TWI227238B - Novel pyranocoumarin compounds and their applications - Google Patents
Novel pyranocoumarin compounds and their applications Download PDFInfo
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- TWI227238B TWI227238B TW92136975A TW92136975A TWI227238B TW I227238 B TWI227238 B TW I227238B TW 92136975 A TW92136975 A TW 92136975A TW 92136975 A TW92136975 A TW 92136975A TW I227238 B TWI227238 B TW I227238B
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- ZGFASEKBKWVCGP-UHFFFAOYSA-N cyclocoumarol Chemical class C12=CC=CC=C2OC(=O)C2=C1OC(OC)(C)CC2C1=CC=CC=C1 ZGFASEKBKWVCGP-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 238000003379 elimination reaction Methods 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 238000007273 lactonization reaction Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- -1 Q-C6 alkyl Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 101150041968 CDC13 gene Proteins 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 238000005100 correlation spectroscopy Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 229930184135 calanolide Natural products 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical group CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001336 alkenes Chemical group 0.000 description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 125000002299 monoterpene group Chemical group 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NIDRYBLTWYFCFV-UHFFFAOYSA-N (-)-calanolide b Chemical compound C1=CC(C)(C)OC2=C1C(OC(C)C(C)C1O)=C1C1=C2C(CCC)=CC(=O)O1 NIDRYBLTWYFCFV-UHFFFAOYSA-N 0.000 description 2
- CHOOCIQDWNAXQQ-UHFFFAOYSA-N 1,5,5-trimethylcyclohexene Chemical compound CC1=CCCC(C)(C)C1 CHOOCIQDWNAXQQ-UHFFFAOYSA-N 0.000 description 2
- 101150046236 CNR1 gene Proteins 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 230000019522 cellular metabolic process Effects 0.000 description 2
- 239000007805 chemical reaction reactant Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000001671 coumarin Nutrition 0.000 description 2
- 229960000956 coumarin Drugs 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 208000029483 Acquired immunodeficiency Diseases 0.000 description 1
- 241000218993 Begonia Species 0.000 description 1
- WMAJMUHAAGXJIK-UHFFFAOYSA-N Calophynsaeure Natural products O=C1C(C)C(C)OC(C(C2=O)(CC=C(C)C)CC(CC=C(C)C)C(C)=C)=C1C(O)=C2C(CC(O)=O)C1=CC=CC=C1 WMAJMUHAAGXJIK-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- WMAJMUHAAGXJIK-IANRPZNTSA-N Inocalophyllin A Natural products O=C(O)C[C@@H](c1ccccc1)C=1C(=O)[C@](C[C@@H](C(=C)C)C/C=C(\C)/C)(C/C=C(\C)/C)C=2O[C@H](C)[C@H](C)C(=O)C=2C=1O WMAJMUHAAGXJIK-IANRPZNTSA-N 0.000 description 1
- WMAJMUHAAGXJIK-YMGGUQHFSA-N Inocalophyllin A Chemical compound O([C@@H]([C@H](C1=O)C)C)C(C(C2=O)(CC=C(C)C)CC(CC=C(C)C)C(C)=C)=C1C(O)=C2C(CC(O)=O)C1=CC=CC=C1 WMAJMUHAAGXJIK-YMGGUQHFSA-N 0.000 description 1
- BGZGGCFNSXHMDD-LUSGHDGPSA-N Inocalophyllin B Chemical compound CC(C)=CCC(C(C)=C)CC1(CC=C(C)C)C(=O)C(C(CC(O)=O)CCC)=C(O)C2=C1O[C@H](C)[C@@H](C)C2=O BGZGGCFNSXHMDD-LUSGHDGPSA-N 0.000 description 1
- 229930187380 Inophyllum Natural products 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- 238000002485 combustion reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
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- 210000001808 exosome Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
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- BGZGGCFNSXHMDD-CAQDASKBSA-N inocalophyllin B Natural products O=C(O)C[C@@H](CCC)C=1C(=O)[C@@](C[C@H](C(=C)C)C/C=C(\C)/C)(C/C=C(\C)/C)C=2O[C@H](C)[C@H](C)C(=O)C=2C=1O BGZGGCFNSXHMDD-CAQDASKBSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
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- 239000007937 lozenge Substances 0.000 description 1
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- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
1227238 玖、發明說明： 【發明所屬之技術領域】 本發明係關於新穎之哌喃香豆素，其係使用罕見之消去反應將原料之異戊二烯單位 進行消去並進行選擇性烯類環合反應所製成，並可作爲醫藥用途。 【先前技術】 發明背景 病毒對於許多難解的疾病來說是一種重要的病因，而且因其基因之變異性大而容易 對於藥物之處理產生抵抗性，對於這些疾病之控制或是預防上也特別困難，使得此領域 之人莫不致力於尋找可以對抗病毒之新穎物質以期更安全且有效地對抗病毒。對於造成 人類後天免疫不全症之病因人類免疫不全病毒（HIV Virus)來說，化學治療是目前最具 有挑戰性的課題因爲到目前爲止幾乎所有核准在臨床上使用的藥物都只是在延長生命 而並非將疾病治癒，而且因爲病毒種系的抗藥性出現也無法將藥物用於長期治療之規 劃，所以硏發對於抵抗該疾病更有選擇性也更有活性的藥物實爲趨勢所需。胡桐烯烴酸 內酯（calanolides)與瓊崖海棠素（inophyllum)是近來較新用於人類免疫不全病毒（HIV virus)第一型反轉錄酶之非核苷類抑制物（見 Yang，S. S.et al·，Nat. Prod.2001，64,265-277; Matthee, G. et al., Planta Medica, 1999, 65,493-506; Vlietinck A. J. et al., Planta Medica, 1998,64, 97-109; Spino, C· et al” Bioorg. & Med. Chem· Lett· 1998, 8, 3475-3478)。尤其發現胡桐烯烴 酸內酯對AZT藥物具有抗性的病毒仍具有對抗活性，因此對HIV的病人來說胡桐烯烴 酸內酯（calanolides)類之藥物也許可以成爲與AZT及/或蛋白酶作爲合倂療法之有力候 選者。 目前仍需尋找一可以替代而且可以更爲經濟的胡桐烯烴酸內酯（calanolides)來源。 最近被發現的兩種新穎之峨喃香豆素，胡桐瓊崖海棠素A (inocalophyllin A)與胡桐瓊崖 海棠素B (inocalophyllin B )，係從瓊崖海棠（C池p如ώφΛκ/扁2)的種子所單離出 來的（Chiu Ν· Υ· et al·，The Illustrated Medicinal Plants of Taiwan; Institute of Chinese Pharmaceutical Science, China Medical College, Taichung, Taiwan, 1995, Vol 4, pi 17; Shen, Y. C. et al·，Chem· Pharm· Bull. 2003, 51，802-806) ’其爲一類新穎的哌喃香豆素，特點爲帶有一 異戊二烯單位以及在其獨特之哌喃香豆素環上第8a碳的位置有一單萜取代基，針對此 1227238 類化合物可進一步進行反應而產生結構與胡桐烯烴酸內酯（calanolide)更爲類似的化合 物，本發明則是因此而發明出。 【發明内容】 發明槪述 本發明係關於一種新穎的哌喃香豆素及其鹽類，其具有如以下之式（I)或（II)結構， 其中R代表氫基、C1〜C6烷基、苯基或經α〜C6烷基取代之苯基；R1代表氫基、C1〜C6 烷基、苯基或經C1〜C6烷基取代之苯基。1227238 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel piperancoumarin, which uses a rare elimination reaction to eliminate isoprene units of a raw material and perform selective olefinic cyclization. The reaction is made and can be used for medical purposes. [Prior Art] Background of the Invention Viruses are an important cause of many intractable diseases, and because of the large variability of their genes, they are prone to develop resistance to the treatment of drugs, and it is particularly difficult to control or prevent these diseases. Therefore, people in this field are committed to finding new substances that can fight the virus in order to fight the virus more safely and effectively. For the human immunodeficiency virus (HIV Virus), the cause of acquired immunodeficiency in humans, chemotherapy is currently the most challenging issue because almost all drugs approved for clinical use so far are only prolonging life rather than To cure the disease, and because of the emergence of drug resistance in the virus, the use of drugs for long-term treatment planning is not possible. Therefore, it is a trend to develop more selective and active drugs against the disease. Calcutides and inophyllum are newer non-nucleoside inhibitors recently used in human immunodeficiency virus (HIV virus) type 1 reverse transcriptase (see Yang, SSet al ·, Nat. Prod. 2001, 64, 265-277; Matthee, G. et al., Planta Medica, 1999, 65, 493-506; Vlietinck AJ et al., Planta Medica, 1998, 64, 97-109; Spino, C. et al "Bioorg. & Med. Chem · Let · 1998, 8, 3475-3478). In particular, it is found that eutelenolides are resistant to AZT-resistant viruses, and are therefore effective for HIV patients. Drugs of the class of alkaloids (calanolides) may be a strong candidate for combination therapy with AZT and / or protease. There is still a need to find an alternative and more economical alkaloids ( calanolides). Two new types of onancoumarins recently discovered, Hu Tong Qiong Ya Begonia A (inocalophyllin A) and Hu Tong Qiong Ya Begonia A (inocalophyllin B), are derived from Qiong Ya Begonia (C pond p such as freely φΛκ / Flat 2) of the seeds (Chiu Ν · Υ · et al ·, The Illustrated Medicinal Plants of Taiwan; Institute of Chinese Pharmaceutical Science, China Medical College, Taichung, Taiwan, 1995, Vol 4, pi 17; Shen, YC et al ·, Chem · Pharm · Bull. 2003, 51, 802 -806) 'It is a novel class of piperancoumarins characterized by having an isoprene unit and a monoterpene substituent at the 8a carbon position on its unique piperancoumarin ring. For this 1227238 The compounds can be further reacted to produce compounds having a structure more similar to that of calanolide, and the present invention is thus invented. [Summary of the Invention] The invention is described as a novel piperan Coumarin and its salts, which have the following formula (I) or (II) structure, wherein R represents a hydrogen group, a C1 to C6 alkyl group, a phenyl group, or a phenyl group substituted with an α to C6 alkyl group; R1 Represents a hydrogen group, a C1-C6 alkyl group, a phenyl group, or a phenyl group substituted with a C1-C6 alkyl group.
本發明亦包含一哌喃香豆素化合物，其係將式（I)與式（π)化合物上所含之羥基以其 他取代基進行修飾或保護後所獲得之衍生物。 本發明式⑴、（Π)結構化合物之製法如以下之製法槪圖所示，其係將式0Π)結構之 化合物於有機溶劑環境下進行內酯化反應及消去反應而獲得式（II)化合物，或是再進 一步將所獲得的式（II)化合物進行烯類環合反應而獲得式（I)結構之化合物；若有需 要，亦可將式⑴與式（Π)化合物上之活性官能基羥基以其他官能基或保護基進行取 代，而獲得更穩定或是更符合欲應用用途之哌喃香豆素衍生物。 本發明之哌喃香豆素衍生物亦可作爲醫藥組合物之主要活性成份，而應用於一些醫藥相 關應用如抗病毒、抗菌、抗血小板凝集或是其他應用範圍。 1227238 本發明化合物之製法槪圖The present invention also includes a piperanocoumarin compound, which is a derivative obtained by modifying or protecting the hydroxyl groups contained in the compounds of formula (I) and formula (π) with other substituents. The preparation method of the compound of the formula (II) and (II) of the present invention is shown in the following production method diagram. The compound of the formula (II) is subjected to a lactonization reaction and an elimination reaction in an organic solvent environment to obtain a compound of the formula (II). Or, the obtained compound of the formula (II) is further subjected to an olefinic cyclization reaction to obtain a compound of the structure of the formula (I); if necessary, the active functional group on the compound of the formula (II) may also be used The hydroxyl group is substituted with other functional groups or protecting groups to obtain a piperancoumarin derivative that is more stable or more suitable for the intended application. The piperanocoumarin derivative of the present invention can also be used as the main active ingredient of a pharmaceutical composition, and can be applied to some medical related applications such as antiviral, antibacterial, antiplatelet aggregation, or other applications. 1227238 Preparation method of the compound of the present invention
\/ 31 32\ / 31 32
烯類環合反應Olefinic cyclization
7 1227238 發明之詳細說明 本發明所例示之化合物起始反應原料雖如發明背景所述最初來自植物瓊崖海棠，然 而本發明化合物之原料並不限定一定需從該類植物種子取得，亦可爲他種植物取得或是 從其他部位取得，只要可以純化出足夠之量或純度之結構爲式（III)之化合物供本發明 之製法使用便可，原料亦可爲經由化學合成或半化學合成所製得。7 1227238 Detailed description of the invention Although the starting compounds of the compounds illustrated in the present invention are originally derived from the plant Qiongya begonia as described in the background of the invention, the raw materials of the compounds of the present invention are not necessarily obtained from the seeds of such plants, and may also It can be obtained from other plants or from other parts, as long as the compound of formula (III) with sufficient structure or purity can be purified for use in the production method of the present invention, and the raw materials can also be obtained through chemical synthesis or semi-chemical synthesis be made of.
(III) 本發明之化合物除可用作醫藥組合物之活性物質外，亦可用作中間物質或原料以合 成其他具有醫藥活性化合物，即進一步合成爲其他具有活性之曖喃香豆素相似物。本發 明之化合物亦可經由修飾而作爲細胞代謝之前驅體，並經由細胞酵素之代謝而另產生具 有活性作用之哌喃香豆素。 製作本發明化合物之特點在於反應原料帶有一異戊二烯單位以及在哌喃香豆素環 上第8a碳的位置有一單萜取代基，藉由將哌喃香豆素環第2碳位上之竣酸進行內酯化 反應，並且進行消去反應以成與哌喃香豆素（calanolide)具有相似結構之化合物，即本 發明式（II)結構之化合物，此反應可在約80至100°C之溫度下進行。但若反應溫度較 高，例如於ll〇°C的環境下，則所形成的化合物會進行烯類環合反應，形成本發明式（〇 結構之化合物。式（I )與式（II)結構的化合物皆可進一步以取代基或是保護基進行 取代，像是將所含羥基進一步乙醯化、烷基化等，而利於本發明化合物進一步作反應修 飾或是符合醫藥上之應用用途。 1227238 式（I)與式（II)化合物可以多於一種異構形式存在，本發明擴展至全部之互變異 _形式或幾何異構形式。鏡像異構物、非鏡像異構物及混合物包含外消旋混合物亦爲本 發明所欲保護之範圍。 本發明之哌喃香豆素衍生物在作爲預防、治療或保健之應用上可與有機酸、醫藥可 容許酸形成鹽類，並可添加各種賦形劑如稀釋劑、潤滑劑、矯味劑、崩散劑、黏合劑或 箸色劑、甜味劑製成錠劑或是其他種之固形製劑，或是利用醫藥可接受緩衝液調整酸鹼 度而製成注射劑、其他液劑或是其他各種齊I型；本發明之哌喃香豆素衍生物因應實際運 用需求，可與其他非本發明之藥劑並用，亦可運用組合二種以上本發明之化合物以達成 最好之應用效果。 【實施方式】 實施例1 命名爲InocalocyclideA化合物（化合物（la))之製備(III) In addition to being used as an active substance in a pharmaceutical composition, the compound of the present invention can also be used as an intermediate substance or raw material to synthesize other medicinal active compounds, that is, further synthesized into other active coumarin coumarin analogs . The compounds of the present invention can also be modified to act as precursors for cell metabolism, and to produce another active piperancoumarin through metabolism of cell enzymes. The preparation of the compound of the present invention is characterized in that the reaction raw material has an isoprene unit and a monoterpene substituent at the 8th carbon position on the piperanocoumarin ring. The end acid is subjected to a lactonization reaction and an elimination reaction to form a compound having a structure similar to calanolide, that is, a compound of the formula (II) structure of the present invention. This reaction can be performed at about 80 to 100 °. At a temperature of C. However, if the reaction temperature is high, for example, at an environment of 110 ° C, the formed compound will undergo an olefinic cyclization reaction to form a compound of the formula (0). The structure of the formula (I) and the formula (II) All of the compounds can be further substituted with a substituent or a protecting group, such as further ethylation and alkylation of the contained hydroxyl groups, which is beneficial to the compounds of the present invention for further reaction modification or to meet the medical application. The compounds of formula (I) and formula (II) may exist in more than one isomeric form, and the present invention extends to all intervariable forms or geometrically isomeric forms. Mirror isomers, non-mirror isomers and mixtures include exosome The spinomix is also within the scope of the present invention. The piperancoumarin derivative of the present invention can be used as a preventive, therapeutic or health-care application to form salts with organic acids and pharmaceutical tolerable acids, and various additives can be added. Forms such as diluents, lubricants, flavoring agents, disintegrating agents, binders or tinting agents, sweeteners are made into lozenges or other solid preparations, or the acid can be adjusted with a pharmaceutically acceptable buffer It can be made into injections, other liquids, or other various types I; the piperancoumarin derivatives of the present invention can be used in combination with other non-invention medicaments according to actual application requirements, and can also be used in combination of two or more kinds. The compound of the invention achieves the best application effect. [Embodiment] Example 1 Preparation of the compound named InocalocyclideA (compound (la))
使用化合物（A)作爲反應起始物，在80°C下以甲苯磺酸在甲苯中處理五小時，以 產生內酯化（lactonization)及消去反應（elimination)，消去反應完成後再利用矽膠柱狀 色層分離法，以正己烷和乙酸乙脂混合溶液。依下列比例沖流(1〇〇 ·· 1，90 ·· 1，80 : 1， 70 : 1，60 ·· 1，50 ·· 1，40 : 1，30 : 1，20 ·· 1，10 ·· 1)，得到產量 30%之不定形固態化 合物（la)，其反應如下所示，並稱作 InocalocyclideA。[a]25D - 12。卜 1.0, CH2C12); UV λ max (MeOH) nm: 240,276, 285, 303, 332; IR (neat) υ max 3058, 1779,1633, 1449,1378， 1269 cm-1; FABMS m/z : 441 [M+H]+; EIMS m/z (rel. int·) 440 [M]+, 317, 275, 233, 219, 217,177,123,109, 81，69; iHNMR (CDC13, 300 MHz): δ 2,50 (1H，m，H-3A)，2.70 (1H，m， H-3B), 3.34 (1H, m5 H-4), 4.15 (1H? m, H-10), 2.55 (1H? m, H-ll), 1.45 (1H, m, H-15)? 1.50 (1H, m? H-16), 0.88 (t, J= 6.9 Hz? H-17), 1.48 (3H, d, J= 6.3 Hz, H-21), 1.21 (1H5 d, 6.9 Hz，H-22)，2·65 (2H，m，H-23)，2·35 (1H，m，H-24)，2.10 (2H，m，H-25)，5.05 (1H，t，《/= 8 Hz， H-26), 4.42 (1H, d, J= 2.1 Hz, H-28A), 4.57 (1H, s, H-28B), 1.70 (3H? s? H-30)? 1.54 (3H, s? 9 1227238 H-31)，1.66 (3H，s，Η-32)，12·2 (1H，s，OH); 13C NMR (CDC13, 75 MHz): δ 167.4 (s? C-2), 34.1 (t，C-3)，28.2 (d，C-4)，106.9 (s，C-5)，156.6 (s，C-6)，108.2 (s，C-7)，158.6 (s，C-8)，79·0 (d，C-10)，46·1 (d，CM1)，200.1 (s，C-12)，103.9 (s，13)，157.4 (s，014)，36.4 (t，C-15)，19.8 (t，C-16)，14.0 (q，C-17)，19·6 (q，C-21)，10.0 (q，C-22)，26.7 (t，C-23)，47.7 (d，C-24)，31.4 (t， C-25)，123.1 (d，C-26)，131.1 (s，C-27)，111.2 (t，C-28)，147.7 (s，C-29)，18.7 (q，C-30)，17·9 (q，C-31)，25.7(q，C-32)。Compound (A) was used as the starting material of the reaction, and was treated with toluenesulfonic acid in toluene at 80 ° C for five hours to produce lactonization and elimination. After the elimination reaction was completed, a silica gel column was used. A chromatographic separation method, a mixed solution of n-hexane and ethyl acetate. Surge flow according to the following ratio (10.00 ... 1,90 ... 1,80: 1,70: 1,60 ... 1,50 ... 1,40: 1,30: 1,20 ... 1,10 1) An amorphous solid compound (la) having a yield of 30% is obtained. The reaction is shown below and is called InocalocyclideA. [a] 25D-12. Bu 1.0, CH2C12); UV λ max (MeOH) nm: 240,276, 285, 303, 332; IR (neat) υ max 3058, 1779,1633, 1449,1378, 1269 cm-1; FABMS m / z: 441 [ M + H] +; EIMS m / z (rel. Int ·) 440 [M] +, 317, 275, 233, 219, 217,177,123,109, 81, 69; iHNMR (CDC13, 300 MHz): δ 2,50 (1H , M, H-3A), 2.70 (1H, m, H-3B), 3.34 (1H, m5 H-4), 4.15 (1H? M, H-10), 2.55 (1H? M, H-ll) , 1.45 (1H, m, H-15)? 1.50 (1H, m? H-16), 0.88 (t, J = 6.9 Hz? H-17), 1.48 (3H, d, J = 6.3 Hz, H- 21), 1.21 (1H5 d, 6.9 Hz, H-22), 2.65 (2H, m, H-23), 2.35 (1H, m, H-24), 2.10 (2H, m, H- 25), 5.05 (1H, t, "/ = 8 Hz, H-26), 4.42 (1H, d, J = 2.1 Hz, H-28A), 4.57 (1H, s, H-28B), 1.70 (3H ? s? H-30)? 1.54 (3H, s? 9 1227238 H-31), 1.66 (3H, s, Η-32), 12 · 2 (1H, s, OH); 13C NMR (CDC13, 75 MHz ): δ 167.4 (s? C-2), 34.1 (t, C-3), 28.2 (d, C-4), 106.9 (s, C-5), 156.6 (s, C-6), 108.2 ( s, C-7), 158.6 (s, C-8), 79.0 (d, C-10), 46.1 (d, CM1), 200.1 (s, C-12), 103.9 (s, 13 ), 157.4 (s, 014), 36.4 (t, C-15), 19 .8 (t, C-16), 14.0 (q, C-17), 19.6 (q, C-21), 10.0 (q, C-22), 26.7 (t, C-23), 47.7 ( d, C-24), 31.4 (t, C-25), 123.1 (d, C-26), 131.1 (s, C-27), 111.2 (t, C-28), 147.7 (s, C-29 ), 18.7 (q, C-30), 17.9 (q, C-31), 25.7 (q, C-32).
(A) ： R=C3H7(A): R = C3H7
(la) ： R^CsHv(la): R ^ CsHv
產物的分子結構(C27H3605)係由快速原子撞擊質譜（FABMS )與Gc核磁共振光譜 (NMR Spectra)以準分子離子（quasimolecular ion)於質荷比（/n/z) 441下所推得。 1H-NMR光譜顯示一酚類質子訊號(δ 12.2s)、三個烯烴質子訊號（δ 5.05、δ 4.42、δ 4·57)、三個嫌烴甲基單峰(δ 1·70、1.54 及δ 1.66)以及在δ 1.21 (Me-22)與δ 1.50 (Me-21) 10 1227238 顯示二個甲基雙峰。本化合物之13C NMR光譜顯示一共轭酮羰基訊號(δ 2〇〇1)、一內酯 羰基訊號(δ 167.4)，及10個sp2軌域的碳，其中三個爲氧化態四級結構(δ 156.6、158.6、 157.4)。化合物之結構（如第1圖）並用同核化學位移相關光譜（C0SY)、異核單量子 相關光譜(HSQC )及異核多重鍵結相關光譜(HMBC )實驗法推得。H_4 (δ 3.34)與δ 106.9 (C-5)、156.6 (C-6)之碳關聯。同時在δ 2.65 (C-23)之亞甲基質子與C-6及C-7 (δ 108.2) 關聯。由COSY法所做出在Η-23/Η-24、Η-24/Η-25及Η·25/Η_26之關聯以及由HMBC 法所做出C-26分別與H_31、H-32、H-24間之關聯及H-24分別與C-28及C-30間之關 聯決定出C-7上具有單萜側鏈。 實施例2 命名爲Inocalocyclide B化合物（化合物（lb ))之製備The molecular structure (C27H3605) of the product was derived from fast atomic impact mass spectrometry (FABMS) and Gc nuclear magnetic resonance spectroscopy (NMR Spectra) using an excimer ion (quasimolecular ion) at a mass-to-charge ratio (/ n / z) of 441. The 1H-NMR spectrum showed a phenolic proton signal (δ 12.2s), three olefin proton signals (δ 5.05, δ 4.42, δ 4.57), three single hydrocarbon methyl peaks (δ 1.70, 1.54, and δ 1.66) and two methyl doublets at δ 1.21 (Me-22) and δ 1.50 (Me-21) 10 1227238. The 13C NMR spectrum of this compound shows a conjugated ketone carbonyl signal (δ 20001), a lactone carbonyl signal (δ 167.4), and 10 carbons in the sp2 orbital region, three of which are oxidation state quaternary structures (δ 156.6, 158.6, 157.4). The structure of the compound (as shown in Figure 1) was derived by experimental methods of homonuclear chemical shift correlation spectroscopy (C0SY), heteronuclear single quantum correlation spectroscopy (HSQC), and heteronuclear multiple bond correlation spectroscopy (HMBC). H_4 (δ 3.34) is associated with carbons of δ 106.9 (C-5), 156.6 (C-6). At the same time, the methylene protons at δ 2.65 (C-23) are associated with C-6 and C-7 (δ 108.2). The associations COS-23 / Η-24, Η-24 / Η-25 and Η · 25 / Η_26 made by the COSY method and C-26 made by the HMBC method are respectively H_31, H-32, and H- The association between 24 and H-24 with C-28 and C-30, respectively, determine that C-7 has a monoterpene side chain. Example 2 Preparation of Compound Named as Inocalocyclide B (Compound (lb))
亦使用化合物（A)作爲反應起始物，並進行與實施例1相似的反應步驟，但反應 溫度改爲110°c，而在內酯化（lactonization)及消去反應(elimination)後，進行燃類 環合反應（ene cyclization)，環合反應完成後再利用矽膠柱狀色層分離法，以正己烷和 乙酸乙脂混合溶液。依下列比例沖流(100 : 1，90 ·· 1，80 : 1，70 : 1，60 : 1，50 : 1， 40 ·· 1，30 : 1，20 : 1，10 : 1)，得到產量28%之不定形固態化合物（lb)，其反應如下 所示，並稱作爲 Inocalocyclide B。[ap5D -18.5。(c 1 ·0, CH2C12); UV λ max (MeOH) nm: 257,268, 300, 350; IR (neat) υ max 1779,1634, 1450,1381，737 cnr1; EIMS m/z (rel. int.) 440 [M]+，372, 371，331，318, 317, 275, 233, 219, 217, 177, 123, 109, 84, 81，69;屯 NMR (CDC13, 300 MHz): δ 2,84 (1H，m，H-3A)，2·78 (1H，m，H-3B)，3·37 (1H，m，H-4)，4.19 (1H， m，H-10)，2·58 (1H，m，H-ll)，1·22 (1H，m，H-15)，1·21 (1H，H-16)，0.89 (t，·/= 7.2 Hz， H-17)，1·50 (3H，d，6·6 Hz，H-21)，1.20 (1H，d，·/= 6.9 Hz，H-22)，3.48 (1H，s，H-23)，1·78 (2H，m，H-25)，1·31 (2H，m，H-26)，1.74 (2H，s，H-28)，1·78 (3H，s，H_30)，0·80 (3H，s，H-31)， 0.81 (3H, s, H-32), 12.3 (1H, s, OH); 13C NMR (CDCI3, 75 MHz): δ 166.7 (s，C-2)，34.1 (t， C-3)，29.1 (d，C-4)，11U (s，C-5)，156.8 (s，C-6)，113.8 (s，C-7)，158.9 (s，C-8)，79.4 (d，C-10)， 46.6 (d，C-ll), 199.8 (s，C-12)，108.1 (s，13)，156.8 (s，C-14)，35.9 (t，C-15)，20.0 (t，C-16)， 14·1 (q，C-17)，19.6 (q，C-21)，10.1 (q，C-22)，25.6 (t，C-23)，126·1 (d，C-24)，25.9 (t，C-25)， 11 1227238 35·4 (d，C-26)，29.1 (s，C-27)，45.8 (t，C-28)，125.5 (s，029)，18·9 (q，C-30)，28.1 (q，C-31， 32)。 \/The compound (A) was also used as a reaction starting material, and a reaction step similar to that in Example 1 was performed, but the reaction temperature was changed to 110 ° C, and after lactonization and elimination reaction, combustion was performed. Ene cyclization-like reaction. After the completion of the cyclization reaction, a silica gel columnar separation method is used to prepare a mixed solution of n-hexane and ethyl acetate. Flow according to the following ratio (100: 1,90 ·· 1,80: 1,70: 1,60: 1,50: 1,40 ·· 1,30: 1,20: 1,10: 1), get The amorphous solid compound (lb) with a yield of 28%, its reaction is shown below, and is called Inocalocyclide B. [ap5D -18.5. (c 1 · 0, CH2C12); UV λ max (MeOH) nm: 257,268, 300, 350; IR (neat) υ max 1779,1634, 1450,1381,737 cnr1; EIMS m / z (rel. int.) 440 [M] +, 372, 371, 331, 318, 317, 275, 233, 219, 217, 177, 123, 109, 84, 81, 69; Tun NMR (CDC13, 300 MHz): δ 2,84 ( 1H, m, H-3A), 2.78 (1H, m, H-3B), 3.37 (1H, m, H-4), 4.19 (1H, m, H-10), 2.58 ( 1H, m, H-11), 1.22 (1H, m, H-15), 1.21 (1H, H-16), 0.89 (t, · = 7.2 Hz, H-17), 1. · 50 (3H, d, 6.6 Hz, H-21), 1.20 (1H, d, // = 6.9 Hz, H-22), 3.48 (1H, s, H-23), 1.78 (2H, m, H-25), 1.31 (2H, m, H-26), 1.74 (2H, s, H-28), 1.78 (3H, s, H_30), 0 · 80 (3H, s, H-31), 0.81 (3H, s, H-32), 12.3 (1H, s, OH); 13C NMR (CDCI3, 75 MHz): δ 166.7 (s, C-2), 34.1 (t, C- 3), 29.1 (d, C-4), 11U (s, C-5), 156.8 (s, C-6), 113.8 (s, C-7), 158.9 (s, C-8), 79.4 ( d, C-10), 46.6 (d, C-ll), 199.8 (s, C-12), 108.1 (s, 13), 156.8 (s, C-14), 35.9 (t, C-15), 20.0 (t, C-16), 14 · 1 (q, C-17), 19.6 (q, C -21), 10.1 (q, C-22), 25.6 (t, C-23), 126.1 (d, C-24), 25.9 (t, C-25), 11 1227238 35.4 (d, C-26), 29.1 (s, C-27), 45.8 (t, C-28), 125.5 (s, 029), 18.9 (q, C-30), 28.1 (q, C-31, 32 ). \ /
(A) ： R=C3H7 31 32(A): R = C3H7 31 32
(lb) : R=C3H7 烯 f 類 反(lb): R = C3H7 ene f
化合物（lb)具有與化合物（la)相同的分子式C27H3605。本化合物之1H- and 13C NMR光譜數據與化合物（la)非常類似，除了缺少在C-26與C-28所個別出現的烯烴 12 1227238 亞甲基與次甲基（methine)訊號。詳細分析HMBC數據發現本化合物含有一個2,4,4· 三甲基環己烯部位。在δ 1.78 (Me-30)之甲基單峰與在δ 126·1、125.5 (C-24, 29)之烯烴碳 以及在δ 45.8 (C-28)之亞甲基關聯，其並與在δ 0·80 (Η-31)之甲基質子關聯，並因此找出 inocalocyclide Β 之結構。 實施例3 命名爲Inocalocyclide C化合物（化合物（lc))之製備 使用化合物（B)作爲反應起始物，並進行與實施例2相似的反應步驟，反應溫度 爲110°C，而在內酯化（lactonization)及消去反應（elimination)後，進行嫌類環合反 應（ene cyclization)，環合反應完成後再利用矽膠柱狀色層分離法，以正己烷和乙酸乙 脂混合溶液。依下列比例沖流(100 ·· 1，90 : 1，80 : 1，70 : 1，60 : 1，50 : 1，40 : 1， 30 ··卜20 : ：1，10 : 1)，得到產量28%之不定形固態化合物（lc)，其反應如下所示， 並稱作爲 Inocalocyclide C。[a]25D - 60。(c 1 ·0, CH2C12); UV λ max (MeOH) nm: 253,263, 299, 347; IR (neat) υ max 3404, 3054, 1778, 1634, 1428, 896, 738 cm·1; FABMS m/z : [M+H]+; EIMS m/z (rel. int.) 474 [M]+ 352, 351, 338? 310, 309, 253, 136, 121, 115, 93, 77; !H NMR (CDC13, 300 MHz): δ 2.96 (1H, m, H-3A), 3.02 (1H, m, H-3B), 4.66 (1H? dd, J =6·6, 2.0 Hz，H-4)，4·19 (1H, m，Η·10)，2.61 (1H，m，H-ll), 7.18 (2H，overlap，H-16, 20)， 7·28 (2H，overlap, H-17, 19)，7,26 (1H，overlap, H-18)，1.53 (3H，d，J= 6·3 Hz，H-21)，U8 (1H，d，6.9 Hz，H-22)，3·48 (2H，m，H-23)，1.83 (2H，m，H-25)，1·31 (1H，m，H-26)，1.80 (2H，s，H-28)，1·83 (3H，s，H-30)，0.85 (6H，s，H-31，32)，12.4 (1H，s，OH); 13C NMR (CDC13? 75 MHz): δ 166.4 (s, C-2), 36.5 (t, C-3), 34.1 (d, C-4), 105.1 (s? C-5), 157.5 (s, C-6), 108.2 (s，C-7)，159.2 (s，C-8)，79.2 (d，C-10)，46.0 (d，C-ll)，200.1 (s，C-12)，104.1 (s，C-13)， 156.8 (s，C-14)，140.9 (s，C-15)，126.7 (d，C-16)，128.9 (d，C-17)，127.3 (d，C-18)，128.9 (d， C-19)，126.7 (d，C-20)，19.6 (q，C-21)，10.1 (q，022)，25.5 (t，C-23)，125.9 (d，C-24)，25.9 (t， C_25)，35.9 (d，C-26)，29.2 (s，C-27)，46·6 (t，C-28)，125.4 (s，C-29)，19·7 (q，C-30)，28.0 (q， C-31,32)。 13 1227238The compound (lb) has the same molecular formula C27H3605 as the compound (la). The 1H- and 13C NMR spectral data of this compound are very similar to those of compound (la), except that the olefins 12 1227238 methylene and methine (12) are missing in C-26 and C-28. Detailed analysis of HMBC data revealed that this compound contained a 2,4,4 · trimethylcyclohexene site. The methyl single peak at δ 1.78 (Me-30) is associated with the olefin carbon at δ 126.1, 125.5 (C-24, 29) and the methylene at δ 45.8 (C-28), which is also associated with the The methyl proton association of δ 0 · 80 (Η-31), and therefore the structure of incalocyclide B was found. Example 3 Preparation of the compound named Inocalocyclide C (compound (lc)) Using compound (B) as a reaction starting material, and performing a reaction step similar to that in Example 2, the reaction temperature was 110 ° C, and the lactonization was carried out After lactonization and elimination, an ene cyclization reaction is performed. After the cyclization reaction is completed, a silica gel columnar separation method is used to mix a solution of n-hexane and ethyl acetate. Flow according to the following ratio (100 ·· 1, 90: 1, 80: 1, 70: 1, 60: 1, 50: 1, 40: 1, 30 · · 20: 1: 1, 10: 1), get The amorphous solid compound (lc) with a yield of 28%, the reaction is shown below, and is called Inocalocyclide C. [a] 25D-60. (c 1 · 0, CH2C12); UV λ max (MeOH) nm: 253,263, 299, 347; IR (neat) υ max 3404, 3054, 1778, 1634, 1428, 896, 738 cm · 1; FABMS m / z : [M + H] +; EIMS m / z (rel. Int.) 474 [M] + 352, 351, 338? 310, 309, 253, 136, 121, 115, 93, 77;! H NMR (CDC13 , 300 MHz): δ 2.96 (1H, m, H-3A), 3.02 (1H, m, H-3B), 4.66 (1H? Dd, J = 6.6, 2.0 Hz, H-4), 4. · 19 (1H, m, Η · 10), 2.61 (1H, m, H-ll), 7.18 (2H, overlap, H-16, 20), 7.28 (2H, overlap, H-17, 19), 7,26 (1H, overlap, H-18), 1.53 (3H, d, J = 6.3 Hz, H-21), U8 (1H, d, 6.9 Hz, H-22), 3.48 (2H , M, H-23), 1.83 (2H, m, H-25), 1.31 (1H, m, H-26), 1.80 (2H, s, H-28), 1.83 (3H, s , H-30), 0.85 (6H, s, H-31, 32), 12.4 (1H, s, OH); 13C NMR (CDC13? 75 MHz): δ 166.4 (s, C-2), 36.5 (t , C-3), 34.1 (d, C-4), 105.1 (s? C-5), 157.5 (s, C-6), 108.2 (s, C-7), 159.2 (s, C-8) , 79.2 (d, C-10), 46.0 (d, C-ll), 200.1 (s, C-12), 104.1 (s, C-13), 156.8 (s, C-14), 140.9 (s, C-15), 126.7 (d, C-16), 128.9 (d, C-17), 1 27.3 (d, C-18), 128.9 (d, C-19), 126.7 (d, C-20), 19.6 (q, C-21), 10.1 (q, 022), 25.5 (t, C-23) ), 125.9 (d, C-24), 25.9 (t, C_25), 35.9 (d, C-26), 29.2 (s, C-27), 46.6 (t, C-28), 125.4 (s , C-29), 19.7 (q, C-30), 28.0 (q, C-31, 32). 13 1227238
XX
烯類環合一 應Olefinic ring unification
應 R尸苯基 化合物（lc)之lH-andl3C-NMR數據幾乎與化合物（lb)相同除了化合物（lc) 多含有一苯基部位(δ 7.18-7.28)以及因此多出的碳訊號(δ 140.9s、126.7d、127.3d、128.9d)， 因此判別其與化合物（lb)爲相似物。化合物（lc)之結構進一步以HMBC實驗確認 (第 1 圖），其中 Η-4 (δ 4.66)與在δ 166.4 (C-2)、105.1 (C-5)、106.9 (C-15)、126.7 (C-16)及 156.8(〇14)之碳關聯。此外也觀察到2,4,4-三甲基環己烯部位之1^80關聯性。 14 1227238 實施例4 命名爲InocalocyclideD (化合物（Id))之製備The lH-andl3C-NMR data of the R-phenyl compound (lc) is almost the same as the compound (lb), except that the compound (lc) contains a single phenyl moiety (δ 7.18-7.28) and therefore an extra carbon signal (δ 140.9 s, 126.7d, 127.3d, 128.9d), so it is judged to be similar to compound (lb). The structure of compound (lc) was further confirmed by HMBC experiments (Figure 1), in which Η-4 (δ 4.66) and δ 166.4 (C-2), 105.1 (C-5), 106.9 (C-15), 126.7 (C-16) and 156.8 (〇14). In addition, the 1 ^ 80 correlation of 2,4,4-trimethylcyclohexene sites was also observed. 14 1227238 Example 4 Preparation named InocalocyclideD (compound (Id))
以實施例1所製得之化合物（la)即Inocalocydide A進一步進行乙醯化反應，反應 3小時後加入冰水等待20分鐘，以乙酸乙酯淬取並使其濃縮之，得到產量100%之化合 物（Id)，其反應如下所示，並稱作爲 Inocalocyclide D。[oc]25d -15.4。(c 1 ·0, CH2CI2); IRInocalocydide A, which is the compound (la) prepared in Example 1, was further subjected to acetylation reaction. After 3 hours of reaction, ice water was added to wait for 20 minutes, and it was quenched with ethyl acetate and concentrated to obtain a yield of 100%. The compound (Id), whose reaction is shown below, is called Inocalocyclide D. [oc] 25d -15.4. (c 1 · 0, CH2CI2); IR
(neat) υ max 1776,1685, 1606,1456, 1374 cnr1; EIMS w/z (rel· int·) 482 [M]+，440, 331， 318, 317, 275, 233, 219, 217,177, 123,109, 84, 69; iHNMR (CDC13, 300 MHz): δ 2,62 (1H， m，H-3A)，2.80 (1H，m，H-3B)，3·10 (1H，m，H-4)，4.20 (1H，m，H-10)，2·48 (1H, m，H-ll)， 1.45 (2H，m，H-15,16)，0.88 (t，/= 7.0 Hz, H-17)，1.50 (3H，d5 J= 6.0 Hz，H-21)，1.15 (1H，d， 6.7 Hz，H-22)，2·75 (2H，m，H-23)，2·39 (1H5 m，H-24)，2·10 (2H，t，《/= 6·5 Hz，Η·25)， 5·06 (1H，dd，J= 6·6,6·5 Hz，H-26)，4.44 (1H，s，H-28A)，4.60 (1H，s，H-28B)，1·72 (3H，s， H-30)，1·56 (3H，s，H-31)，1.66 (3H，s，H-32)，2.39 (3H，s，OAc); 13C NMR (CDCI3,75 MHz)·· δ 166.8 (s，C-2)，33.9 (t，03)，29.4 (d，C-4)，114.2 (s，C-5)，159.6 (s，06)，116.3 (s， C-7)，159.8 (s，C-8)，78.9 (d，C-10)，47.1 (d，Oil)，192.7 (s，C-12)，109.4 (s，13)，154.3 (d， C-14)，36.2 (t，C-15)，19.7 (d，C-16)，13.8 (q，C-17)，19.7 (q，C-21)，10.2 (q，C-22)，27·2 (t， C-23)，47·5 (d，C-24)，31·5 (t，C-25)，123.0 (d，C-26)，132.0 (s，027)，111·3 (t，C-28)，147.5 (s， C-29), 18.7 (q? C-30), 17.9 (q, C-31), 25.8 (q? C-32), 21.1 (q? OCOCH3)5 169.3 (s,(neat) υ max 1776,1685, 1606,1456, 1374 cnr1; EIMS w / z (rel · int ·) 482 [M] +, 440, 331, 318, 317, 275, 233, 219, 217,177, 123,109, 84, 69; iHNMR (CDC13, 300 MHz): δ 2,62 (1H, m, H-3A), 2.80 (1H, m, H-3B), 3.10 (1H, m, H-4), 4.20 (1H, m, H-10), 2.48 (1H, m, H-ll), 1.45 (2H, m, H-15, 16), 0.88 (t, / = 7.0 Hz, H-17) , 1.50 (3H, d5 J = 6.0 Hz, H-21), 1.15 (1H, d, 6.7 Hz, H-22), 2.75 (2H, m, H-23), 2.39 (1H5 m, H-24), 2 · 10 (2H, t, "/ = 6 · 5 Hz, Η · 25), 5 · 06 (1H, dd, J = 6 · 6, 6 · 5 Hz, H-26), 4.44 (1H, s, H-28A), 4.60 (1H, s, H-28B), 1.72 (3H, s, H-30), 1.56 (3H, s, H-31), 1.66 ( 3H, s, H-32), 2.39 (3H, s, OAc); 13C NMR (CDCI3, 75 MHz) ... δ 166.8 (s, C-2), 33.9 (t, 03), 29.4 (d, C -4), 114.2 (s, C-5), 159.6 (s, 06), 116.3 (s, C-7), 159.8 (s, C-8), 78.9 (d, C-10), 47.1 (d , Oil), 192.7 (s, C-12), 109.4 (s, 13), 154.3 (d, C-14), 36.2 (t, C-15), 19.7 (d, C-16), 13.8 (q , C-17), 19.7 (q, C-21), 10.2 (q, C-22), 27.2 (t, C-23), 47.5 (d, C-24), 31.5 (t, C-25), 123.0 (d, C-26) , 132.0 (s, 027), 111.3 (t, C-28), 147.5 (s, C-29), 18.7 (q? C-30), 17.9 (q, C-31), 25.8 (q? C-32), 21.1 (q? OCOCH3) 5 169.3 (s,
OCOCH3) 〇 15 1227238OCOCH3) 〇 15 1227238
A乙 醯 化A acetylation
(la) ： Ri=C3H7 由本化合物之反應例示可知，化合物所含羥基可以用任何已知之化學反應進行取代 基取代或保護基取代，而使化合物可進一步作反應修飾或是符合醫藥上之應用用途。 於此所引用之不同科學文章倂入爲參考資料。每一資料皆可作爲本說明書揭示之一 部分。熟於此技藝者將可從本發明之具體例示而運用改良之而不偏離本發明之應用14及 原則。也就是，本發明雖然藉由特定較佳具體例來敘述，但對熟於此技藝者爲明顯可知 之其他具體例改良也落於本發明之範圍內。 【圖式簡單說明】 隨附圖式欲倂入並成爲說明書之一部份，僅是描述本發明之具體例。與說明書的其 他部分一起欲提供熟於此技藝者解釋本發明之原則。在圖式中： 第1圖爲以異核多重鍵結相關光譜（HMBC)實驗法所推得本發明化合物（la)與 (lc)之結構(la): Ri = C3H7 It can be seen from the reaction examples of this compound that the hydroxyl group contained in the compound can be substituted with any known chemical reaction for substituent substitution or protection group, so that the compound can be further modified for reaction or meet the medical application . The various scientific articles cited herein are incorporated by reference. Each piece of information can be used as part of the disclosure in this manual. Those skilled in the art will be able to apply improvements from the specific examples of the invention without departing from the application 14 and principles of the invention. That is, although the present invention is described by using specific preferred specific examples, improvements to other specific examples that are obvious to those skilled in the art also fall within the scope of the present invention. [Brief description of the drawings] The accompanying drawings are intended to be incorporated into and become a part of the description, and are merely specific examples describing the present invention. Together with the rest of the description, it is intended to provide those skilled in the art to explain the principles of the invention. In the diagram: Figure 1 shows the structures of the compounds (la) and (lc) of the present invention derived from the heteronuclear multiple bond correlation spectrum (HMBC) experimental method.
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