阅读说明：本技术 一种高尿酸血症药物组合物 (Hyperuricemia pharmaceutical composition ) 是由 徐海霞 陈佳玲 逄龙 于 2019-03-20 设计创作，主要内容包括：本发明属于化学医药领域,具体涉及一种高尿酸血症药物组合物,包括具有如式(I)所示结构的倍半萜内酯类化合物及其药学上可接受的盐、酯、前药、溶剂合物、多晶型物、水合物或衍生物联合高尿酸血症药物在制备治疗高尿酸血症联合用药物中的用途,还提供了一种高尿酸血症药物组合物,包括上述化合物,以及苯溴马隆或雷西纳德中的一种。所述高尿酸血症药物组合物,可起到与现有技术中高尿酸血症药物相当,甚至更好的降尿酸效果,但可以明显降低现有技术中高尿酸血症药物的毒副作用,提高安全性,可用于高尿酸血症和高尿酸血症引起的痛风或痛风并发症的治疗。<Image he="523" wi="582" file="DDA0002001316050000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the field of chemical medicine, and particularly relates to a hyperuricemia drug composition, which comprises a sesquiterpene lactone compound with a structure shown in formula (I) and application of the sesquiterpene lactone compound in combination with a hyperuricemia drug, wherein the sesquiterpene lactone compound has a structure shown in formula (I), and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives of the sesquiterpene lactone compound in preparation of the hyperuricemia drug, and also provides a hyperuricemia drug combination for treating hyperuricemiaThe uricemia pharmaceutical composition comprises the compound and one of benzbromarone or Racinade. The hyperuricemia drug composition can achieve the effect of reducing uric acid equivalent to or even better than that of a hyperuricemia drug in the prior art, can obviously reduce the toxic and side effects of the hyperuricemia drug in the prior art, improves the safety, and can be used for treating gout or gout complications caused by hyperuricemia and hyperuricemia.)

1. An application of sesquiterpene lactone compounds with a structure shown in a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparation of combined drugs for treating hyperuricemia in combination.

2. A hyperuricemia pharmaceutical composition, comprising: an active ingredient having a synergistic effect with a hyperuricemia drug, and a hyperuricemia drug; wherein the hyperuricemia drug is a uric acid excretion promoting drug; the active ingredient is sesquiterpene lactone compounds with the structure shown in the formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:

wherein:

is selected from ═ or-,represents a group selected from-or no bond; two adjacentNot being equal to;

R₁、R₂、R₃、R₄、R₆independently of one another, from H, OH, unsubstituted or substituted C₁-C₄Alkyl, unsubstituted or substituted C₁-C₄Alkoxy, OAc or

R₈、R₉independently of one another, selected from H, OH, or R₈、R₉Forming an unsubstituted or substituted oxirane group;

form C ═C or C-R_7a；

R_7a、R_11aIndependently of one another, from H, unsubstituted or substituted C₁-C₄One of the alkyl groups of (a);

R₉,R₁₀form a five-membered ring

R₁₀,R₁₁form a five-membered ring

3. The hyperuricemia pharmaceutical composition according to claim 2, wherein the active ingredient has a structure as shown below:

4. the hyperuricemia pharmaceutical composition of claim 2 or 3, wherein the hyperuricemia drug is one of benzbromarone or rexinader.

5. The hyperuricemia pharmaceutical composition according to any one of claims 2 to 4, wherein the mass of the active ingredient accounts for 14% to 91% of the sum of the mass of the active ingredient and the hyperuricemia pharmaceutical composition.

6. The hyperuricemia pharmaceutical composition according to any one of claims 2 to 5, further comprising a pharmaceutically acceptable carrier.

7. A medicine for treating hyperuricemia, which is characterized by comprising the hyperuricemia pharmaceutical composition as claimed in any one of claims 2 to 6, wherein the medicine is prepared by adding conventional auxiliary materials into the hyperuricemia pharmaceutical composition and preparing clinically acceptable tablets, capsules, pills, granules, paste, mixtures or suspensions according to a conventional process.

8. Use of the pharmaceutical composition for hyperuricemia according to any one of claims 2 to 6 in preparation of a drug or health product for hyperuricemia.

9. The use of the pharmaceutical composition for hyperuricemia according to claim 8, wherein the hyperuricemia comprises gout or gout complications caused by hyperuricemia.

10. Use of the hyperuricemia pharmaceutical composition according to claim 8 or 9, for preparing a hyperuricemia drug or health product, wherein the gout comprises acute gout or chronic gout; the gout complications comprise gouty arthritis, gout attack, gouty nephropathy or uric acid renal calculus.

Technical Field

The invention relates to the field of chemical medicine, and particularly relates to a hyperuricemia pharmaceutical composition.

Background

In the field of chemical medicine, uric acid is the final metabolite of human purine compounds. Disorders of purine metabolism lead to hyperuricemia. Under normal purine diet, the level of uric acid in fasting blood twice a day is higher than 416 mu mol/L in male and higher than 360 mu mol/L in female, namely hyperuricemia (hyperuricemia). Generally, there is no subjective symptom when the patient is in a hyperuricemia symptom state, but if the patient is in the hyperuricemia symptom state for a long time, urate in blood is crystallized and deposited on joints, subcutaneous tissues, kidneys and other parts, and a series of clinical manifestations such as gout and gout complications occur. Recently published '2017 Chinese gout status report white paper', the number of hyperuricemia patients in China reaches 1.7 hundred million, wherein the number of gout patients exceeds 8000 ten thousand, and the annual growth rate is rapidly increased by 9.7% per year. In 2020, the number of gout people is estimated to reach 1 hundred million. Nowadays, gout becomes the second major metabolic disease of China, which is second only to diabetes, and seriously harms the life and health of people.

At present, when treating hyperuricemia, gout caused by hyperuricemia and gout complications, uric acid in blood needs to be controlled: for patients with uric acid dysexcretion (90% of the patients) are applicable to drugs for promoting uric acid excretion, such as: benzbromarone, rasidone, etc.; for patients with hyperuricemia, drugs (mainly xanthine oxidase inhibitors) for inhibiting uric acid production are suitable, such as: allopurinol, febuxostat. However, as the clinical application of these drugs increases, adverse reactions are gradually exposed.

Benzbromarone is a drug for promoting uric acid excretion, is marketed in France in 1976, brings a new way for treating chronic gout, has a remarkable curative effect on hyperuricemia, but can cause gastrointestinal discomfort, particularly diarrhea; the use of the medicine is limited by European market due to the possibility of causing serious liver function damage, and FDA refuses the application on the market due to adverse reaction, however, some countries including China still allow the use, but the effect of reducing uric acid is reduced by regulating the dosage of the medicine according to the intoxication clearance.

Leisinrad (Lesinurad) was originally developed by AstraZeneca (AstraZeneca), and was marketed in the united states at 12 months 2015 and in the european union at 2 months 2016, respectively, under the trade name Zurampic, and is the first uric acid transporter 1 inhibitor on the market, and is clinically used mainly in combination with xanthine oxidase inhibitors (such as allopurinol and febuxostat) for treating hyperuricemia associated with gout, and the common adverse reactions caused by Lesinurad include headache, influenza, increase in serum creatinine, and gastroesophageal reflux disease, and the use of lesioned alone increases the risk of acute renal failure.

The drugs have large toxic and side effects under the conventional dosage, and the tolerance of the drugs is generally low, so that the clinical application of the drugs is limited to a certain extent.

Sesquiterpene lactone compounds are compounds with various structural types formed by structural evolution of geraniol (germanolide), are one of bioactive components of medicinal plants, and widely exist in plants of Compositae, Umbelliferae, Magnoliaceae, Menispermaceae, Euphorbiaceae, Acanthaceae, Leguminosae, etc. Over 3000 sesquiterpene lactones isolated from Asteraceae plants alone. According to their structure, they are classified into Guaianolide (Guaianolide), pseudo-Guaianolide (pesudoaianolide), germanolide (germanolide), elenanolide (elemanolide), Eudesmanolide (eremophilanolide), eremophilane-type lactone (Eremophiladien), and the like. Researches show that the sesquiterpene lactone has various biological activities, such as anti-tumor, cardiotonic, neurotoxicity, antimalarial, antibacterial and the like, and Chinese patent documents CN103251667A and CN103417532A also disclose that the sesquiterpene lactone can be used for developing medicines for treating rheumatoid arthritis and tumors.

Disclosure of Invention

The first technical problem to be solved by the invention is to overcome the defect that the drugs for treating hyperuricemia in the prior art have toxic and side effects, so that the invention provides the application of the sesquiterpene lactone compound with the structure shown in the formula (I) and the pharmaceutically acceptable salt, ester, prodrug, solvate, polymorph, hydrate or derivative thereof in combination with the hyperuricemia drugs in preparing the combined drugs for treating hyperuricemia.

The second technical problem to be solved by the invention is to overcome the defect that the drugs for treating hyperuricemia in the prior art have toxic and side effects, so that the invention provides the hyperuricemia drug composition which can reduce the toxic and side effects while maintaining the ideal effect of reducing the uric acid.

The third technical problem to be solved by the invention is to overcome the defect that the drugs for treating hyperuricemia in the prior art have toxic and side effects, so that the drug for treating hyperuricemia, which can reduce the toxic and side effects while maintaining the ideal effect of reducing uric acid, is provided.

The invention also provides application of the hyperuricemia pharmaceutical composition.

Therefore, the invention provides an application of sesquiterpene lactone compounds with a structure shown in a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparation of combined drugs for treating hyperuricemia. Further, the hyperuricemia drug is one of benzbromarone or resinide.

The invention provides a hyperuricemia pharmaceutical composition, which comprises the following components: an active ingredient having a synergistic effect with a hyperuricemia drug, and a hyperuricemia drug; wherein the hyperuricemia drug is a uric acid excretion promoting drug; the active ingredients are sesquiterpene lactone compounds with the structure shown in the formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:

wherein:

is selected fromOrIs selected fromOr no bond; two adjacent

Is not simultaneouslyRepresentsWhen, with

Adjacent to each otherIs not simultaneously

R₁、R₂、R₃、R₄、R₆Independently of one another, from H, OH, unsubstituted or substituted C₁-C₄Alkyl, unsubstituted or substituted C₁-C₄Alkoxy, OAc orOne of (1);

R₈、R₉independently of one another, selected from H, OH, or R₈、R₉Forming an unsubstituted or substituted oxirane group;

form aOr

Form aOr

R_7a、R_11aIndependently of one another, from H, unsubstituted or substituted C₁-C₄One of the alkyl groups of (a);

R₉,R₁₀form a five-membered ringForm aOr

R_12a、R_12bIndependently of one another, selected from H, OH or C₁-C₄One of the alkyl groups of (a);

R₁₀,R₁₁form a five-membered ringWherein X is selected from N or O, and when X is O, it is linked to X

And is-notAt the same time areAndform aOr

Form a

Or C-R_14a；R_13a、R_14aIndependently of one another, from H, unsubstituted or substituted C₁-C₄One of the alkyl groups of (1).

The hyperuricemia pharmaceutical composition comprises the following active ingredients:

the hyperuricemia drug is one of benzbromarone or Racinade.

The hyperuricemia drug composition comprises 14-91% of the active component and the hyperuricemia drug by mass.

The hyperuricemia pharmaceutical composition also comprises a pharmaceutically acceptable carrier.

The invention also provides a medicine for treating hyperuricemia, which comprises the hyperuricemia medicine composition, wherein the medicine is prepared by adding conventional auxiliary materials into the hyperuricemia medicine composition and preparing clinically acceptable tablets, capsules, pills, granules, paste, mixtures or suspensions according to a conventional process.

The invention also provides application of the hyperuricemia pharmaceutical composition in preparing hyperuricemia drugs or health care products.

The hyperuricemia pharmaceutical composition is used for preparing a hyperuricemia drug or a health-care product, and the hyperuricemia comprises gout or gout complications caused by the hyperuricemia.

The hyperuricemia pharmaceutical composition is used for preparing hyperuricemia drugs or health care products, wherein the gout comprises acute gout or chronic gout; the gout complications comprise gouty arthritis, gout attack, gouty nephropathy or uric acid renal calculus.

The technical scheme of the invention has the following advantages:

1. the invention provides a hyperuricemia drug composition, which can achieve the equivalent or even better effect of reducing uric acid compared with hyperuricemia drugs in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia drugs in the prior art, improve the safety, and can be used for treating hyperuricemia and gout or gout complications caused by the hyperuricemia.

2. The invention provides a drug for treating hyperuricemia, which can achieve the equivalent or even better effect of reducing uric acid compared with the hyperuricemia drug in the prior art, but can obviously reduce the toxic and side effects of the hyperuricemia drug in the prior art, improve the safety and be used for treating the hyperuricemia and gout or gout complications caused by the hyperuricemia.

Detailed Description