WO2016116059A1 - 用于治疗代谢症候群的组合物及其制备方法 - Google Patents

用于治疗代谢症候群的组合物及其制备方法 Download PDF

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WO2016116059A1
WO2016116059A1 PCT/CN2016/071621 CN2016071621W WO2016116059A1 WO 2016116059 A1 WO2016116059 A1 WO 2016116059A1 CN 2016071621 W CN2016071621 W CN 2016071621W WO 2016116059 A1 WO2016116059 A1 WO 2016116059A1
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compound
carbon units
metabolic syndrome
composition
diabetes
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French (fr)
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张芳荣
吴永昌
谢翠娟
谢其庭
费伦茨•菲勒普
山多尔•鲍拉日•厄特沃什
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高雄医学大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • the present invention is primarily directed to a composition for treating metabolic syndrome and a process for its preparation, particularly a series of compounds of the chalcone type useful in the treatment of diabetes.
  • the number of people with diabetes will reach 360 million in 2030. If compared with 2000 and 2030, the number of people with diabetes in the United States will increase by 102%.
  • TZD drugs drugs that directly act on peripheral tissues such as adipose tissue and muscle on the market today are only TZD drugs. However, these drugs have been removed or discontinued in many countries due to the discovery of adverse side effects. It is worth noting that the market for TZD drugs will be replaced by a large number of other new drugs.
  • Taiwan Patent No. I417088 discloses a chalcone compound for treating diabetes and metabolic diseases, especially when the chalcone compound contains an A ring 2-halogen.
  • the blood glucose concentration can be significantly reduced in the external anti-diabetic test.
  • the lead chalcone compound prevents the deterioration of diabetes, controls blood sugar levels, and has no significant increase in body weight. No liver or kidney toxicity was observed after 7 weeks of administration.
  • the present invention actively develops novel small molecule drugs which can reduce the resistance of peripheral tissues to insulin, and is expected to provide a niche for the new drug development market in Taiwan.
  • the present invention is directed to the optimization design and improvement of the chalcone compound, and it is found that if a triple bond functional group is present in the six carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) structure, cytotoxicity may occur. After optimized modification, the present invention finds a new series of combinations that can also have anti-diabetic activity but avoid cytotoxicity.
  • the present invention relates to a composition of an organic compound containing a C6-C3-C6 dihydrochalcone skeleton.
  • the composition of the dihydrochalcone is disclosed for the treatment of diabetes and metabolic syndrome and a preparation method thereof.
  • the present invention provides a compound having a dihydrochalcone skeleton, such as the structure of Formula I, wherein R1 is one of a group consisting of hydrogen, deuterium, and oxygen, R2 It is one of a group consisting of hydrogen, alkoxy, benzyloxy and halogen, and the C3 moiety in the structure may be composed of a single bond, a double bond or a triple bond.
  • R1 is one of a group consisting of hydrogen, deuterium, and oxygen
  • R2 It is one of a group consisting of hydrogen, alkoxy, benzyloxy and halogen
  • the C3 moiety in the structure may be composed of a single bond, a double bond or a triple bond.
  • the present invention provides a composition for treating one of diabetes and metabolic syndrome, comprising a compound of six carbon units - three carbon units - six carbon units (C6-C3-C6), such as the structure of formula I, wherein R Both 1 and R 2 are hydrogen, and the structure of C3 is a single bond.
  • the present invention also provides a composition for treating one of diabetes and metabolic syndrome, comprising a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula I, wherein R 1 is oxygen, and R 2 is alkoxy, benzyloxy
  • the present invention also provides a composition for treating one of diabetes and metabolic syndrome, comprising a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula I, wherein R The 1 series is one of a group consisting of hydrogen, deuterium, and oxygen, and the R 2 is hydrogen, alkoxy, benzyloxy, and halogen.
  • R The 1 series is one of a group consisting of hydrogen, deuterium, and oxygen
  • the R 2 is hydrogen, alkoxy, benzyloxy, and halogen.
  • One of the groups consisting of (halogen) and the structure of C3 is composed of a single bond or a double bond.
  • the present invention also provides a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula II, wherein R 1 is deuterium and R 2 is halogen (halogen ), and the structure of C3 is composed of a single bond, a double bond or a triple bond.
  • C6-C3-C6 such as the structure of formula II, wherein R 1 is deuterium and R 2 is halogen (halogen ), and the structure of C3 is composed of a single bond, a double bond or a triple bond.
  • the present invention also provides a compound for treating a six carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) which is one of diabetes and metabolic syndrome, such as the structure of formula II, wherein R 1 is ⁇ (deuterium).
  • the present invention also provides a compound for treating a six carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) which is one of diabetes and metabolic syndrome, such as the structure of formula II, wherein R 2 is halogen (halogen).
  • C6-C3-C6 six carbon unit-three carbon unit-hexacarbon unit
  • the present invention also provides a compound for treating a six-carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) which is one of diabetes and metabolic syndrome, such as the structure of formula II, wherein the structure of C3 is The key is composed.
  • C6-C3-C6 six-carbon unit-three carbon unit-hexacarbon unit
  • FIG. 1 - 5 illustrate a C6-C3-C6 according to an embodiment of the present invention
  • 6A-6C illustrate screening results of fat cell activity for glucose utilization
  • Figure 7 shows the screening results of muscle cells for glucose utilization activity
  • Figure 8 shows accumulation of fat cells and oil droplets under a microscope
  • Figure 9 shows the accumulation of fat droplets in fat cells
  • Figures 13-20 show micrographs of undifferentiated adipocytes administered to the same concentration of different compounds and allowed to stand for 24 hours.
  • the C6-C3-C6 compound can be isolated from natural plants such as chrysanthemum, medlar, and lily, and is classified into flavonoids. The case was inspired by natural materials and attempted to make a breakthrough.
  • the halogen elements not present in the plant extract were added to the structure to create a series of chalcone type double bond compounds, and such halogen-containing compounds were first discovered.
  • the structure promotes glucose utilization in fat cells as well as muscle cells. It has been further found in animal experiments that it can prevent or even ameliorate glucose intolerance caused by obesity.
  • the present invention maintains the C6-C3-C6 backbone and the halogen element in the compound, and then reforms the C3 bridge connecting the middle of the biphenyl ring.
  • the C3 moiety is synthesized as a triple bond compound, or reduced to a single bond compound, and tested for activity.
  • the present invention further converts the hydrogen atom bonded to C3 into a stable isotope by a fluid chemical technique, and becomes a completely new compound.
  • the present invention further modifies the C3 structure to produce more artificial halogen-containing or cerium-containing C6-C3-C6 compounds which are not found in nature.
  • various synthetic methods were used to synthesize and structurally modify C6-C3-C6 organic compounds, and fluid chemical techniques were used to synthesize novel compounds containing antimony.
  • C6-C3-C6 synthesis method (I)-(IX)), which illustrate various C6-C3-C6 compounds produced according to the examples of the present invention in FIGS. 1 to 5: 2I3, 2Br3 2Cl3, 2F3, CHT3, 2I2D, 2Br2D, 2Cl2D, 2F2D, CHT2D, 2I1D, 2Br1D, 2Cl1D, 2F1D, CHT1D, 2I1H, 2Br1H, 2Cl1H, 2F1H, CHT1H, 2IOH, 2BrOH, 2I1DOH, 2Br1DOH, and the like.
  • a compound having a triple bond structure (I) is reduced to a C3 moiety in the structure by helium (D 2 ), and a plurality of C6-C3-C6 compounds containing a D element can be obtained.
  • the method is to place the starting material in a helium environment, and a metal catalyst is added to accelerate the deuteration reduction reaction.
  • the C3-C3-C6 compound having a plurality of hydrogen-containing elements can be obtained by reducing the C3 moiety of the structure of the first-type compound having a triple bond structure with hydrogen (H 2 ).
  • the method is to place the starting material in a hydrogen atmosphere and add a metal catalyst to accelerate the hydrogenation reduction reaction.
  • a cerium-containing compound different from the method (III) can be obtained by subjecting a general chalcone compound to a helium gas environment to carry out deuteration reduction with a metal catalyst.
  • Preparation method is used The system, part of which electrolyzes water, electrolyzes water into oxygen and hydrogen and feeds the hydrogen into the pipeline.
  • the starting materials as well as the hydrogen will be thoroughly mixed and passed through the metal catalyst to produce a hydrogenation reduction reaction.
  • the starting material used is (E)-1-(2-iodophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one, (2I 2 H), and This was dissolved in ethyl acetate (1 mg/ml); the metal catalyst used 5% platinum (Pt) / alumina (Al 2 O 3 ) and 5% palladium (Pd) / barium sulfate (BaSO 4 ), The helium gas is generated by electrolytic cerium oxide, and the pressure and temperature are controlled to carry out the hydrazine reduction reaction.
  • results are expressed as mean ⁇ standard error (SE).
  • SE standard error
  • Statistical differences were derived from independent and paired Student T tests for paired and unpaired samples, respectively.
  • ANOVA one-way variation analysis
  • Student-Newman-Keuls assay is used.
  • Significantness was represented in all experiments with a P value of less than 0.05.
  • Data was analyzed and plotted by running SigmaPlot software (Version 8.0/Chicago/IL/U.S.A.) and SigmaStat (Version 2.03/Chicago/IL/U.S.A.) on an IBM compatible computer.
  • the following invention utilizes various cell patterns to determine its toxicity as well as biological activity to identify more potential compounds.
  • the obtained compounds were selected for toxicity testing and cell activity screening.
  • SAR structure and activity
  • This discussion includes the glucose utilization of C6-C3-C6 compounds for adipocytes and muscle cells and their effects on energy metabolism pathways.
  • FIGS. 6A-6C show the screening results of the fat cell glucose utilization activity in the culture solution.
  • Figures 6A-6C further show that a plurality of halogens (such as chlorine, bromine, Compounds of iodine) can increase the glucose utilization rate of fat cells. Many of them contain more new compounds. A number of known compounds are the first to reveal this activity.
  • Symbol Con indicates Control group; symbol 5 indicates compound 2Br2H; symbol 6 indicates compound 2I2H; symbol Met indicates metformin; symbol AI indicates AMPK inhibitor; symbol L indicates use of low dose 15 ug/ml;
  • the fat cell glucose utilization test method is detailed as follows:
  • the glucose utilization rate of the control group was about 20% after 24 hours of changing the culture solution; the glucose utilization rate of the control group added with insulin was increased to 30%; and the cell glucose utilization rate of the commercially available drug Pioglitazone group of 30ug/ml was used. Then increase to 40%.
  • the double-bonded compound starting material 2I2H group has a glucose utilization rate of more than 50%; the single-bond compound product 2I1D group has a glucose utilization rate of more than 50%.
  • the drug concentration of 30 ug/ml neither Compound 2I2H nor 2I1D showed cytotoxicity, and it was found that the structure after reduction can improve the cytotoxicity problem and produce or maintain a certain glucose utilization activity.
  • Figure 7 shows the screening results of muscle cell glucose utilization activity.
  • Figure 7 further shows that a plurality of compounds containing halogens (e.g., chlorine, bromine, iodine) can increase the glucose utilization of fat cells. Many of them contain more new compounds. Multiple known combinations The first time this activity was revealed.
  • the symbol Con is the Control group; the symbol Ins indicates the Insulin group; the symbol Rosi indicates the Rosiglitazone group; the symbol Pio indicates the pioglitazone group; the symbol 1 indicates the compound CHT; the symbol 2 indicates the compound 2OH2H; the symbol 3 indicates the compound 2F2H; the symbol 4 indicates the compound 2Cl2H; The compound 2Br2H is indicated; the symbol 6 indicates the compound 2I2H.
  • halogens e.g., chlorine, bromine, iodine
  • Figure 8 shows the accumulation of fat cells and oil droplets under the microscope, the symbol Con indicates the Control group; the symbol 1 indicates the compound CHT; the symbol 2 indicates the compound 2OH2H; the symbol 3 indicates the compound 2F2H; the symbol 4 indicates the compound 2Cl2H; the symbol 5 indicates the compound 2Br2H; Symbol 6 indicates the compound 2I2H. It can be seen that the fat cells in each experimental group are substantially maintained in a normal form, and it can be inferred that in the case of using a low drug concentration, the various compounds of the present invention have no obvious cytotoxicity.
  • Fig. 9 shows the accumulation of fat cell oil droplets in the culture solution.
  • the figure shows that a plurality of compounds containing halogens such as chlorine (symbol 4), bromine (symbol 5), and iodine (symbol 6) can increase the glucose utilization rate of fat cells without increasing the accumulation of cell oil droplets. Many of them contain more new compounds.
  • a number of known compounds are the first to reveal this activity.
  • the symbol Con indicates the Control group; the symbol 1 indicates the compound CHT; the symbol 2 indicates the compound 2OH2H; the symbol 3 indicates the compound 2F2H; the symbol 4 indicates the compound 2Cl2H; the symbol 5 indicates the compound 2Br2H; and the symbol 6 indicates the compound 2I2H.
  • this C6-C3-C6 activates the AMPK pathway, increases cellular glucose utilization, and regulates the way energy is used, in which no fatty oil is accumulated in the cells. Further, it can affect the resistance of insulin and achieve the effect of improving metabolic syndrome.
  • undifferentiated adipocytes are administered to the same concentration of different compounds (control, CHT3, 2I3, 2I2H, 2F3, 2Cl3, 2Br3, and 2Br2H), respectively.
  • control CHT3, 2I3, 2I2H, 2F3, 2Cl3, 2Br3, and 2Br2H
  • the microscope photographs were allowed to stand for 24 hours. Compared with the complete cell arrangement of the control group, it can be inferred from the broken cell type in each test group that the triple bond compound is cytotoxic.
  • the organic compound of the C6-C3-C6 skeleton disclosed in the present invention has a halogen or a stable isotope substituent, which is completely different from the compound present in the natural substance.
  • Such compounds are novel compounds and no activity has been reported in the literature, indicating that the case is novel.
  • some specific compounds in the present invention not only have the functions of regulating fat cell and muscle cell glucose utilization and metabolic pathway, but also the activity of the TZD drugs. Not identical, and reduced cytotoxicity, indicating that the invention is both novel and progressive.
  • the future development in the new drug development and pharmaceutical industry is very niche.
  • the cerium-containing compound still had the same degree of biological activity. Compared with the triple bond compound, its cytotoxicity is also greatly reduced. There are no drugs containing strontium in the currently marketed drugs, and the invention is extremely novel, progressive, and industrially useful.
  • the triple bond compound was found to be cytotoxic to adipocytes, but the single bond compound maintained drug activity and reduced cytotoxicity.
  • Such halogen-containing C6-C3-C6 single bond compounds have not been found to have regulatory cell glucose utilization.
  • the activity of the rate, the invention has the requirements of progress and novelty.
  • a composition for treating one of diabetes and metabolic syndrome comprising a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula I, wherein R 1 and R 2 is hydrogen and the structure of C 3 is a single bond.
  • a composition for treating one of diabetes and metabolic syndrome comprising a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula I, wherein the R 1 system In the case of oxygen, R 2 is one of a group consisting of alkoxy, benzyloxy and halogen, and the structure of C3 is a single bond.
  • a composition for treating one of diabetes and metabolic syndrome comprising a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6), such as the structure of formula I, wherein the R 1 system One of a group consisting of hydrogen, deuterium, and oxygen, R 2 is hydrogen, alkoxy, benzyloxy, and halogen (halogen) One of the groups formed, and the structure of C3 consists of a single bond or a double bond.
  • composition of embodiment 3 further for regulating and stabilizing the blood glucose level of the cells.
  • composition of embodiment 4 further for inhibiting poor glucose tolerance or weight gain in an animal.
  • composition of embodiment 4 further for inhibiting or delaying the onset of metabolic syndrome in an animal.
  • a compound of a six carbon unit - a three carbon unit - a six carbon unit (C6-C3-C6) such as the structure of formula II, wherein R1 is deuterium, R2 is halogen, and C3
  • the structure consists of a single bond, a double bond or a triple bond.
  • a compound for treating a six-carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) which is one of diabetes and metabolic syndrome, such as the structure of formula II, wherein R 1 is deuterium (deuterium) ).
  • a compound of the six carbon unit - three carbon unit - six carbon unit (C6-C3-C6) for treating one of diabetes and metabolic syndrome such as the structure of formula II:
  • R 2 is a halogen
  • a compound of the six carbon unit-three carbon unit-hexacarbon unit (C6-C3-C6) for treating one of diabetes and metabolic syndrome such as the structure of formula II, wherein the structure of C3 is represented by a single bond Composition.

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Abstract

一种用于治疗糖尿病和代谢综合症的组合物，包括下式所示的六碳单元-三碳单元-六碳单元（C6-C3-C6）的化合物，其中R1和R2为H，C3的结构为单键。

Description

用于治疗代谢症候群的组合物及其制备方法 【技术领域】
本发明主要相关于一种用于治疗代谢症候群的组合物及其制备方法，特别是可用于治疗糖尿病的一系列查耳酮(chalcone)类型的化合物。
【先前技术】
根据世界卫生组织(World Health Organization,WHO)预估，2030年糖尿病人数到将达到3.6亿，若以2000年和2030年相较，推估美国糖尿病人数将增加102％。
同样地，推估欧洲将增加43％，亚太地区将增加130％，全球糖尿病人数呈现快速累进。而药品市场更预估2015年糖尿病药物销售总额将达到430～480亿美元。
日前由生物技术开发中心统计2010年全球糖尿病药物市占率前三名分别是胰岛素(Insulin)及类似物(52.8％)、Glitazone(TZD类药物，17.2％)及DPP 4抑制剂(Dipeptidyl peptidase 4inhibitors，10.4％)。
然而现今市场上直接作用于周边组织，例如脂肪组织以及肌肉之药物仅有TZD类药物。但此类药物因发现不良副作用已遭多国下架或停用。值得注意的是TZD类药物之市场将被其他新型药物大量瓜分病取代。
台湾专利号I417088公开一种治疗糖尿病及新陈代谢疾病的查耳酮(chalcone)化合物，尤其当查耳酮化合物含有A环2-卤素时，在体 外抗糖尿病实验中能显着地降低血糖浓度。在体内的动物实验中，先导查耳酮化合物可预防糖尿病症的恶化、控制血糖值，且体重无明显增加。经七周给药后未发现有肝、肾毒性反应。
【发明内容】
为了促进病患福祉，本发明积极开发可减少周边组织胰岛素抗阻性之新型小分子药物，并期待能为台湾新药开发市场提供利基。
本发明针对查耳酮类的化合物进行优化设计以及改良后，发现若六碳单元-三碳单元-六碳单元(C6-C3-C6)结构中若存在三键官能基会造成细胞毒性，经优化修饰后，本发明找到同样可以具有抗糖尿病活性，但可避免细胞毒性之新一系列化合。
本发明涉及含有C6-C3-C6的二氢查耳酮(dihydrochalcone)骨架的有机化合物的组合物。并揭露此二氢查耳酮的组合物用于治疗糖尿病和代谢症候群及其制备方法。
本发明提供一种具有二氢查耳酮骨架的化合物，如式I的结构，其中R1系为氢(hydrogen)、氘(deuterium)和氧(oxygen)所组成的群组其中之一，R2系为氢(hydrogen)、甲氧基(alkoxy)、苄氧基(benzyloxy)和卤素(halogen)所组成的群组其中之一，结构中C3部分可由单键、双键或三键构成。
Figure PCTCN2016071621-appb-000001
Figure PCTCN2016071621-appb-000002
本发明提供了一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1和R2皆系为氢(hydrogen)，且C3的结构系属单键。
Figure PCTCN2016071621-appb-000003
本发明还提供一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1系为氧(oxygen)，R2系为甲氧基(alkoxy)、苄氧基
(benzyloxy)和卤素(halogen)所组成的群组其中之一，且C3的结构系属单键。
Figure PCTCN2016071621-appb-000004
Figure PCTCN2016071621-appb-000005
本发明还提供一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1系为氢(hydrogen)、氘(deuterium)和氧(oxygen)所组成的群组其中之一，R2系为氢(hydrogen)、甲氧基(alkoxy)、苄氧基(benzyloxy)和卤素(halogen)所组成的群组其中之一，且C3的结构由单键或双键所构成。
Figure PCTCN2016071621-appb-000006
本发明还提供一种六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中R1系为氘(deuterium)，R2系为卤素(halogen)，且C3的结构由单键、双键或三键所构成。
Figure PCTCN2016071621-appb-000007
本发明还提供一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中R1系为氘(deuterium)。
Figure PCTCN2016071621-appb-000008
本发明还提供一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中R2系为卤素(halogen)。
Figure PCTCN2016071621-appb-000009
本发明还提供一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中C3的结构由单键所构成。
Figure PCTCN2016071621-appb-000010
Figure PCTCN2016071621-appb-000011
在参考下列说明和其图式之后，对本领域人士而言，本发明的目的与优点将变得更加明显，其中：
【图式简单说明】
图1-图5绘示根据本发明之实施例的C6-C3-C6；
图6A-图6C绘示脂肪细胞对于葡萄糖利用率活性之筛选结果；
图7绘示肌肉细胞对于葡萄糖利用率活性之筛选结果；
图8绘示在显微镜下脂肪细胞及油滴累积；
图9绘示脂肪细胞油滴累积之情形；
图10-12绘示C6-C3-C6可活化AMPK路径；
图13-20绘示未分化脂肪细胞分别给予相同浓度之不同化合物，并静置24小时后之显微镜照相图片。
【实施方式】
更多的实施例可衍生自将以下某一实施例之中一或多个元素另行取代，或将一实施例之中一或多个元素以一或多个其他实施例之中一或多个元素予以取代而变化得出。
以下的实施例系用于示例特定实施方式，而其可支持以下一或多个例子中的一或多个细节，或一例子之中一或多个元素以一或多个其 他例子之中一或多个元素予以取代的情况。
C6-C3-C6化合物在天然物中可由菊、樟、百合等植物中分离而得到，其分类为黄酮类。而本案自天然物中获得灵感并尝试获得突破，在结构中加入植物萃取物中不存在的卤素元素，创造一系列查耳酮(chalcone)类型双键化合物，并且首次发现此类含卤素之化合物结构可以促进脂肪细胞以及肌肉细胞的葡萄糖利用率。在动物实验中更进一步发现可以预防、甚至改善肥胖造成的葡萄糖不耐症。
以查耳酮为基础，本发明维持C6-C3-C6骨架以及化合物中含有卤素要件，随即针对连接两苯环中间之C3架桥进行改造。例如将C3部分合成为三键化合物，或是还原为单键化合物，并测试其活性。
此外，药物化学家一向对于稳定同位素化合物极感兴趣，在药物生体可利用率研究中占有极重要之角色。不但可以做为追踪标的(Tracer)，甚至可以改变药物在人体中的代谢速率。但以旧技术而言，此项研究过于昂贵，而导致许多研究无法进行。
但本案使用先进之流体化学技术，可以将氘元素接在化合物特定位置上，成本大幅降低后，可以进行更深入之药物研究。于是本发明更进一步将C3上连结之氢原子以流体化学技术改为稳定同位素氘，成为全新之化合物。
结合以上概念，本发明更进一步对于C3结构进行修饰，制造更多非自然界存在之人造含卤素或含氘之C6-C3-C6化合物。本案利用各种合成方法技术进行C6-C3-C6类有机化合物之合成及结构修饰，并利用流体化学技术合成含氘元素之全新化合物。
以下系关于C6-C3-C6合成方法((Ⅰ)-(Ⅸ))，其示例图1-图5之中根据本发明之实施例所产生的各种C6-C3-C6化合物：2I3、2Br3、2Cl3、2F3、CHT3、2I2D、2Br2D、2Cl2D、2F2D、CHT2D、2I1D、2Br1D、2Cl1D、2F1D、CHT1D、2I1H、2Br1H、2Cl1H、2F1H、CHT1H、2IOH、2BrOH、2I1DOH、2Br1DOH等。
(Ⅰ)使用薗头耦合(Sonogashira coupling)的合成方法制造各种含有三键官能基类型之C6-C3-C6化合物，其两苯环间中间连接之C3结构含有酮基(ketone)以及碳-碳三键(Alkyne)。
Figure PCTCN2016071621-appb-000012
(Ⅱ)一般双键类型查耳酮合成方法：使用醛醇缩合(Aldol condensation)反应合成方法组合苯甲醛(Benzaldehyde)类化合物以及苯乙酮(Acetophenone)类化合物。
Figure PCTCN2016071621-appb-000013
(Ⅲ)将(I)含三键结构之化合物以氘气(D2)还原结构中C3部分，可得到多种含D元素之C6-C3-C6化合物。方法为将起始物置于氘气环境中，并加入金属催化剂加速氘化还原反应。
Figure PCTCN2016071621-appb-000014
(Ⅳ)将第Ⅰ类含三键结构之化合物以氢气(H2)还原结构中C3部分，可得到多种含氢元素之C6-C3-C6化合物。方法为将起始物置于氢气环境中，并加入金属催化剂加速氢化还原反应。
Figure PCTCN2016071621-appb-000015
(Ⅴ)从一般查耳酮化合物置于氘气环境中以金属催化剂进行氘化还原，可得到与方法(Ⅲ)不同之含氘化合物。
Figure PCTCN2016071621-appb-000016
(Ⅵ)trans-β-benzylstyrene以及cis-β-benzylstyrene类的衍生物制备方法。
Figure PCTCN2016071621-appb-000017
(Ⅶ)含氘trans-β-benzylstyrene以及cis-β-benzylstyrene类的衍生物制备方法。
Figure PCTCN2016071621-appb-000018
(Ⅷ)自(Ⅵ)获得之产物进行氢化还原反应可得到1,3-di-phenylpropane类的衍生物。
Figure PCTCN2016071621-appb-000019
(Ⅸ)自(Ⅶ)获得之产物进行氘化还原反应可得到含氘元素之1,3-di-phenylpropane类的衍生物。
Figure PCTCN2016071621-appb-000020
关于含氘化合物的合成方法的实施例:
2,3-dideutero-1-(2-iodophenyl)-3-(4-methoxyphenyl)propan-1-one的制备
制备方法系使用
Figure PCTCN2016071621-appb-000021
系统，其电解水系统的部分可将水电解为氧气以及氢气，并将氢气送入管线中。起始物以及氢气将充分混合，并流经金属催化剂，以产生氢化还原反应。
在本实施例中，所使用的该起始物为(E)-1-(2-iodophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one，(2I2H)，并将其溶于乙酸乙酯中(1mg/ml)﹔该金属催化剂使用5％铂(Pt)/三氧化二铝(Al2O3)以及5％钯(Pd)/硫酸钡(BaSO4)，并改以电解氧化氘产生氘气，并控制压力以及温度以进行氘化还原反应。
结果发现以5％钯(Pd)/硫酸钡(BaSO4)无法对于此起始物进行还原反应，于是改使用5％铂(Pt)/三氧化二铝(Al2O3)进行反应。优化反应条件后，以100℃以及压力100bar，而流速设定为1ml/min，可以得 到产物2,3-dideutero-1-(2-iodophenyl)-3-(4-methoxyphenyl)propan-1-one，(2I1D)。
物理数据
2,3-dideutero-1-(2-iodophenyl)-3-(4-methoxyphenyl)propan-1-one(2I1D)
淡黄色油状化合物：1H NMR(400MHz,CHLOROFORM-d),δ＝2.96-2.98(m,1H),3.15-3.17(m,1H),3.77(s,3H),6.82(d,J＝8.81Hz,2H),7.09(t,J＝7.62Hz,1H),7.14(d,J＝8.56Hz,2H),7.30(dd,J＝7.68,1.64Hz,1H),7.36(t,J＝7.60Hz,1H),7.89ppm(d,J＝8.06Hz,1H)；13C NMR(101MHz,CHLOROFORM-d),δ＝28.81,43.86,55.23,90.91,113.88(2C),127.74,127.99,129.35(2C),131.53,132.68,140.49,144.52,157.99,204.07ppm；MS(EI):m/z(％):367.91,241.13,122.11,109.14.
CHT1D 2,3-dideutero-1,3-diphenylpropan-1-one
无色油状化合物：1H NMR(400MHz,CHLOROFORM-d,25℃,TMS):δ＝3.07(br.s.,1H),3.21-3.35(m,1H),7.16-7.41(m,5H,and solvent peak),7.44-7.48(m,2H),7.54-7.58(m,1H),7.97ppm(d,J＝7.55Hz,2H)；13C NMR(101MHz,CHLOROFORM-d,25℃,TMS),δ＝29.51,39.69,126.04,127.96(2C),128.32(2C),128.44(2C),128.50(2C),132.94,136.81,141.15,199.16ppm.MS(EI):m/z(％):212.06,105.05,77.1,51.09.
2F1D
2,3-dideutero-1-(2-florophenyl)-3-(4-methoxyphenyl)propan-1-one(2dA)
无色油状化合物：1H NMR(400MHz,CHLOROFORM-d),δ＝2.98-2.99(m,1H),3.27-3.29(m,1H),3.80(s,3H),6.85(d,J＝8.56Hz,2H),7.11-7.27(m,4H),7.51-7.52(m,1H),7.84-7.88ppm(m,1H)；13C NMR(101MHz,CHLOROFORM-d)δ＝28.67,45.03,55.18,113.81(2C),116.72,124.41,129.32(2C),130.61,133.06,134.00,134.44,157.81,163.1,197.79ppm；MS(EI):m/z(％):260.07,122.10,109.13.
2Cl1D
2,3-dideutero-1-(2-chlorophenyl)-3-(4-methoxyphenyl)propan-1-one
无色油状化合物：1H NMR(400MHz,CHLOROFORM-d)δ＝2.97–2.98(m,1H),3.20-3.22(m,1H),3.77(s,3H),6.83(d,J＝8.56Hz,2H),7.14(d,J＝8.56Hz,2H),7.27-7.41ppm(m,4H)；13C NMR(101MHz,CHLOROFORM-d),δ＝28.82,44.26,55.11,113.78(2C),126.81,128.81,129.22(2C),130.37,130.73,131.58,132.61,139.25,157.88,202.60ppm；MS(EI):m/z(％):276.09,241.14,139.01,122.11,109.14.
2Br1D
2,3-dideutero-1-(2-bromophenyl)-3-(4-methoxyphenyl)propan-1-one(4dA)
无色油状化合物：1H NMR(400MHz,CHLOROFORM-d),δ＝3.02-3.04(m,1H),3.23-3.25(m,1H),3.82(s,3H),6.87(d,J＝8.56Hz,2H),7.18(d,J＝8.31Hz,2H),7.30–7.37(m,3H),7.63ppm(d,J＝7.55Hz,1H)；13C NMR(101MHz,CHLOROFORM-d),δ＝28.74,44.36,55.11,113.77(2C),118.51,127.30,128.33,129.23(2C),131.43,132.54,133.49,141.51,157.87,203.44ppm；MS(EI):m/z(％):321.96,319.98,241.14,240.12,184.99,183.00,122.12,108.12.
2I1D
2,3-dideutero-1-(2-iodophenyl)-3-(4-methoxyphenyl)propan-1-one(5dA)
淡黄色油状化合物：1H NMR(400MHz, CHLOROFORM-d),δ＝2.96-2.98(m,1H),3.15-3.17(m,1H),3.77(s,3H),6.82(d,J＝8.81Hz,2H),7.09(t,J＝7.62Hz,1H),7.14(d,J＝8.56Hz,2H),7.30(dd,J＝7.68,1.64Hz,1H),7.36(t,J＝7.60Hz,1H),7.89ppm(d,J＝8.06Hz,1H)；13C NMR(101MHz,CHLOROFORM-d),δ＝28.81,43.86,55.23,90.91,113.88(2C),127.74,127.99,129.35(2C),131.53,132.68,140.49,144.52,157.99,204.07ppm；MS(EI):m/z(％):367.91,241.13,122.11,109.14.
统计估计数据
结果系以平均值(mean)±标准误差(SE)表示。统计差异分别来自于针对配对与未配对样本的独立和配对的学生T检定。当一控制组和一或多个实验组进行比较时，采用单向变异数分析(ANOVA)或双向重复量测变异数分析。当上述变异数分析呈现一统计差异时，便采用Dunnett或Student-Newman-Keuls检定。在所有实验中以P值小于0.05代表具有显着性。藉由运行于与IBM相容的电脑上的SigmaPlot软体(Version 8.0/Chicago/IL/U.S.A.)和SigmaStat(Version 2.03/Chicago/IL/U.S.A.)而分析数据并绘图。
以下本发明利用各种细胞模式测定其毒性以及生物活性，找出更多潜力化合物。挑选获得之化合物，进行毒性测试和细胞活性筛选。另外，进行结构与活性的关系(SAR)探讨。该探讨包括C6-C3-C6化合物对于脂肪细胞以及肌肉细胞之葡萄糖利用率以及其对能量代谢途径之影响。
请参阅图6A-图6C，其显示在培养液之中的脂肪细胞葡萄糖利用率活性之筛选结果。图6A-图6C进一步显示多项含有卤素(例如氯、溴、 碘)之化合物可以增加脂肪细胞之葡萄糖利用率。其中多项含氘化合物更为新化合物。多项已知化合物为首次揭露此活性。符号Con指示Control组；符号5指示化合物2Br2H；符号6指示化合物2I2H；符号Met指示metformin；符号AI指示AMPK inhibitor；符号L指示使用低剂量15ug/ml；符号H指示使用高剂量30ug/ml。
其中，脂肪细胞葡萄糖利用率测试方法详述如下：
2,3-dideutero-1-(2-iodophenyl)-3-(4-methoxyphenyl)propan-1-one测试药物浓度30ug/ml与成熟脂肪细胞共培养24小时，测试其培养液中葡萄糖浓度之变化。
首先观察控制组在更换培养液24小时后其葡萄糖利用率约20％；加入胰岛素之对照组细胞之葡萄糖利用率则提升至30％；使用30ug/ml市售药物Pioglitazone组别之细胞葡萄糖利用率则提升至40％。
请继续参阅图6A，其中含三键结构之化合物：
1-(2-iodophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one，(2I3)，产生明显细胞毒性。双键化合物起始物2I2H组别之细胞葡萄糖利用率可超过50％；加入单键化合物产物2I1D组别之细胞，其葡萄糖利用率亦超过50％。在使用药物浓度30ug/ml情况下，化合物2I2H以及2I1D均无显示细胞毒性，可见经由还原后之结构可以改善细胞毒性的问题，并产生或维持一定之葡萄糖利用率活性。
请参阅图7，图7显示肌肉细胞葡萄糖利用率活性之筛选结果。图7进一步显示多项含有卤素(例如氯、溴、碘)之化合物可以增加脂肪细胞之葡萄糖利用率。其中多项含氘化合物更为新化合物。多项已知化合 物为首次揭露此活性。符号Con为Control组；符号Ins指示Insulin组；符号Rosi指示Rosiglitazone组；符号Pio指示pioglitazone组；符号1指示化合物CHT；符号2指示化合物2OH2H；符号3指示化合物2F2H；符号4指示化合物2Cl2H；符号5指示化合物2Br2H；符号6指示化合物2I2H。
图8绘示在显微镜下脂肪细胞及油滴累积，符号Con指示Control组；符号1指示化合物CHT；符号2指示化合物2OH2H；符号3指示化合物2F2H；符号4指示化合物2Cl2H；符号5指示化合物2Br2H；符号6指示化合物2I2H。可以看出在各个实验组之中的脂肪细胞大致维持正常型态，可以推知在使用低药物浓度的情况下，本案的各式化合物并无明显细胞毒性。
请参阅图9，其显示在培养液之中脂肪细胞油滴累积之情形。图中显示多项含有卤素，例如氯(符号4)、溴(符号5)、碘(符号6)之化合物可以增加脂肪细胞之葡萄糖利用率，但不增加细胞油滴累积。其中多项含氘化合物更为新化合物。多项已知化合物为首次揭露此活性。符号Con指示Control组；符号1指示化合物CHT；符号2指示化合物2OH2H；符号3指示化合物2F2H；符号4指示化合物2Cl2H；符号5指示化合物2Br2H；符号6指示化合物2I2H。
请参阅图10-12，其显示此C6-C3-C6可活化AMPK路径，增加细胞葡萄糖利用率，并调节能量的运用方式，其中不累积脂肪油滴于细胞内。进一步可影响胰岛素抗阻性，并达到改善代谢症候群之效果。
请参阅图13-20，其显示未分化脂肪细胞分别给予相同浓度之不同化合物(control、CHT3、2I3、2I2H、2F3、2Cl3、2Br3以及2Br2H)， 并静置24小时后之显微镜照相图片。相较于控制组的完整细胞排列，由各受试组之中破碎的细胞型态而可推知，三键化合物多具有细胞毒性。
总之，本案所揭露之C6-C3-C6骨架之有机化合物，具有卤素或稳定同位素之取代基，与天然物中所存在之化合物完全不同。此类化合物为新化合物，亦无文献报导过此活性，显示本案具有新颖性。
经由结构与活性的关系(SAR)研究结果显示，本发明之中某些特定化合物不但具有调节脂肪细胞以及肌肉细胞葡萄糖利用率及代谢途径之功能，其活性机转与已下架之TZD类药物并不相同，并且减少细胞毒性，显示此发明同时具备新颖性以及进步性。未来在新药开发及制药产业上之发展极具利基。
经由活性测试后发现含氘元素之化合物仍然具有相同程度的生物活性。与三键化合物相比，其细胞毒性亦大幅降低。目前市售药物中并无含氘元素之药物，此发明极具新颖性、进步性，以及产业利用性。
本案发现三键化合物对脂肪细胞造成细胞毒性，但单键化合物却能维持药物活性并降低细胞毒性，而此类含卤素之C6-C3-C6单键化合物并未被发现过具有调节细胞葡萄糖利用率之活性，此发明具备进步性以及新颖性之要件。
实施例
1.一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1和R2皆系为氢(hydrogen)，且C3的结构系属单键。
Figure PCTCN2016071621-appb-000022
2.一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1系为氧(oxygen)，R2系为甲氧基(alkoxy)、苄氧基(benzyloxy)和卤素(halogen)所组成的群组其中之一，且C3的结构系属单键。
Figure PCTCN2016071621-appb-000023
3.一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构，其中R1系为氢(hydrogen)、氘(deuterium)和氧(oxygen)所组成的群组其中之一，R2系为氢(hydrogen)、甲氧基(alkoxy)、苄氧基(benzyloxy)和卤素(halogen)所组成的群组其中之一，且C3的结构由单键或双键所构成。
Figure PCTCN2016071621-appb-000024
Figure PCTCN2016071621-appb-000025
4.如实施例3所述之组合物，还用以调节并稳定细胞之血糖值。
5.如实施例4所述的组合物，还用以抑制一动物体之不良葡萄糖耐受性或体重增加。
6.如实施例4所述的组合物，还用以抑制或延缓一动物体之代谢症候疾病的发生。
7.一种六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中R1系为氘(deuterium)，R2系为卤素(halogen)，且C3的结构由单键、双键或三键所构成。
Figure PCTCN2016071621-appb-000026
8.一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中R1系为氘(deuterium)。
Figure PCTCN2016071621-appb-000027
9.一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构：
Figure PCTCN2016071621-appb-000028
其中R2系为卤素(halogen)。
10.一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构，其中C3的结构由单键所构成。
Figure PCTCN2016071621-appb-000029
在本文提出的实施例及许多修改将提示熟悉本领域人士所作出的发明，然而这些发明已涉及上述说明和相关图示所提出的教导。因此，可以理解的是，发明不局限于已公开的特定的实施例，修改和其他实施例将被包含在所附请求项的范围之中，再者，尽管上述说明和相关图示只描述了含盖某些单元和/或功能示例性的组合的一示例性实施例，应当理解的是，不同单元和/或功能的组合可以由不同实施例所提供，却不偏离所附请求项的范围。在这方面，例如不仅前述所明确地描述的，单元和/或功能上的不同组合也包括于一些衍生的请求项之内。虽然本文使用特定名词，它们被只用于通例和描述之用，而不应受局限。
【符号说明】
Con：Control
Ins：Insulin
Rosi：Rosiglitazone
Pio：pioglitazone
1：CHT
2：2OH2H
3：2F2H
4：2Cl2H
5：2Br2H
6：2I2H

Claims (10)

  1. 一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构：
    Figure PCTCN2016071621-appb-100001
    其中R1和R2皆系为氢，且C3的结构系属单键。
  2. 一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构：
    Figure PCTCN2016071621-appb-100002
    其中R1系为氧，R2系为甲氧基(alkoxy)、苄氧基和卤素所组成的群组其中之一，且C3的结构系属单键。
  3. 一种用于治疗糖尿病及代谢症候群其中之一的组合物，包括六碳单
    元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式I的结构：
    Figure PCTCN2016071621-appb-100003
    其中R1系为氢、氘和氧所组成的群组其中之一，R2系为氢、甲氧基(alkoxy)、苄氧基和卤素所组成的群组其中之一，且C3的结构由单键或双键所构成。
  4. 如权利要求第3项所述的组合物，还用以调节并稳定细胞之血糖值。
  5. 如权利要求第4项所述的组合物，还用以抑制动物体之不良葡萄糖耐受性或体重增加。
  6. 如权利要求第4项所述的组合物，还用以抑制或延缓动物体之代谢症候疾病的发生。
  7. 一种六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构：
    Figure PCTCN2016071621-appb-100004
    其中R1系为氘，R2系为卤素，
    且C3的结构由单键、双键或三键所构成。
  8. 一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构：
    Figure PCTCN2016071621-appb-100005
    其中R1系为氘。
  9. 一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构：
    Figure PCTCN2016071621-appb-100006
    其中R2系为卤素。
  10. 一种用于治疗糖尿病及代谢症候群其中之一的六碳单元-三碳单元-六碳单元(C6-C3-C6)的化合物，如式II的结构：
    Figure PCTCN2016071621-appb-100007
    其中C3的结构由单键所构成。
PCT/CN2016/071621 2015-01-22 2016-01-21 用于治疗代谢症候群的组合物及其制备方法 WO2016116059A1 (zh)

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