1.Brief Introducing the Product
Leonurine(C14H21O5N3)was extracted from the effective component of Leonurus sibiricus which was a traditional Chinese medicine,our company obtained this products by synthesis, Because the method was novel,we had obtained the chinese invention patent (ZL02138364.2).The products could accelerate the post-natal parturient woman womb to restore, treated the menstruation which was irregular, the uterine hemorrhage and the dysmenorrhea etc;The animal experimentation also indicated that the product could the increase the peripheral vascular ,the coronary artery and the cardiac muscle nutrition,increased the hematic flux,improved the micro circulation,and had the antithrombus to form and so on.
The content of Leonurine was very low in the Leonurus sibiricus,the tradition method of extraction need lots of raw materials, moreover the product was more difficult to purify,and was difficult for the industrial production,therefore we considered to obtained the Leonurine by chemical synthesis method.The synthesis used the domestically raw material,the cost was low.We had completed the pharmaceutical research of synthesis technics,the quality specification clinically front and so on. The product was belong to the innovation medicine, which had solved the shortcoming of the Chinese native medicine which was used in big quantity, and the quality was difficult to control, went onto a new road of the westernization of traditional Chinese medicine.
2.The Related Research and Invention at China and Abroad
In regarding to the synthesis of Leonurine, We had found only a report in<<Acta Pharmaceutica Sinca>>(1984;19:419) at China.they took Leonuramine for starting material,but not disclosed how to obtain Leonuramine.In overseas, the correlation report was very few, there were only statemented in<<Tetrahedron>>(25:5155;1969),4-carboethoxysyringic acid took for starting material in this article,it could't obtain directly,and also used the hydrogenation in the process,all those increased the difficulty of synthesis, it requested the reaction instruments with a higher level. Therefore, we improved and innovated the Synthesis technics of Leonurine on the basis of previous documents.
By a lot of repeated experiments, we had created a new route of synthesize Leonurine, This way decreased the separating process and the reacting instruments, increasing the yield of the product, reducing the production costs greatly and being more helpful for the industrial production.The process had applied for and obtained the Chinese patent (ZL02138364.2), the drug delivery system also had applied for the Chinese patent (patent number 02138220.4),the process is belong to the appropriation technology,for the independent development product, this technic of synthesis had been at the middle-experimental stage.
The improved technics employed a new method synthesize Leonurine by took syringic acid for starting material, After through carbonylation ,acylation��esterification amination,the Leonuramine was obtained.then reacting with S-methyl isothiourea sulfate to obtain highly purified Leonurine. This way decreased the reacting process and the instruments, increasing the yield of the product, reducing the production costs greatly and being more helpful for the industrial production.
The improved process as follows:
syringic acid took for starting material,reacted with ethyl chloroformate to obtain 4-carboethoxysyringic acid,then reacted with thionyl chloride,the excessive thionyl chloride was removed under reduced pressure, the residue reacted with THF, the excessive THF was removed under reduced pressure,then extracting, separating, drying and contracting to obtain 4-carboethoxysyringic acid 4-chloro-1-butyl ester,then the potassium salt of phthalimide was added,after the reaction mixture had been evaporated to dryness under reduced pressure, hydrolyzed and obtained Leonuramine,which reacted with S-methyl isothiourea sulfate to obtain Leonurine, highly purified Leonurine was obtained by recrystallized.
The improved Synthesis route obviously shortened and decreased the separating process. It was easy to manipulate with the mildly reacting condition, easy controlling, easily getting the raw materials, and the product with high purity. Its purity could reach 99.7% according to the analysis of High Performance Liquid Chromatography.
4.The Procedure of Research and Invention
Our company had finished the Synthesis technics, structure certification and quality research of the medical material and preparation of Leonurine. We gave a systematic research to the product��s quality standard such as character,identification, inspectation, dissolution rate, the related compounds and assay,the content in the light of CP2005 requirement for the quality of the medical material and capsule.So we made up the corresponding standard of quality controlling according to the experiment results. The results showed that the purity of the medical material from this technics could reach above 99.5%, related material less than 0.5%, and other standard of physics and chemistry being in line with the documents�� reports. Besides, we were dealing with the research of the stability. So far we had finished the inspectation of stability for the product being tested as long as 24 months. The results showed us this product was stable under the room temperature condition, and the long-time experiment was proceeding. At the same time, the related patent application and administration protection were application.
5.Aim of market
Leonurine and its the tablet or the capsule could accelerate the post-natal parturient woman womb to restore, treat the menstruation which was irregular, the uterine hemorrhage and the dysmenorrhea etc. According to 1999 census structure demonstrated that the total number of Chinese population was 1.25909 billion.from the age structure that the Chinese population proportion below the 14 years old was 25.4%, above 65 years old was 6.9%. According to the extrapolation,the people in 20-55 year-old approximated 50%,the proportion of men and women was 1: 1,so the age woman are more than 300 million. The menstruation excessively and uterine hemorrhage was a general gynecology diseasem, the post-natal parturient woman womb to restore must be treated. dysmenorrhea was a general gynecology diseasem also,the incidence of disease high, the scope broad, the week short, suffering was much,it had interfered with womens in general's work and the study seriously, depressed the life quality, according to the incidence of dysmenorrhea rate 33.19% at least,the patient who had dysmenorrhea were more than 100 million.
The above diseases were treated with the related preparation of Leonurus sibiricus in present, for example: extractum leonuri inspkissatum, drop preparation and so on,these preparations all existed not convenient to take,the feeling of mouth was inferior, Patient's compatibility was bad. the dosage of Leonurine was 5-10mg,the preparation volume was small,tasteless,easy to take, the success development of Leonurine would be able to provide the good treatment method for the womens patient in general,and also would be able to gain the bigger market benefit and the social efficiency for the product.