New application of polyacetylene compound
阅读说明：本技术 一种聚炔类化合物的新用途 (New application of polyacetylene compound ) 是由 徐洁 崔卫波 夏增华 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,具体涉及一种聚炔类化合物的新用途,包括具有如式(I)所示结构的聚炔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,以及非布司他或别嘌呤醇中的一种。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="232" wi="620" file="DDA0002001562600000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the field of chemical medicine, and particularly relates to a new application of a polyacetylene compound, which comprises the application of the polyacetylene compound with the structure shown as formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in combination with a hyperuricemia drug in preparation of a combined drug for treating hyperuricemia, and also provides hyperuricemiaThe pharmaceutical composition comprises the compound and one of febuxostat or allopurinol. The hyperuricemia drug composition can achieve the effect of reducing uric acid equivalent to or even better than that of hyperuricemia drugs in the prior art, can obviously reduce the toxic and side effects of the hyperuricemia drugs, improves the safety, and can be used for treating gout or gout complications caused by hyperuricemia and hyperuricemia.)
1. Application of a polyacetylene compound with a structure shown as a formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparation of combined drugs for treating hyperuricemia.
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 xanthine oxidase inhibitor; the active ingredients are polyacetylene compounds with the structure shown in formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:
wherein the content of the first and second substances,
R1Selected from H, OH,
R2one selected from H, OH, or R1、R2To form unsubstituted or substituted phenyl;
R3is selected from
R4One selected from H, OH.
3. The hyperuricemia pharmaceutical composition according to claim 2, wherein the active ingredient has a structure as shown below:
4. the hyperuricemia pharmaceutical composition according to claim 2 or 3, wherein the hyperuricemia drug is one of febuxostat or allopurinol.
5. The hyperuricemia pharmaceutical composition according to any one of claims 2 to 4, wherein the mass of the active ingredient is 20% to 97% of the sum of the mass of the active ingredient and the hyperuricemia drug.
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 and a 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, in particular to a new application of a polyacetylene compound.
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 and febuxostat. However, as the clinical application of these drugs increases, adverse reactions are gradually exposed.
Allopurinol (allopurinol) is the earliest marketed drug for inhibiting the generation of uric acid, and has been the main drug for treating chronic gout because of low price and good uric acid reducing effect since the application in clinic in 1963. However, with the popularization of allopurinol, the reports of adverse reactions are increased gradually, and the reports from the 70 th of the 20 th century show that allopurinol can cause adverse reactions such as liver and kidney injury, leucopenia, rash and the like, has about 1.5% of allergy risks, can cause fatal allergy seriously, and arouses worldwide attention. Therefore, to reduce adverse reactions, a small dose of allopurinol is required.
Febuxostat (trade name: Uloric, pharmaceutical company in north america of the wutian) is a non-purine selective xanthine oxidase inhibitor, which is marketed in the european union in 5 months in 2008, approved by the FDA in the united states in 3 months in 2009, and introduced into the chinese market in 2013, and is used for the long-term treatment of hyperuricemia associated with gout. Compared with other drugs for treating hyperuricemia, the febuxostat has higher selectivity and stronger activity. However, related research and clinical practice show that febuxostat also has certain adverse reactions: common adverse reactions include liver dysfunction (3.5%), diarrhea (2.7%), headache (1.8%), nausea (1.7%), rash (1.5%), and the like. 11/15/2017, the FDA issued a febuxostat heart-related death risk warning; day 7/2/2018, CFDA issued a pharmacological alert "a preliminary result of a safety clinical trial involving 6000 gout patients indicated that febuxostat may increase the risk of heart-related death compared to allopurinol.
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.
Polyacetylenes or polyacetylenes are a special class of natural compounds, mostly having two or more conjugated triple bonds, and thus having considerable unsaturation and high reactivity. The polyacetylene compounds and the derivatives thereof are very important plant secondary metabolites and are widely distributed in the plant world, and more than 750 natural polyacetylenes and the derivatives thereof are reported only in compositae plants. Some plants (Compositae, Umbelliferae, etc.) containing polyacetylene components have long been used as medicines, but because such components are generally contained in small amounts and are not stable enough, the relationship between the effect of the medicines and the polyacetylene components is less studied. With the progress of chemical and pharmacological research methods, the compounds are reported to have physiological activities such as anti-inflammation, antifungal, sensitization, antitumor, antimicrobial, anticonvulsant and the like.
Disclosure of Invention
The first technical problem to be solved by the invention is to overcome the defect that the drug for treating hyperuricemia in the prior art has toxic and side effects, so that the application of the polyacetylene compound with the structure shown as the formula (I) and the pharmaceutically acceptable salt, ester, prodrug, solvate, polymorph, hydrate or derivative thereof in combination with the hyperuricemia drug in preparing the combined drug for treating hyperuricemia is provided.
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 a polyacetylene compound with a structure shown as a formula (I) and application of pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof in preparing a combined drug for treating hyperuricemia. Further, the hyperuricemia drug is one of febuxostat or allopurinol.
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 xanthine oxidase inhibitor; the active ingredients are polyacetylene compounds with the structure shown in formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, polymorphs, hydrates or derivatives thereof:
wherein the content of the first and second substances,represents selected from ___ or ═ a;
R1selected from H, OH,Unsubstituted or substituted C1-C4Alkyl, unsubstituted or substituted C1-C4An alkenyl group of,One of (1); r1aIs selected from 1 to 2RaSubstituted C1-C3Alkyl of RaSelected from H, OCOCH3One of (1);
R2one selected from H, OH, or R1、R2To form unsubstituted or substituted phenyl;
R3is selected from
R4One selected from H, OH.
The hyperuricemia pharmaceutical composition comprises the following active ingredients:
in the hyperuricemia drug composition, the hyperuricemia drug is one of febuxostat or allopurinol.
The hyperuricemia drug composition comprises 20-97% 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
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