HK1217015B - Positively charged water-soluble prodrugs of diflunisal and related compounds - Google Patents

Description

Positively charged water-soluble prodrugs of diflunisal and related compounds

This application is a divisional application of Chinese invention patent application No. 200680055458.0. The original application was filed on July 26, 2006, and is entitled "Positively charged water-soluble prodrugs of diflunisal and related compounds with rapid skin penetration."

Technical Field

The present invention relates to positively charged, water-soluble prodrugs of 5-(2,4-difluorophenyl)salicylic acid (diflunisal), salicyloylsalicylic acid, or other salicylic acid analogs, and their use in treating any diflunisal, salicyloylsalicylic acid, or salicylic acid-treatable disease in humans or animals. Specifically, the present invention is intended to overcome the side effects associated with the use of diflunisal, salicyloylsalicylic acid, or salicylic acid. These prodrugs can be administered orally or transdermally.

Technical Background

Diflunisal and salicylic acid are two of the many salicylate nonsteroidal anti-inflammatory drugs (NSAIDs) that have been used clinically for over 20 years. Diflunisal is one of the 200 most commonly prescribed medications. Diflunisal has a more potent anti-inflammatory effect than aspirin, and its biological half-life is 3-4 times longer than aspirin (W.O.Faye, T.L.Lemke, D.A.Williams, Medicinal Chemistry, fourth edition, Williams & Wilkins, pg 549). "PDR Generics" (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 243) lists many clinical applications of diflunisal and salicylic acid. Diflunisal can treat acute or chronic mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Diflunisal can also be used alone or as an adjunct to treat dysmenorrhea and gout. Diflunisal can also be used alone or as an adjunct to treat blindness caused by corneal surgery (Hirsch-Kauffmann, Dan J., U.S. Patent No. 5,134,165). Some esters of diflunisal and related compounds can inhibit platelet aggregation and improve vision loss caused by cystoid macular edema in warm-blooded animals (Yung-Yu Hung et al., U.S. Patent No. 6,593,365).

However, the use of diflunisal, salicylic acid, or salicylic acid can cause numerous side effects, most notably gastrointestinal discomfort such as indigestion, gastroduodenal bleeding, gastric ulcers, and gastritis. Numerous reports exist in the prior art regarding diflunisal derivatives, which exhibit superior analgesic and antipyretic activity compared to the original drug. A U.S. patent (U.S. Patent No. 4,044,049 (Ruyle et al.)) discloses diflunisal-related compounds. Fishman (U.S. Patent No. 7,052,715) has highlighted another issue associated with oral medication: the requirement for very high circulating drug concentrations to effectively treat pain or inflammation at distal sites. These concentrations are often far higher than would be practical if the drug were to be directly targeted to the site of pain or injury. Fishman and others (Van Engelen et al., U.S. Patent No. 6,416,772; Macrides et al., U.S. Patent No. 6,346,278; Kirby et al., U.S. Patent No. 6,444,234; Pearson et al., U.S. Patent No. 6,528,040; and Botknech et al., U.S. Patent No. 5,885,597) have attempted to develop drug delivery systems for transdermal administration through formulations. However, achieving effective therapeutic plasma concentrations of diflunisal through formulations has been difficult. Susan Milosovich et al. designed and synthesized 4-dimethylaminobutyrate testosterone hydrochloride (TSBH), which has a lipophilic moiety and a tertiary amine structure that exists in a protonated form at physiological pH. They found that this prodrug (TSBH) penetrates the skin nearly 60 times faster than the parent drug (TS) itself. (Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)).

Summary of the Invention

Technical issues

Diflunisal and salicylic acid have been used clinically for over 20 years, while salicylic acid has been used for over 100 years. Diflunisal is more effective than aspirin in terms of anti-inflammatory and prostaglandin biosynthesis inhibition. Diflunisal is one of the 200 most commonly prescribed medications. Diflunisal can treat acute or chronic mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Diflunisal can also be used alone or as an adjunct to treat dysmenorrhea and gout.

However, taking diflunisal, salicylic acid, and salicylic acid can cause many side effects, the most common of which is gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. They are insoluble in aqueous solutions and gastric juice.

Solution

The present invention relates to novel positively charged prodrugs of diflunisal, salicylsalicylic acid, salicylic acid, or their analogs and their use in medicine. These compounds have two functional groups that can be modified to form positively charged hydrophilic side chains, as shown in the general formulas "Structure 1" and "Structure 2."

wherein R ₁ represents OH, OCOCH ₃ , OCOC ₂ H ₅ , OCOC ₃ H ₇ , OCOC ₄ H ₉ , OCOC ₅ H ₁₁ , OCOC ₆ H ₁₃ , 2-hydroxybenzoyloxy (salicyloyloxy, 2-OCO-C ₆ H ₄ -OH), 2-acetoxybenzoyloxy (acetylsalicyloyloxy, 2-OCO-C ₆ H ₄ -OCOCH ₃ ), 2-propionyloxybenzoyloxy (propionylsalicyloyloxy, 2-OCO-C ₆ H ₄ -OCOC ₂ H ₅ ), or 2-butyryloxybenzoyloxy (butyrylsalicyloyloxy, 2-OCO-C ₆ H ₄ -OCOC ₃ H ₇ ); R ₂ represents H or 2,4-difluorophenyl; R _{R 3} represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; R ₄ represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; R ₅ represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; X represents O, S or NH; A ^- represents Cl ^- , Br ^- , F ^- , I ^- , AcO ^- , citrate or other negative ions; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ...; All R groups can contain C, H, O, S, or N atoms and can have single, double, or triple bonds; any _CH2 group can be substituted by O, S, or NH.

wherein X represents O or 2-OCO-C ₆ H ₄ -O); R ₂ represents H or 2,4-difluorophenyl; R ₃ represents H, any alkyl group of 1 to 12 carbon atoms, any alkyl group of 1 to 12 carbon atoms, any alkenyl group of 1 to 12 carbon atoms, or any alkynyl group of 1 to 12 carbon atoms, or an aryl group; R ₄ represents H, any alkyl group of 1 to 12 carbon atoms, any alkoxy group of 1 to 12 carbon atoms, any alkenyl group of 1 to 12 carbon atoms, or any alkynyl group of 1 to 12 carbon atoms, or an aryl group; R ₅ represents H, any alkyl group of 1 to 12 carbon atoms, any alkoxy group of 1 to 12 carbon atoms, any alkenyl group of 1 to 12 carbon atoms, or any alkynyl group of 1 to 12 carbon atoms, or an aryl group; R ₆ represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms or alkynyl group of 1-12 carbon atoms, or aryl group; Z represents O or S; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , citrate or other negative ions; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... All R groups can contain C, H, O, S, N atoms, and can have single bonds, double bonds and triple bonds; any _CH2 group can be substituted by O, S or NH.

Whether absorbed through the gastrointestinal tract or other routes, drugs must cross the barrier membrane as single molecules. The drug must first dissolve, and if it possesses desirable biopharmaceutical properties, it diffuses from areas of high concentration to areas of low concentration, crossing the membrane and entering the bloodstream or systemic circulation. All biological membranes contain lipids as a primary component. The molecules that dominate the membrane structure possess a highly polar head structure containing a phosphate and, in most cases, two highly hydrophobic hydrocarbon tails. Biological membranes have a bilayer structure, with the hydrophilic head structure facing the aqueous phase on either side. Extremely hydrophilic drugs are unable to penetrate the lipid layer of the membrane, while very hydrophobic drugs, due to similar compatibility, remain within the membrane and are unable to effectively enter the cytoplasm within.

The present invention aims to improve the solubility of diflunisal, salicylic acid, and salicylic acid in gastric fluid and their penetration rate through biological membranes and skin barriers, thereby enabling transdermal administration (for external use) and avoiding their side effects. These novel prodrugs share two structural characteristics: a lipophilic moiety (oil-soluble portion) and a primary, secondary, or tertiary amine group (water-soluble portion) that is protonated at physiological pH. This water-oil solubility balance is essential for effective drug penetration through barrier membranes (Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)). The positively charged amino group significantly increases the drug's solubility. The solubilities of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, diethylaminoethyl salicylate acetate, diflunisal, salicylic acid, and salicylic acid in water are >400 mg, >350 mg, >400 mg, 0.05 mg, 0.07 mg, and 0.1 mg/ml, respectively. In most cases, drug dissolution is the slowest and rate-limiting step in the absorption process. Diflunisal, salicylic acid, and salicylic acid have very low solubility in gastric fluid. They remain in the gastrointestinal tract for extended periods, potentially causing damage to gastric mucosal cells. These novel prodrugs rapidly dissolve in gastric fluid when administered orally in dosage forms such as tablets, capsules, solutions, and suspensions. The positive charges on the amino groups of these prodrug molecules bind to the negative charges on the phosphate end groups of biological membranes. As a result, the drug concentration is high locally on the outer side of the membrane, facilitating the passage of these prodrugs from areas of high to low concentration. After these prodrug molecules enter the biofilm, the hydrophilic portion pushes the prodrug into the cytoplasm, a semi-liquid concentrated aqueous solution or suspension. Due to the short residence time in the gastrointestinal tract, the prodrug does not damage the gastric mucosal cells. The transdermal rates of 5-(2,4-difluorophenyl) salicylic acid diethylaminoethyl ester acetate, salicylic acid diethylaminoethyl ester acetate, salicylic acid diethylaminoethyl ester acetate, diflunisal, salicylic acid, and salicylic acid in human skin were measured in vitro using a modified Franz cell, wherein the human skin was isolated from human skin tissue (360-400 μm thick) at the front or back of the thigh. The receptor solution consisted of 10 ml of normal saline solution containing 2% bovine serum globulin and stirred at 600 rpm. The cumulative total amount of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate, salicyloylsalicylic acid diethylaminoethyl acetate, salicylic acid diethylaminoethyl acetate, diflunisal, salicyloylsalicylic acid, and salicylic acid permeated through the skin versus time was determined using a specific high performance liquid chromatography method. A solution containing 30% diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate dissolved in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4, a solution containing 30% diethylaminoethyl salicylate acetate dissolved in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4, or a solution containing 30% diethylaminoethyl salicylate acetate dissolved in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4, or a suspension of 30% diflunisal suspended in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4, a suspension of 30% salicyloylsalicylic acid suspended in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4, or a suspension of 30% salicylic acid suspended in 2 ml of phosphate buffered saline (0.2 M) at pH 7.4 was used as the donor solution. The results are shown in FIG1 . Apparent penetration values calculated for diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, diethylaminoethyl salicylate acetate, diflunisal, salicylic acid, and salicylic acid through human skin were 100 mg, 80 mg, 60 mg, 0.7 mg, 0.8 mg, and 0.8 mg/ ^cm² /h, respectively. The results indicate that the prodrug diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate diffuses through human skin nearly 150 times faster than diflunisal itself, the prodrug diethylaminoethyl salicylate acetate diffuses through human skin nearly 100 times faster than salicylic acid itself, and the prodrug diethylaminoethyl salicylate acetate diffuses nearly 75 times faster than salicylic acid itself. These results suggest that the positive charge on the dialkylaminoethyl group is crucial for drug penetration through biological membranes and the skin barrier. The other prodrugs in the general formula "Structure 1" or "Structure 2" have a very high transdermal penetration rate, which is very close to that of diethylaminoethyl salicylate acetate.

In vivo experiments compared the rate at which diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, diethylaminoethyl salicylate acetate, diflunisal, salicylic acid, and salicylic acid penetrated the skin of live, hairless, uninjured mice. A donor solution consisting of a 30% solution of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate in 1 ml of isopropyl alcohol, a 30% solution of diethylaminoethyl salicylate acetate in 1 ml of isopropyl alcohol, a 30% solution of diethylaminoethyl salicylate acetate in 1 ml of isopropyl alcohol, a 30% solution of diflunisal in 1 ml of isopropyl alcohol, or a 30% solution of salicylic acid in 1 ml of isopropyl alcohol was applied to a 1 ^cm² area on the back of the hairless mice. The plasma concentrations of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, diethylaminoethyl salicylate acetate, diflunisal, salicylic acid, and salicylic acid were determined using a specific high-performance liquid chromatography method. The results (Figures 2, 3, and 4) show that the concentrations of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, and diethylaminoethyl salicylate acetate reached peak values approximately 40 minutes after administration of the donor system. Oral administration of diflunisal, salicylic acid, and salicylic acid requires 1-2 hours to reach their respective peak concentrations. The peak concentration of diflunisal was approximately 0.02 mg/ml, the peak concentration of salicylic acid was approximately 0.01 mg/ml, the peak concentration of salicylic acid was approximately 0.01 mg/ml, the peak concentration of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate was approximately 5 mg/ml, the peak concentration of diethylaminoethyl salicylate acetate was approximately 4 mg/ml, and the peak concentration of diethylaminoethyl salicylate acetate was approximately 4 mg/ml (a difference of approximately 200 to 400 times). A plasma concentration of approximately 5 mg/ml of diflunisal is 25 times higher than the plasma concentration of diflunisal that is effective for analgesia and anti-inflammatory effects. This is an exciting result. These prodrugs can easily and rapidly deliver effective plasma concentrations of diflunisal, salicylic acid, and salicylic acid to a host. These results demonstrate that the prodrugs can be used not only orally but also transdermally for various therapeutic applications. The skin penetration rates of other prodrugs in the general formula "Structure 1" and the general formula "Structure 2" in vivo are close to that of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl ester acetate.

To examine the effects of these drugs on gastric and duodenal bleeding, we orally administered 100 mg/kg of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate, salicyloylsalicylic acid diethylaminoethyl acetate, salicylic acid diethylaminoethyl acetate, diflunisal, salicyloylsalicylic acid, and salicylic acid to rats (two groups of 10 rats each) daily for 21 consecutive days. An average of 4 mg of blood per gram of feces was observed in the salicylic acid group, and an average of 3 mg of blood per gram of feces was observed in the diflunisal group. However, no blood was observed in the 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate group, salicyloylsalicylic acid diethylaminoethyl acetate group, or salicylic acid diethylaminoethyl acetate group.

We also studied the acute toxicity of the prodrugs. The oral _LD50 values in rats were 1.0 g/kg, 2.0 g/kg, and 1.6 g/kg for diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, diethylaminoethyl salicylate acetate, and diethylaminoethyl salicylate acetate, respectively. These results suggest that the prodrugs are less toxic than diflunisal ( _LD50 = 0.5 g/kg), salicylate ( _LD50 = 1.5 g/kg), and salicylic acid ( _LD50 = 1.3 g/kg).

Diflunisal, salicylic acid, and salicylic acid have been shown to have anti-inflammatory, analgesic, antipyretic, and anti-rheumatic effects. A good prodrug should be able to revert to the parent drug in plasma. The diethylaminoethyl ester group of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate, salicylic acid diethylaminoethyl acetate, and salicylic acid diethylaminoethyl acetate is rapidly cleaved in vitro by enzymes in human plasma, with over 90% of the prodrug reverting to the parent drug, diflunisal, salicylic acid, and salicylic acid. Due to the higher absorption rate of the prodrug, the prodrug is more effective than the parent drug at the same dose. We tested the analgesic, antipyretic, and anti-inflammatory effects of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate, salicylic acid diethylaminoethyl acetate, and salicylic acid diethylaminoethyl acetate, and compared them with diflunisal. Other compounds of the general formula "Structure 1" and "Structure 2" were also tested using the same method, and the results were very similar to those of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate.

Analgesic Effect: Prolongation of the pain threshold in the tail of mice was measured according to the D'Amour-Smith method (J. Pharmacol. Exp. Ther., 72, 74 (1941)). Mice were orally administered 200 mg/kg of diflunisal, salicylic acid, and salicylic acid, and transdermally administered 200 mg/kg of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl ester acetate, salicylic acid diethylaminoethyl ester acetate, and salicylic acid diethylaminoethyl ester acetate. The tails of the mice were then exposed to heat stimulation, and the prolongation of the pain threshold was measured. The results are shown in Figure 5. The groups receiving transdermal administration of 200 mg/kg of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl ester acetate (C), salicylic acid diethylaminoethyl ester acetate (D), and salicylic acid diethylaminoethyl ester acetate (E) showed stronger analgesic activity than the group receiving 200 mg/kg of diflunisal.

The number of writhing events after intraperitoneal administration of acetic acid solution was counted, and the writhing inhibition rate was calculated based on the control group. Fifty-four mice were divided into nine groups (six mice per group). Mice in groups B1 and B2 were administered diflunisal (50 mg/kg and 100 mg/kg), while groups C1 and C2 were transdermally administered 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl ester acetate (50 mg/kg and 100 mg/kg). Groups D1 and D2 were transdermally administered salicylic acid diethylaminoethyl ester acetate (50 mg/kg and 100 mg/kg). Groups E1 and E2 were transdermally administered salicylic acid diethylaminoethyl ester acetate (50 mg/kg and 100 mg/kg). Group A served as the control group. The test compound was administered to mice 30 minutes before administration of the acetic acid solution. The results are shown in Table 1.

Table 1. Inhibitory effect of diflunisal and its prodrug on writhing in mice

Group A B1 B2 C1 C2 D1 D2 E1 E2 Dosage (mg/kg) 0 50 100 50 100 50 100 50 100 Number of twists 35.0 18.1 13.2 13.2 10.2 14.2 12.0 14.0 11.9 percentage(%) - 48 62 62 71 59 65 60 66

The results showed that diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate had a better analgesic effect than 5-(2,4-difluorophenyl)salicylic acid (diflunisal). The other compounds in the general formula "Structure 1" and "Structure 2" showed similar analgesic activity.

Antipyretic Effect: Rats were administered a suspension of inactivated Escherichia coli as a pyrogen. Fifty-six rats were divided into nine groups. Group A served as the control group. Two hours later, diflunisal (100 mg/kg in Group B1 and 150 mg/kg in Group B2) was administered orally, and diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate (100 mg/kg in Group C1 and 150 mg/kg in Group C2), diethylaminoethyl salicylate acetate (100 mg/kg in Group D1 and 150 mg/kg in Group D2), and diethylaminoethyl salicylate acetate (100 mg/kg in Group E1 and 150 mg/kg in Group E2) were administered transdermally. Body temperature was measured every 90 minutes before and after administration of the test compound. The results are shown in Table 2 below.

Table 2. Antipyretic effect of diflunisal and its prodrugs

The results showed that diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate at a dose of 100 mg/kg had better antipyretic activity than diflunisal. Other compounds in the general formula "Structure 1" and "Structure 2" showed similar antipyretic activity.

Anti-inflammatory Effect: Rats were administered 50 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate orally or transdermally. Diflunisal was also administered orally at 50 mg/kg. Sixty minutes later, a carrageenan solution was administered subcutaneously under the rat's paw pad. The volume of the rat's hind paw was measured every hour after carrageenan administration, and the rate of increase in hind paw volume was calculated and reported as the swelling rate (%). The results are shown in Figure 6. The results show that oral and transdermal administration of 50 mg/kg of diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate demonstrated a greater anti-inflammatory effect than oral administration of the same dose of diflunisal. Other compounds represented by the general formulae "Structure 1" and "Structure 2" exhibited similar anti-inflammatory effects.

When taken orally at high doses, diflunisal exhibits anti-reactive and anti-asthmatic effects by inhibiting cyclooxygenase activity. Due to their high biomembrane permeability, these prodrugs can be used to treat asthma via oral or nasal spray. Due to their anti-inflammatory properties and high transdermal penetration rates, these prodrugs can be used to treat acne.

These prodrugs are water-soluble neutral salts that are well tolerated by the eye. They can also be used to treat ocular inflammation, to treat eye pain after corneal surgery, to treat glaucoma, or to treat inflammatory and/or painful ear conditions (otitis).

The present invention relates to pharmaceutical products containing prodrugs represented by the general formula "Structure 1" and "Structure 2" and their commonly used additives and excipients, such as tablets, capsules, or solutions for oral administration, or solutions, emulsions, ointments, latexes, or gels for transdermal administration. The novel active compounds of the general formula "Structure 1" or "Structure 2" can be used in combination with vitamins such as vitamins A, B, C, and E, β-carotene, or other drugs such as folic acid to treat any disease in humans or animals that can be treated with diflunisal, salicylic acid, or salicylic acid.

Transdermal therapeutic application systems containing compounds represented by the general formula "Structure 1" or "Structure 2," or compositions containing at least one compound represented by the general formula "Structure 1" or "Structure 2," as an active ingredient, can be used to treat any diflunisal, salicylic acid, or salicylic acid-treatable condition in humans or animals. These systems can be bandages or patches, comprising a matrix layer containing the active substance and an impermeable protective layer. The most preferred system is an active substance reservoir with a permeable base facing the skin. By controlling the release rate, these systems can maintain optimal therapeutic blood concentrations of diflunisal, salicylic acid, or salicylic acid, thereby improving efficacy and reducing side effects of diflunisal, salicylic acid, or salicylic acid. These systems can be worn on the wrist, ankle, arm, leg, or anywhere else on the body.

The compound represented by the general formula (1) "Structure 1" can be prepared by reacting 5-(2,4-difluorophenyl)acetylsalicylic acid, acetylsalicylic acid, or a functionalized derivative of acetylsalicylic acid, for example, an acid halide or mixed anhydride of the general formula (3) "Structure 3" with a compound of the general formula (4) "Structure 4", followed by removal of the acetyl group by hydrolysis. Removal of the acetyl group is not necessary because it is rapidly cleaved by enzymes in human plasma in vitro.

In structural formula 3, R ₁ represents acetoxy (OCOCH ₃ ) or 2-acetyloxybenzoyloxy (salicyloyloxy, 2-OCO-C ₆ H ₄ -OCOCH ₃ ); R ₂ represents H or 2,4-difluorophenyl; and Y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy.

In structural formula 4, _R3 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, alkynyl group of 1-12 carbon atoms, or aryl group; R4 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; X represents O, S, or NH; n = 0, 1, 2, 3 _{, 4} , 5, 6, 7, 8, 9, 10...

The compound represented by the above general formula "Structure 1" can be prepared by a coupling reaction of 5-(2,4-difluorophenyl)acetylsalicylic acid, acetylsalicylic acid or acetylsalicylic acid with a compound represented by general formula (4) "Structure 4" through a coupling agent such as: N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium-hexafluorophosphate, etc.

When X represented by the general formula "Structure 1" represents O, the compound represented by the above general formula (1) "Structure 1" can be obtained by reacting 5-(2,4-difluorophenyl)acetylsalicylic acid, acetylsalicylic acid or a metal salt or organic base salt of acetylsalicylic acid with a compound represented by the general formula (5) "Structure 5".

In structural formula 5, _R2 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; _R3 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; _R4 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; Z represents halogen or p-toluenesulfonyl; ^A- represents ^Cl- , ^Br- , F- ^{, I-} , AcO-, ^citrate , or other negative ions; n = 0, 1, 2, 3, 4, 5...

When X represented by the general formula (1) "Structure 1" represents O, the compound represented by the above general formula (1) "Structure 1" can be obtained by reacting 5-(2,4-difluorophenyl)acetylsalicylic acid, acetylsalicylic acid or an immobilized alkali salt of acetylsalicylic acid represented by the general formula (6) "Structure 6" with the compound represented by the general formula (5) "Structure 5".

In structural formula 6, R represents a cross-linked resin; R ₁ represents an acetoxy group (OCOCH ₃ ) or a 2-acetoxybenzoyloxy group (acetylsalicyloyloxy, 2-OCO-C ₆ H ₄ -OCOCH ₃ ); R ₂ represents H or a 2,4-difluorophenyl group; and B represents any basic group, such as a pyridyl group, a piperidyl group, triethylamine, or other basic groups.

The compound of the above general formula (2) "Structure 2" can be synthesized by reacting 5-(2,4-difluorophenyl)salicylic acid, salicyloylsalicylic acid, or salicylic acid represented by general formula (7) "Structure 7" with the compound of general formula (8) "Structure 8".

In structural formula 7, R ₂ represents H or 2,4-difluorophenyl; R ₆ represents H, any alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, alkenyl group having 1 to 12 carbon atoms, or alkynyl group having 1 to 12 carbon atoms, or aryl group.

In structural formula 8, R <3> represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; R <4> represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; R <5> represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, or alkynyl group of 1-12 carbon atoms, or aryl group; X represents halogen, alkoxycarbonyl, or substituted aromatic oxycarbonyl; A -  represents Cl-, Br-, F-, I-, AcO- , citrate, or other negative ions; n = 0, 1 , 2 , 3, 4, 5, 6, 7, 8, 9, 10...

Advantages

These prodrugs of diflunisal, salicylic acid, and salicylic acid are partially hydrophobic and partially hydrophilic (the amine group exists in a protonated form at physiological pH). The positively charged amino groups of these prodrugs offer two major advantages. First, they significantly enhance drug solubility; when administered orally in the form of tablets, capsules, solutions, or suspensions, these new prodrugs rapidly dissolve in gastric fluid. Second, the positively charged amino groups of these prodrugs can bond with the negatively charged phosphate head groups of biological membranes. Consequently, local concentrations outside the membranes are high, facilitating drug transport from areas of high concentration to areas of low concentration. Once these prodrug molecules enter the biological membrane, the hydrophilic portion propels the drug into the cytoplasm, a concentrated, semi-liquid aqueous solution or suspension. Because these prodrugs spend only a short time in the gastrointestinal tract, they do not damage the gastric mucosa. Experimental results show that 90% of the prodrugs can be converted back to the parent drug. These prodrugs have better absorption rates, resulting in greater efficacy than diflunisal, salicylic acid, and salicylic acid at the same dose. Experiments have shown that the prodrug, diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate, penetrates human skin nearly 150 times faster than diflunisal itself. Diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate exhibits a very high in vivo percutaneous penetration rate through the skin of live, hairless mice. While diflunisal plasma concentrations reach peak levels 1-2 hours after oral administration of diflunisal tablets, diethylaminoethyl 5-(2,4-difluorophenyl)salicylate acetate takes only 40 minutes to reach peak diflunisal plasma concentrations. The most exciting result is that the prodrugs can be administered not only orally but also transdermally for any drug therapy and can avoid most of the side effects of diflunisal, salicylic acid, and salicylic acid, most notably gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. Another major advantage of transdermal administration of these prodrugs is that they are more convenient to administer, especially to children.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: 5-(2,4-Difluorophenyl)salicylic acid diethylaminoethyl ester acetate (A, 30% solution), salicyloylsalicylic acid diethylaminoethyl ester acetate (B, 30% solution), salicylic acid diethylaminoethyl ester acetate (C, 30% solution), diflunisal (D, 30% suspension), salicyloylsalicylic acid (E, 30% suspension), and salicylic acid (F, 30% suspension) in human skin tissue isolated using Franz cells (n=5). The carrier solution for each condition was phosphate buffer (0.2 M) at pH 7.4.

Figure 2: Total plasma concentrations of 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl ester acetate solution (A) or 5-(2,4-difluorophenyl)salicylic acid (diflunisal, B) after topical application to the back of hairless mice (n=5).

Figure 3: Total plasma concentrations after topical application of a 30% solution of diethylaminoethyl salicylate acetate in 1 ml of isopropyl alcohol (A) or salicylic acid (B) to the back of hairless mice (n=5).

Figure 4: Total blood drug concentrations after topical application of a 30% solution of diethylaminoethyl salicylate acetate in 1 ml of isopropyl alcohol (A) or salicylic acid (B) to the back of hairless mice (n=5).

Figure 5: Prolongation of tail pain threshold in mice following oral administration of 200 mg/kg diflunisal (B), transdermal administration of 200 mg/kg 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate (C), transdermal administration of salicyloylsalicylic acid diethylaminoethyl acetate (D), and transdermal administration of salicylic acid diethylaminoethyl acetate (E). A represents the control group.

Figure 6: Swelling rate (%) after carrageenan injection. 50 mg/kg 5-(2,4-difluorophenyl)salicylic acid (diflunisal, B) was administered orally 1 hour before carrageenan injection. 50 mg/kg 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate was administered orally (C) and transdermally (D). A is the control group.

Figure 7: _In structural formula 1, _R1 represents OH, _OCOCH3 , _OCOC2H5 , _OCOC3H7 , _{OCOC4H9 , OCOC5H11} , _OCOC6H13 , 2-hydroxybenzoyloxy (salicyloyloxy, 2 _- OCO- _C6H4 - _OH ), 2 _- acetoxybenzoyloxy (acetylsalicyloyloxy, 2-OCO- _C6H4 - _OCOCH3 ), 2-propionyloxybenzoyloxy (propionylsalicyloyloxy, ₂ - _{OCO-C6H4 - OCOC2H5} ), 2-butyryloxybenzoyloxy ₍ butyrylsalicyloyloxy, 2-OCO- _{C6H4 - OCOC3H7} ); _R2 represents H _or 2,4 _- difluorophenyl; R _{R 3} represents H, any alkyl group of 1 to 12 carbon atoms, alkoxy group of 1 to 12 carbon atoms, alkenyl group of 1 to 12 carbon atoms or alkynyl group of 1 to 12 carbon atoms, or aryl group; R ₄ represents H, any alkyl group of 1 to 12 carbon atoms, alkoxy group of 1 to 12 carbon atoms, alkenyl group of 1 to 12 carbon atoms or alkynyl group of 1 to 12 carbon atoms, or aryl group; R ₅ represents H, any alkyl group of 1 to 12 carbon atoms, alkoxy group of 1 to 12 carbon atoms, alkenyl group of 1 to 12 carbon atoms or alkynyl group of 1 to 12 carbon atoms, or aryl group; X represents O, S or NH; A ^- represents Cl ^- , Br ^- , F ^- , I ^- , AcO ^- , citrate or other negative ions; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... All R groups can contain C, H, O, S, N atoms, and can have single bonds, double bonds and triple bonds; any _CH2 group can be replaced by O, S or NH.

In structural formula 2, X represents O or 2-OCO-C ₆ H ₄ -O); R ₂ represents H or 2,4-difluorophenyl; R ₃ represents H, any alkyl group of 1-12 carbon atoms, any alkyl group of 1-12 carbon atoms, any alkenyl group of 1-12 carbon atoms, any alkynyl group of 1-12 carbon atoms, or any aryl group; R ₄ represents H, any alkyl group of 1-12 carbon atoms, any alkoxy group of 1-12 carbon atoms, any alkenyl group of 1-12 carbon atoms, or any alkynyl group of 1-12 carbon atoms, or any aryl group; R ₅ represents H, any alkyl group of 1-12 carbon atoms, any alkoxy group of 1-12 carbon atoms, any alkenyl group of 1-12 carbon atoms, or any alkynyl group of 1-12 carbon atoms, or any aryl group; R ₆ represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms or alkynyl group of 1-12 carbon atoms, or aryl group; Z represents O or S; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , citrate or other negative ions; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10... All R groups can contain C, H, O, S, N atoms, and can have single bonds, double bonds and triple bonds; any _CH2 group can be substituted by O, S or NH.

Best Practice

Synthesis of Diethylaminoethyl 5-(2,4-difluorophenyl)salicylate Acetate

Dissolve 11.7 g of diethylaminoethanol in 200 ml of 10% sodium bicarbonate solution and 100 ml of acetone. Add 31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicylic acid chloride to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Suspend the residue in 500 ml of ethyl acetate. Add 200 ml of 5% sodium bicarbonate to the reaction mixture with stirring. Collect the ethyl acetate layer and wash it with water three times, each time with 500 ml. Dry the ethyl acetate solution over anhydrous sodium sulfate. Remove the sodium sulfate by filtration. Add 6 g of acetic acid to the reaction mixture with stirring. Evaporate the organic phase. After drying, 35 g of the _hygroscopic target product is obtained, with a yield of 88%. Solubility in water: 400 mg/ml; elemental analysis: _{C₂₁H₂₅F₂NO₅} ; _{molecular weight} : 409.42. Theoretical value (%): C: 61.60; H: 6.15; F: 9.28; N: 3.42; O: 19.54; Found value (%): C: 61.56; H: 6.18; F: 9.27; N: 3.40; O: 19.59. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H), 7.0 (b, H), 7.06 (b, 1H), 7.15 (m, 1H), 7.44 (m, 1H), 7.86 (m, 1H).

Implementation Plan

1. Synthesis of Diethylaminoethyl Salicylate Acetate

Dissolve 31.8 g (0.1 mol) of acetylsalicyloylsalicylic acid chloride in 100 ml of chloroform. Cool the mixture to 0°C. Add 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the reaction solvent. Dissolve the residue in 300 ml of methanol, and add 200 ml of a 5% aqueous sodium bicarbonate solution to the reaction mixture. Stir the mixture for 3 hours. Evaporate the mixture to dryness, and stir-add 300 ml of methanol to the residue. Remove the solid by filtration and wash with methanol. Evaporate the solution to dryness, and add 200 ml of chloroform to the residue. Add 6 g of acetic acid to the reaction mixture with stirring. Remove the solid by filtration. Add another 6 g of acetic acid to the reaction mixture with stirring. Evaporate the organic phase. After _{drying ,} 32 g of the hygroscopic target product was obtained, with a yield of 82%. Solubility in water: 400 mg/ml; Elemental analysis: _{C₂OH₂NO₇} ; Molecular weight: 389.40. Theoretical value (%): C: 61.69; H: 5.95; N: 3.60; O: 28.76; Found value (%): C: 61.66; H: 5.98; N: 3.58; O: 28.78. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (b, 1H), 6.88 (m, 1H), 7.0 (b, H), 7.26 (b, 1H), 7.27 (m, 1H), 7.35 (m, 1H), 7.54 (m, 1H), 7.97 (m, 1H), 8.06 (m, 1H).

2. Synthesis of Dimethylaminoethyl Salicylate Acetate

Dissolve 19.9 g (0.1 mol) of acetylsalicylic acid chloride in 100 ml of chloroform. Cool the mixture to 0°C. Add 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Dissolve the residue in 300 ml of methanol, and add 200 ml of a 5% aqueous sodium bicarbonate solution to the reaction mixture. Reflux the mixture for 2 hours. Evaporate the mixture to dryness. Stir 300 ml of methanol to the residue. Remove the solid by filtration and wash with methanol. Evaporate the solution to dryness and dissolve the residue in 200 ml of chloroform. Add 6 g of acetic acid to the reaction mixture with stirring. Remove the solid by filtration. Add another 6 g of acetic acid to the reaction mixture with stirring. Evaporate the organic phase. After drying _, 23 g of the hygroscopic target product was obtained, with a yield of 88%. Solubility in water: 350 mg/ml; Elemental analysis: _{C₁₃H₁₆NO₅} ; Molecular _weight : 269.29. Theoretical value (%): C: 57.98; H: 7.11; N: 5.20; O: 29.71; Found (%): C: 57.96; H: 7.13; N: 5.17; O: 29.74. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 2.21 (s, 3H), 2.90 (s, 6H), 3.70 (m, 2H), 4.69 (t, 2H), 4.9 (b, 1H), 6.74 (b, 1H), 6.84 (m, 1H), 6.93 (b, 1H), 6.98 (b, 1H), 7.30 (b, 1H).

3. Synthesis of S-5-(2,4-difluorophenyl)salicylic acid dimethylaminoethyl thioester acetate

Dissolve 31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicylic acid chloride in 100 ml of chloroform. Cool the mixture to 0°C. Add 15 ml of triethylamine and 9.3 g of dimethylaminoethanethiol to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Dissolve the residue in 300 ml of methanol, and add 200 ml of a 5% aqueous sodium bicarbonate solution to the reaction mixture. Reflux the mixture for 2 hours. Evaporate the mixture to dryness. Stir and add 300 ml of methanol to the residue. Remove the solid by filtration and wash with methanol. Evaporate the solution to dryness, and dissolve the residue in 200 ml of chloroform. Stir and add 6 g of acetic acid to the reaction mixture. Remove the solid by filtration. Add another 6 g of acetic acid to the reaction mixture by stirring. Evaporate the organic solvent. After drying, 32 g of the hygroscopic target product is obtained with a yield of 80.5%. Solubility in water: 400 mg/ml; Elemental analysis: C ₁₉ H ₂₁ F ₂ NO ₄ S; Molecular weight: 397.44. Theoretical value (%): C: 57.42; H: 5.33; F: 9.56; N: 3.52; O: 16.10, S: 8.07; Found (%): C: 57.40; H: 5.35; F: 9.53; N: 3.51; O: 16.15; S: 8.06. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.31 (t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.74 (m, 1H), 6.84 (m, 1H); 7.14 (m, 1H), 7.23 (m, 1H), 7.44 (m, 1H), 7.87 (m, 1H).

Synthesis method of 4,5-(2,4-difluorophenyl) salicyldimethylaminoacetamide acetate

Dissolve 31.1 g (0.1 mol) of 5-(2,4-difluorophenyl)acetylsalicylic acid chloride in 100 ml of chloroform. Cool the mixture to 0°C. Add 15 ml of triethylamine and 8.8 g (0.1 mol) of dimethylaminoethylamine to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Dissolve the residue in 300 ml of methanol, and add 200 ml of a 5% aqueous sodium bicarbonate solution to the reaction mixture. Reflux the mixture for 2 hours. Evaporate the mixture to dryness. Stir and add 300 ml of methanol to the residue. Remove the solid by filtration and wash with methanol. Evaporate the solution to dryness, and dissolve the residue in 200 ml of chloroform. Stir and add 6 g of acetic acid to the reaction mixture. Remove the solid by filtration. Add another 6 g of acetic acid to the reaction mixture by stirring. Evaporate the organic solution. After drying, 33 g of the hygroscopic target product is obtained with a yield of 86.8%. Solubility in water: 400 mg/ml; Molecular formula: C ₁₉ H ₂₂ F ₂ N ₂ O ₄ ; Molecular weight: 380.39. Theoretical value (%): C: 59.99; H: 5.83; F: 9.99; N: 7.36; O: 16.82; Measured value (%): C: 59.97; H: 5.85; F: 9.98; N: 7.35; O: 16.85. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 2.20 (s, 3H), 2.90 (s, 6H), 3.54 (t, 2H), 3.64 (t, 2H), 5.0 (b, 1H), 6.7 (b, 1H), 6.73 (m, 1H), 6.80 (m, 1H); 7.15 (m, 1H), 7.22 (m, 1H), 7.44 (m, 1H), 7.87 (m, 1H), 8.01 (b, 1H).

5. Synthesis of S-salicylic acid diethylamino ethyl thioester acetate

Dissolve 18 g (0.1 mol) of acetylsalicylic acid in 100 ml of dichloromethane (DCM). Cool the mixture to 0°C. Add 20.6 g of 1,3-dicyclohexylcarbodiimide (DCC) to the reaction mixture. Stir the mixture at 0°C for 30 minutes. Add 13.4 g (0.1 mol) of diethylaminoethanethiol to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Dissolve the residue in 300 ml of methanol, and add 200 ml of a 5% aqueous sodium bicarbonate solution to the reaction mixture. Stir the mixture at room temperature for 20 hours. Evaporate the mixture to dryness. Add 300 ml of methanol to the residue with stirring. Evaporate the solution to dryness, and dissolve the residue in 200 ml of chloroform. Add 6 g of acetic acid to the reaction mixture with stirring. Remove the solid by filtration. Add another 6 g of acetic acid to the reaction mixture with stirring. Evaporate the organic solvent. After drying, 29 g of the hygroscopic target product is obtained with a yield of 92.5%. Solubility in water: 400 mg/ml; Elemental analysis: C ₁₅ H ₂₃ NO ₄ S; Molecular weight: 313.41. Theoretical value (%): C: 57.48; H: 7.40; N: 4.47; O: 20.42, S: 10.23; Found (%): C: 57.43; H: 7.42; N: 4.46; O: 20.47; S: 10.21. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.56 (t, 6H); 2.20 (s, 3H), 3.26 (m, 4H), 3.31 (t, 2H), 3.91 (t, 2H), 5.0 (b, 1H), 6.8 (b, 1H), 6.92 (d, 1H), 7.41 (d, 1H), 7.81 (d, 1H).

Synthesis method of 6.5-(2,4-difluorophenyl)salicylic acid 3-N,N-diethylaminopropyl ester acetate

Dissolve 27.8 g (0.1 mol) of ethyl 5-(2,4-difluorophenyl)salicylate in 100 ml of chloroform. Cool the mixture to 0°C. Add 21 ml of triethylamine (0.2 mol) and 20.0 g (0.1 mol) of 3-N,N-diethylaminopropionyl chloride hydrochloride to the reaction mixture. Stir the mixture at room temperature for 3 hours. Remove the solid by filtration. Add 6 g of acetic acid to the reaction mixture with stirring. Add 200 ml of hexane. Collect the solid product by _filtration . After drying, 40 g of the hygroscopic target product was obtained with a yield of 85.9%. Solubility in water: ₄₀₀ mg/ml; Elemental analysis: _{C₂₄H₂₆F₂NO₆} ; Molecular _weight : 465.49. Theoretical value (%): C: 61.93; H: 6.28; F: 8.16; N: 3.01; O: 20.62; Found value (%): C: 61.90; H: 6.30; F: 8.15; N: 3.00; O: 20.65. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.30 (t, 3H), 1.56 (t, 6H), 2.20 (s, 3H), 2.67 (t, 2H); 3.28 (m, 4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H), 6.70 (m, 1H), 6.81 (m, 1H), 7.40 (m, 2H), 7.44 (d, 1H), 7.9 (d, 1H).

Synthesis method of 7.5-(2,4-difluorophenyl)salicylic acid 3-N,N-diethylaminopropyl ester acetate

Dissolve 28.6 g (0.1 mol) of ethyl salicyloylsalicylate in 100 ml of chloroform. Cool the mixture to 0°C. Add 21 ml of triethylamine (0.2 mol) and 17.2 g (0.1 mol) of 3-N,N-diethylaminopropionyl chloride hydrochloride to the reaction mixture. Stir the mixture at room temperature for 3 hours. Remove the solid by filtration. Add 6 g of acetic acid to the reaction mixture with stirring. Add 200 ml of hexane. Collect the solid product by filtration. After drying, 42 g of the hygroscopic target product was obtained with a yield of 88.7%. Solubility in water: 380 _mg /ml; Elemental analysis: _{C₂₅H₃₁NO₂} ; Molecular _weight : 473.52. Theoretical value (%): C: 63.41; H: 6.60; N: 2.96; O: 27.03; Found value (%): C: 63.40; H: 6.62; N: 2.93; O: 27.05. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.30 (t, 3H), 1.57 (t, 6H); 2.20 (s, 3H), 2.68 (t, 2H); 3.28 (m, 4H), 3.50 (m, 2H), 4.29 (m, 2H), 6.8 (b, 1H), 7.21 (m, 2H), 7.26 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.54 (m, 1H); 8.05 (m, 1H); 8.12 (m, 1H).

8. Synthesis of 3-N,N-dimethylaminopropyl salicylate acetate

Dissolve 16.6 g (0.1 mol) of ethyl salicylate in 100 ml of chloroform. Cool the mixture to 0°C. Add 21 ml of triethylamine (0.2 mol) and 17.2 g (0.1 mol) of 3-N,N-dimethylaminopropionyl chloride hydrochloride to the reaction mixture with stirring. Stir the mixture at room temperature for 3 hours. Remove the solid by filtration. Add 6 g of acetic acid to the reaction mixture with stirring. Add 200 ml of hexane. Collect the solid product by filtration. After drying _, 28 g of the hygroscopic target product was obtained with a yield of 85.9%. Solubility in water: 400 mg/ml; Elemental analysis: _{C₁₆H₂₃NO₆} ; Molecular _weight : 325.36. Theoretical value (%): C: 59.06; H: 7.13; N: 4.31; O: 29.50; Found (%): C: 59.03; H: 7.15; N: 4.30; O: 29.52. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.31 (t, 3H), 2.20 (s, 3H), 2.68 (t, 2H); 2.92 (m, 4H), 3.50 (m, 2H), 4.30 (m, 2H), 6.8 (b, 1H), 7.18 (m, 2H), 7.44 (m, 1H), 7.92 (m, 1H).

Industrial Applications

The prodrugs represented by Formula (1), "Structure 1" and "Structure 2," are superior to diflunisal, salicylic acid, and salicylic acid. They can be used to treat any condition in humans and animals that is treatable by diflunisal, salicylic acid, and salicylic acid. They can be used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, reduce fever, and treat dysmenorrhea. They can be used alone or as an adjunct to treat Bartter's syndrome and chronic anterior and posterior uveitis. They can also treat intrauterine device-induced uterine bleeding and prevent and treat nausea and vomiting in patients undergoing pelvic radiation therapy. These prodrugs can also be used to treat diabetic neuropathy, acute migraine, and hemophilic arthritis. They can treat bone loss and prevent or treat sunburn. They may also be used to prevent cancer. Due to their high biomembrane permeability, these prodrugs can also be used to treat asthma by inhalation into the host. Because these prodrugs have anti-inflammatory effects, they can also treat acne.

Claims (21)

1. Compounds represented by general formula (1) "structural formula 1": in, _{R1 represents OH} , _OCOCH3 , _OCOC2H5 , _OCOC3H7 , _OCOC4H9 , _{OCOC5H11 ,} or _{OCOC6H13 ; and} R ₂ represents 2,4-difluorophenyl; or R ₁ represents 2-hydroxybenzoyloxy, 2-acetoxybenzoyloxy, 2-propionyloxybenzoyloxy, or 2-butyryloxybenzoyloxy; and R ₂ represents H or 2,4-difluorophenyl; R ₃ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₄ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₅ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; X represents O; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , or citrate; n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The alkenyl group does not include alkenyl groups having one carbon atom and the ynyl group does not include ynyl groups having one carbon atom. 2. The compound represented by general formula (1) "structural formula 1" as claimed in claim 1, wherein the compound is 5-(2,4-difluorophenyl)salicylic acid diethylaminoethyl acetate. 3. The compound represented by general formula (1) "structural formula 1" as claimed in claim 1, wherein the compound is salicylsalicylic acid diethylaminoethyl acetate. 4. A method for preparing a compound represented by general formula (1) "structural formula 1" as described in claim 1, wherein the compound of general formula (3) "structural formula 3" reacts with the compound of general formula (4) "structural formula 4": in: R ₁ represents OCOCH ₃ ; and R ₂ represents 2,4-difluorophenyl; or _R1 represents 2-OCO- _{C6H4 - OCOCH3} ; _R2 represents H or 2,4-difluorophenyl; and Y represents halogen, alkoxy, or substituted aryloxycarbonyloxy; in: R ₃ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₄ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; X represents O; and n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The alkenyl group does not include alkenyl groups having one carbon atom and the ynyl group does not include ynyl groups having one carbon atom. 5. Use of a compound of general formula (1) "structural formula 1" as claimed in any one of claims 1 to 3 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient for the preparation of a medicament, wherein the medicament is administered orally or transdermally for the treatment of a human or animal condition treatable with diflunisal, salicylsalicylic acid and salicylic acid. 6. Use of one or more compounds as claimed in any one of claims 1 to 3, or a composition containing at least one compound as an active ingredient as claimed in any one of claims 1 to 3, for the preparation of a medicament, wherein the medicament is administered transdermally to any part of the body of a human or animal in the form of a solution, spray, emulsion, ointment, latex, or gel to treat any diflunisal, salicylsalicylic acid, or salicylic acid-treatable condition. 7. Use of one or more compounds as claimed in any one of claims 1 to 3, or a composition containing at least one compound as an active ingredient as claimed in any one of claims 1 to 3, for the preparation of a medicament, wherein the medicament is administered topically to treat pain in a human or animal, wherein the pain is selected from headache, toothache, muscle pain, arthritis, and other inflammatory pain. 8. A compound of general formula (1) “Structural Formula 1” as claimed in any one of claims 1 to 3, or a composition containing at least one compound of general formula (1) “Structural Formula 1” as claimed in any one of claims 1 to 3 as an active ingredient, for the treatment of acne, sunburn or other skin diseases, wherein said compound or said composition is administered transdermally in the form of a solution, spray, lotion, ointment, latex or gel. 9. A compound of general formula (1) “Structural Formula 1” as claimed in any one of claims 1 to 3, or a composition containing at least one compound of general formula (1) “Structural Formula 1” as claimed in any one of claims 1 to 3 as an active ingredient, for the treatment of asthma, wherein said compound or said composition is administered by spraying onto the mouth or nose or other parts of the body. 10. The use of a compound of general formula (1) "structural formula 1" as claimed in any one of claims 1 to 3 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient in the preparation of a medicament for treating ocular inflammation, post-corneal surgery ocular pain, glaucoma, or ear inflammation and/or pain in humans or animals. 11. A transdermal therapeutic application system comprising one or more compounds of general formula (1) "structural formula 1" as claimed in any one of claims 1 to 3, or comprising a composition containing at least one compound of general formula (1) "structural formula 1" as claimed in any one of claims 1 to 3 as an active ingredient, for treating diflunisal, salicylsalicylic acid and salicylic acid treatable conditions in humans or animals. 12. The transdermal therapeutic application system of claim 11, wherein the system is a bandage or patch comprising a matrix layer containing an active substance and a non-permeable protective layer. 13. The transdermal therapeutic application system of claim 11 or 12, wherein the system comprises an active substance reservoir having a permeable, skin-facing base. 14. The transdermal therapeutic application system as described in claim 11 or 12, characterized in that, by controlling the release rate, the system can stabilize diflunisal, salicylsalicylic acid, or salicylic acid at the optimal therapeutic blood concentration, thereby improving efficacy and reducing the side effects of diflunisal, salicylsalicylic acid, or salicylic acid. 15. The use as claimed in claim 5, wherein the diflunisal, salicylsalicylic acid or salicylic acid is therapeutic for conditions such as toothache, headache, inflammatory pain, fever, cancer, dysmenorrhea, uterine bleeding caused by intrauterine devices, nausea, vomiting caused by radiation therapy, diabetic neuropathy, acute migraine, hemophilic arthropathy, bone loss or sunburn. 16. The transdermal therapeutic application system of claim 13, wherein by controlling the release rate, the system can stabilize diflunisal, salicylsalicylic acid, or salicylic acid at an optimal therapeutic blood concentration, thereby improving efficacy and reducing the side effects of diflunisal, salicylsalicylic acid, or salicylic acid. 17. The compound represented by general formula (1) "structural formula 1" as claimed in claim 1, wherein... _R1 represents OH; R ₂ represents 2,4-difluorophenyl; R ₃ represents H; R ₄ represents an alkyl group having 1-12 carbon atoms; R ₅ represents an alkyl group having 1-12 carbon atoms; and n = 2. 18. The compound represented by general formula (1) "structural formula 1" as claimed in claim 1, wherein... R ₁ represents 2-hydroxybenzoyloxy; _R2 represents H; R ₃ represents H; R ₄ represents an alkyl group having 1-12 carbon atoms; R ₅ represents an alkyl group having 1-12 carbon atoms; and n = 2. 19. Compounds represented by general formula (1), "structural formula 1", excluding diethylaminoethylsalicylate: in, _{R1 represents OH} , _OCOCH3 , _OCOC2H5 , _OCOC3H7 , _OCOC4H9 , _{OCOC5H11 ,} or _{OCOC6H13 ; and} R ₂ represents 2,4-difluorophenyl; or R ₁ represents 2-hydroxybenzoyloxy, 2-acetoxybenzoyloxy, 2-propionyloxybenzoyloxy, or 2-butyryloxybenzoyloxy; and R ₂ represents H or 2,4-difluorophenyl; R ₃ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₄ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₅ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; X represents S or NH; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , or citrate; n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The alkenyl group does not include alkenyl groups having one carbon atom and the ynyl group does not include ynyl groups having one carbon atom. 20. A method for preparing the compound represented by general formula (1) "Structural Formula 1" as claimed in claim 1, wherein a compound selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate is reacted with the compound represented by general formula (4) "Structural Formula 4" using a coupling agent selected from N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate: in: R ₃ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₄ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; X represents O; and n = 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; The alkenyl group does not include alkenyl groups having one carbon atom and the ynyl group does not include ynyl groups having one carbon atom. 21. A method for preparing the compound represented by general formula (1) "Structural Formula 1" as described in claim 1, wherein 5-(2,4-difluorophenyl)acetylsalicylic acid, acetylsalicylic acid or a metal salt or organic base salt of acetylsalicylic acid reacts with the compound represented by general formula (5) "Structural Formula 5": in R ₂ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₃ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₄ represents H, an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; Z represents halogen or p-toluenesulfonyl group; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , or citrate; and n = 1, 2, 3, 4 or 5; The alkenyl group does not include alkenyl groups having one carbon atom and the ynyl group does not include ynyl groups having one carbon atom.