CN111803499B - Medicine composition II for treating gout and hyperuricemia - Google Patents
Medicine composition II for treating gout and hyperuricemia Download PDFInfo
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- CN111803499B CN111803499B CN202010838794.4A CN202010838794A CN111803499B CN 111803499 B CN111803499 B CN 111803499B CN 202010838794 A CN202010838794 A CN 202010838794A CN 111803499 B CN111803499 B CN 111803499B
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- hyperuricemia
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- 201000001431 Hyperuricemia Diseases 0.000 title claims abstract description 14
- 201000005569 Gout Diseases 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 7
- 229940079593 drug Drugs 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000000853 adhesive Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 230000001070 adhesive effect Effects 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- 108010093894 Xanthine oxidase Proteins 0.000 abstract description 26
- 102100033220 Xanthine oxidase Human genes 0.000 abstract description 26
- 230000000694 effects Effects 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 12
- 102000004190 Enzymes Human genes 0.000 abstract description 9
- 108090000790 Enzymes Proteins 0.000 abstract description 9
- 238000002474 experimental method Methods 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 4
- 229960002708 antigout preparations Drugs 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 description 12
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical group N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 9
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 8
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229940116269 uric acid Drugs 0.000 description 8
- 239000000523 sample Substances 0.000 description 7
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 6
- 239000008055 phosphate buffer solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960003459 allopurinol Drugs 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 229940075420 xanthine Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- UBVZQGOVTLIHLH-UHFFFAOYSA-N 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC(C=2N=C(NN=2)C=2C=CN=CC=2)=C1 UBVZQGOVTLIHLH-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 229960005101 febuxostat Drugs 0.000 description 2
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000004144 purine metabolism Effects 0.000 description 2
- 229950004176 topiroxostat Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PVQKQWMEXZGTMR-UHFFFAOYSA-N 1,5-dimethylpyrazolo[3,4-d]pyrimidin-4-one Chemical group N1=CN(C)C(=O)C2=C1N(C)N=C2 PVQKQWMEXZGTMR-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- YHHPQOPHDNWCAD-UHFFFAOYSA-N prop-2-enenitrile;1,3-thiazole Chemical class C=CC#N.C1=CSC=N1 YHHPQOPHDNWCAD-UHFFFAOYSA-N 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- -1 quinoline amide Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a pharmaceutical composition II for treating gout and hyperuricemia, which has a general structure shown in formula II. The application of a series of compounds with xanthine oxidase inhibitory activity in the preparation of anti-gout and anti-hyperuricemia drugs provided by the invention is proved by in vitro enzyme activity experiments to have obvious Xanthine Oxidase (XO) inhibitory effect.
Description
Technical Field
The invention relates to application of a compound in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating gout and hyperuricemia based on the division with the application number of 201810609568.1, wherein the application date is 2018, 6 and 13, and the invention is named as the application of the compound in inhibiting xanthine oxidase activity and the pharmaceutical composition for treating gout and hyperuricemia, belongs to the technical field of medicines, and particularly relates to the application of the compound in inhibiting xanthine oxidase activity and the pharmaceutical composition for treating gout and hyperuricemia.
Background
Gout (Gout) is a group of clinical syndromes formed by deposition of urate on joints and soft tissues due to hyperuricemia caused by in vivo purine metabolic disorders or decreased excretion of Uric Acid (UA), etc. The end product of human purine metabolism is uric acid, a weak acid with very low solubility, which can cause hyperuricemia with either excessive production or poor excretion. Statistically, about 6% to 12% of patients with hyperuricemia develop gout, which has become the second major metabolic disease after diabetes.
During purine metabolism, xanthine oxidase catalyzes the oxidation of xanthine and/or hypoxanthine to form uric acid. Therefore, inhibition of xanthine oxidase activity can reduce uric acid production, and thus, can play a role in treating hyperuricemia and gout.
The currently marketed drugs mainly include Allopurinol (Allopurinol), febuxostat (Febxostat) and Topiroxostat (Topiroxostat), although all of the three have the effect of obviously reducing uric acid, the types of the Allopurinol are very limited, the Allopurinol has certain toxic and side effects, the febuxostat has selectivity on xanthine oxidase inhibition, and other enzymes in purine and pyrimidine synthesis and metabolic processes cannot be inhibited at the treatment concentration.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide the use of the compound in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating anti-gout and anti-hyperuricemia.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the application of the compound with the general formula I in inhibiting the activity of xanthine oxidase,
the general formula I is shown as formula I:
the general formula I is a pyridylthiophene derivative;
wherein the R1 radical is
The R2 radical being
The R3 radical being
The R4 radical being
Or R3R4 is:
further, the compounds represented by the above general formula I are
Use of a compound having the general formula ii:
wherein the R1 group is:
the R2 group is:
further, the compound represented by the above general formula II is
Use of a compound having the general formula iii, wherein the general formula iii is represented by the formula iii:
wherein the R1 radical is
The R2 radical being
Further, the compound represented by the above general formula III is
Further, the invention provides a pharmaceutical composition, which comprises the compounds shown in the general formulas I, II and III, or pharmaceutically acceptable salts, hydrates or solvates of the compounds.
Further, the pharmaceutical composition comprises 12-20 parts by weight of the compounds shown in the general formulas I, II and III or pharmaceutically acceptable salts, hydrates or solvates of the compounds, and the balance of excipients, based on 100 parts by weight.
Further, the excipient comprises one or more of a filler, a binder, a disintegrant, a lubricant, or a glidant; the filler comprises starch, sugar powder, microcrystalline cellulose, mannitol, compressible starch or lactose; the adhesive comprises starch slurry, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone or sodium carboxymethyl cellulose; the disintegrant comprises sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, or hydroxypropyl starch; the lubricant is 0.1-5% of magnesium stearate; the glidant is 0.1-3% of talcum powder.
Furthermore, the adhesive of the invention is 0.1 to 15 percent of hydroxypropyl cellulose, the filling agent is 5 to 70 percent of microcrystalline cellulose, and the disintegrating agent is 10 to 60 percent of crospovidone.
Further, the dosage form of the pharmaceutical composition comprises tablets, capsules, pills or suspensions.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides application of compounds shown as formulas I, II and III in inhibiting xanthine oxidase activity and a pharmaceutical composition for treating gout resistance and hyperuricemia resistance, and in vitro enzyme activity experiments prove that the compounds have obvious Xanthine Oxidase (XO) inhibition effect.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
First, source of target compound
All compounds of the invention were purchased from specs, Netherlands (website: http:// www.specs.com, compounds from the specs library, corresponding numbers as follows:
table 1: numbering and Structure of Compounds of the invention
In vitro pharmacological testing of the Compounds of the invention
2.1 principle of the experiment
Xanthine oxidase catalyzes xanthine to form uric acid. If the compound has an inhibitory effect on xanthine oxidase, the amount of xanthine catalyzed by xanthine oxidase decreases, uric acid produced accordingly decreases, and absorbance accordingly decreases.
2.2 materials of the experiment
13 test compounds, KH2PO4，K2HPO4NaOH, xanthine oxidase, allopurinol, dimethyl sulfoxide (DMSO), and distilled water.
2.3 in vitro Activity test method
1) Preparing a buffer solution: 0.9560g KH are precisely weighed2PO4，5.3020g K2HPO4Adding distilled water for dissolving, and diluting to 500mL to obtain Phosphate Buffer Solution (PBS) containing 75mM phosphate ions and having pH of 7.4.
2) Preparation of a substrate: 3.65mg of xanthine is precisely weighed, a small amount of 0.5M NaOH solution is added for dissolving, and PBS is used for fixing the volume to 50mL to obtain 0.48mM substrate solution which needs to be prepared for use.
3) Preparing an enzyme solution: the liquid transfer gun takes 100 mu L of xanthine oxidase, adds PBS, and fixes the volume to 25ml to obtain a xanthine oxidase solution of 0.04U.mL < -1 >, and the enzyme solution needs to be prepared for use.
4) Preparation of a test sample: an appropriate amount of sample was weighed precisely, and the sample was dissolved with a small amount of DMSO (content: less than 5%) and then diluted with PBS buffer so that the concentration of the sample at the time of reaction was 15. mu.M, 25. mu.M, 35. mu.M, 50. mu.M, and 100. mu.M.
5) Using allopurinol (IC)502.68 μ M) was added to the test tube, 200 μ L of each of the test sample solution, the positive control solution, and a blank solution (blank is PBS), and 500 μ L, PBS2800 μ L of the enzyme solution and 2800 μ L of the enzyme solution were added to the test tube, incubated at 37 ℃ for 15min, then 500 μ L of the substrate was added to initiate the reaction, and the reaction was read 1 time at 295nm every 30 seconds, and the absorbance a was recorded for a total of 5 min.
2.4 results of the experiment
The inhibition (%) was calculated from the change in A values in the sample group and blank group using the following formula, wherein the inhibition (%) was (1-A)Sample (I)/ABlank space) X 100%, inhibition results are shown in the table below.
Table 2: inhibition of Xanthine Oxidase (XO) by compounds
2) As shown in the inhibition tables, the compounds PJL-1, PJL-2 and PJL-3 exhibited high enzyme inhibition.
Thirdly, the compounds PJL-1, PJL-2 and PJL-3 of the present invention have Xanthine Oxidase (XO) inhibitory activity IC50Measurement of (2)
Compounds having slightly higher inhibitory activity against Xanthine Oxidase (XO), i.e., compounds PJL-1, PJL-2 and PJL-3, have been screened through the above-mentioned experiments, and IC of inhibitory activity thereof was further measured50The value is obtained.
The specific experimental procedures are as above, and the experimental results are shown in table 3:
(1) inhibition ratio (%) - (1-A)Sample (I)/ABlank space) X 100%, results are shown in the table below.
Table 3: inhibition rate of compounds PJL-1, PJL-2 and PJL-3 at different concentrations
(2)IC50The value: converting the inhibition rate into corresponding enzyme activity, and calculating IC50Values, results see table 4:
table 4: IC of Compounds PJL-1, PJL-2, PJL-350Value of
Pharmaceutical compositions of the compounds of the present invention and their pharmaceutically acceptable salts, hydrates or solvates
(1) The pharmaceutical composition is made into tablets according to the following formulation
The preparation method comprises the following steps: the method adopts dry granulation and tabletting. The compound is sequentially mixed with microcrystalline cellulose, hydroxypropyl methylcellulose and the added crospovidone, the mixture is sieved for three times by a 80-mesh sieve, and is granulated by a dry granulation machine, and the granules are dried at 80 ℃ after being granulated, wherein the moisture content is less than 3%. Adding crospovidone, magnesium stearate and pulvis Talci, mixing, tabletting, and coating film.
(2) The pharmaceutical composition is prepared into capsules according to the following formula
| Name (R) | Mass/g | Percent/%) | Function of |
| Compounds of the invention | 12 | 12％ | Main medicine |
| Microcrystalline cellulose | 40 | 40％ | Filler |
| Lactose | 30 | 30％ | Filler |
| Low-substituted hydroxypropyl cellulose | 7 | 7％ | Adhesive agent |
| Magnesium stearate | 2 | 2％ | Lubricant agent |
| Talcum powder | 1 | 1％ | Glidants |
The preparation method comprises the following steps: mixing the compound of the invention and the auxiliary materials, sieving by a 60-mesh sieve, granulating, drying, finishing granules, and filling capsules to obtain the compound.
The above examples of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention. Variations and modifications in other variations will occur to those skilled in the art upon reading the foregoing description. Not all embodiments are exhaustive. All obvious changes and modifications of the present invention are within the scope of the present invention.
Claims (4)
1. The application of a compound II or a pharmaceutically acceptable salt thereof in preparing a medicament for treating gout and hyperuricemia is characterized in that the structural formula of the compound II is as follows:
2. the use according to claim 1, comprising 12 to 20 parts by weight of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, based on 100 parts by weight, with the balance being excipients.
3. The use according to claim 2, wherein the excipient comprises one or more of a filler, a binder, a disintegrant, a lubricant, or a glidant; the filler comprises starch, sugar powder, microcrystalline cellulose, mannitol, and lactose; the adhesive comprises starch slurry, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinylpyrrolidone or sodium carboxymethyl cellulose; the disintegrant comprises sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, or hydroxypropyl starch; the lubricant is magnesium stearate; the glidant is talcum powder.
4. The use according to claim 3, wherein the pharmaceutical composition is in a dosage form comprising a tablet, capsule, pill or suspension.
Priority Applications (1)
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| CN202010838794.4A CN111803499B (en) | 2018-06-13 | 2018-06-13 | Medicine composition II for treating gout and hyperuricemia |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003064401A1 (en) * | 2002-01-29 | 2003-08-07 | Nippon Soda Co., Ltd. | Acrylonitrile compounds and pest controllers |
| WO2005068443A1 (en) * | 2004-01-19 | 2005-07-28 | Nippon Soda Co., Ltd. | Acrylonitriles and pest controlling agents |
| CN101195617A (en) * | 2007-12-29 | 2008-06-11 | 浙江工业大学 | 2-thiazolyl-3-pyridinyl vinyl cyanide compounds and production and application thereof |
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| JPH0366669A (en) * | 1989-08-03 | 1991-03-22 | Shionogi & Co Ltd | Heterocyclic compound |
| EP2079699A1 (en) * | 2006-07-25 | 2009-07-22 | Envivo Pharmaceuticals, Inc. | Quinoline derivatives |
| JP5854841B2 (en) * | 2009-02-27 | 2016-02-09 | シガ・テクノロジーズ・インコーポレーテッド | Thienopyridine derivatives for treating and preventing dengue virus infection |
| WO2014141129A2 (en) * | 2013-03-14 | 2014-09-18 | Grueneberg Dorre A | Novel methods, compounds, and compositions for inhibition of ros |
| US10174000B2 (en) * | 2015-08-27 | 2019-01-08 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds as IRAK4 modulators |
| CN106478619B (en) * | 2015-08-29 | 2019-09-24 | 江苏新元素医药科技有限公司 | A kind of xanthine oxidase inhibitor and its application |
| DK3388420T3 (en) * | 2015-12-07 | 2022-09-26 | Hinova Pharmaceuticals Inc | Quinoline compounds, method of preparation thereof and use thereof as urate transporter inhibiting drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003064401A1 (en) * | 2002-01-29 | 2003-08-07 | Nippon Soda Co., Ltd. | Acrylonitrile compounds and pest controllers |
| WO2005068443A1 (en) * | 2004-01-19 | 2005-07-28 | Nippon Soda Co., Ltd. | Acrylonitriles and pest controlling agents |
| CN101195617A (en) * | 2007-12-29 | 2008-06-11 | 浙江工业大学 | 2-thiazolyl-3-pyridinyl vinyl cyanide compounds and production and application thereof |
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| 860092-56-4;STN;《STN register》;20050812;1-2 * |
Also Published As
| Publication number | Publication date |
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| CN111803499A (en) | 2020-10-23 |
| CN111920811A (en) | 2020-11-13 |
| CN111920811B (en) | 2021-09-21 |
| CN108853112A (en) | 2018-11-23 |
| CN108853112B (en) | 2021-02-02 |
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