CN104610077B

CN104610077B - Positively charged water-soluble prodrugs of ketoprofen and related compounds with rapid skin penetration rate

Info

Publication number: CN104610077B
Application number: CN201410820198.8A
Authority: CN
Inventors: 于崇曦; 徐丽娜
Original assignee: Techfields Pharma Co Ltd
Current assignee: Taifeier Biomedical Suzhou Co ltd; Yu Chongxi
Priority date: 2006-07-27
Filing date: 2006-07-27
Publication date: 2020-04-14
Anticipated expiration: 2026-07-27
Also published as: HK1208214A1; CN104610077A

Abstract

A positively charged water-soluble prodrug of ketoprofen and related compounds having a rapid skin penetration rate. The application discloses a compound shown as a structural formula I, a preparation method thereof and application of the compound in preparing a medicament for treating ketoprofen or fenoprofen-treatable conditions of human beings or animals. Transdermal therapeutic applications comprising the compounds are also disclosed.

Description

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

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 and fenoprofen-treatable conditions in humans or animals. In particular, the invention aims to overcome the side effects caused by using ketoprofen and fenoprofen. These prodrugs can be administered orally or transdermally.

Technical Field

Ketoprofen and fenoprofen are propionic acid nonsteroidal anti-inflammatory drugs. Ketoprofen was synthesized artificially in 1986 and was then widely used to alleviate signs and symptoms of rheumatoid arthritis and osteoarthritis, and to treat dysmenorrhea. Ketoprofen may be used alone or as an adjunct in the treatment of acute biliary colic, renal colic, pain resulting from oral surgery, severe post-partum pain, and fever (PDRGenerics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1812). Ketoprofen is also used for bone regeneration (Alfano, m.c.; Troullos, e.s., US Patent No.5,902,110). Fenoprofen may be used to treat acute or chronic mild to moderate pain conditions, osteoarthritis and rheumatoid arthritis. Fenoprofen may be used alone or as an adjuvant drug in the treatment of acute gout, pain from episiotomy, and migraine (PDRGenerics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg 1290). Fenoprofen may also be used for the treatment of shock (Toth, p.d., U.S. patent No. 4,472,431).

However, ketoprofen and fenoprofen administration produce many side effects, most notably gastrointestinal distress such as dyspepsia, gastroduodenal bleeding, gastric ulcerations and gastritis. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) states that another problem associated with oral administration is that the concentration of the drug in the blood circulation must be very high in order to effectively treat pain or inflammation at the distal site. These concentrations are often much higher than is actually necessary given the direct targeting of the drug 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 by means of formulation. However, due to the slow skin penetration rate of these drugs, it is difficult to achieve therapeutically effective plasma levels by formulation. Susan Miloovich et al designed and synthesized testosterone 4-dimethylaminobutyrate hydrochloride (TSBH) having a lipophilic portion and a tertiary amine structure that exists in protonated form at physiological pH. They found that the pro-drug (TSBH) penetrated the skin approximately 60 times faster than the parent drug (TS) itself. [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993) ].

Disclosure of Invention

Technical problem

Ketoprofen and fenoprofen have been used clinically for over 30 years. It is widely used to alleviate signs and symptoms of rheumatoid arthritis and osteoarthritis, to treat dysmenorrhea, and to prevent intraoperative pupil constriction. However, ketoprofen and fenoprofen administration cause many side effects, most notably gastrointestinal discomfort such as dyspepsia, gastroduodenal bleeding, gastric ulcerations and gastritis. Ketoprofen and fenoprofen are insoluble in water and gastric juices.

Solution scheme

The invention relates to synthesis of a novel prodrug of ketoprofen and fenoprofen with positive charges and application thereof in the field of medicines. These prodrugs have the general formula (1) 'Structure 1'.

In the formula 1, R₁Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₄Represents the following structure:

x represents O, S or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate or other negative ion, n ═ 0, 1, 2, 3,' 4, 5,6, 7, 8, 9, 10 … …; all R groups can contain C, H, O, S and N atoms and can have single bonds, double bonds and triple bonds; any CH₂The groups may be substituted with O, S or NH.

Absorption of drugs, whether via the gastrointestinal tract or other routes, requires the passage of the drug in a molecular form across a barrier membrane. The drug must first dissolve and, if the drug has the desired biopharmaceutical properties, it will diffuse from a region of high concentration to a region of low concentration across the biological membrane into the blood or systemic circulatory system. All biofilms contain lipids as a major component. The molecules that play a dominant role in biofilm architecture all have a highly polar head structure containing phosphate and, in most cases, two highly hydrophobic hydrocarbon tails. The biological membrane has a double-layer structure, and the hydrophilic head structure faces the water phase areas on two sides. Very hydrophilic drugs cannot pass through the lipid layer of the biofilm while very hydrophobic drugs stay in the biofilm as part of the biofilm for similar compatibility reasons and thus cannot effectively enter the inner cytoplasm.

The object of the present invention is to avoid the side effects of ketoprofen and fenoprofen by increasing the solubility of ketoprofen and fenoprofen in gastric juices and increasing their rate of penetration through biological membranes and skin barriers, allowing transdermal administration (external application). These prodrugs have two identical structural features: they have a lipophilic moiety and a primary, secondary, or tertiary amine group (hydrophilic moiety) in the protonated form at physiological pH. Such a water-oil balance is necessary for the drug to effectively cross the biological membrane [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]. The positively charged amino groups greatly increase the solubility of the drug. The solubilities of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, 2- (3-benzoylphenyl) propionate (ketoprofen) and 2- (3-phenoxyphenyl) propionate (fenoprofen) in water were: > 450mg, 0.1mg, and 0.1 mg/ml. In most cases, dissolution of the drug is the slowest or rate-limiting step in the absorption process. Ketoprofen and fenoprofen have very little solubility in gastric juice. It remains in the gastrointestinal tract for a long time and may cause damage to gastric mucosal cells. When these novel prodrugs are administered orally in a dosage form such as a tablet, capsule, solution or suspension, they dissolve rapidly in the gastric fluid. The positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of the cell membrane. Thus, the local concentration of the drug outside the membrane is high and thus helps the pro-drugs pass 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 cytoplasm, a semi-liquid stateConcentrated aqueous solutions or suspensions. Due to the short residence time in the gastrointestinal tract, the prodrug does not cause damage to gastric mucosal cells. The speed of passage of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, ketoprofen and fenoprofen through human skin isolated from human skin tissue (360-400 μm thick) in front of and behind the thigh region was measured in vitro by means of a modified Franz cell. The receiving solution consisted of 10ml of physiological saline containing 2% bovine serum albumin and was stirred at 600 rpm. The cumulative total amount of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, ketoprofen and fenoprofen that permeated through the skin was measured with respect to time by a specific high performance liquid chromatography. As donor solutions, a solution of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate 30% in phosphate-buffered saline solution (0.2M) pH 7.4 (2 ml), diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate 30% in phosphate-buffered saline solution pH 7.4 (0.2M) 2ml, or a suspension of ketoprofen 30% in phosphate-buffered saline solution pH 7.4 (0.2M) 2ml, or a suspension of fenoprofen 30% in phosphate-buffered saline solution pH 7.4 (0.2M) 2ml, was used, and the results are shown in FIG. 1. The apparent penetration values of the acetate to human skin, which are calculated by the acetate of 2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester, the acetate of 2- (3-phenoxyphenyl) propionic acid diethylaminoethyl ester, ketoprofen and fenoprofen, are respectively 115mg/cm²/h、125mg/cm²/h、0.9mg/cm²H and 1mg/cm²H is used as the reference value. The results show that the prodrug diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate penetrate human skin approximately 125 times faster than ketoprofen and fenoprofen. The results indicate that the positive charge on the dialkylaminoethyl group is important for the drug to penetrate the biological membrane and skin barrier. The transdermal speed of the other prodrugs in the general formula "formula 1" is very close to that of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate.

In vivo experiments compare diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and 2- (3-phenoxyphenyl)) The rate of passage of diethylaminoethyl propionate acetate, ketoprofen, fenoprofen through the skin of live hairless, atraumatic mice. The donor consisted of 10% diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate solution in 1ml isopropanol, 10% diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate solution in 1ml isopropanol, 10% ketoprofen solution in 1ml isopropanol or 10% fenoprofen solution in 1ml isopropanol. It is applied to the back of hairless mouse by 1cm²And (4) the part. The plasma concentrations of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, ketoprofen and fenoprofen were determined by a specific high performance liquid chromatography method. The results (FIGS. 2, 3) show that the concentrations of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate peaked after about 40 minutes using the donor system. Ketoprofen and fenoprofen took orally, the peak drug concentration in the plasma only reached 1-2 hours. The peak plasma levels of ketoprofen and fenoprofen were approximately 0.02mg/ml, and the peak plasma levels of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate were approximately 2mg/ml (approximately 100-fold difference). The plasma concentrations of ketoprofen and fenoprofen, 2mg/ml, were as much as 50 times higher than the analgesic and anti-inflammatory plasma concentrations of ketoprofen and fenoprofen. This is an exciting result. By these prodrugs, ketoprofen and fenoprofen can be easily and rapidly administered to a host in effective plasma concentrations. These results show that the prodrugs can be used not only orally, but also transdermally for any kind of medical treatments. The transdermal speed of other prodrugs in the general formula 'structure 1' in vivo is close to that of diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate.

To examine the bleeding of the stomach and duodenum caused by these drugs, we orally administered 100mg/kg2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate, 2- (3-phenoxyphenyl) propionic acid diethylaminoethyl ester acetate, ketoprofen, fenoprofen to rats (six groups, 10 rats each) every day for 21 consecutive days. In the ketoprofen group we found an average of 5mg of fecal blood per gram of rat feces, in the fenoprofen group an average of 4mg of fecal blood per gram of rat feces, and in the groups of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, no fecal blood was found.

The acute toxicity of these prodrugs was experimentally determined. Oral LD for rats₅₀Comprises the following steps: the acetate content of diethylaminoethyl 2- (3-benzoylphenyl) propionate was 0.2g/kg, and the acetate content of diethylaminoethyl 2- (3-phenoxyphenyl) propionate was 1.2 g/kg. The results indicate the toxicity of the prodrug, ketoprofen (LD)₅₀0.1g/kg) and fenoprofen (LD)₅₀0.8g/kg) low.

Ketoprofen and fenoprofen have demonstrated anti-inflammatory, analgesic, antipyretic and antirheumatic effects. A good prodrug should return to the parent drug quickly in plasma. In vitro tests demonstrated that diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate in human plasma are rapidly hydrolyzed by the enzyme, with more than 90% of the prodrug returning to ketoprofen and fenoprofen. Because of their better absorption rates, prodrugs are more efficacious than the parent drug at the same dosage. 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 of the general formula "Structure 1" in the same manner, and the results are very close to those of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate.

The analgesic effect is as follows: the time to prolongation of the mouse's carnosic threshold was determined according to the method of D' Amour-Smith (j. pharmacol. exp. ther., 72, 74(1941)). After 50mg/Kg of ketoprofen and fenoprofen, respectively, was orally administered to mice, 50mg/Kg of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate was transdermally administered, or 50mg/Kg of diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate was transdermally administered, the tails of the mice were exposed to thermal stimulation, and the pain threshold extension time was measured. The results are shown in FIG. 4. The group (C) administered 50mg/kg of 2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate and the group (D) administered 50mg/kg of 2- (3-phenoxyphenyl) propionic acid diethylaminoethyl ester acetate had significantly better analgesic effects than the group (B) administered 50mg/kg of ketoprofen.

The number of writhing appeared after the abdominal cavity of the mouse was administered with the acetic acid solution was counted, and the inhibition rate of writhing was calculated based on the control group. 30 mice were divided into 5 groups (6 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 diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate, group E mice were transdermally administered 50mg/kg diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate. A is a control group. Mice were dosed 30 minutes before the acetic acid solution. The results are shown in Table 1.

TABLE 1 inhibition of writhing by ketoprofen, fenoprofen and related compounds

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

The results show that diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate has a better analgesic effect than 2- (3-benzoylphenyl) propionate (ketoprofen). Other compounds in the general formula "Structure 1" show similar analgesic activity.

Antipyretic action: rats received inactivated E.coli suspension as pyrogen. 30 rats were divided into 6 groups. Group A is a control group. After 2 hours, ketoprofen (50mg/kg, group B) and fenoprofen (50mg/kg, group C) were orally administered, diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate (50mg/kg, group D) and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate (50mg/kg, group E) were transdermally administered. Rats were body temperature measured every 90 minutes before and after test compound administration. The results are shown in Table 2.

TABLE 2 antipyretic effect of ketoprofen and related compounds

Group of	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，(50mg/kg)	37.25±0.06	36.81±0.05	36.82±0.08	36.78±0.07
					C，(50mg/kg)	37.22±0.07	36.82±0.06	36.80±0.05	36.77±0.08
D，(50mg/kg)	37.28±0.06	36.65±0.06	36.58±0.08	36.60±0.07
					E，(50mg/kg)	37.28±0.06	36.65±0.06	36.58±0.08	36.56±0.07

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

Anti-inflammatory action: 50mg/kg2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate and 50mg/kg ketoprofen were administered orally or transdermally to rats. After 60 minutes the carrageenan solution was administered subcutaneously under the flesh pad of the rat paw. The volume of the hind paw of the rat was measured every 1 hour after the administration of carrageenan, and the rate of increase in the volume of the hind paw was calculated and used as the swelling rate (%). The results obtained are shown in FIG. 5. The results show that oral and transdermal administration of 50mg/kg2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate has better anti-inflammatory effect than oral administration of the same dose of ketoprofen. The anti-inflammatory effects of the other compounds represented by the general formula "structural formula 1" are similar.

Ketoprofen exhibits anti-reactive-anti-asthmatic effects when administered orally at high doses by inhibiting cyclooxygenase activity. Because of their rapid penetration across biological membranes, these pro-drugs can be sprayed into the mouth or nose to treat asthma. Because of their anti-inflammatory effects and faster transdermal speed, these prodrugs can treat acne.

The medicines are water-soluble neutral salts and have good tolerance to eyes. They may also be used for the treatment of ocular inflammation, for the treatment of ocular pain after corneal surgery, for the treatment of glaucoma or for the treatment of inflammation of the ear and/or states of ear pain (otitis).

The invention relates to pharmaceutical preparations containing the prodrugs of the general formula "formula 1" together with customary additives, auxiliaries, such as, for example, tablets, capsules or solutions for oral administration or solutions, emulsions, ointments, emulsions or gels for transdermal administration, the novel active compounds of the general formula "formula 1" can be used in combination with vitamins, such as vitamin A, B, C, E, β -carotene or the like, or other drugs, such as folic acid, for the treatment of any ketoprofen and fenoprofen treatable conditions in humans or animals.

Transdermal therapeutic application systems containing a compound represented by the general formula "formula 1" or a composition containing at least one compound represented by the general formula "formula 1" as an active ingredient are useful for treating any ketoprofen and fenoprofen-treatable conditions in humans or animals. These systems may be bandages or patches comprising a matrix layer containing the active substance and a non-permeable protective layer. The most preferred system is an active agent reservoir having a permeable skin-facing base. By controlling the release rate, the system can stabilize ketoprofen and fenoprofen at optimal therapeutic blood levels to improve therapeutic efficacy and reduce the side effects of ketoprofen and fenoprofen. These systems may be worn on the wrist, ankle, arm, leg, or any part of the body.

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

In structural formula 2, R4 represents:

y represents halogen, alkoxycarbonyl, or substituted aryloxycarbonyloxy.

In the formula 3, R₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r4 represents H, any 1-12 carbonsAn alkyl group of atoms, an alkoxy group of 1 to 12 carbon atoms, an alkenyl group of 1 to 12 carbon atoms or an alkynyl group of 1 to 12 carbon atoms, or an aryl group; x represents O, S or NH; n is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …

The compounds of the general formula (1) 'structure 1' indicated above can be prepared from 2- (3-benzoylphenyl) propionic acid (ketoprofen), 2- (3-phenoxyphenyl) propionic acid (fenoprofen), and the compounds of the general formula (3) 'structure 3' indicated above by reacting with coupling agents, such as N, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (HBTU), O-benzotriazol-N, N' -tetramethyluronium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), etc.

When X represents O, the compound represented by the general formula (1) 'structure 1' described above can be prepared by reacting a metal salt or an 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 the formula 4, R₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r4 represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl or alkynyl of 1 to 12 carbon atoms, or aryl; z represents halogen, or p-toluenesulfonyl; a. the^-Represents C1^-，Br^-，F^-，I^-，AcO^-Citrate, or any negative ion; n is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …

When X represents O, the compound represented by the general formula (1) 'structure 1' described above can be obtained by reacting an immobilized base salt of 2- (3-benzoylphenyl) propionic acid (ketoprofen) and 2- (3-phenoxyphenyl) propionic acid (fenoprofen), which are represented by the general formula (5) 'structure 5', with a compound represented by the general formula (4) 'structure 4'.

In the structural formula 5, R represents a crosslinked resin; r₄Represents the following structure:

b represents any basic group, such as pyridyl, piperidyl, triethylamine or other basic groups.

Advantages of the invention

Some of these pro-drugs of ketoprofen and fenoprofen are lipophilic in structure and others are hydrophilic (amine groups present in protonated form at physiological pH). The positively charged amino group has two major advantages: first, it greatly improves the solubility of the drug; when administered orally, such as in tablets, capsules, solutions or suspensions, these novel prodrugs are rapidly dissolved in the gastric fluid. Second, the positively charged amino groups of these prodrugs can bond to the negative charge of the phosphate head group of the biofilm. Thus, the local concentration outside the membrane will be high, facilitating the permeation of these pro-drugs from regions of high concentration to regions of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the drug into the cytoplasm, which is a concentrated semi-liquid aqueous solution or suspension. Since these prodrugs stay in gastric juice for a short time, they do not cause damage to the gastric mucosa. The results of the experiment show that 90% of the prodrug can be converted back to the parent drug. These prodrugs have a better absorption rate and therefore, at the same dose, are more effective than ketoprofen and fenoprofen. Experiments prove that the prodrugs of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate permeate human skin approximately 125 times faster than ketoprofen or fenoprofen. The peak plasma concentrations of ketoprofen and fenoprofen reached 1-2 hours after oral administration, whereas the peak plasma concentrations of ketoprofen and fenoprofen reached 40 minutes after administration of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate or diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate. The most exciting result is that the prodrug can be administered not only orally, but also transdermally for any kind of medical treatments, avoiding most of the side effects of ketoprofen or fenoprofen, most notably gastrointestinal disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Another great benefit of transdermal administration is the ease of administration, particularly to children.

Drawings

FIG. 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) from human skin tissue isolated by Franz cells (n ═ 5). The support solution under each condition was a phosphate buffered solution (0.2M) at pH 7.4.

FIG. 2: the total amount of ketoprofen in the plasma after (a) or 2- (3-benzoylphenyl) propionic acid (ketoprofen, B) was applied topically to the back of hairless mice (n ═ 5) in 10% diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate solution in 1ml isopropanol.

FIG. 3: the total amount of fenoprofen in the plasma after (a) or fenoprofen (B) was applied topically to the back of hairless mice (n ═ 5) 10% diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate dissolved in 1ml isopropanol.

FIG. 4: after 50mg/kg ketoprofen (B) was orally administered, 50mg/kg2- (3-benzoylphenyl) propionic acid diethylaminoethyl ester acetate (C) was transdermally administered, and 2- (3-phenoxyphenyl) propionic acid diethylaminoethyl ester acetate (D) was transdermally administered, the pain threshold of the tail of the mouse was prolonged. A is a control group.

FIG. 5: swelling rate (%) after carrageenan injection. Carrageenan was administered orally 1 hour prior to injection at 50mg/kg2- (3-benzoylphenyl) propanoic acid (ketoprofen, B), (C) and transdermally (D) at 50mg/kg2- (3-benzoylphenyl) propanoic acid diethylaminoethyl ester acetate. A is a control group.

FIG. 6: structural formula 1: in the formula 1, R₁Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms or alkynyl of 1 to 12 carbon atoms, or aryl; r₄Represents the following structure:

x represents O, S or NH; a-represents C1^-，Br^-，F^-，I^-，AcO^-Citrate or other negative ions; all R groups, where n is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …, may contain C, H, O, S, N atoms, and may have single, double, and triple bonds. Any CH₂The groups may be substituted with O, S or NH.

Best mode for carrying out the invention

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

11.7g (0.1mol) of diethylaminoethanol are dissolved in 200m 110% aqueous sodium hydrogencarbonate solution and 100ml of acetone. 27.3g (0.1mol) of 2- (3-benzoylphenyl) propionyl chloride are added to the reaction mixture. The reaction solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue is suspended in 500ml of ethyl acetate. 200ml of 5% aqueous sodium bicarbonate solution were added with stirring. The ethyl acetate layer was collected and washed with water three times, 500ml each. The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. The organic phase was evaporated to dryness. After drying, 36g of the target product, which is hygroscopic, were obtained with a yield of 87%. Solubility in water: 400 mg/ml; elemental analysis: c₂₄H₃₁NO₅(ii) a Molecular weight: 413.51. theoretical value (%)69.71, respectively; h: 7.56; n: 3.39; o: 19.35; found value (%) C: 69.69; h: 7.59; n: 3.36; o: 19.36.¹H-NMR (400MHz, 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).

Detailed description of the preferred embodiments

1.2 Synthesis of dimethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate

26.1g (0.1mol) of 2- (3-phenoxyphenyl) propionyl chloride were dissolved in 100ml of chloroform. The mixture was cooled to 0 ℃. To the reaction mixture were added 15ml of triethylamine and 8.9g (0.1mol) of dimethylaminoethanol with stirring. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in 300ml of methanol. 200ml of 5% aqueous sodium bicarbonate solution were added to the reaction mixture. The mixture was stirred for 3 hours. The mixture was evaporated to dryness. To the residue was added 300ml of methanol with stirring. The solid was removed by filtration and washed with methanol. The solution was evaporated to dryness and the residue was dissolved in 200ml chloroform. To the reaction mixture was added 6g of acetic acid with stirring. The solid was removed by filtration. An additional 6g of acetic acid was added to the reaction mixture with stirring. The organic phase was evaporated to dryness. After drying, 32g of the target product which is hygroscopic and has a yield of 85.7% was obtained. Solubility in water: 500 mg/ml; elemental analysis: c₂₁H₂₇NO₅(ii) a 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 of; n: 3.74 of; o: 21.45.¹H-NMR (400MHz, 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).

2.2 Synthesis of Dimethylaminoethylthioester acetate 2- (3-phenoxyphenyl) propanoate

10.4g (0.1mol) of N, N-dimethylaminoethanethiol are dissolved in 200m 110% sodium bicarbonate solution and 100ml acetone. 27.3g (0.1mol) of 2- (3-phenoxyphenyl) propionyl chloride are added to the reaction mixture with stirring. MixingThe mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue is suspended in 500ml of ethyl acetate. To the reaction mixture was added 200ml of 5% aqueous sodium bicarbonate solution with stirring. The ethyl acetate layer was collected and washed 3 times with 500ml of water each time. The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. The organic phase was evaporated to dryness. After drying, 34g of the target product, which is hygroscopic, 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 parts of; n: 3.61; o: 16.46 of; s: 8.22.¹H-NMR (400MHz, 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 dimethylamino ethyl 2- (3-benzoylphenyl) malonamic acid acetate

8.8g (0.1mol) of N, N-dimethylaminoethylamine are dissolved in 200m of 110% sodium bicarbonate solution and 100ml of acetone, and 27.3g (0.1mol) of 2- (3-benzoylphenyl) propionyl chloride are added to the reaction mixture with stirring. The reaction solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue is suspended in 500ml of ethyl acetate. To the reaction mixture was added 200ml of 5% aqueous sodium bicarbonate solution with stirring. The ethyl acetate layer was collected and washed 3 times with 500ml of water each time. The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. The organic solvent was evaporated to dryness. After drying, 33g of the target product which is hygroscopic and has a yield of 85.9% were obtained. Solubility in water: 400 mg/ml; elemental analysis: c₂₂H₂₈N₂O₅(ii) a Molecular weight: 384.20. theoretical value (%) C: 68.73; h: 7.34; n: 7.29; o: 16.65. found value (%) C: 68.70 of the total weight of the powder; h: 7.35; n: 7.29; o: 16.66.¹H-NMR (400MHz, 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 ester) propionamide acetate

25.7g (0.1mol) of 2- (3-benzoylphenyl) propionic acid are dissolved in 100ml of acetonitrile. 32.1g O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and 30ml triethylamine were added to the reaction mixture. 11.7g of dimethylaminoethylamine was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The reaction solvent was evaporated to dryness. 250ml of ethyl acetate are added to the reaction mixture and the mixture is washed 3 times with 100ml of water each time. The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. 200ml of hexane were added. The solid product was collected by filtration. After drying, 32g of the target product, which is hygroscopic, was obtained with a yield of 83.3%. Solubility in water: 400 mg/ml; elemental analysis: c₂₂H₂₈N₂O₅(ii) a Molecular weight: 384.20. theoretical value (%) C: 68.73; h: 7.34; n: 7.29; o: 16.65. found value (%) C: 68.70 of the total weight of the powder; h: 7.35; n: 7.29; o: 16.66.¹H-NMR (400MHz, 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).

5.2 Synthesis of diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate

60g of polymer-solidified triethylamine (3mol/g, 100-mesh 200 mesh) was suspended in 180ml of chloroform. To the mixture was added 25.7g (0.1mol) of 2- (3-benzoylphenyl) propionic acid with stirring. 43g (0.15mol) of diethylaminoethyl bromide hydrogen salt were 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 50ml of tetrahydrofuran each time. 8.2g (0.1mol) of sodium acetate are added to the reaction mixture with stirring. The mixture was stirred for 2 hours. The solid was removed by filtration and washed 3 times with 50ml of chloroform. The solution was concentrated to 100ml in vacuo. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed three times with 100ml of hexane each time. After drying 36g were obtainedThe yield of the target product which is easy to absorb moisture is 87 percent. Solubility in water: 400 mg/ml; elemental analysis: c₂₄H₃₁NO₅(ii) a Molecular weight: 413.51. theoretical value (%) C: 69.71, respectively; h: 7.56; n: 3.39; o: 19.35; found value (%) C: 69.69; h: 7.59; n: 3.36; o: 19.36.¹H-NMR (400MHz, 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 of the general formula (1) 'Structure 1' are superior to ketoprofen and fenoprofen. They may be used in the treatment of any ketoprofen and fenoprofen-treatable conditions in humans or animals. They can be used for relieving signs and symptoms of rheumatoid arthritis and osteoarthritis, for reducing fever, and for treating dysmenorrhea. They are also useful in diabetic neuropathy and acute migraine. These prodrugs can also be used to treat asthma by inhalation into the host, due to the rapid rate of membrane penetration of these prodrugs. These prodrugs can be used to treat acne due to their anti-inflammatory effects. These prodrugs are water-soluble neutral salts and are well tolerated by the eye. They are useful in the treatment of inflammatory disorders of the eye, in the treatment of ocular pain following corneal surgery, glaucoma or ear inflammation and/or pain states (otitis).

Claims

A compound represented by "structural formula 1":

wherein the content of the first and second substances,

R₁represents H, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms or alkynyl of 2 to 12 carbon atoms;

R₂represents H, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms or alkynyl of 2 to 12 carbon atoms；

R₃Represents H;

R₄represents the following structure:

x represents O or S;

represents Cl^-，Br^-，F^-，I^-，AcO^-Or citrate; and is

n is 1, 2, 3, 4, 5 or 6.
2. A process for the preparation of a compound according to claim 1, which comprises:

reacting an acid halide or mixed acid anhydride represented by formula 2 with a compound represented by formula 3;

in the formula 2, R₄Represents:

and is

Y represents halogen, alkoxycarbonyl, or substituted aryloxycarbonyloxy;

in the structural formula 3, the first polymer,

R₁represents H, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms or alkynyl of 2 to 12 carbon atoms;

R₂represents H, alkyl with 1-12 carbon atoms, alkoxy with 1-12 carbon atoms, 2-Alkenyl of 12 carbon atoms or alkynyl of 2-12 carbon atoms;

x represents O or S; and is

n is 1, 2, 3, 4, 5 or 6.
3. A product for transdermal therapeutic use comprising as active substance a compound according to claim 1.
4. The product for transdermal therapeutic application of claim 3, wherein the product is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.
5. A product for transdermal therapeutic application according to claim 3 wherein the product comprises an active substance reservoir comprising a permeable skin facing base.
6. A product for transdermal therapeutic use according to claim 3 wherein the product is capable of stabilizing the at least one active agent at an optimal therapeutic blood level by controlling the release rate of the at least one active agent.
7. Use of one or more compounds according to claim 1 in the manufacture of a medicament for the treatment of asthma in a human or animal by spray administration to the mouth or nose or other parts of the body of said human or animal.
8. Use of one or more compounds according to claim 1 in the manufacture of a medicament for the treatment of a ketoprofen or fenoprofen treatable condition in a human or animal, wherein the condition is selected from: pain, fever, cancer, radiation-induced emesis, diabetic neuropathy, hemophilic arthropathy, bone loss, glaucoma, sunburn, acne, or other skin disorders.
9. Use according to claim 8, wherein the pain is selected from headache, dental pain, muscular pain, dysmenorrhoea, acute migraine, ocular pain after corneal surgery, ear pain, and arthritis and other inflammatory pain.
10. The use according to claim 8 or 9, wherein the medicament is administered orally or transdermally.
11. The use of claim 10, wherein the therapeutically effective amount of the medicament is administered transdermally in the form of a solution, spray, lotion, ointment, emulsion, or gel.
12. The compound of claim 1, wherein in structural formula 1,

R₁represents H, or an alkyl group of 1 to 12 carbon atoms;

R₂represents H, or an alkyl group of 1 to 12 carbon atoms;

R₃represents H;

R₄represents

X represents O or S;

represents AcO^-(ii) a And is

n is 1, 2, or 3.
13. The compound of claim 12, wherein R₁And R₂Is methyl, R₄Is composed of
14. The compound of claim 12, wherein R₁And R₂Is methyl, R₄Is composed of
15. A process for preparing a compound of claim 12, comprising:

reacting an acid halide or mixed acid anhydride represented by formula 2 with a compound represented by formula 3;

in the formula 2, R₄Represents:

y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy;

in the structural formula 3, the first polymer,

R₁represents H, or an alkyl group of 1 to 12 carbon atoms;

R₂represents H, or an alkyl group of 1 to 12 carbon atoms;

x represents O or S;

n is 1, 2, or 3.