HK1208184B - Positively charged water-soluble prodrugs of ketoprofen and related compounds with very fast skin penetration rate - Google Patents

Description

Positively charged water-soluble prodrugs of ketoprofen and related compounds with rapid skin penetration

Technical Field

The present invention relates to positively charged, water-soluble prodrugs of 2-(3-benzoylphenyl)propionic acid (ketoprofen) and 2-(3-phenoxyphenyl)propionic acid (fenoprofen) and their use in treating any ketoprofen- or fenoprofen-treatable condition in humans or animals. Specifically, the present invention is intended to overcome the side effects associated with the use of ketoprofen and fenoprofen. These prodrugs can be administered orally or transdermally.

Technical Background

Ketoprofen and fenoprofen are propionic acid nonsteroidal anti-inflammatory drugs. Ketoprofen was synthesized in 1986 and has since been widely used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, as well as to treat dysmenorrhea. Ketoprofen can be used alone or as an adjuvant to treat acute biliary colic, renal colic, pain caused by oral surgery, severe postpartum pain, and fever (PDRGenerics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1812). Ketoprofen can also be used for bone regeneration (Alfano, M.C.; Troullos, E.S., US Patent No. 5,902,110). Fenoprofen can be used to treat symptoms of acute or long-term mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Fenoprofen can be used alone or as an adjunct to treat acute gout, episiotomy pain, and migraine (PDRGenerics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1290). Fenoprofen can also be used to treat shock (Toth, P.D., U.S. Patent No. 4,472,431).

However, ketoprofen and fenoprofen are associated with numerous side effects, most notably gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. Fishman (Robert Fishman, U.S. Patent No. 7,052,715) notes that another problem associated with oral medications is that, to effectively treat pain or inflammation at distal sites, the drug concentrations in the circulating blood must be very high. 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 et al. (Van Engelen et al., U.S. Pat. No. 6,416,772; Macrides et al., U.S. Pat. No. 6,346,278; Kirby et al., U.S. Pat. No. 6,444,234; Roentsch et al., U.S. Pat. No. 5,654,337; Park et al., U.S. Pat. No. 6,190,690; Pearson et al., U.S. Pat. No. 6,528,040; and Botknech et al., U.S. Pat. No. 5,885,597) have attempted to develop drug delivery systems for transdermal administration through formulations. However, due to the slow skin penetration of these drugs, achieving effective plasma concentrations through formulations is difficult. Susan Milosovich et al. designed and synthesized testosterone 4-dimethylaminobutyrate 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). [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)].

Summary of the Invention

Technical issues

Ketoprofen and fenoprofen have been used clinically for over 30 years. They are widely used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, treat dysmenorrhea, and prevent pupil constriction during surgery. However, ketoprofen and fenoprofen can cause a number of side effects, most notably gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. Ketoprofen and fenoprofen are insoluble in water and gastric juice.

Solution

The present invention relates to the synthesis of novel prodrugs of ketoprofen and fenoprofen with positive charge and their application in the medical field. These prodrugs have the structure of general formula (1) "Structure 1".

In structural formula 1, _R1 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; _R2 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; _R3 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; _R4 represents the following structure:

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 CH ₂ group can be replaced by O, S or NH.

Whether absorbed through the gastrointestinal tract or other routes, drugs must cross the barrier membrane in molecular form. 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. The membrane has a bilayer structure, with the hydrophilic head structure facing the aqueous phase on either side. Highly hydrophilic drugs are unable to penetrate the lipid layer of the membrane, while highly 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 ketoprofen and fenoprofen in gastric juice and the speed at which they penetrate biological membranes and skin barriers, thereby enabling them to be administered transdermally (for external use) to avoid the side effects of ketoprofen and fenoprofen. These prodrugs have two common structural features: they have a lipophilic portion and a primary, secondary, or tertiary amine group (hydrophilic portion) that exists in a protonated form under physiological pH conditions. Such a water-soluble-oil-soluble balance is necessary for the drug to effectively penetrate biological membranes [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)]. The positively charged amino group greatly increases the solubility of the drug. The solubility of diethylaminoethyl 2-(3-benzoylphenyl) propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl) propionate acetate, 2-(3-benzoylphenyl) propionic acid (ketoprofen), and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) in water is >450 mg, >450 mg, 0.1 mg, and 0.1 mg/ml, respectively. In most cases, drug dissolution is the slowest or rate-limiting step in the absorption process. Ketoprofen and fenoprofen have very low solubility in gastric fluid. They remain in the gastrointestinal tract for extended periods and may damage gastric mucosal cells. When these novel prodrugs are taken orally in dosage forms such as tablets, capsules, solutions, or suspensions, they dissolve rapidly in gastric fluid. The positive charge on the amino group of these prodrug molecules bonds with the negative charge on the phosphate end group of the cell membrane. As a result, the local concentration of the drug is high on the outer side of the biological membrane, facilitating the passage of these prodrugs from areas of high concentration to areas of low concentration. Once these prodrug molecules enter the biological membrane, their hydrophilic moieties propel the prodrugs into the cytoplasm, where they are concentrated in a semi-liquid aqueous solution or suspension. Due to their short residence time in the gastrointestinal tract, the prodrugs do not damage gastric mucosal cells. The permeation rates of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, and fenoprofen through human skin were measured in vitro using a modified Franz cell. The skin was isolated from the anterior or posterior thigh (360-400 μm thick). The receptor solution consisted of 10 ml of saline solution containing 2% bovine serum albumin and stirred at 600 rpm. The cumulative total amount of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, and fenoprofen permeated through the skin versus time was determined using a specific high-performance liquid chromatography method. A 30% solution of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate dissolved in 2 ml of pH 7.4 phosphate buffered saline (0.2 M), a 30% solution of diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate dissolved in 2 ml of pH 7.4 phosphate buffered saline (0.2 M), a 30% suspension of ketoprofen dissolved in 2 ml of pH 7.4 phosphate buffered saline (0.2 M), or a 30% suspension of fenoprofen dissolved in 2 ml of pH 7.4 phosphate buffered saline (0.2 M) was used as the donor solution. The results are shown in FIG1 . Apparent human skin penetration values calculated for diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, and fenoprofen were 115 mg/ ^cm² /h, 125 mg/ ^cm² /h, 0.9 mg/ ^cm² /h, and 1 mg/ ^cm² /h, respectively. These results indicate that the prodrugs diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate penetrate human skin nearly 125 times faster than ketoprofen and fenoprofen. These results demonstrate that the positive charge on the dialkylaminoethyl group is crucial for drug penetration through biological membranes and the skin barrier. The other prodrugs in Formula 1 exhibited skin penetration rates very close to that of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate.

In vivo experiments compared the rate of penetration of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, and fenoprofen through the skin of live, hairless, uninjured mice. Donors consisted of a 10% solution of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate in 1 ml of isopropyl alcohol, a 10% solution of diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate in 1 ml of isopropyl alcohol, a 10% solution of ketoprofen in 1 ml of isopropyl alcohol, or a 10% solution of fenoprofen in 1 ml of isopropyl alcohol. These solutions were applied to a 1 ^cm² area on the back of the hairless mice. Plasma concentrations of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, and fenoprofen were determined using a specific high-performance liquid chromatography method. The results (Figures 2 and 3) show that diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate reached peak concentrations approximately 40 minutes after administration of the donor system. Oral administration of ketoprofen and fenoprofen requires 1-2 hours to reach peak plasma drug concentrations. Ketoprofen and fenoprofen peaked at approximately 0.02 mg/ml, while diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate peaked at approximately 2 mg/ml (a difference of nearly 100-fold). A plasma concentration of 2 mg/ml for ketoprofen and fenoprofen is 50 times higher than the plasma concentrations of ketoprofen and fenoprofen, which are effective analgesics and anti-inflammatory agents. This is an encouraging result. These prodrugs allow for the rapid and easy delivery of effective plasma concentrations of ketoprofen and fenoprofen to the host. These results show that the prodrugs can be used not only orally but also transdermally for various treatments. The transdermal penetration rates of other prodrugs in the general formula "Structure 1" in vivo are close to that of diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate.

To examine whether these drugs cause gastric and duodenal bleeding, we orally administered 100 mg/kg of 2-(3-benzoylphenyl)propionic acid diethylaminoethyl acetate, 2-(3-phenoxyphenyl)propionic acid diethylaminoethyl acetate, ketoprofen, and fenoprofen to rats (six groups of 10 rats each) daily for 21 consecutive days. An average of 5 mg of hematochezia per gram of feces was observed in the ketoprofen group and 4 mg of hematochezia per gram of feces in the fenoprofen group. No hematochezia was observed in the 2-(3-benzoylphenyl)propionic acid diethylaminoethyl acetate and 2-(3-phenoxyphenyl)propionic acid diethylaminoethyl acetate groups.

The acute toxicity of these prodrugs was experimentally determined. The oral _LD50 values in rats were 0.2 g/kg for diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and 1.2 g/kg for diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate. These results suggest that the prodrugs are less toxic than ketoprofen ( _LD50 = 0.1 g/kg) and fenoprofen ( _LD50 = 0.8 g/kg).

Ketoprofen and fenoprofen have been shown to have anti-inflammatory, analgesic, antipyretic, and anti-rheumatic effects. A good prodrug should quickly convert to the parent drug in plasma. In vitro testing has demonstrated that the diethylaminoethyl ester groups in diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate are rapidly enzymatically hydrolyzed in human plasma, with over 90% of the prodrug converting to ketoprofen and fenoprofen. Due to their improved absorption, the prodrugs exhibit greater efficacy than the parent drugs at the same dose. We tested the analgesic, antipyretic, and anti-inflammatory effects of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate and compared them with ketoprofen and fenoprofen. We also tested other compounds in the general formula "Structure 1" using the same method, and the test results were very close to those of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate.

Analgesic Effect: The 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 50 mg/kg of ketoprofen and fenoprofen, followed by transdermal administration of 50 mg/kg of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate or 50 mg/kg of diethylaminoethyl 2-(3-phenoxyphenyl)propionate 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 4. The analgesic effect of the group (C) receiving 50 mg/kg of diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate transdermally and the group (D) receiving 50 mg/kg of diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate transdermally was significantly superior to that of the group (B) receiving 50 mg/kg of ketoprofen.

The number of writhing events that occurred after intraperitoneal administration of acetic acid solution to mice was counted, and the inhibition rate of writhing was calculated based on the control group. 30 mice were divided into 5 groups (6 mice per group). Group B mice were administered 50mg/kg ketoprofen, Group C mice were administered 50mg/kg fenoprofen, Group D mice were transdermally administered 50mg/kg 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate, and Group E mice were transdermally administered 50mg/kg 2-(3-phenoxyphenyl) diethylaminoethyl propionate acetate. Group A was the control group. Mice were given medication 30 minutes before administration of acetic acid solution. The results are shown in Table 1.

Table 1. Inhibition rate of writhing by ketoprofen, fenoprofen and its related compounds

Group A B C D E Dosage (mg/kg) 0 50 50 50 50 Number of twists 35.0 18.1 13.2 14.2 14.0 Inhibition rate (%) - 48 62 59 60

The results showed that the analgesic effect of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate was better than that of 2-(3-benzoylphenyl)propionic acid (ketoprofen). Other compounds in the general formula "Structure 1" showed similar analgesic activity.

Antipyretic Effect: Rats were administered a suspension of inactivated Escherichia coli as a pyrogen. Thirty rats were divided into six groups. Group A served as the control group. Two hours later, ketoprofen (50 mg/kg, Group B) and fenoprofen (50 mg/kg, Group C) were administered orally, and diethylaminoethyl 2-(3-benzoylphenyl) propionate acetate (50 mg/kg, Group D) and diethylaminoethyl 2-(3-phenoxyphenyl) propionate acetate (50 mg/kg, Group E) were administered transdermally. Body temperatures were measured every 90 minutes before and after administration of the test compounds. The results are shown in Table 2.

Table 2. Antipyretic effects of ketoprofen and related compounds

Group t＝0min. t＝90min. t＝180min. t＝270min. A, blank group 37.33±0.05 37.26±0.07 37.32±0.05 37.34±0.08 B, (50 mg/kg) 37.25±0.06 36.81±0.05 36.82±0.08 36.78±0.07 C, (50 mg/kg) 37.22±0.07 36.82±0.06 36.80±0.05 36.77±0.08 D, (50 mg/kg) 37.28±0.06 36.65±0.06 36.58±0.08 36.60±0.07 E, (50 mg/kg) 37.28±0.06 36.65±0.06 36.58±0.08 36.56±0.07

The results showed that the antipyretic activity of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate at a dose of 50 mg/kg was better than that of ketoprofen or fenoprofen. Other compounds in the general formula "Structure 1" showed similar antipyretic activity.

Anti-inflammatory Effect: Rats were administered 50 mg/kg of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate orally or transdermally, and 50 mg/kg of ketoprofen orally. Sixty minutes later, a carrageenan solution was administered subcutaneously under the paw pads of the rats. The volume of the rats' hind paws 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 5. The results show that oral and transdermal administration of 50 mg/kg of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate had a greater anti-inflammatory effect than the same oral dose of ketoprofen. Other compounds represented by the general formula "Structure 1" exhibited similar anti-inflammatory effects.

When taken orally at high doses, ketoprofen can exhibit anti-allergic and anti-asthmatic effects by inhibiting cyclooxygenase activity. Because these prodrugs penetrate biological membranes rapidly, they can be administered orally or nasally to treat asthma. Due to their anti-inflammatory effects and rapid transdermal penetration, these prodrugs can also 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 the prodrug represented by the general formula "Structure 1" and 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 compound of the general formula "Structure 1" can be used in combination with vitamins such as vitamins A, B, C, E, β-carotene, or other drugs such as folic acid to treat any condition in humans or animals that can be treated with ketoprofen and fenoprofen.

Transdermal therapeutic application systems containing compounds represented by the general formula "Structure 1" or compositions containing at least one compound represented by the general formula "Structure 1" as an active ingredient can be used to treat any ketoprofen- and fenoprofen-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 bottom layer facing the skin. By controlling the release rate, this system can stabilize ketoprofen and fenoprofen at optimal therapeutic blood concentrations, thereby improving efficacy and reducing side effects of ketoprofen and fenoprofen. These systems can be worn on the wrist, ankle, arm, leg, or anywhere else on the body.

The compound represented by the above general formula (1) "Structure 1" can be prepared by reacting functionalized derivatives of 2-(3-benzoylphenyl)propionic acid and 2-(3-phenoxyphenyl)propionic acid, such as the acyl halide or mixed anhydride represented by the general formula (2) "Structure 2", with the compound of the general formula (3) "Structure 3".

In structural formula 2, R4 represents:

Y represents halogen, alkoxycarbonyl, or substituted aryloxycarbonyloxy.

In structural formula 3, _R3 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; _R4 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; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...

The compound represented by the above-mentioned general formula (1) "Structure 1" can be prepared by reacting 2-(3-benzoylphenyl)propionic acid (ketoprofen), 2-(3-phenoxyphenyl)propionic acid (fenoprofen), and the compound represented by the general formula (3) "Structure 3" with a coupling agent, such as N,N'-dicyclohexylcarbamide (DCC), N,N'-diisopropylcarbamide (DIC), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (HBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphine-hexafluorophosphate, etc.

When X represents O, the compound represented by the above general formula (1) "Structure 1" can be prepared by reacting a metal salt or organic base salt of 2-(3-benzoylphenyl)propionic acid (ketoprofen) and 2-(3-phenoxyphenyl)propionic acid (fenoprofen) with a compound represented by the general formula (4) "Structure 4".

In structural formula 4, _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 any negative ion; n = 0, ¹ , 2, 3, 4, 5, 6, 7, 8, 9, 10...

When X represents O, the compound represented by the above general formula (1) "Structure 1" can be obtained by reacting the immobilized alkaline salt of 2-(3-benzoylphenyl)propionic acid (ketoprofen) and 2-(3-phenoxyphenyl)propionic acid (fenoprofen) represented by the general formula (5) "Structure 5" with the compound represented by the general formula (4) "Structure 4".

In structural formula 5, R represents a cross-linked resin; _R4 represents the following structure:

B represents any basic group, such as pyridyl, piperidyl, triethylamino or other basic groups.

advantage

These prodrugs of ketoprofen and fenoprofen have a lipophilic portion and a hydrophilic portion (an amine group that exists in a protonated form at physiological pH). The positively charged amino group offers two major advantages: First, it significantly enhances drug solubility; when these new prodrugs are administered orally in the form of tablets, capsules, solutions, or suspensions, they rapidly dissolve in gastric fluid. Second, the positively charged amino group of these prodrugs can bond with the negatively charged phosphate groups of biological membranes. This results in high local concentrations outside the membranes, facilitating the permeation of these prodrugs from areas of high to 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 gastric fluid, they do not damage the gastric mucosa. Experimental results show that 90% of the prodrugs are converted back to the parent drug. These prodrugs have better absorption rates, resulting in greater efficacy than ketoprofen or fenoprofen at the same dose. Experiments have shown that the prodrugs, 2-(3-benzoylphenyl)propionic acid diethylaminoethyl acetate and 2-(3-phenoxyphenyl)propionic acid diethylaminoethyl acetate, penetrate human skin nearly 125 times faster than ketoprofen or fenoprofen. Peak plasma concentrations of ketoprofen or fenoprofen are reached 1-2 hours after oral administration, while peak plasma concentrations of 2-(3-benzoylphenyl)propionic acid diethylaminoethyl acetate or 2-(3-phenoxyphenyl)propionic acid diethylaminoethyl acetate are reached 40 minutes after administration. Most excitingly, the prodrugs can be administered not only orally but also transdermally for any drug treatment, thus avoiding most of the side effects of ketoprofen or fenoprofen, most notably gastrointestinal upset such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. Another major advantage of transdermal administration is its ease of use, particularly for children.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate (A, 30% solution), diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate (B, 30% solution), ketoprofen (C, 30% suspension), and fenoprofen (D, 30% suspension) in human skin tissue isolated in Franz cells (n=5). The carrier solution for each condition was phosphate buffer solution (0.2 M) at pH 7.4.

Figure 2: Total amount of ketoprofen in plasma after topical application of a 10% solution of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate dissolved in 1 ml of isopropanol, (A) or 2-(3-benzoylphenyl)propionic acid (ketoprofen, B) to the back of hairless mice (n=5).

Figure 3: Total amount of fenoprofen in plasma after topical application of 10% diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate (A) or fenoprofen (B) in 1 ml of isopropanol to the back of hairless mice (n=5).

Figure 4: Prolongation of tail pain threshold in mice after oral administration of 50 mg/kg ketoprofen (B), transdermal administration of 50 mg/kg 2-(3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate (C), and transdermal administration of 2-(3-phenoxyphenyl) propionic acid diethylaminoethyl ester acetate (D). A represents the control group.

Figure 5: Swelling rate (%) after carrageenan injection. 50 mg/kg of 2-(3-benzoylphenyl) propionic acid (ketoprofen, B) was administered orally 1 hour before carrageenan injection. 50 mg/kg of diethylaminoethyl 2-(3-benzoylphenyl) propionate acetate was administered orally (C) and transdermally (D). A represents the control group.

Figure 6: Structural Formula 1: In Structural Formula 1, _R1 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; _R2 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; _R3 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; _R4 represents the following structure:

X represents O, S, or NH; A- represents ^Cl- , ^Br- , F- ^{, I-} , ^AcO- , citrate, or other anions; 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 replaced by O, S, or NH.

Best Practice

Synthesis of Diethylaminoethyl 2-(3-Benzoylphenyl) Propionate Acetate

Dissolve 11.7 g (0.1 mol) of diethylaminoethanol in 200 ml of 10% aqueous sodium bicarbonate solution and 100 ml of acetone. Add 27.3 g (0.1 mol) of 2-(3-benzoylphenyl)propionyl chloride to the reaction mixture. Stir the reaction solution at room temperature for 3 hours. Evaporate the solvent. Suspend the residue in 500 ml of ethyl acetate. Add 200 ml of 5% aqueous sodium bicarbonate solution with stirring. Collect the ethyl acetate layer and wash it three times with 500 ml of water each time. 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 to dryness. After drying, 36 g of the hygroscopic target product is obtained with a yield of 87%. Solubility in water: 400 _mg /ml; Elemental analysis: _{C₂₄H₃₁NO₅} ; Molecular _weight : 413.51. Theoretical value (%): 69.71; H: 7.56; N: 3.39; O: 19.35; Found value (%): C: 69.69; H: 7.59; N: 3.36; O: 19.36. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.51 (d, 3H), δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 7.0 (b, 1H), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, 1H), 7.51 (m, 1H), 7.56 (m, 1H), 7.70 (m, 2H).

Implementation Plan

1. Synthesis of dimethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate

Dissolve 26.1 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl 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 with stirring. Stir the mixture at room temperature for 3 hours. Evaporate the solvent. Dissolve the residue in 300 ml of methanol. Add 200 ml of 5% aqueous sodium bicarbonate solution to the reaction mixture. Stir the mixture for 3 hours. Evaporate the mixture to dryness. Add 300 ml of methanol to the residue with stirring. 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 to dryness. After _drying , 32 g of the hygroscopic target product was obtained with a yield of 85.7%. Solubility in water: 500 _mg /ml; Elemental analysis: _{C₂₁H₂₇NO₅} ; Molecular weight: 373.44. Theoretical value (%): C: 67.54; H: 7.29; N: 3.75; O: 21.42; Found value (%): C: 67.51; H: 7.30; N: 3.74; O: 21.45. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.51 (d, 3H), δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.52 (m, 2H), 3.78 (m, 1H), 4.51 (t, 2H), 6.70 (b, 1H), 6.74 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 6.92 (m, 2H), 6.98 (m, 1H), 7.17 (m, 1H), 7.22 (m, 2H).

2. Synthesis of 2-(3-phenoxyphenyl)propionic acid dimethylaminoethyl thioester acetate

Dissolve 10.4 g (0.1 mol) of N,N-dimethylaminoethanethiol in 200 ml of 10% sodium bicarbonate solution and 100 ml of acetone. Add 27.3 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride to the reaction mixture with stirring. 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% aqueous sodium bicarbonate solution to the reaction mixture with stirring. Collect the ethyl acetate layer and wash it with water three times, 500 ml each time. 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 to dryness. After drying, ₃₄ g of the hygroscopic target product was obtained, with a yield of 87.3%. Solubility in water: 400 _mg /ml; Elemental analysis: _{C₂₁H₂₇NO₄S} ; Molecular weight: 389.51. Theoretical value (%): C: 64.75; H: 6.99; N: 3.60; O: 16.43; S: 8.23. Found value (%): C: 64.73; H: 6.98; N: 3.61; O: 16.46; S: 8.22. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.52 (d, 3H), δ: 2.20 (s, 3H), 2.91 (s, 6H), 3.31 (t, 2H), 3.81 (m, 1H), 3.91 (t, 2H), 6.70 (b, 1H), 6.74 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 6.92 (m, 2H), 6.98 (m, 1H), 7.17 (m, 1H), 7.22 (m, 2H).

3. Synthesis of dimethylaminoethyl 2-(3-benzoylphenyl)propionamide acetate

Dissolve 8.8 g (0.1 mol) of N,N-dimethylaminoethylamine in 200 ml of 10% sodium bicarbonate solution and 100 ml of acetone. Add 27.3 g (0.1 mol) of 2-(3-benzoylphenyl)propionyl chloride to the reaction mixture with stirring. Stir the reaction solution at room temperature for 3 hours. Evaporate the solvent. Suspend the residue in 500 ml of ethyl acetate. Add 200 ml of 5% aqueous sodium bicarbonate solution to the reaction mixture with stirring. Collect the ethyl acetate layer and wash it three times with 500 ml of water each time. 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 solvent. After drying, 33 g of the hygroscopic target product was obtained with a yield of 85.9%. Solubility in water: 400 _mg /ml; Elemental analysis: _{C₂₂H₂₈N₂O₅} ; Molecular _weight : _384.20 . Theoretical value (%): C: 68.73; H: 7.34; N: 7.29; O: 16.65. Found value (%): C: 68.70; H: 7.35; N: 7.29; O: 16.66. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50 (t, 2H), 3.65 (t, 2H), 3.89 (m, 1H), 7.0 (b, 1H), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, 1H), 7.52 (m, 1H), 7.57 (m, 1H), 7.72 (m, 2H), 7.80 (b, 1H).

4. Synthesis of dimethylaminoethyl 2-(3-benzoylphenyl)propionamide acetate

Dissolve 25.7 g (0.1 mol) of 2-(3-benzoylphenyl)propionic acid in 100 ml of acetonitrile. Add 32.1 g of O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine to the reaction mixture. Add 11.7 g of dimethylaminoethylamine to the reaction mixture. Stir the mixture at room temperature for 3 hours. Evaporate the reaction solvent. Add 250 ml of ethyl acetate to the reaction mixture, and wash the mixture with water three times, 100 ml each time. Dry the organic solution over anhydrous sodium sulfate. Remove the sodium sulfate 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, 32 g of the hygroscopic target product was obtained, with a yield of 83.3%. Solubility in water: 400 _mg /ml; Elemental analysis: _{C₂₂H₂₈N₂O₅} ; _{Molecular weight} : 384.20. Theoretical value (%): C: 68.73; H: 7.34; N: 7.29; O: 16.65. Found value (%): C: 68.70; H: 7.35; N: 7.29; O: 16.66. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50 (t, 2H), 3.65 (t, 2H), 3.89 (m, 1H), 7.0 (b, 1H), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, 1H), 7.52 (m, 1H), 7.57 (m, 1H), 7.72 (m, 2H), 7.80 (b, 1H).

5. Synthesis of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate

60 g of polymer-solidified triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 25.7 g (0.1 mol) of 2-(3-benzoylphenyl)propionic acid was added to the mixture with stirring. 43 g (0.15 mol) of diethylaminoethyl bromide was added to the mixture, and the mixture was stirred at room temperature for 5 hours. The polymer was removed by filtration and washed three times with 50 ml of tetrahydrofuran each time. 8.2 g (0.1 mol) of sodium acetate was added to the reaction mixture with stirring. The mixture was stirred for 2 hours. The solid was removed by filtration and washed three times with 50 ml of chloroform each time. The solution was concentrated in vacuo to 100 ml. 300 ml of hexane was then added to the solution. The solid product was collected by filtration and washed three times with 100 ml of hexane each time. After drying, 36 g of the hygroscopic target product was obtained with a yield of 87%. Solubility in water: 400 mg/ml; Elemental analysis: C ₂₄ H ₃₁ NO ₅ ; Molecular weight: 413.51. Theoretical value (%): C: 69.71; H: 7.56; N: 3.39; O: 19.35; Found (%): C: 69.69; H: 7.59; N: 3.36; O: 19.36. ¹ H-NMR (400 MHz, deuterated chloroform solvent): δ: 1.51 (d, 3H), δ: 1.56 (t, 6H), 2.21 (s, 3H), 3.27 (m, 4H), 3.52 (m, 2H), 3.78 (m, 1H), 4.52 (t, 2H), 7.0 (b, 1H), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, 1H), 7.51 (m, 1H), 7.56 (m, 1H), 7.70 (m, 2H).

Industrial Applicability

The prodrugs represented by the general formula (1) "Structure 1" are superior to ketoprofen and fenoprofen. They can be used to treat any condition in humans or animals that can be treated by ketoprofen and fenoprofen. They can be used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, reduce fever, and treat dysmenorrhea. They can also be used for diabetic neuropathy and acute migraine. Because these prodrugs penetrate biological membranes quickly, they can also be used to treat asthma by inhalation into the host. Because they have anti-inflammatory effects, these prodrugs can be used to treat acne. These prodrugs are water-soluble neutral salts that are well tolerated by the eye. They can be used to treat ocular inflammatory conditions, treat eye pain after corneal surgery, glaucoma, or ear inflammation and/or painful conditions (otitis).

Claims (26)

1. A compound represented by structural formula 1: in, R ₁ represents an alkyl group with 1-12 carbon atoms; R ₂ represents an alkyl group with 1-12 carbon atoms; R ₃ represents H; R ₄ represents the following structure: X represents O or S; ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , or citrate; and n = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 2. A pharmaceutical composition comprising at least one compound as claimed in claim 1, wherein the pharmaceutical composition is a solution, emulsion, ointment, latex, or gel. 3. A transdermal therapeutic application system comprising at least one active substance, wherein the active substance is a compound as claimed in claim 1 or a pharmaceutical composition as claimed in claim 2. 4. The transdermal therapeutic application system of claim 3, wherein the system comprises a bandage or patch having a matrix layer containing an active substance and a non-permeable protective layer. 5. The transdermal therapeutic application system as described in claim 3, characterized in that the system contains an active substance reservoir having a permeable, skin-facing base. 6. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating asthma in humans or animals, wherein the medicament is administered by spraying onto the mouth or nose or other part of the body of the human or animal. 7. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for treating a ketoprofen or phenoprofen-treatable condition in humans or animals. 8. The use as described in claim 7, wherein the condition that can be treated by ketoprofen or fenprofen is selected from: pain, fever, cancer, radiation-induced vomiting, diabetic neuropathy, arthritis, bone loss, glaucoma, and skin diseases. 9. The use as claimed in claim 8, wherein the pain is selected from headache, toothache, muscle pain, dysmenorrhea, eye pain after corneal surgery, ear pain, and inflammatory pain. 10. The use as claimed in claim 8, wherein the pain is an acute migraine. 11. The use as claimed in claim 8, wherein the skin condition is selected from sunburn and acne. 12. The use as claimed in claim 8, wherein the arthritis is hemophilic arthritis. 13. The use as described in any one of claims 7 to 12, wherein the drug is administered orally or transdermally. 14. The use as described in any one of claims 7 to 12, wherein the drug is administered transdermally to a site of the body via a solution, spray, emulsion, ointment, latex, or gel formulation to achieve a therapeutically effective plasma concentration of the compound represented by structural formula 1. 15. The use as described in any one of claims 7 to 12, wherein the drug is an oral dosage form or a transdermal dosage form. 16. The use as described in any one of claims 7 to 12, wherein the drug is a transdermal dosage form. 17. A compound selected from: diethylaminoethyl acetate of 2-(3-benzoylphenyl)propionate, diethylaminoethyl acetate of 2-(3-phenoxyphenyl)propionate, dimethylaminoethyl acetate of 2-(3-phenoxyphenyl)propionate, dimethylaminoethyl thioester acetate of 2-(3-phenoxyphenyl)propionate and N,N-dimethylaminoethyl 2-(3-benzoylphenyl)propionamide acetate. 18. A pharmaceutical composition comprising at least one compound as claimed in claim 1, which may be used to treat a condition treatable with ketoprofen or phenoprofen by transdermal administration to a human or animal. 19. A pharmaceutical composition comprising at least one compound as claimed in claim 1, which may be administered transdermally to humans or animals in the form of a solution, spray, emulsion, ointment, latex or gel for the treatment of acne, sunburn or other skin conditions. 20. A pharmaceutical composition comprising at least one compound as claimed in claim 1, which can be administered to a person or animal by spraying it into the mouth or nose or other part of the body to treat asthma. 21. A pharmaceutical composition comprising at least one compound as claimed in claim 1, for treating eye diseases, post-corneal surgery eye pain, glaucoma, ear inflammation or ear pain in humans or animals. 22. The pharmaceutical composition of the compound of claim 21, for treating otitis media in humans or animals. 23. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for external treatment of pain in a human or animal, wherein the medicament is administered to an inflamed area of the human or animal to deliver a therapeutically effective dose of the compound or the pharmaceutical composition. 24. The use as claimed in claim 23, wherein the pain is selected from headache, toothache, muscle pain, arthritis, and inflammatory pain. 25. The compound of claim 1, wherein the compound is diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate or diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate. 26. A method for preparing the compound according to claim 1, comprising: The acyl halide or mixed anhydride represented by structural formula 2 reacts with the compound represented by structural formula 3; In structural formula 2, _R4 represents: and Y represents halogen; In structural formula 3, R ₁ represents an alkyl group with 1-12 carbon atoms; R ₂ represents an alkyl group with 1-12 carbon atoms; X represents O or S; and n = 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.