圖譜……….. 110
圖12-4 化合物12之13C-NMR (CDCl3, 50 MHz)圖譜………… 110
圖13-1,圖13-2 化合物13之MS圖譜及IR光譜圖…………... 111
圖13-3 化合物13之1H-NMR (CDCl3, 200 MHz)圖譜………... 112
圖13-4 化合物13之13C-NMR (CDCl3, 50 MHz)圖譜………… 112
圖14-1,圖14-2 化合物14之MS圖譜及IR光譜圖…………... 113
圖14-3 化合物14之1H-NMR (CDCl3, 200 MHz)圖譜………... 114
圖14-4 化合物14之13C-NMR (CDCl3, 50 MHz)圖譜………… 114
圖15-1,圖15-2 化合物15之MS圖譜及IR光譜圖…………... 115
圖15-3 化合物15之1H-NMR (CDCl3, 200 MHz)圖譜………... 116
圖15-4 化合物15之13C-NMR (CDCl3, 50 MHz)圖譜………… 116
圖16-1,圖16-2 化合物16之MS圖譜及IR光譜圖…………... 117
圖16-3 化合物16之1H-NMR (CDCl3, 200 MHz)圖譜………... 118
圖16-4 化合物16之13C-NMR (CDCl3, 50 MHz)圖譜………… 118
圖17-1,圖17-2 化合物17之MS圖譜及IR光譜圖…………... 119
圖17-3 化合物17之1H-NMR (CDCl3, 200 MHz)圖譜……….. 120
圖17-4 化合物17之13C-NMR (CDCl3, 50 MHz)圖譜………… 120
圖20-1,圖20-2 化合物20之MS圖譜及IR光譜圖…………... 121
圖20-3 化合物20之1H-NMR (CDCl3, 200 MHz)圖譜………... 122
圖20-4 化合物20之13C-NMR (CDCl3, 50 MHz)圖譜………… 122
圖21-1,圖21-2 化合物21之MS圖譜及IR光譜圖…………... 123
圖21-3 化合物21之1H-NMR (CDCl3, 200 MHz)圖譜………... 124
圖21-4 化合物21之13C-NMR (CDCl3, 50 MHz)圖譜………… 124
圖I-1,圖I-2 化合物I之MS圖譜及IR光譜圖…………….. 125
圖I-3 化合物I之1H-NMR (CDCl3, 200 MHz)圖譜…………. 126

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