Description

POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF KETOPROFEN AND RELATED COMPOUNDS WITH VERY

FAST SKIN PENETRATION RATE

Technical Field

[1] The present invention relates to the preparations of positively charged and water- soluble prodrugs of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) and their medicinal use in treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of ketoprofen and fenoprofen. These prodrugs can be administered orally or transdermally.

Background Art

[2] Both ketoprofen and fenoprofen are members of the propionic acid group of nonsteroidal anti-inflammatory drugs. Ketoprofen was introduced in 1986 and has gained wide acceptance and is used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for the treatment of dysmenorrhea. Ketoprofen is used alone or as an adjunct in the treatment of acute biliary colic, pain due to renal colic, pain associated with oral surgery, severe postpartum pain and for fever. (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1812) . Ketoprofen may be used for bone regeneration (Alfano, M.C.; Troullos, E.S., US Patent No. 5,902,110). Fenoprofen is used for acute or long-term use for symptomatic treatment of mild to moderate pain, osteoarthritis, and rheumatoid arthritis. Fenoprofen is used alone or as an adjunct in the treatment of acute gout, episiotomy pain, and migraine headache (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1290) . Fenoprofen may be used for treatment of shock (Toth, P.D., U.S. Pat. No. 4,472,431).

[3] Unfortunately, a number of side effects are associated with the use of ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. Fishman and many others (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 Botknecht et al. U.S. Pat. No. 5,885,597) have tried to develop a delivery system for transdermal application by formulation. It is very difficult, however, to deliver therapeutically effective plasma levels of these kind drugs into the host by formulation, due to the slow skin penetration rate. Susan Milosovich, et. al. designed and prepared testosteronyl- 4-dimethylaminobutyrate.HCl (TSBH), which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin -60 times faster than does the drug (TS) itself [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993). Disclosure of Invention

Technical Problem

[4] Ketoprofen and fenoprofen have been used medicinally for more than 30 years.

They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, for the treatment of dysmenorrhea, and for inhibition of intraoperative miosis.

[5] Unfortunately, a number of side effects are associated with the use of ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. They are not soluble in aqueous solution and gastric juice.

Technical Solution

[6] This invention relates to the preparation of novel positively charged pro-drugs of ketoprofen and fenoprofen and their use medicinally. These pro-drugs have the general formula (1) 'Structure 1'.

Structure 1

In structure 1, R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents

X represents O, S or NH; A ^" represents Cl ^" , Br ^" , F ^" , I ^" , AcO ^" , citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10 All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.

[7] Drug absorption, whether from the gastrointestinal tract or other sites, requires the passage of the drug in a molecular form across the barrier membrane. The drug must first dissolve, and if the drug possesses the desirable biopharmaceutical properties, it will pass from a region of high concentration to a region of low concentration across the membrane into the blood or general circulation. All biological membranes contain lipids as major constituents. The molecules that play the dominant roles in membrane formation all have phosphate-containing highly polar head groups, and, in most cases, two highly hydrophobic hydrocarbon tails. Membranes are bilayered, with the hy- drophilic head groups facing outward into the aqueous regions on either side. Very hy- drophilic drugs cannot pass the hydrophobic layer of membrane and very hydrophobic drugs will stay in the hydrophobic layer as part of the membrane due to their similarities and cannot enter the cytosol on the inside efficiently.

[8] The goal of this invention is to avoid the side effects of ketoprofen and fenoprofen by increasing the their solubility in gastric juice and their penetration rate through the membrane and skin barrier which will make it administrable transdermally (topical application). These novel pro-drugs have two structural features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the protonated form (hydrophilic part) at physiological pH. Such a hydrophilic-lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich, et al., J. Pharm. ScL, 82, 227(1993)]. The positively charged amino groups largely increase the solubility of the drugs. The solubility of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, 2-(3-benzoylphenyl) propionic acid (ketoprofen), and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) in water are >450 mg, >450 mg, 0.1 mg, and 0.1 mg/ml. In many instances, the slowest or rate-limiting step in the sequence is the dissolution of the drug. Ketoprofen and fenoprofen have a very low solubility in gastric juice. It stays in the GI tract for a long time and thus, may cause gastric mucosal cell damage. When these new pro-drugs are administered orally in a dosage

form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately. The positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration of the outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in GI tract, the pro-drugs will not cause gastric mucosal cell damage. The penetration rates of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 μm thick) of the anterior and posterior thigh areas. The receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm. The cumulative amounts of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen penetrating the skin versus time were determined by a specific high-performance liquid chromatography method. The results using a donor consisting of either a 30% solution of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH or a 30% suspension of ketoprofen and fenoprofen in 2mL of pH 7.4 phosphate buffer (0.2M) are shown in Figure 1. Apparent flux values of 115 mg, 125 mg, 0.9 mg and 1 mg/cm /h were calculated for diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen diffuses through human skin. The results suggest that the pro-drug, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH diffuses through human skin -125 times faster than do ketoprofen and fenoprofen. The results suggest that the positive charge on the dialkyaminoethyl group has a very important role in the passage of the drug across the membrane and skin barrier. Other prodrugs of the general 'Structure 1' have very high penetration rates and are very close to that of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH.

[9] The in vivo rates of penetration of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen through the skin of intact hairless mice were compared. The donor consisted of a 10% solution diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen in 1 mL of isopropanol applied to a 1 cm on the backs of

the hairless mice. Plasma levels of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen were determined by a specific high-performance liquid chromatography method. The results (Figure 2, Figure 3) show that the peak levels of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH, and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, were reached -40 minutes after application of the donor systems. It takes 1-2 hours for ketoprofen and fenoprofen to reach their peak plasma level when they are taken orally. The peaks were -0.02 mg/ml for ketoprofen and fenoprofen and -2 mg/ml for diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (approximately 100 times difference). -2 mg/ml of diflunisal in plasma is more than 50 times higher than kenoprofen and fenoprofen plasma level for effective analgesia and effective anti-inflammatory activity. This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma levels of ketoprofen and fenoprofen into the host by these pro-drugs. These results suggest that the pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments. The in vivo rates of penetration of other Pro-drugs of the general 'Structure 1' are close to that of diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH.

[10] To check the gastroduodenal bleeding caused by drugs, rats (six groups, each group had 10 rats) were orally administered with 100 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH, diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH, ketoprofen, and fenoprofen per day for 21 days. We found an average of 5 mg of fecal blood per gram of feces in the ketoprofen group, 4 mg of fecal blood per gram of feces in the fenoprofen group and none in diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH, and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH.

[11] The acute toxicity of the prodrugs was investigated. The LD orally in rats are: 0.2 g/kg and 1.2 g for diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate AcOH. The results show that the prodrugs are less toxic than ketoprofen (LD =0.1 g/kg) and fenoprofen (LD =0.8 g/

50 50 kg).

[12] Ketoprofen and fenoprofen have demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity. A good prodrug should go back to the drug itself in plasma. Diethylaminoethyl ester group of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH can be rapidly cleaved by the enzymes in human plasma in vitro and more than 90% of the pro-drugs are changed back to ketoprofen and fenoprofen. Due to the pro-drugs having a much better absorption rate, the prodrugs will have more strength than their parent

drugs at the same dosage. The analgetic, antipyretic, and anti-inflammatory activities of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH were tested using ketoprofen and fenoprofen as a comparison. Other compounds of the general 'Structure 1 ' were tested by the same methods and have very similar results as that of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH.

[13] Analgetic activity: The prolongation time of pain the threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74(1941)). After 50mg/kg of ketoprofen and fenoprofen were administered orally and 50mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH were administered transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined. The results obtained are shown in Figure 4. The groups administered 50 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH (C) and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (D) transdermally were shown to exhibit stronger analgetic activity than the group administered 50mg/kg of ketoprofen (B).

[14] The quantity of writhing that occurred when mice were administered an acetic acid solution intraperitoneally were counted, and the rate of inhibition based on the control group was calculated. 30 mice were divided into 5 groups (6 mice each). Ketoprofen (50 mg/kg) was administered to groups B of mice, fenoprofen (50 mg/kg) was administered to groups C of mice, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH (50 mg/kg) was administered transdermally to groups D of mice, and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (50 mg/kg) was administered transdermally to groups E of mice. The A group is the control group. The test compounds were administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 1.

Table 1. The rate of writhings inhibition by and ketoprofen and related compounds.

[15]

The results show that diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

demonstrates better analgetic activity than 2-(3-benzoyphenyl) propionic acid (ketoprofen). Other compounds of the general 'Structure 1' show similar analgetic activity.

[16] Antipyretic activity: Rats received a sterilized E. coli suspension as a pyrogen. 30 rats were divided into 6 groups. The control group is group A. 2 hours later, ketoprofen (50 mg/kg, B) and fenoprofen (50 mg/kg, C) were administered orally and diethy- laminoethyl 2-(3-benzoyphenyl) propionate.AcOH (50mg/kg, D) and diethy- laminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (50 mg/kg, E) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 2. Table 2. Antipyretic Activity of ketoprofen and related compounds

[17]

The results shown that diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH demonstrated antipyretic activity at 50 mg/kg dose and better than does ketoprofen or fenoprofen. Other compounds of the general 'Structure 1' show similar antipyretic activity.

[18] Anti-inflammatory activity: 50 mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH was administered orally or transdermally to rats and 50 mg/kg of ketoprofen was administered orally. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in Figure 5. The results show that diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH by oral administration and transdermal administration demonstrated better Anti-inflammatory activity than that of ketoprofen at 50mg/kg by oral administration. Other compounds of the general 'Structure 1' show similar anti-inflammatory activity.

[19] It is also known that a high dose of oral ketoprofen shows an anti- reactive-antiasthmatic activity by inhibition of the cyclooxygenase activity. Due to

their very high membrane penetration rate, these prodrugs can be used in treating asthma by spraying into the mouth or nose of the host. They can also be used to treat acne due to their anti-inflammatory properties and very high skin penetration rate.

[20] These pro-drugs are water-soluble neutral salt and can be tolerated very well by the eye. They can be used for treating eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/ or painful conditions (otitis).

[21] The present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for administration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration transdermally. The new active compounds of the general 'Structure 1' can be combined with vitamins such as A, B, C or E or beta-carotene, or other pharmaceuticals, such as folic acid, etc., for treating any ketoprofen and fenoprofen-treatable conditions in humans or animals.

[22] Transdermal therapeutic application systems of compounds of the general

'Structure 1' or a composition comprising of at least one compound of the general 'Structure 1', as an active ingredient, can be used for treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen. These systems can be worn on the wrist, ankle, arm, leg, or any part of body.

[23] The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from functional derivatives of 2-(3-benzoyphenyl) propionic acid and 2-(3-phenoxyphenyl) propionic acid, for example, acid halides or mixed anhydrides of the general formula (2) 'Structure 2'.

Structure 2

In structure 2, R 4 represents

, Y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy, by reaction with compounds of the general formula (3) 'Structure 3',

Structure 3

In structure 3, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents O, S or NH; and n=0,l,2,3,4,5,6,7,8,9,10

[24] The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen), by reaction with compounds of the general formula (3) 'Structure 3' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O- (Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol- 1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al.

[25] When X represents O, the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from metal salts or organic base salts of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen), by reaction with compounds of the general formula (4) 'Structure 4'.

Structure 4

In structure 4, R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; Z represents halogen, or p-toluenesulphonyl, A ^" represents Cl ^" , Br ^" , F, I ^" , AcO ^" , citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10

[26] When X represents O, the compounds of the general formula (1) 'Structure 1' indicated above can be prepared from immobilized base salts of 2-(3-benzoylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) of the general formula (5) 'Structure 5',

Structure 5 in structure 5, R represents cross-linked resin; R 4 represents

, B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (4) 'Structure 4' .

Advantageous Effects

[27] These pro-drugs of ketoprofen and fenoprofen have a lipophilic portion and a hy- drophilic portion (the amine groups that exist in the protonated form at physiological pH). The positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new prodrugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the

phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drugs into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in the GI tract, the pro-drugs will not cause gastric mucosal cell damage. Experiment results show that more than 90% of the pro-drugs were changed back to the drugs itself. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than ketoprofen or fenoprofen at the same dosage. The experiment results suggest that the pro-drugs, diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH and diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH diffuses through human skin -125 times faster than does ketoprofen or fenoprofen. It takes 1-2 hours for ketoprofen or fenoprofen to reach the peak ketoprofen or fenoprofen plasma level when they are taken orally, but diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH or diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH only took about 40 minutes to reach the ketoprofen or fenoprofen peak plasma level. The most exciting result is that the pro-drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of ketoprofen or fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description of Drawings

[28] Figure 1 : Cumulative amounts of diethylaminoethyl 2-(3-benzoylphenyl) propionate.AcOH (A, 30% solution), diethylaminoethyl 2-(3-phenoxyphenyl) propionate.AcOH (B, 30% solution), ketoprofen (C, 30% suspension), and fenoprofen (D, 30% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M).

[29] Figure 2: Total plasma levels of ketoprofen after topical application of 1 ml of a

10% solution of diethylaminoethyl 2-(3-benzoylphenyl) propionate. AcOH, (A) or 2-(3-benzoylphenyl) propionic acid (ketoprofen, B) in isopropanol to the backs of hairless mice (n=5).

[30] Figure 3: Total plasma levels of fenoprofen after topical application of 1 ml of a

10% solution of diethylaminoethyl 2-(3-phenyoxyphenyl) propionate .AcOH, (A) or fenoprofen ( B) in isopropanol to the backs of hairless mice (n=5).

[31] Figure 4: The prolongation time of the pain threshold of mice tails after 50mg/kg of ketoprofen (B) was administered orally, 50mg/kg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH (C) and diethylaminoethyl 2-(3-phenoxyphenyl)

propionate.AcOH (D) were administered transdermally. A group is the control group.

[32] Figure 5. The rate of swelling (%) after a carrageenin injection. 1 hour before the carrageenin injection, 50 mg of 2-(3-benzoyphenyl) propionic acid (ketoprofen, B) was administered orally, 50 mg of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH was administered orally (C), and transdermally (D). A group is the control group.

[33] Structure 1. in structure 1, R represents H, one of any alkyl, alkyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R 4 represents

, X represents O, S or NH; A ^" represents Cl ^" , Br ^" , F ^" , I ^" , AcO ^" , citrate, or any negative ions; and n=0,l,2,3,4,5,6,7,8,9,10 All R groups may include C, H, O, S, N atoms and may have single, double, and treble bonds. Any CH groups may be replaced with O, S, or NH.

Best Mode

Preparation of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH [34] 11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate

(200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-benzoyphenyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (87%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H NO ; MW: 413.51. Calculated % 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, CDCl ₃ ): 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, IH), 4.52 (t, 2H), 7.0 (b, IH), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, IH), 7.51 (m, IH), 7.56 (m, IH), 7.70 (m, 2H).

Mode for Invention 1. Preparation of dimethylaminoethyl 2-(3-phenoxyphenyl)

propionate.AcOH

[35] 26.1 g (0.1 mol) of 2-(3-phenoxyphenyl) propionyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 0°C. 15 ml of triethylamine and 8.9 g (0.1 mol) of dimethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 32 g of the desired product (85.7%). Hygroscopic product; Solubility in water: 500 mg/ml; Elementary analysis: C H NO ; MW: 373.44. Calculated % C: 67.54; H: 7.29; N: 3.75 ; O: 21.42; Found % C: 67.51; H: 7.30; N: 3.74; O: 21.45. ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 1.51 (d, 3H), δ: 2.21 (s, 3H), 2.91 (s, 6H), 3.52(m, 2H), 3.78 (m, IH), 4.51 (t, 2H), 6.70 (b, IH), 6.74 (m, IH), 6.78 (m, IH), 6.84 (m, IH), 6.92 (m, 2H), 6.98 (m, IH), 7.17 (m, IH), 7.22 (m, 2H).

2. Preparation of S-dimethylaminoethyl 2-(3-phenoxyphenyl) thio- propionate.AcOH

[36] 10.4 g (0.1 mol) of dimethylaminoethyl mercaptan was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-phenoxyphenyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 34 g of the desired product (87.3%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C ₂₁ H ₂₇ NO ₄ S; MW: 389.51. Calculated % C: 64.75; H: 6.99; N: 3.60; O: 16.43; S: 8.23. Found % C: 64.73; H: 6.98; N: 3.61; O: 16.46; S: 8.22. ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 1.52 (d, 3H), δ: 2.20 (s, 3H), 2.91 (s, 6H), 3.31(t, 2H), 3.81 (m, IH), 3.91 (t, 2H), 6.70 (b, IH), 6.74 (m, IH), 6.78 (m, IH), 6.84 (m, IH), 6.92 (m, 2H), 6.98 (m, IH), 7.17 (m, IH), 7.22 (m, 2H).

3. Preparation of N-dimethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

[37] 8.8 g (0.1 mol) of dimethylaminoethylamine was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 27.3 g (0.1 mol) of 2-(3-benzoyphenyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 33 g of the desired product (85.9 %). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 384.20. Calculated % C: 68.73; H: 7.34; N: 7.29; O: 16.65;

22 28 2 5

Found % C: 68.70; H: 7.35; N: 7.29; O: 16.66. ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50(t, 2H), 3.65 (t, 2H), 3.89 (m, IH), 7.0 (b, IH), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, IH), 7.52 (m, IH), 7.57 (m, IH), 7.72 (m, 2H), 7.80 (b, IH).

4. Preparation of N-dimethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

[38] 25.7 g (0.1 mol) of 2-(3-benzoyphenyl) propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetraflu- oroborate and 30 ml of triethylamine were added into the reaction mixture. 11.7 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 32 g of the desired product (83.3%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 384.20. Calculated % C: 68.73; H: 7.34; N: 7.29; O: 16.65; Found % C: 68.70; H: 7.35; N: 7.29; O: 16.66. ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 1.51 (d, 3H), 2.21 (s, 3H), 2.90 (s, 6H), 3.50(t, 2H), 3.65 (t, 2H), 3.89 (m, IH), 7.0 (b, IH), 7.33 (m, 2H), 7.37 (m, 2H), 7.47 (m, IH), 7.52 (m, IH), 7.57 (m, IH), 7.72 (m, 2H), 7.80 (b, IH). 5. Preparation of diethylaminoethyl 2-(3-benzoyphenyl) propionate.AcOH

[39] 60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in

180 ml of chloroform. 25.7 g (0.1 mol) of 2-(3-benzoyphenyl) propionic acid was added into the mixture with stirring. 43 g (0.15mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer

was removed by filtration and washed with tetrahydrofuran (3 x 50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3 x 50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, it yielded 36 g of the desired product (87%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H NO ; MW: 413.51. Calculated % 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, CDCl ₃ ): 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, IH), 4.52 (t, 2H), 7.0 (b, IH), 7.31 (m, 2H), 7.36 (m, 2H), 7.45 (m, IH), 7.51 (m, IH), 7.56 (m, IH), 7.70 (m, 2H).

Industrial Applicability

[40] The pro-drugs of the general formula (1) 'Structure 1' are superior to ketoprofen and fenoprofen. They may be used medicinally in treating any ketoprofen and fenoprof en-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. They may be also prescribed for diabetic neuropathy and acute migraine headache. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used to treat acne due to their anti-inflammatory properties. These pro-drugs are water-soluble neutral salt and can be tolerated very well by the eye. They can be used for treating eye inflammatory diseases, for treating of ocular pain after corneal surgery, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis).

Sequence List Text

[41]