CN111635309B - Novel antipyretic analgesic medicine and preparation method and application thereof - Google Patents

Novel antipyretic analgesic medicine and preparation method and application thereof Download PDF

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CN111635309B
CN111635309B CN201910157245.8A CN201910157245A CN111635309B CN 111635309 B CN111635309 B CN 111635309B CN 201910157245 A CN201910157245 A CN 201910157245A CN 111635309 B CN111635309 B CN 111635309B
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mice
antipyretic analgesic
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CN111635309A (en
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杨成
张起愿
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Huachuang Synthetic Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/22—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups esterified
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Abstract

The invention provides an antipyretic analgesic drug, or stereoisomers, hydrates, deuterated substances, esters, solvates, crystal forms, metabolites and pharmaceutically acceptable salts or prodrugs thereof, wherein the structure of the antipyretic analgesic drug is shown as a formula I:

Description

Novel antipyretic analgesic medicine and preparation method and application thereof
Technical Field
The invention relates to a novel antipyretic analgesic drug, a preparation method and application thereof, and belongs to the technical field of medicines.
Background
Loxoprofen sodium (Loxoprofen Sodium) is an anti-inflammatory analgesic with an inhibitory effect on both cyclooxygenase COX-1 and COX-2. As a non-steroidal anti-inflammatory drug of the precursor of the first synthesized aryl propionic acid, the curative effect of loxoprofen sodium is mainly obvious in analgesic effect, and the anti-inflammatory and antipyretic effects are equivalent to those of other similar drugs. Clinical trials have shown that drugs which are metabolized to trans-OH form in humans after oral administration, while having a higher concentration profile in the liver and plasma than other sites, are rapidly converted to glucose conjugates, and finally are excreted in the form of urine. The analgesic effect of loxoprofen sodium is 10-20 times stronger than that of ketoprofen, indomethacin and naproxen, and the loxoprofen sodium has the advantages of rapid and obvious effect, small toxic and side effects, wide clinical application range and the like.
COX-2 specific inhibitors, which were previously considered "perfect" through long-term clinical practice, were also gradually exposed as follows:
problems: (1) The curative effect is not increased, and (2) the adverse reaction is not reduced; (3) The ulcer rate is reduced in a short period, and the ulcer rate is not different in long-term use; (4) severe myocardial infarction occurs. Therefore, how to find a safe and effective non-steroidal anti-inflammatory drug with less toxic and side effects and higher bioavailability becomes one of the hot spots developed in the industry.
Various loxoprofen sodium derivatives have been invented so far, for example, japanese patent application laid-open No. 58-4699, japanese patent application laid-open No. 54-103852, international publication No. WO93/02999 and domestic patent application No. 201680000788.3, but they all exhibit various disadvantages.
Therefore, the medicine absorption efficiency is improved, the metabolic stability is improved, and the toxic and side effects are reduced, which is the problem to be solved clinically at present.
Disclosure of Invention
In view of the defects in the prior art, the invention aims to provide a novel antipyretic analgesic drug which has better clinical curative effect, larger bioavailability and smaller toxicity, and can further treat antipyretic analgesic diseases.
The aim of the invention is achieved by the following technical scheme:
the structural general formula of the antipyretic analgesic drug is shown as I:
Ⅰ
a structure shown in formula I, wherein R1 represents halogen, hydrogen, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl and methyl;
r2 represents halogen, hydrogen, formyloxy, ethyl, propyl, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuteromethyl, methyl;
r3 represents hydrogen, oxygen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl;
r4 represents hydrogen, alkali metal, methyl, ethyl, isopropyl, amino acid,；
R5 represents hydrogen, deuterium, ethyl ester group, propyl ester group, fumaric ester group, tartaric ester group, phosphate ester salt.
The structure shown in the formula I comprises the following compounds:
compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
Compound 8
Compound 9
Compound 10
Compound 11
Compound 12
Compound 13
Compound 14
Compound 15
Compound 16
Compound 17
Compound 18
Compound 19
Compound 20
Compound 21
Compound 22
Compound 23
Comparative Compound 1
Comparative Compound 2
Comparative Compound 3
The invention also provides the antipyretic analgesic drug, or stereoisomers, hydrates, deuterated products, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts or prodrugs thereof, which are applied to antipyresis and analgesic.
The invention also provides a antipyretic analgesic pharmaceutical composition, which comprises the antipyretic analgesic drug (namely a compound with a structure shown in a formula I), or stereoisomers, hydrates, deuterides, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts or prodrugs thereof.
The antipyretic analgesic drug with hydroxyl reacts with phosphate to form antipyretic analgesic prodrug. Such prodrugs have superior solubility than compounds that do not form a prodrug; the solubility of the prodrug is greater than 100mg/ml, the prodrug is stable in aqueous solution and is converted into active ingredients by esterases and phosphatases in blood, thereby developing a formulation for injection or oral administration.
The composition of the present invention may include at least one active ingredient having a function similar to that of an antipyretic analgesic drug.
For formulating pharmaceutical compositions, at least one compound of formula I may be admixed with at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include physiological saline, sterile water, ringer's solution, physiological saline buffer solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. The pharmaceutical composition may contain conventional excipients such as antioxidants, buffers, soil-release agents (soil cleaners) and the like, as desired by the user. The composition is also mixed with diluents, disintegrants (diantegrant), surfactants, binders, lubricants, aqueous solutions, suspensions, etc., to form injections, powders, capsules, granules, tablets, etc. Preferably, depending on the disease or component, the formulation is prepared by using the method described by Remington's Pharmaceutical Science (latest edition) (Mack Publishing Company, easton PA, etc.).
The compounds of the present invention may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally, topically, and the like. The dosage of the compound may vary with the particular compound employed, the mode of administration, the symptoms and severity of the condition being treated, and the various physical factors associated with the individual being treated.
In acute toxicity tests, the half-Lethal Dose (LD) of antipyretic analgesic drugs 50 ) Shows more than 300mg/kg, and thus the antipyretic analgesic drug is found to be safe.
The antipyretic analgesic drug of the invention has smaller toxicity, higher bioavailability and higher cure rate. Prodrugs prepared by reacting compounds having hydroxyl groups with phosphate esters have high water solubility.
Therefore, the composition containing the antipyretic analgesic drug is used for antipyresis and analgesia.
The above-mentioned anti-anaerobic pharmaceutical composition may comprise an antipyretic analgesic drug of formula I, wherein at least one of stereoisomers, hydrates, deuterates, esters, solvates, crystal forms, metabolites and pharmaceutically acceptable salts or prodrugs of the antipyretic analgesic drug structure of formula I is used in combination with an antibacterial drug known in the art.
The invention also provides application of the pharmaceutical composition in relieving fever and pain.
The invention has the outstanding effects that:
the antipyretic analgesic drug of the invention, or stereoisomers, hydrates, deuterides, esters, solvates, crystal forms, metabolites, pharmaceutically acceptable salts or prodrugs thereof, has smaller toxicity, higher bioavailability and higher cure rate.
Detailed Description
The technical solution of the present invention will be described in detail below for a clearer understanding of technical features, objects and advantageous effects of the present invention, but should not be construed as limiting the scope of the present invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
Example 1: preparation of Compound 1
10g of (S) -2- (3-fluoro-4- (((1S, 4S) -4-fluoro-2-hydroxycyclopentyl) methyl) phenyl) propionic acid, 0.35g of sulfuric acid, glycine and 100ml are taken, heated and refluxed for 6 hours, and after the reaction is completed, the reaction is evaporated to dryness under reduced pressure, and the residue is separated by chromatography to obtain 11.2g of a compound.
Example 2: preparation of Compound 2
10g of (S) -2- (3-fluoro-4- (((1S, 4S) -4-fluoro-2-hydroxycyclopentyl) methyl) phenyl) propionic acid, 0.3g of sulfuric acid and 50ml of absolute ethyl alcohol are taken, heated and refluxed for 6 hours, then decompressed and evaporated to dryness after the reaction is completed, 100ml of acetic acid is added into the residue, heated and refluxed for 6 hours, then decompressed and evaporated to dryness after the reaction is completed, and the residue is separated by chromatography, thus obtaining 2.4 g of compound.
Example 3: preparation of Compound 3
Taking 1.10 g of compound, adding 50ml of acetonitrile, cooling to 0-5 ℃ for reaction, slowly dripping 6.0g of phosphorus oxychloride, reacting for 8 hours at 0-5 ℃, adding 10ml of water for hydrolysis, performing reduced pressure evaporation to dryness, and separating residues by chromatography to obtain 12.1g of compound.
Experimental example l: drug-induced gastric ulcer formation
Reference Biochemical Pharmacology,2004 (67): the test was carried out by the method described in 575-585.
Male rats (weight: about 200 g) for test were fed intermittently for 24 hours, and the compound of the present invention was orally administered in a molar amount equivalent to that of the comparative compounds 1 to 3, and after 12 hours, the stomach was removed to determine the area of ulcer generated in the stomach. The total area of all ulcers was summed up as the ulcer factor. The dose was 40mg/kg. The results are shown in Table 1.
TABLE 1
Compounds of formula (I) Ulcer coefficient (mm) 2 ）
Compound 1 2.0
Compound 2 1.4
Compound 3 2.2
Compound 4 1.8
Compound 5 2.1
Compound 6 2.2
Compound 7 0.9
Compound 8 1.2
Compound 9 2.3
Compound 10 2.1
Compound 11 2.3
Compound 12 2.0
Compound 13 1.9
Compound 14 1.2
Compound 15 2.0
Compound 16 1.4
Compound 17 1.9
Compound 18 0.9
Compound 19 1.1
Compound 20 1.6
Compound 21 1.8
Compound 22 1.4
Compound 23 1.1
Comparative Compound 1 3.3
Comparative Compound 2 4.2
Comparative Compound 3 3.8
Loxoprofen sodium 10.3
The results were as follows: loxoprofen sodium has an ulcer factor of 10.3 (mm) 2 ) The ulcer coefficients of comparative compounds 1-3 were in the range of 3-4, the compound of the present invention ulcersThe coefficients are all less than 3 (mm) 2 ). This shows that the compounds of the invention form virtually no side-effect ulcers, the area of ulcers in the stomach is small and the ulcer coefficients are very low compared to the control compounds.
Experimental example 2: pain test
The number of writhing occurring after the intraperitoneal administration of acetic acid solution was counted, and the inhibition rate of writhing was calculated based on the control group. 168 mice were divided into 28 groups of 6 mice each. Administration of a blank formulation to a control group; comparative compounds 1-3, loxoprofen, and the present compounds were administered in equimolar amounts. The test compounds were administered to mice 60min before the acetic acid solution was administered, and the results are shown in table 2.
TABLE 2 torsion test results
Compounds of formula (I) Dosage of Number of times of twisting body Percentage of inhibition (%)
Blank solvent 0 46.3 Without any means for
Compound 1 0.15mmol 12.3 84
Compound 2 0.15mmol 24.4 75
Compound 3 0.15mmol 22.5 76
Compound 4 0.15mmol 18.2 81
Compound 5 0.15mmol 21.2 82
Compound 6 0.15mmol 18.3 80
Compound 7 0.15mmol 15.2 88
Compound 8 0.15mmol 17.3 84
Compound 9 0.15mmol 17.9 80
Compound 10 0.15mmol 19.3 82
Compound 11 0.15mmol 20.3 80
Compound 12 0.15mmol 13.2 83
Compound 13 0.15mmol 16.7 82
Compound 14 0.15mmol 16.0 82
Compound 15 0.15mmol 14.8 85
Compound 16 0.15mmol 16.2 82
Compound 17 0.15mmol 19.4 79
Compound 18 0.15mmol 19.3 76
Compound 19 0.15mmol 20.1 75
Compound 20 0.15mmol 18.2 80
Compound 21 0.15mmol 14.4 83
Compound 22 0.15mmol 15.0 85
Compound 23 0.15mmol 10.3 86
Comparative Compound 1 0.15mmol 23.5 53
Comparative Compound 2 0.15mmol 29.4 67
Comparative Compound 3 0.15mmol 31.2 70
Loxoprofen sodium 0.15mmol 36.4 73
The results show that: the compounds of the invention have better analgesic effect than the control compounds.
Experimental example 3: acute toxicity test of Compounds of the invention on intravenous administration to mice
To test the acute toxicity of the compounds of the invention and the comparative compounds, the following experiments were performed.
The compound of the present invention was dissolved in water and administered to 5 ICR mice (5 week old, male, 20g±2g mice). Intravenous administration to determine the median lethal dose (LD 50 Mg/kg). Comparative compounds 1-3, loxoprofen sodium, were used as controls. The results are shown in Table 3.
TABLE 3 Table 3
Compounds of formula (I) half-Life (LD) 50 ，mg/kg）
Loxoprofen sodium 143
Comparative Compound 1 154
Comparative Compound 2 150
Comparative Compound 3 150
Compound 1 ＞300
Compound 2 ＞300
Compound 3 ＞300
Compound 4 ＞300
Compound 5 ＞300
Compound 6 ＞300
Compound 7 ＞300
Compound 8 ＞300
Compound 9 ＞300
Compound 10 ＞300
Compound 11 ＞300
Compound 12 ＞300
Compound 13 ＞300
Compound 14 ＞300
Compound 15 ＞300
Compound 16 ＞300
Compound 17 ＞300
Compound 18 ＞300
Compound 19 ＞300
Compound 20 ＞300
Compound 21 ＞300
Compound 22 ＞300
Compound 23 ＞300
According to Table 3, the compounds of the present invention have lower toxicity than the control drug, indicating excellent low toxicity and higher safety.
Experimental example 4: evaluation of the Effect of bioavailability of the compositions of the Compounds of the invention
The effect on bioavailability of the compositions containing the present invention was evaluated as follows.
Step 1. Preparation and treatment of test animals and samples
432 male ICR mice with an average body weight of 23.55g were prepared as test animals. They were divided into 27 groups (4 control groups, 23 test groups), each group having 16. After feeding with normal feed for one week, the samples were orally administered to the mice as described in table 4, following a 12 hour fast.
TABLE 4 Table 4
Group of Treatment method
Control group 1 (comparative compound 1) The composition containing comparative compound 1 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Control group 2 (comparative compound 2) The composition containing comparative compound 2 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Control group 3 (comparative compound 3) The composition containing comparative compound 3 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Control group 4 (loxoprofen sodium) The composition containing loxoprofen sodium was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 1 (Compound 1) Taking a composition containing compound 1, and then orally administering to a mouse at a dose of 0.15mmol/kg
Test group 2 (Compound 2) The composition containing Compound 2 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 3 (Compound 3) Taking a composition containing compound 3, and then orally administering to a mouse at a dose of 0.15mmol/kg
Test group 4 (Compound 4) Taking a composition containing compound 4, and then orally administering to a mouse at a dose of 0.15mmol/kg
Test group 5 (Compound 5) Taking a composition containing compound 5, and then orally administering to a mouse at a dose of 0.15mmol/kg
Test group 6 (Compound 6) The composition containing Compound 6 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test set 7 (Compound 7) The composition containing Compound 7 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 8 (Compound 8) Taking a composition containing compound 8, and then orally administering to a mouse at a dose of 0.15mmol/kg
Test group 9 (Compound 9) The composition containing Compound 9 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 10 (Compound 10) The composition containing compound 10 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 11 (Compound 11) The composition containing Compound 11 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 12 (Compound 12) The composition containing Compound 12 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 13 (Compound 13) The composition containing Compound 13 was taken and then orally administered at a dose of 0.15mmol/kgTo mice
Test group 14 (Compound 14) The composition containing compound 14 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 15 (Compound 15) The composition containing compound 15 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 16 (Compound 16) The composition containing Compound 16 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test set 17 (Compound 17) The composition containing compound 17 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 18 (Compound 18) The composition containing compound 18 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test set 19 (Compound 19) The composition containing compound 19 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 20 (Compound 20) The composition containing compound 20 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test set 21 (Compound 21) The composition containing Compound 21 was taken and then 0.15mmol was takenOral administration of a dose of/kg to mice
Test set 22 (Compound 22) The composition containing compound 22 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 23 (Compound 23) The composition containing compound 23 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Step 2, blood sample collection and serum separation
Blood was collected from the retroorbital venous plexus of mice using flat capillaries after 10, 20, 30 and 60 minutes and 2, 4, 8 and 24 hours of oral administration. Each group of 16 mice was subdivided into 4 groups and 2 blood samples were collected from 4 mice at each time period (10 minutes and 2 hours; 20 minutes and 4 hours; 30 minutes and 8 hours; 60 minutes and 24 hours). The blood was centrifuged (Micro 12, hanil, korea) at 13000rpm for 10 minutes to separate serum for analysis.
Step 3, pharmacological analysis
Serum was treated for pharmacological analysis according to the previously reported method (Wang BYG et al, biol. Pharm. Bull. 30 (9) 1657-1662). The amount of test compound was analyzed by UPLC/MS (SIR mode). The accuracy of the quantification was 5ng/mL (limit of detection: 1 ng/mL), and used as an internal standard. Bioavailability of a compound of the invention can be expressed as Cmax, tmax and AUC values. The results are shown in Table 5.
TABLE 5
Experimental group C max （ng/ml） T max （hr） AUC（ng·hr/ml）
Control group 1 (comparative compound 1) 20.4±13.2 0.8±0.2 123.4±49.2
Control group 2 (comparative compound 2) 12.4±10.2 0.4±0.2 78.3±44.2
Control group 3 (comparative compound 3) 17.1±19.2 0.4±0.2 68.3±40.3
Control group 4 (loxoprofen sodium) 11.7±14.2 0.4±0.2 54.5±55.1
Test group 1 (Compound 1) 28.9±21.1 0.8±0.2 161.2±88.8
Test group 2 (Compound 2) 33.2±20.0 0.8±0.2 143.0±74.1
Test group 3 (Compound 3) 34.1±18.9 0.8±0.2 153.2±69.3
Test group 4 (Compound 4) 29.3±22.1 0.8±0.2 165.3±70.4
Test group 5 (Compound 5) 32.1±22.1 0.8±0.2 174.2±70.3
Test group 6 (Compound 6) 26.9±27.3 0.8±0.2 159.7±79.4
Test set 7 (Compound 7) 29.4±20.7 0.8±0.2 184.7±84.1
Test group 8 (Compound 8) 38.3±22.1 0.8±0.2 155.7±72.8
Test group 9 (Compound 9) 37.2±22.9 0.8±0.2 183.2±72.1
Test group 10 (Compound 10) 32.8±21.1 0.8±0.2 173.2±66.3
Test group 11 (Compound 11) 28.6±21.8 0.8±0.2 163.9±63.8
Test group 12 (Compound 12) 33.1±20.1 0.8±0.2 161.5±55.8
Test group 13 (Compound 13) 30.4±19.3 0.4±0.2 181.3±44.2
Test group 14 (Compound 14) 32.1±28.1 0.4±0.2 159.0±66.9
Test group 15 (Compound 15) 27.1±19.1 0.4±0.2 175.4±72.1
Test group 16 (Compound 16) 32.9±20.7 0.8±0.2 163.2±71.1
Test set 17 (Compound 17) 30.1±18.8 0.8±0.2 182.1±82.1
Test group 18 (Compound 18) 28.3±20.8 0.8±0.2 193.2±90.3
Test set 19 (Compound 19) 33.2±19.5 0.8±0.2 177.3±86.3
Test group 20 (Compound 20) 30.2±20.6 0.8±0.2 180.4±85.4
Test set 21 (Compound 21) 33.2±19.1 0.8±0.2 181.4±82.2
Test set 22 (Compound 22) 31.1±18.4 0.8±0.2 186.3±82.1
Test group 23 (Compound 23) 29.3±21.1 0.8±0.2 183.4±85.4
*C max (ng/mL): the maximum serum concentration is calculated or estimated from the observed serum concentration or concentration versus time curve.
*T max (hr)：C max The point in time of occurrence.
* AUC (ng-hr/ml) (area under curve; ng-hr/ml): area under the serum concentration versus time curve.
As shown in Table 5, control group 2,3, 4T max Both 0.4 hours, control group 1 and test groups 1-20T max There was no significant difference between 0.4 and 0.8 hours. However, C, which represents bioavailability, was compared to the control group in the test group max The values and AUC values increased 3-fold and 2-fold, respectively. Thus, this suggests that the bioavailability of the compounds of the present invention is significantly better than the control group.
Formulation example l: tablet formulation
100g of the compound according to the invention
Starch 100g
Hydroxypropyl cellulose 150g
Magnesium stearate 0.5g
The preparation process comprises the following steps: sieving the compound of the invention with a 100-mesh sieve, sieving starch and hypromellose with an 80-mesh sieve, uniformly mixing the compound with the starch and the hypromellose, preparing a soft material, granulating with 30 meshes, drying at 60 ℃ for 1.5 hours to obtain a dry material, adding magnesium stearate, mixing for 10 minutes, finishing with 24 meshes, and tabletting to obtain the compound.
Formulation example 2: tablet formulation
50g of a compound of the invention
Starch 30g
Microcrystalline cellulose 150g
Sodium carboxymethyl starch 20g
Proper amount of 1.5% sodium carboxymethyl cellulose solution
Magnesium stearate 0.8g
The preparation process comprises the following steps: sieving the compound of the invention with a 100-mesh sieve, sieving lactose, starch and sodium carboxymethyl starch with an 80-mesh sieve, uniformly mixing the compound with sodium carboxymethyl starch, starch and lactose, adding 1.5% sodium carboxymethyl cellulose solution to prepare a soft material, granulating with 30 meshes, drying at 60 ℃ for 1.5h to obtain a dry material, adding magnesium stearate, mixing for 10min, finishing with 24 meshes, and tabletting.
Formulation example 3: granule preparation
250mg of compound
Sucrose l00mg
Corn starch 150mg
Based on the above formulation, particles containing 50mg of the active ingredient in 500mg of the particles were prepared by a conventional method.
Formulation example 4: injection preparation
60g of the compound according to the invention
Sodium chloride 20g
Proper amount of PH regulator
10L of water for injection
The preparation method comprises the following steps: dissolving the compound with the formula amount in 70% of water for injection, adding sodium chloride with the formula amount, regulating the pH value of the solution with a pH regulator to be 4.0-9.0, then fixing the volume with water for injection, adding 0.1% (g/ml) active carbon into the solution with the fixed volume for adsorption for 20min, filtering to remove carbon, finely filtering the solution with a 0.22um filter membrane, filling each l0ml of solution after the intermediate detection content is qualified, sterilizing the filled semi-finished product in a sterilizing cabinet at 121 ℃ for 15min, and packaging after the lamp inspection is qualified to obtain the finished product.

Claims (2)

1. An antipyretic analgesic drug, comprising in particular the following compounds, deuterides or pharmaceutically acceptable salts:
2. a pharmaceutical composition for reducing fever and easing pain, comprising a compound, deuterated compound or pharmaceutically acceptable salt according to claim 1.
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CN102333754A (en) * 2009-02-26 2012-01-25 国立大学法人熊本大学 Loxoprofen verivate and the medicine that contains it
CN106661061A (en) * 2015-07-22 2017-05-10 南京海融医药科技股份有限公司 Aryl propionic acid derivative composition and pharmaceutical purpose

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CN102333754A (en) * 2009-02-26 2012-01-25 国立大学法人熊本大学 Loxoprofen verivate and the medicine that contains it
CN106661061A (en) * 2015-07-22 2017-05-10 南京海融医药科技股份有限公司 Aryl propionic acid derivative composition and pharmaceutical purpose

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