阅读说明：本技术 益母草碱及其晶体在制备抗高同型半胱氨酸血症药物中的用途 (Application of leonurine and crystal thereof in preparation of medicines for resisting hyperhomocysteinemia ) 是由 朱依纯 朱依谆 宁可 慕雪盼 陈莹 于 2019-02-21 设计创作，主要内容包括：本发明属中药现代化制药领域,涉及中草药益母草提取物及其在制药中的应用,具体涉及一种中草药益母草提取物益母草碱的药用晶型在制备药物中的应用,所述益母草碱化学名称：3,5-二甲氧基-4-羟基-苯甲酸(4-胍基)-1-丁酯；本发明中将益母草碱制成1种水合物晶型,实验证实其具有降低同型半胱氨酸(Homocysteine,Hcy)的作用；本发明所述的益母草碱及其晶型可用于制备抗高Hcy导致的各种疾病的药物,包括心脑血管疾病、老年痴呆症、脑卒中、静脉栓塞、新生儿缺陷和习惯性流产,特别适用于早期干预上述疾病的发生,具有减低早期心血管危险因素和其他相关疾病发生率的作用,以及在特定的其他危险因子如甘油三脂、胆固醇和低密度脂蛋白等不增高但易发生心脑血管疾病的疾病状态。(The invention belongs to the field of modern pharmacy of traditional Chinese medicines, relates to a Chinese herbal medicine motherwort extract and application thereof in pharmacy, and particularly relates to application of a medicinal crystal form of leonurine of the Chinese herbal medicine motherwort extract in preparation of a medicine, wherein the leonurine has the chemical name: 3, 5-dimethoxy-4-hydroxy-benzoic acid (4-guanidino) -1-butyl ester; in the invention, leonurine is prepared into 1 hydrate crystal form, and experiments prove that leonurine has the function of reducing Homocysteine (Hcy); the leonurine and the crystal form thereof can be used for preparing medicines for resisting various diseases caused by high Hcy, including cardiovascular and cerebrovascular diseases, senile dementia, cerebral apoplexy, venous embolism, neonatal defect and habitual abortion, are particularly suitable for early intervention of the diseases, have the function of reducing the incidence of early cardiovascular risk factors and other related diseases, and have the disease states that specific other risk factors such as triglyceride, cholesterol, low-density lipoprotein and the like are not increased but the cardiovascular and cerebrovascular diseases are easy to occur.)

1. The use of Leonurine (British name: Leonurine; chemical name: 3, 5-dimethoxy-4-hydroxy-benzoic acid (4-guanidino) -1-butyl ester) with the following chemical structural formula in the preparation of medicaments for treating hypercy hemaemia,

the drug reduces the Hcy level in vivo.

2. The use according to claim 1, wherein the leonurine further comprises leonurine hemisulfate monohydrate crystals prepared according to the molecular structure below for the preparation of a medicament for the treatment of hypercycy blood disease, said medicament reducing the level of Hcy in the body;

3. the use according to claim 2, wherein the leonurine hemisulfate monohydrate crystals are colorless plate crystals belonging to monoclinic system, and have space group P-1, and comprise 2 leonurine molecules, 1 sulfate ion and 2 water molecules in an asymmetric unit; wherein, the guanidyl of the two leonurine molecules and the negative ions of the sulfate radical form an ionic bond trimer, and a two-dimensional structure is formed between the trimer and the guanidyl through the hydrogen bonding of the guanidyl and the sulfate radical to form a polymer molecule plane layer;

4. use according to claim 2, characterized in that the planes of the molecules of the multilayer polymer of the crystals of leonurine hemisulfate monohydrate are arranged in a superimposed parallel manner, the planes of the molecules of the two-dimensional structure thereof forming, by hydrogen bonding of water molecules, a three-dimensional layered network of crystals of leonurine hemisulfate monohydrate, the hydrophilic layers of guanidino and sulfate groups thereof forming alternating arrangements with the hydrophobic groups of leonurine;

5. the use according to claim 2, characterized in that the leonurine hemisulfate monohydrate crystals have the spatial positions of all atoms in the single crystal molecules in accordance with the following functional atomic coordinates and the parameters of equirectangular or rather equirectangular displacement;

6. use according to claim 2, characterized in that the crystalline leonurine hemisulfate monohydrate has the following X-ray powder diffraction parameters:

7. the use of leonurine and its hemisulfate monohydrate crystals as claimed in claims 1-6, wherein the leonurine and its hemisulfate monohydrate crystals are used for preparing a medicament for preventing secondary diseases caused by high Hcy, wherein the secondary diseases are various diseases caused by high Hcy, including cardiovascular and cerebrovascular diseases, senile dementia, cerebral apoplexy, venous embolism, neonatal deficiency and habitual abortion.

8. The use according to claims 1-6, characterized in that leonurine and its hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high Hcy, such as cardiovascular and cerebrovascular diseases, senile dementia, cerebral stroke, venous embolism, neonatal deficiency or habitual abortion.

9. Use according to claims 1-6, wherein leonurine and its hemisulfate monohydrate crystals are used for the preparation of a medicament for the prevention of secondary diseases caused by high Hcy, i.e. cardiovascular and cerebrovascular diseases caused by high Hcy and disease states which are not elevated but still susceptible to development of cardiovascular and cerebrovascular diseases at specific other risk factors such as triglycerides, cholesterol and low density lipoproteins etc.

Technical Field

The invention belongs to the field of modern pharmacy of traditional Chinese medicines, and relates to a new application of a crystal of leonurine extracted from Chinese herbal medicine motherwort herb in pharmacy, in particular to an application in preparing a medicine for resisting hyperhomocysteinemia (Hcy). The medicine for resisting the hypercycy blood disease is suitable for preventing and treating diseases caused by the Hcy, including cardiovascular and cerebrovascular diseases, senile dementia, cerebral apoplexy, venous embolism, neonatal defect and habitual abortion.

Background

Disclosure of Invention

The invention aims to provide a new medicinal application of an active component leonurine of a Chinese medicinal motherwort herb and a medicinal crystal form thereof in preparing medicaments for treating high Hcy blood based on the current situation and the foundation of the prior art, in particular to preparing medicaments for early intervention before blood vessels and important organs are damaged caused by Hcy, and preventing or reducing the occurrence or degree of various diseases caused by the high Hcy blood. In view of the fact that the Hcy blood disease is an independent major disease risk factor recognized in the medical field at present, the Hcy blood disease is an important early disease needing to be treated in time; if not treated in time, the disease will cause damage to the vital organs of human body and result in a series of serious secondary diseases.

Research shows that the hypercy's disease is an independent and important cardiovascular risk factor, and can directly damage human cells, especially damage vascular endothelial cells, resulting in various cardiovascular and cerebrovascular diseases and peripheral vascular diseases; coronary atherosclerosis can lead to myocardial ischemia, angina pectoris, and myocardial infarction; cerebrovascular diseases can cause severe diseases such as cerebral apoplexy; the medicine for resisting the hypercy-emia provided by the invention is suitable for preventing and treating diseases caused by Hcy, including cardiovascular and cerebrovascular diseases, peripheral vascular diseases, cerebral apoplexy, diabetes, senile dementia and other neurodegenerative diseases, neonatal defects, habitual abortion, gestational hypertension and the like; is especially suitable for early intervention of the occurrence of the diseases and has the function of reducing the occurrence rate of early cardiovascular risk factors and other related diseases.

The invention further aims to use the active ingredients as raw materials of pharmaceutical preparations to prepare the medicine for resisting the hyperpycy blood disease.

The leonurine is an effective component separated from motherwort and is prepared in large quantities by artificial synthesis, and the chemical structural formula of the leonurine is as follows:

the leonurine has the English name: leonurine; chemical name: 3, 5-dimethoxy-4-hydroxy-benzoic acid (4-guanidino) -1-butyl ester.

The application further analyzes the crystal structure of the leonurine to obtain the optimal medicinal crystal form, and researches show that the leonurine and the crystal form thereof have the effect of resisting the Hcy blood disease.

The leonurine is prepared into 6 crystals with different crystal forms by a specific method, in particular to 6 crystals with different structures of leonurine sulfate, wherein 2 are hydrates, 2 are anhydrous crystal forms, one is a methanol compound and the other is an ethanol compound.

For convenience of description, the 6 leonurine crystals described above are respectively named as crystal form a, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F.

The leonurine crystal with the high Hcy blood disease resistance is preferably in a crystal form A, and has the following characteristics:

the molecular structure of the crystal form A leonurine hemisulfate monohydrate crystal is shown in figure 1;

the leonurine hemisulfate monohydrate crystal represented by the crystal form A is a colorless flaky crystal, belongs to a triclinic crystal system, has a space group of P-1, and comprises 2 leonurine molecules, 1 sulfate ion and 2 water molecules in an asymmetric unit; wherein the guanidyl of the two leonurine molecules and the negative ions of the sulfate radical form an ionic bond trimer, and the trimer form a two-dimensional structure through the hydrogen bonding action of the guanidyl and the sulfate radical to form a following polymer molecule plane layer (as shown in figure 2);

in the application, the molecular planes of the multilayer polymers of the leonurine hemisulfate monohydrate crystal represented by the crystal form A are arranged in a superposition manner in a parallel mode, the molecular planes with two-dimensional structures form a three-dimensional laminated network structure of the leonurine hemisulfate monohydrate crystal through the hydrogen bonding action of water molecules, and hydrophilic layers formed by guanidino and sulfate radicals and leonurine hydrophobic groups are alternately arranged (as shown in figure 3).

In the present application, the spatial positions of all atoms in the single crystal molecules of the leonurine hemisulfate monohydrate crystal represented by the crystal form a conform to the functional atomic coordinates and the isotropic or equivalent isotropic displacement parameters as shown in table 1 below.

TABLE 1 coordinate and equi-or equi-displacement parameters for all atoms in single crystal molecules of leonurine hemisulfate monohydrate crystals

To further characterize the 6 crystal forms of leonurine described above, the present invention separately performed X-ray powder diffraction (XRPD) analysis to obtain XRPD data as shown in table 2 below:

table 2 XRPD data for six leonurine crystals:

more specifically, the 6 crystal forms of leonurine according to the present invention particularly refer to crystals having the aforementioned XRPD characteristics.

Furthermore, the leonurine and the crystal thereof can be used for preparing medicines for treating hypercycy blood disease.

The invention provides a novel medicine for resisting high Hcy blood disease, which is used for preventing and treating various diseases caused by Hcy, including cardiovascular and cerebrovascular diseases, peripheral vascular diseases, cerebral apoplexy, diabetes, senile dementia and other neurodegenerative diseases, neonatal defects, habitual abortion, gestational hypertension and the like. Is especially suitable for early intervention of the occurrence of the diseases and has the function of reducing the occurrence rate of early cardiovascular risk factors and other related diseases.

The leonurine and the crystal thereof are also suitable for being applied to specific types of patients with amino acid metabolic disorder in precise medical practice, namely patients with high Hcy blood disease; in view of the above, the present invention provides a preventive medicine for early blockade before clinical lesions occur; the medicine can be used for treating diseases secondary to high Hcy and preventing the following human body important organ damages caused by high Hcy, including but not limited to: the injury and lesion of important human blood vessels such as heart, coronary artery, cerebral artery, carotid artery, femoral artery, kidney, brain, liver and the like, especially the injury of vascular endothelium in each important organ.

The leonurine crystal can be used as a medicine raw material, and can be directly prepared into suitable preparations, including capsules, tablets, powder, suspensions and compound preparations, or be mixed with solid or liquid auxiliary materials which are usually used for the preparations in pharmacy.

The invention carries out a large number of pharmacological studies, and results show that the leonurine and the A-type crystal thereof have the effect of reducing the Hcy level of high-fat diet animals.

The experiments of the invention were performed with ApoE gene knock-out (ApoE)^-/-) The mice are high-fat animal models and are fed with high-fat feed; on the basis of the genetic defect, the leonurine and the A-type crystal thereof are in a metabolic disorder state caused by high-fat diet, so as to cause the disorder of lipid metabolism and amino acid metabolism, and are used for verifying the regulating effect of the leonurine and the A-type crystal thereof on the blood Hcy level;

the experimental result shows that the leonurine and the type A crystal thereof reduce high-fat feeding ApoE^-/-Hcy levels in the blood of mice.

The application provides an application of leonurine crystals in preparing a medicine for resisting high Hcy blood disease, and the medicine for resisting high Hcy blood disease is particularly suitable for early intervention of the diseases and has the effect of reducing early cardiovascular risk factors and the incidence rate of other related diseases. In view of the fact that no specific medicine for treating the Hcy blood disease exists at present, the invention provides a novel method and a novel medicine for treating the Hcy blood disease.

Drawings

Figure 1 is the molecular structure of leonurine form a.

Figure 2 is the two-dimensional structure of the leonurine crystalline form a molecule.

Figure 3 is the three-dimensional structure of the leonurine crystalline form a molecule.

FIG. 4 is a statistical chart of experimental data for reducing the Hcy level of a model mouse with leonurine A-type crystals, wherein the leonurine A-type crystals can effectively reduce the Hcy level of the model mouse; wherein the content of the first and second substances,

from left to right, the total of 5 groups are: control group (ApoE)^-/-Normal feed feeding of mice, intragastric administration of daily control solvent); ApoE^-/-Feeding mice with high-fat feed, and intragastrically administering a contrast solvent every day; ApoE^-/-Feeding mice with high-fat feed, and intragastrically (10 mg/kg/day) with leonurine A crystal solution every day; ApoE^-/-Feeding mice with high-fat feed, and intragastrically (20 mg/kg/day) with leonurine A crystal solution every day; ApoE^-/-Mice were fed on high-fat diet and gavage daily (40 mg/kg/day) with leonurine form a crystal solution. The numbers of samples in the above 5 groups are: 14, 16,8,8,8. Data are mean ± sem; p<0.05 represents a statistically significant difference.

Detailed Description