CN111635309A - Novel antipyretic analgesic drug and preparation method and application thereof - Google Patents

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

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CN111635309A
CN111635309A CN201910157245.8A CN201910157245A CN111635309A CN 111635309 A CN111635309 A CN 111635309A CN 201910157245 A CN201910157245 A CN 201910157245A CN 111635309 A CN111635309 A CN 111635309A
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antipyretic analgesic
analgesic drug
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CN111635309B (en
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杨成
张起愿
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Shaanxi Synthetic Pharmaceutical Co ltd
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Abstract

The invention provides an antipyretic analgesic drug, or a stereoisomer, a hydrate, a deuteron, an ester, a solvate, a crystal form, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein the antipyretic analgesic drug has a structure shown in a formula I:

Description

Novel antipyretic analgesic drug and preparation method and application thereof
Technical Field
The invention relates to a novel antipyretic analgesic drug, a preparation method and application thereof, belonging to the technical field of medicines.
Background
Loxoprofen Sodium (Loxoprofen Sodium) is an anti-inflammatory analgesic drug which has the inhibition effect on cyclooxygenase COX-1 and COX-2. The loxoprofen sodium as the first synthesized aryl propionic acid precursor type non-steroidal anti-inflammatory drug has the advantages of obvious analgesic effect, and comparable anti-inflammatory and antipyretic effects with other similar drugs. Clinical trials show that after oral administration, the drug is metabolized to trans-OH type drug in human body, and meanwhile, the concentration distribution in liver and plasma is higher than that in other parts, and then the drug is rapidly converted into glucose conjugate and finally discharged out of body in the form of urine. The loxoprofen sodium has the analgesic effect which is 10 to 20 times stronger than that of ketoprofen, indometacin and naproxen, and also has the advantages of quick and obvious effect, small toxic and side effect, wide clinical application range and the like.
Through long-term clinical practice, COX-2 specific inhibitors that were previously considered "perfect" were also gradually exposed as follows:
the problems are as follows: (1) the curative effect is not increased, (2) the adverse reaction is not reduced; (3) the ulcer rate is reduced in a short term, and no difference exists in long-term use; (4) severe myocardial infarction occurs. Therefore, how to search for a non-steroidal anti-inflammatory drug with less toxic and side effects, higher bioavailability, and higher safety and effectiveness becomes one of the hot spots in the research and development of the industry.
There are many loxoprofen sodium derivatives that have been proposed so far, and for example, loxoprofen sodium derivatives have been proposed in Japanese patent application laid-open Nos. 58-4699 and 54-103852, International publication No. WO93/02999, and domestic patent application No. 201680000788.3, but they have various disadvantages.
Therefore, the problems to be solved clinically at present are that the absorption efficiency of the medicine is improved, the metabolic stability is improved, and the toxic and side effects are reduced.
Disclosure of Invention
In view of the defects in the prior art, the invention aims to provide a novel antipyretic analgesic, which has better clinical curative effect, higher bioavailability and lower toxicity, and can further treat antipyretic analgesic diseases.
The purpose of the invention is realized by the following technical scheme:
an antipyretic analgesic drug, which has a structural general formula I:
Figure RE-984602DEST_PATH_IMAGE001
Ⅰ
a structure represented by formula I, wherein R1 represents halogen, hydrogen, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl, methyl;
r2 represents halogen, hydrogen, formate, carbethoxy, propiolate, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl, methyl;
r3 represents hydrogen, oxygen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl;
r4 represents hydrogen, alkali metal, methyl, ethyl, isopropyl, amino acid,
Figure RE-228502DEST_PATH_IMAGE002
；
R5 represents hydrogen, deuterium, ethyl ester group, propyl ester group, fumarate group, tartrate group, phosphate group and phosphate ester salt.
The structure of formula I, which includes the following compounds:
Figure RE-480492DEST_PATH_IMAGE003
compound 1
Figure RE-442631DEST_PATH_IMAGE004
Compound 2
Figure RE-71059DEST_PATH_IMAGE005
Compound 3
Figure RE-435044DEST_PATH_IMAGE006
Compound 4
Figure RE-872584DEST_PATH_IMAGE007
Compound 5
Figure RE-322019DEST_PATH_IMAGE008
Compound 6
Figure RE-754138DEST_PATH_IMAGE009
Compound 7
Figure RE-707050DEST_PATH_IMAGE010
Compound 8
Figure RE-566422DEST_PATH_IMAGE011
Compound 9
Figure RE-237575DEST_PATH_IMAGE012
Compound 10
Figure RE-473384DEST_PATH_IMAGE013
Compound 11
Figure RE-546382DEST_PATH_IMAGE014
Compound 12
Figure RE-579585DEST_PATH_IMAGE015
Compound 13
Figure RE-738034DEST_PATH_IMAGE016
Compound 14
Figure RE-DEST_PATH_IMAGE017
Compound 15
Figure RE-636588DEST_PATH_IMAGE018
Compound 16
Figure RE-564093DEST_PATH_IMAGE019
Compound 17
Figure RE-765267DEST_PATH_IMAGE020
Compound 18
Figure RE-411012DEST_PATH_IMAGE021
Compound 19
Figure RE-725975DEST_PATH_IMAGE023
Compound 20
Figure RE-773565DEST_PATH_IMAGE024
Compound 21
Figure RE-145640DEST_PATH_IMAGE025
Compound 22
Figure RE-278682DEST_PATH_IMAGE026
Compound 23
Figure RE-DEST_PATH_IMAGE027
Comparative Compound 1
Figure RE-519039DEST_PATH_IMAGE028
Comparative Compound 2
Figure RE-DEST_PATH_IMAGE029
Comparative Compound 3
The invention also provides the antipyretic analgesic drug, or a stereoisomer, a hydrate, a deuteron, an ester, a solvate, a crystal form, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which is applied to antipyretic analgesia.
The invention also provides an antipyretic analgesic pharmaceutical composition, which comprises the antipyretic analgesic drug (namely the compound with the structure of the formula I), or a stereoisomer, a hydrate, a deuteron, an ester, a solvate, a crystal form, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.
The antipyretic analgesic drug with hydroxyl reacts with phosphate to form an antipyretic analgesic prodrug. Such prodrugs have superior solubility than compounds that do not form prodrugs; the prodrug has a solubility of more than 100mg/ml, is stable in an aqueous solution, and is converted into an active ingredient by esterase and phosphatase in blood, thereby developing a formulation for injection or oral administration.
The composition of the present invention may include at least one effective ingredient having a function similar to that of antipyretic analgesic drugs.
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, glucose solution, maltodextrin solution, glycerol, ethanol, etc. The pharmaceutical composition may contain conventional excipients such as antioxidants, buffers, detergents (soil cleaners) and the like, according to the needs of the user. The composition is also mixed with a diluent, a disintegrant (diaitent), a surfactant, a binder, a lubricant, an aqueous solution, a suspension, etc. to form an injection, a powder, a capsule, a granule, a tablet, etc. Preferably, the preparation is prepared by using the method described in Remington's pharmaceutical Science (latest edition) (Mack Publishing Company, Easton PA, etc.), depending on the disease or component.
The compounds of the invention may be administered orally or parenterally, for example intravenously, subcutaneously, intraperitoneally, topically, etc. The dosage of the compounds may vary with the particular compound employed, the mode of administration, the symptoms and severity of the condition being treated, and various physical factors related to the individual being treated.
semi-Lethal Dose (LD) of antipyretic analgesic drugs in acute toxicity test50) It was shown to be more than 300mg/kg, and therefore, the antipyretic-analgesic drug was found to be safe.
The antipyretic analgesic drug of the invention has the advantages of lower toxicity, higher bioavailability and higher cure rate. The prodrug to be prepared by reacting a compound having a hydroxyl group with a phosphate ester has high water solubility.
Therefore, the composition containing the antipyretic analgesic medicine is used for antipyretic analgesic.
The anti-anaerobe pharmaceutical composition can comprise an antipyretic analgesic shown in formula I, and at least one of stereoisomer, hydrate, deuteron, ester, solvate, crystal form, metabolite and pharmaceutically acceptable salt or prodrug of the antipyretic analgesic shown in formula I is combined with antibacterial drugs known in the field.
The invention also provides application of the pharmaceutical composition in antipyretic and analgesic.
The invention has the outstanding effects that:
the antipyretic analgesic drug, or a stereoisomer, a hydrate, a deuteron, an ester, a solvate, a crystal form, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof has the advantages of lower toxicity, higher bioavailability and higher cure rate.
Detailed Description
The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
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, reduced pressure is evaporated to dryness after the reaction is finished, and the residue is chromatographed for separation to obtain 111.2 g of a compound.
Example 2: preparation of Compound 2
Taking 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, heating and refluxing for 6 hours, reducing pressure and evaporating after the reaction is finished, adding 100ml of acetic acid into the residue, heating and refluxing for 6 hours, reducing pressure and evaporating after the reaction is finished, and carrying out chromatography on the residue to separate to obtain 29.4 g of a compound.
Example 3: preparation of Compound 3
Taking 110 g of the compound, adding 50ml of acetonitrile, cooling to 0-5 ℃ for reaction, slowly dropwise adding 6.0g of phosphorus oxychloride, reacting for 8 hours at 0-5 ℃, adding 10ml of water for hydrolysis, completing hydrolysis, evaporating to dryness under reduced pressure, and carrying out chromatography separation on residues to obtain 112.1 g of the compound.
Experimental example i: drug-induced gastric ulcer formation
Reference to Biochemical Pharmacology, 2004 (67): 575-.
The test male rats (body weight: about 200g) were fed on a chow for 24 hours, orally administered with the compound of the present invention in a molar amount equivalent to that of the comparative compounds 1 to 3, and after 12 hours, the stomach was removed to measure the area of ulcer developed in the stomach. The total area of all ulcers was used as the ulcer coefficient. The dosage was 40 mg/kg. The results are shown in Table 1.
TABLE 1
Compound (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 are as follows: the ulcer coefficient of loxoprofen sodium is 10.3 (mm)2) The ulcer coefficients of comparative compounds 1 to 3 are in the range of 3 to 4, and the ulcer coefficients of the compounds of the present invention are all less than 3 (mm)2). This indicates that the compounds of the present invention hardly form ulcer of side effect, the ulcer area of stomach is small, and the ulcer coefficient is lower than that of the comparative compound.
Experimental example 2: analgesic test
The number of writhing appeared after the abdominal cavity of the mouse was administered with the 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. The control group was given a blank formulation; comparative compounds 1 to 3, loxoprofen and the compounds of the invention were administered in equimolar amounts. The test compounds were administered to the mice 60min before the administration of the acetic acid solution, and the results are shown in table 2.
TABLE 2 twist test results
Compound (I) Dosage form Number of times of body twisting Percent inhibition (%)
Blank solvent 0 46.3 Is free of
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 for 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, mice weighing 20 g. + -.2 g). Intravenous administration to determine median Lethal Dose (LD)50Mg/kg). Comparative compounds 1-3, loxoprofen sodium, were used as controls. The results are shown in Table 3.
TABLE 3
Compound (I) Median Lethal Dose (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 toxicity of the compound of the present invention is less than that of the control drug, indicating that the compound of the present invention has excellent low toxicity and higher safety.
Experimental example 4: evaluation of the Effect of the bioavailability of compositions of the Compounds of the invention
The effect on bioavailability of the composition 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) of 16 each. After one week feeding with normal feed, fasting was performed for 12 hours, and the samples were orally administered to mice as described in table 4.
TABLE 4
Group of Processing method
Control group 1 (comparative Compound 1) A composition containing comparative Compound 1 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Control 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) A 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) Taking the composition containing loxoprofen sodium, and then orally administering the loxoprofen sodium into mice at a dose of 0.15mmol/kg
Test group 1 (Compound 1) The composition containing the compound 1 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 2 (Compound 2) Taking the composition containing compound 2, and orally administering to mice at a dose of 0.15mmol/kg
Test group 3 (Compound 3) Taking the composition containing the compound 3, and then adding 0.1The dosage of 5mmol/kg is orally administered to mice
Test group 4 (Compound 4) The composition containing compound 4 was taken and then orally administered to mice at a dose of 0.15mmol/kg
Test group 5 (Compound 5) Taking the composition containing compound 5, and orally administering to mice 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 group 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) The composition containing compound 8 was taken and then orally administered to mice 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 to mice at a dose of 0.15mmol/kg
Test group 14 (Compound 14) Taking the composition containing compound 14, then adding the mixture at a ratio of 0.15mmol/kgDose oral administration to mice
Test group 15 (Compound 15) Taking the composition containing compound 15, and orally administering 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 group 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 group 19 (Compound 19) The composition containing compound 19 was taken and administered orally 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 group 21 (Compound 21) The composition containing compound 21 was taken and administered orally to mice at a dose of 0.15mmol/kg
Test group 22 (Compound 22) The composition containing compound 22 was taken and administered orally 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. Collection of blood sample and separation of serum
Blood was collected from the retro-orbital venous plexus of the mice using flat capillaries 10, 20, 30 and 60 minutes and 2, 4, 8 and 24 hours after 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 isolate serum for analysis.
Step 3 pharmacological analysis
Sera were treated for pharmacological analysis according to the method previously reported (Wang BYG et al, Biol. Pharm Bull. 30 (9) 1657-1662). The content of the test compound was analyzed by UPLC/MS (SIR mode). The quantization accuracy was 5ng/mL (detection limit: 1ng/mL), and the internal standard was used. Bioavailability of the compounds of the invention can be expressed as Cmax, Tmax and AUC values. The results are shown in Table 5.
TABLE 5
Experimental group Cmax（ng/ml） Tmax（hr） AUC（ng·hr/ml）
Control group 1 (comparative Compound 1) 20.4±13.2 0.8±0.2 123.4±49.2
Control 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 group 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 group 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 group 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 group 21 (Compound 21) 33.2±19.1 0.8±0.2 181.4±82.2
Test group 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
*Cmax(ng/mL): the maximum serum concentration calculated or evaluated from the observed serum concentration or concentration-time curve.
*Tmax(hr)：CmaxThe point in time of occurrence.
AUC (ng hr/ml) (area under curve; ng hr/ml): area under the serum concentration-time curve.
As shown in Table 5, control group 2,3, 4TmaxBoth 0.4 hr, control 1 and test 1-20TmaxAll have no significant difference in 0.4-0.8 hours. However, C, which indicates bioavailability, in the test group compared with the control groupmaxValues and AUC values increased 3-fold and 2-fold, respectively. Thus, this indicates that the bioavailability of the compounds of the present invention is significantly better than that of the control group.
Formulation example i: tablet formulation
Compound of the invention 100g
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 the starch and the hydroxypropyl methylcellulose with a 80-mesh sieve, uniformly mixing the compound, the starch and the hydroxypropyl methylcellulose, preparing a soft material, granulating by 30 meshes, drying for 1.5h at 60 ℃ to obtain a dry material, adding magnesium stearate, mixing for 10min, granulating by 24 meshes, and tabletting to obtain the compound.
Formulation example 2: tablet formulation
Compound of the present invention 50g
Starch 30g
Microcrystalline cellulose 150g
Sodium carboxymethyl starch 20g
Proper amount of 1.5 percent 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 the lactose, the starch and the sodium carboxymethyl starch with a 80-mesh sieve, uniformly mixing the compound with the sodium carboxymethyl starch, the starch and the lactose, adding a 1.5% sodium carboxymethyl cellulose solution to prepare a soft material, granulating by 30 meshes, drying for 1.5h at 60 ℃ to obtain a dry material, adding magnesium stearate, mixing for 10min, granulating by 24 meshes, and tabletting to obtain the compound.
Formulation example 3: granules
Compound 250mg
Sucrose l00mg
Corn starch 150mg
Based on the above formulation, granules containing 50mg of the active ingredient in 500mg of granules were prepared by a conventional method.
Formulation example 4: injection preparation
Compound of the invention 60g
Sodium chloride 20g
Proper amount of pH regulator
10L of water for injection
The preparation method comprises the following steps: dissolving a compound with a formula amount in 70% water for injection, adding sodium chloride with a formula amount, adjusting the pH of the solution to be =4.0-9.0 by using a pH regulator, metering the volume by using the water for injection, adding 0.1% (g/ml) of activated carbon into the solution with the metered volume for adsorption for 20min, filtering to remove the carbon, finely filtering the solution by using a 0.22um filter membrane, filling the solution into l0ml each tube after the content of an intermediate is detected to be qualified, sterilizing the filled semi-finished product at 121 ℃ for 15min in a sterilizing cabinet, and subpackaging the sterilized semi-finished product to obtain the finished product after the lamp inspection is qualified.

Claims (5)

1. An antipyretic analgesic drug, which has the structure as shown in formula I:
Figure DEST_PATH_IMAGE002
Ⅰ。
2. the antipyretic analgesic drug according to claim i, characterized in that: the antipyretic analgesic drug comprises a stereoisomer, a hydrate, a deutero-compound, an ester, a solvate, a crystal form, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.
3. The antipyretic analgesic drug according to claim i, characterized in that: in the structure shown in the formula I, R1 represents halogen, hydrogen, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl and methyl;
r2 represents halogen, hydrogen, formate, carbethoxy, propiolate, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl, methyl;
r3 represents hydrogen, oxygen, methyl, trifluoromethyl, difluoromethyl, fluoromethyl, deuterated methyl;
r4 represents hydrogen, alkali metal, methyl, ethyl, isopropyl, amino acid,
Figure DEST_PATH_IMAGE004
；
R5 represents hydrogen, deuterium, ethyl ester group, propyl ester group, fumarate group, tartrate group, phosphate group and phosphate ester salt.
4. The antipyretic analgesic drug according to claim i, characterized in that: the antipyretic analgesic drug comprises the following compounds:
Figure DEST_PATH_IMAGE006
compound 1
Figure DEST_PATH_IMAGE008
Compound 2
Figure DEST_PATH_IMAGE010
Compound 3
Figure DEST_PATH_IMAGE012
Compound 4
Figure DEST_PATH_IMAGE014
Compound 5
Figure DEST_PATH_IMAGE016
Compound 6
Figure DEST_PATH_IMAGE018
Compound 7
Figure DEST_PATH_IMAGE020
Compound 8
Figure DEST_PATH_IMAGE022
Compound 9
Figure DEST_PATH_IMAGE024
Compound 10
Figure DEST_PATH_IMAGE026
Compound 11
Figure DEST_PATH_IMAGE028
Compound 12
Figure DEST_PATH_IMAGE030
Compound 13
Figure DEST_PATH_IMAGE032
Compound 14
Figure DEST_PATH_IMAGE034
Compound 15
Figure DEST_PATH_IMAGE036
Compound 16
Figure DEST_PATH_IMAGE038
Compound 17
Figure DEST_PATH_IMAGE040
Compound 18
Figure DEST_PATH_IMAGE042
Compound 19
Figure DEST_PATH_IMAGE044
Compound 20
Figure DEST_PATH_IMAGE046
Compound 21
Figure DEST_PATH_IMAGE048
Compound 22
Figure DEST_PATH_IMAGE050
Compound 23.
5. An antipyretic analgesic composition, which is characterized in that: the composition comprises the antipyretic analgesic drug as claimed in claim I, or a stereoisomer, hydrate, deutero-compound, ester, solvate, crystal form, metabolite, pharmaceutically acceptable salt or prodrug thereof.
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CN115557839A (en) * 2021-12-23 2023-01-03 南京海融医药科技股份有限公司 Fat emulsion containing aryl propionic acid derivative and preparation method thereof
CN115836047A (en) * 2021-12-24 2023-03-21 南京海融医药科技股份有限公司 Aryl propionic acid derivative and emulsion preparation thereof
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WO2023115511A1 (en) * 2021-12-24 2023-06-29 南京海融医药科技股份有限公司 Arylpropionic acid derivative and emulsion preparation thereof
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