CN101500984A - Positively charged water-soluble prodrugs of ketoprofen and related compounds with rapid skin penetration rate - Google Patents

Abstract

The novel positively charged pro-drugs of ketoprofen and fenoprofen in the general formula (1) 'Structure 1' were designed and synthesized. These compounds of the general formula (1) 'Structure 1' can be synthesized from functional derivatives of ketoprofen and fenoprofen (e.g. acid halides or mixed anhydrides) by reaction with suitable alcohols, thiols, or amines. The positively charged amino group on the prodrug molecule not only greatly increases the solubility of the drug, but also binds to the negative charge on the phosphate head group of membranes and pushes the prodrug into the cytosol. The experimental result shows that the prodrug, namely diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate and diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate, penetrates through the human skin 125 times faster than ketoprofen or fenoprofen. The blood concentration of ketoprofen or fenoprofen reaches the peak value after 1-2 hours of oral administration of ketoprofen or fenoprofen, but the blood concentration of the ketoprofen or fenoprofen can reach the peak value only in about 40 minutes after the diethylaminoethyl 2- (3-benzoylphenyl) propionate acetate or the diethylaminoethyl 2- (3-phenoxyphenyl) propionate acetate. In plasma, more than 90% of the pro-drugs can return to the parent drug within a few minutes. These prodrugs can be used medicinally in treating any ketoprofen or fenoprofen-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of ketoprofen and fenoprofen, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enable ketoprofen and fenoprofen to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of ketoprofen and fenoprofen. Another great advantage of transdermal administration of these pro-drugs is that administration is more convenient, especially to children.

Description

Positively charged, water-soluble prodrugs of ketoprofen and related compounds with fast skin penetration rates

technical field

The present invention relates to positively charged water-soluble precursors of 2-(3-benzoylphenyl)propionic acid (ketoprofen) and 2-(3-phenoxyphenyl)propionic acid (phenoprofen). Medicine and its use in the treatment of any ketoprofen and fenoprofen treatable condition in man or animal. Specifically, the present invention is to overcome the side effects caused by using ketoprofen and fenoprofen. These prodrugs can be administered orally or transdermally.

technical background

Ketoprofen and fenoprofen are propionate NSAIDs. 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 adjunct in the treatment of acute biliary colic, renal colic, pain from oral surgery, severe postpartum pain, and fever (PDR Generics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg1812). Ketoprofen is also useful for bone regeneration (Alfano, M.C.; Troullos, E.S., US Patent No. 5,902,110). Fenoprofen can be used to treat acute or long-term symptoms of mild to moderate pain, osteoarthritis and rheumatoid arthritis. Fenoprofen can be used alone or as an adjunctive drug in the treatment of acute gout, pain caused by episiotomy, and migraine (PDR Generics, 1996, secondedition, Medical Economics, Montvale, New Jersey, pg1290). Fenoprofen can also be used to treat shock (Toth, P.D., US Patent No. 4,472,431).

However, taking ketoprofen and fenoprofen can cause many side effects, the most important being gastrointestinal discomfort, such as indigestion, gastric and duodenal bleeding, gastric ulcer and gastritis. Fishman (Fishman; Robert, US Pat. No. 7,052,715) pointed out that another problem with oral administration is that in order to be effective in treating pain or inflammation in a remote location, the drug must circulate in very high concentrations. These concentrations are often much higher than would be required if the drug were to be directly targeted to the painful or injured site. Fishman et. Formulation approach to develop drug delivery systems for transdermal drug delivery. However, due to the slow skin penetration of these drugs, it is difficult to achieve therapeutically effective plasma concentrations through formulation. 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 the prodrug (TSBH) penetrated the skin nearly 60 times faster than the parent drug (TS) itself. [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)].

Contents of the invention

technical problem

Ketoprofen and fenoprofen have been used clinically for more than 30 years. It is widely used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, treat dysmenorrhea, and prevent pupil constriction during surgery.

However, taking ketoprofen and fenoprofen can produce many side effects, the most important ones are gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcer and gastritis. Ketoprofen and fenoprofen are insoluble in water and gastric juice.

solution

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

Structural Formula 1

In structural formula ₁ , R represents H, any alkyl group with 1-12 carbon atoms, alkoxy group with 1-12 carbon atoms, alkenyl group with 1-12 carbon atoms or alkynyl group with 1-12 carbon atoms , or _aryl ; R 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 alkyne group of 1-12 carbon atoms base, or aryl; R ₃ represents H, any 1-12 carbon atom alkyl, 1-12 carbon atom alkoxy, 1-12 carbon atom alkenyl or 1-12 carbon atom Alkynyl, or aryl; R ₄ represents the following structure:

或

or

X represents O, S or NH; A ^- represents Cl ^- , Br ^- , F ^- , I ^- , AcO ^- , citrate or other negative ions; all R groups can contain C, H, O, S, N atoms, and can have Single, double and triple bonds; any _CH2 group can be replaced by O, S or NH.

Whether drugs are absorbed through the gastrointestinal tract or other routes, they need to pass through the barrier membrane in the form of molecules. The drug needs to dissolve first, and if the drug has desirable biopharmaceutical properties, it diffuses from areas of high concentration to areas of low concentration, across biofilms and into the blood or systemic circulation. All biological membranes contain lipids as major components. The dominant molecules in biofilm structure have a highly polar head structure containing phosphate and, in most cases, two highly hydrophobic hydrocarbon tails. The biofilm has a bilayer structure with hydrophilic head structures facing the aqueous phase regions on both sides. Very hydrophilic drugs cannot pass through the lipid layer of the biomembrane while very hydrophobic drugs remain as part of the biomembrane for similarly compatible reasons and thus cannot effectively enter the inner cytoplasm.

The purpose of the present invention is by improving the dissolubility of ketoprofen and fenoprofen in gastric juice and improving its speed through biofilm and skin barrier, so that it can be administered through the skin (external use), thereby avoiding ketoprofen and fenoprofen side effects. These prodrugs share two common structural features: they have a lipophilic moiety and a primary, secondary, or tertiary amine group (hydrophilic moiety) that exists in protonated form at physiological pH. Such a water-oil solubility balance is necessary for drugs to cross biomembranes efficiently [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)]. The positively charged amino group greatly increases the solubility of the drug. 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate, 2-(3-phenoxyphenyl)propionate diethylaminoethyl acetate, 2-(3-benzene The solubility of formylphenyl) propionic acid (ketoprofen) and 2-(3-phenoxyphenyl) propionic acid (fenoprofen) in water are: >450mg, >450mg, 0.1mg, and 0.1 mg/ml. In most cases, drug dissolution is the slowest and rate-limiting step in the absorption process. The solubility of ketoprofen and fenoprofen in gastric juice is very small. It stays in the gastrointestinal tract for a long time and may cause gastric mucosal cell damage. When these novel prodrugs are orally administered in dosage forms such as tablets, capsules, solutions or suspensions, they dissolve rapidly in gastric juice. The positive charge on the amino group of these prodrug molecules bonds to the negative charge on the phosphate end group of the cell membrane. Therefore, the local concentration of drugs on the outside of the biofilm is high to facilitate the passage of these prodrugs from areas of high concentration to areas of low concentration. When these prodrug molecules enter the biomembrane, the hydrophilic part pushes the prodrug into the cytoplasm, a semi-liquid concentrated aqueous solution or suspension. Due to the short residence time in the gastrointestinal tract, the prodrug will not cause damage to gastric mucosal cells. Diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, Diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, Ketoprofen and Fenol The rate of penetration of profen through human skin was measured in vitro using a modified Franz cell in which human skin was isolated from human skin tissue (360-400 μm thick) on the front or back of the thigh. The receiving solution consisted of 10 ml of physiological saline containing 2% bovine serum globulin and was stirred at 600 rpm. Diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, Diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, Ketoprofen and Fenol The cumulative amount of iprofen through the skin versus time was determined using a specific high performance liquid chromatography method. 30% diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate dissolved in 2ml pH7.4 phosphate buffered saline (0.2M) or dissolved in 2ml pH7.4 phosphate buffered saline A solution of 30% diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate (0.2M), or 30% ketone in 2ml pH 7.4 phosphate buffered saline (0.2M) The suspension of profen or the suspension of 30% fenoprofen dissolved in 2ml pH7.4 phosphate buffered saline solution (0.2M) was used as the donor solution, and the results are shown in FIG. 1 . Diethylaminoethyl p-2-(3-benzoylphenyl)propionate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate, ketoprofen and phenanthrene The calculated apparent penetration values of noprofen to human skin are 115mg, 125mg, 0.9mg and 1mg/cm ² /h respectively. The results showed that the prodrugs 2-(3-benzoylphenyl) propionate diethylaminoethyl acetate and 2-(3-phenoxyphenyl) propionate diethylaminoethyl acetate passed through The speed of human skin is nearly 125 times faster than that of ketoprofen and fenoprofen. The results indicated that the positive charge on the diethylaminoethyl group is very important for the drug to pass through the biomembrane and skin barriers. The skin penetration rate of other prodrugs in the general formula "Structure 1" is very close to that of diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate.

In vivo experiments compared diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate, ketorol The speed of fen and fenoprofen through the skin of live hairless and uninjured mice. The donor was prepared from a solution of 10% diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate in 1 ml of isopropanol, 10% 2-(3-benzene) in 1 ml of isopropanol Oxyphenyl) diethylaminoethyl propionate acetate solution, 10% ketoprofen solution dissolved in 1ml isopropanol or 10% fenoprofen solution dissolved in 1ml isopropanol. It was applied to a 1 cm ² site on the back of a hairless mouse. In plasma, 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate, 2-(3-phenoxyphenyl)propionate diethylaminoethyl acetate, ketoprofen, The concentration of fenoprofen was determined by a specific high performance liquid chromatography method. The results (Fig. 2, Fig. 3) show that diethylaminoethyl 2-(3-benzoylphenyl)propanoate acetate and 2-(3-phenoxybenzene Base) diethylaminoethyl propionate acetate reached the peak concentration. After oral administration of ketoprofen and fenoprofen, the drug concentration in plasma reaches its peak value after 1-2 hours. The peak blood concentration of ketoprofen and fenoprofen is about 0.02mg/ml, 2-(3-benzoylphenyl) propionate diethylaminoethyl acetate and 2-(3-phenoxy The peak blood concentration of diethylaminoethyl acetate of phenyl)propionate is about 2mg/ml (the difference is about 100 times). The concentration of diflunisal in plasma is about 2 mg/ml, which is 50 times higher than the plasma concentration of ketoprofen and fenoprofen, which are effective in analgesia and anti-inflammation. This is an exciting result. Through these prodrugs, effective plasma concentrations of ketoprofen and fenoprofen can be easily and rapidly administered into the host. These results show that the prodrugs can be used not only orally but also transdermally in various treatments. The transdermal speed of other prodrugs in the general formula "structural formula 1" is close to that of 2-(3-phenoxyphenyl) diethylaminoethyl propionate acetate.

In order to check the gastric and duodenal bleeding caused by these drugs, we orally administered 100 mg/kg 2-(3-benzoylphenyl) diethylaminopropionate to rats (two groups, 10 rats in each group) every day. Ethyl acetate, diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate, ketoprofen, fenoprofen, for 21 consecutive days. In the ketoprofen group, we found an average of 5 mg of blood in the feces per gram of rat feces, and an average of 4 mg of blood in the feces of the fenoprofen group, and in 2-(3-benzoylphenyl) diethylamino propionate Hematochezia was not found in ethyl acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate groups.

The acute toxicity of these prodrugs was determined experimentally. The oral LD ₅₀ of rats is: 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate is 0.2g/kg, 2-(3-phenoxyphenyl)propionate diethyl Aminoethyl acetate is 1.2g. The results indicated that the toxicity of the prodrug was lower than that of ketoprofen (LD ₅₀ =0.1 g/kg) and fenoprofen (LD ₅₀ =0.8 g/kg).

Ketoprofen and fenoprofen have been proven to have anti-inflammatory, analgesic, antipyretic and anti-rheumatic effects. A good prodrug should quickly return to the parent drug in plasma. In vitro tests have shown that in human plasma, diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate The diethylaminoethyl ester group in the acid salt can be rapidly hydrolyzed by enzymes, and more than 90% of the prodrug returns to ketoprofen and fenoprofen. Due to the better absorption rate of the prodrug, the curative effect of the prodrug is stronger than that of the parent drug at the same dose. Our analgesic and antidepressant effects on diethylaminoethyl 2-(3-benzoylphenyl)propionate and diethylaminoethyl 2-(3-phenoxyphenyl)propionate Thermal and anti-inflammatory effects were tested and compared with ketoprofen and fenoprofen. We also tested other compounds in the general formula "structural formula 1" by the same method, and the test results were very close to the results of 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate.

Analgesic effect: According to the method of D'Amour-Smith (J. Pharmacol. Exp. Ther., 72, 74 (1941)). The prolongation time of mouse tail pain threshold was measured. Mice were orally administered 50 mg/kg of ketoprofen and fenoprofen respectively, and transdermally administered 50 mg/kg of 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate or transdermally administered After administering 50 mg/Kg of 2-(3-phenoxyphenyl) diethylaminoethyl propionate acetate, the tail of the mice was exposed to thermal stimulation, and the pain threshold extension time was measured. The result is shown in Figure 4. Group (C) of transdermal administration of 50 mg/kg 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate and transdermal administration of 50 mg/kg 2-(3-phenoxybenzene Base) the group (D) of diethylaminoethyl propionate acetate, its analgesic effect will be obviously better than the group (B) of administering 50mg/kg ketoprofen.

The number of times of writhing after intraperitoneal administration of acetic acid solution in 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 in each group). B group mice were administered 50mg/kg ketoprofen, C group mice were administered 50mg/kg fenoprofen, and D group mice were administered 50mg/kg 2-(3-benzoylphenyl)propane 2-(3-phenoxyphenyl)propionate diethylaminoethyl acetate, E group mice transdermally administered 50mg/kg 2-(3-phenoxyphenyl) propionate diethylaminoethyl acetate. A is the control group. Mice were dosed 30 min before administration of the acetic acid solution. The measurement results are shown in Table 1.

Table 1. Inhibition rate of ketoprofen, fenoprofen and their related compounds on writhing

group A B C D. E. Dose (mg/kg) 0 50 50 50 50 Number of twists 35.0 18.1 13.2 14.2 14.0 % - 48 62 59 60

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

Antipyretic effect: Rats received a suspension of inactivated Escherichia coli as a pyrogen. 30 rats were divided into 6 groups. Group A is the control group. After 2 hours, ketoprofen (50mg/kg, group B) and fenoprofen (50mg/kg, group C) were administered orally, and 2-(3-benzoylphenyl)propionic acid was transdermally administered Diethylaminoethyl acetate (50 mg/kg, group D) and diethylaminoethyl 2-(3-phenoxyphenyl)propionate acetate (50 mg/kg, group E). The body temperature of the rats was measured every 90 minutes before and after administration of the test compound. 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, (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 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate and 2-(3-phenoxyphenyl)propionate diethylaminoethyl acetate at a dose of 50mg/kg The antipyretic activity is better than ketoprofen and fenoprofen. Other compounds of the general formula "Structure 1" showed similar antipyretic activity.

Anti-inflammatory effect: Orally or transdermally administer 50mg/kg 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate to rats, orally administer 50mg/kg ketoprofen. After 60 minutes, the carrageenan solution was subcutaneously administered under the pads of the paws of the rats. The volume of the rat's hind paw was measured every 1 hour after administration of carrageenan, and the growth rate of the volume of the hind paw was calculated as the swelling rate (%). The results obtained are shown in Figure 5. The results show that the anti-inflammatory effect of oral and transdermal administration of 50mg/kg 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate is better than that of ketoprofen of the same dose administered orally. Other compounds represented by the general formula "Structure 1" have similar anti-inflammatory effects.

Ketoprofen exhibits an anti-reactive-anti-asthma effect by inhibiting the activity of cyclooxygenase when taken orally in high doses. Because these prodrugs penetrate biomembranes quickly, they can be sprayed into the mouth or nose to treat asthma. These prodrugs can treat acne due to their anti-inflammatory effects and fast skin penetration.

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

The present invention relates to pharmaceutical preparations containing the prodrug represented by the general formula "Structural Formula 1" and commonly used additives and excipients, such as tablets, capsules or solutions for oral administration, or solutions, emulsions, etc. for transdermal administration. Ointment, latex or gel etc. The novel active compound of the general formula "structural formula 1" can be used in combination with vitamins such as vitamins A, B, C, E, beta-carotene, etc., or other drugs, such as folic acid, for the treatment of any ketoprofen and phenanthrene in humans or animals. Noprofen can treat the condition.

Transdermal therapeutic application system, containing the compound represented by the general formula "structural formula 1" or a composition containing at least one compound represented by the general formula "structural formula 1" as an active ingredient, which can be used to treat any ketoprofen and Fenoprofen treatable condition. These systems may be bandages or patches comprising a matrix layer comprising the active substance and an impermeable protective layer. The most preferred system is an active substance reservoir comprising a permeable skin-facing base. By controlling the release rate, the system can stabilize ketoprofen and fenoprofen at the optimal therapeutic blood concentration so as to improve the curative effect and reduce the side effects of ketoprofen and fenoprofen. These systems can be worn on the wrist, ankle, arm, leg or anywhere on the body.

The compound represented by the above-mentioned general formula (1) "structural formula 1" can be made of functionalized derivatives of 2-(3-benzoylphenyl)propionic acid and 2-(3-phenoxyphenyl)propionic acid, for example The acid halide or mixed acid anhydride represented by the general formula (2) "structural formula 2" is prepared by reacting the compound in the general formula (3) "structural formula 3".

Structural formula 2

In structural formula 2, _R represents:

or

Y represents halogen, alkoxycarbonyl, or substituted aryloxycarbonyloxy.

Structural formula 3

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

The compound represented by above-mentioned general formula (1) " structural formula 1 " can be by 2-(3-benzoylphenyl) propionic acid (ketoprofen), 2-(3-phenoxyphenyl) propionic acid (phenanthrene) Noprofen), and the compound represented by the general formula (3) "structural formula 3" is prepared by reacting with a coupling agent, such as N, N'-dicyclohexylcarboimide (DCC), N, N'-di Isopropylcarboimide (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)phosphorus-hexafluorophosphate, etc. .

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

Formula 4

In structural formula 4, R represents H, any alkyl group with 1-12 carbon atoms, alkoxy group with 1-12 carbon atoms, alkenyl _group with 1-12 carbon atoms or alkynyl group with 1-12 carbon atoms , or _aryl ; R 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 alkyne group of 1-12 carbon atoms base, or aryl; R ₄ represents H, any 1-12 carbon atom alkyl, 1-12 carbon atom alkoxy, 1-12 carbon atom alkenyl or 1-12 carbon atom Alkynyl, or aryl; Z represents halogen, or p-toluenesulfonyl; A ^- represents Cl ^- , Br ^- , F ^- , I ^- , AcO ^- , citrate, or other negative ions; n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...

When X represents O, the compound represented by the above-mentioned general formula (1) "structural formula 1" can be represented by 2-(3-benzoylphenyl) propionic acid (ketorol) represented by general formula (5) "structural formula 5". Fen) and the immobilized alkali salt of 2-(3-phenoxyphenyl) propionic acid (fenoprofen) react with the compound represented by general formula (4) "structural formula 4".

Structural formula 5

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

or

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

advantage

Some of the prodrug structures of these ketoprofen and fenoprofen are hydrophobic, and the other part is hydrophilic (the amine group exists in the protonated form under the physiological pH value). The positively charged amino group has two major advantages: First, it greatly increases the solubility of the drug; when these new prodrugs are administered orally, such as tablets, capsules, solutions or suspensions, they dissolve rapidly in gastric juice . Second, the positively charged amino group of these prodrugs can bond to the negative charge of the phosphate end group of the biomembrane. Consequently, the local concentration outside the membrane will be high, facilitating the permeation of these prodrugs from areas of high concentration to areas of low concentration. When these prodrug molecules enter the biomembrane, the hydrophilic part will push the drug into the cytoplasm, which is a concentrated semi-liquid aqueous solution or suspension. Because these prodrugs stay in the gastric juice for a short time, they will not cause damage to the gastric mucosa. Experimental results show that 90% of the prodrugs can be converted back to the parent drug. These prodrugs have a better absorption rate, so at the same dose, the efficacy of the prodrugs is better than ketoprofen or fenoprofen. Experiments show that the prodrugs 2-(3-benzoylphenyl)propionate diethylaminoethyl acetate and 2-(3-phenoxyphenyl)propionate diethylaminoethyl acetate pass through human The speed of the skin is nearly 125 times faster than ketoprofen or fenoprofen. Oral ketoprofen or fenoprofen peak plasma concentration after 1-2 hours, while taking 2-(3-benzoylphenyl) propionate diethylaminoethyl acetate or 2-(3-benzene Formylphenyl) propionate diethylaminoethyl acetate 40 minutes after the concentration of ketoprofen or fenoprofen in plasma can reach the peak value. The most exciting result is that the prodrug can not only be taken orally, but also can be used for any drug treatment in a transdermal way, thereby avoiding most of the side effects of ketoprofen or fenoprofen, the most important of which is It can prevent gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcer, and gastritis. Another great advantage of transdermal administration is the convenience of administration, especially for children.

Description of drawings

Figure 1: Diethylaminoethyl 2-(3-benzoylphenyl)propionate acetate (A, 30% solution) passed through human skin tissue isolated in a Franz cell (n=5), 2-( 3-phenoxyphenyl)propionate diethylaminoethyl acetate (B, 30% solution), ketoprofen (C, 30% suspension), and fenoprofen (D, 30% mixed suspension). The carrier solution under various conditions is a phosphate buffer solution (0.2M) with a pH of 7.4.

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

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

Figure 4: After oral administration of 50 mg/kg ketoprofen (B), transdermal administration of 50 mg/kg 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate (C), and transdermal After administration of 2-(3-phenoxyphenyl) diethylaminoethyl propionate acetate (D), the tail pain threshold of mice was prolonged. A is the control group.

Figure 5: Swelling rate (%) after carrageenan injection. Orally 50mg 2-(3-benzoylphenyl) propionic acid (ketoprofen, B) 1 hour before carrageenan injection, oral (C) and transdermal administration (D) 50mg 2-(3-benzoyl) Acylphenyl) diethylaminoethyl propionate acetate. A is the control group.

Structural formula 1: In structural formula 1, _R represents H, any alkyl group with 1-12 carbon atoms, alkoxy group with 1-12 carbon atoms, alkenyl group with 1-12 carbon atoms or 1-12 carbon atoms Atomic alkynyl, or aryl; R ₂ represents H, any alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, alkenyl of 1-12 carbon atoms or 1-12 Alkynyl of carbon atoms, or aryl; R ₃ represents H, any alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, alkenyl of 1-12 carbon atoms or 1-12 an alkynyl group of carbon atoms, or an aryl group; R ₄ represents the following structure:

或

or

X stands for O, S or NH; A- stands for 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, double, and triple bonds. Any _CH2 group can be substituted by O, S or NH.

best practice

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

11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 200 ml of 10% aqueous sodium bicarbonate solution and 100 ml of acetone. To the reaction mixture was added 27.3 g (0.1 mol) of 2-(3-benzoylphenyl)propionyl chloride. The reaction solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was suspended in 500 ml ethyl acetate. 200 ml of 5% aqueous sodium bicarbonate solution was added with stirring. The ethyl acetate layer was collected and washed three times with 500 ml of water each time. The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. The organic phase was evaporated to dryness. After drying, 36 g of the hygroscopic target product was obtained with a yield of 87%. Solubility in water: 400mg/ml; Elemental analysis: C ₂₄ H ₃₁ NO ₅ ; 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 (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).

implementation plan

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

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 to the reaction mixture with stirring. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was dissolved in 300 ml methanol. 200 ml of 5% aqueous sodium bicarbonate solution was added to the reaction mixture. The mixture was stirred for 3 hours. The mixture was evaporated to dryness. 300 ml of methanol were added to the residue with stirring. The solid was removed by filtration and washed with methanol. The solution was evaporated to dryness, and the residue was dissolved in 200 ml of chloroform. 6 g of acetic acid was added to the reaction mixture with stirring. The solids were removed by filtration. An additional 6 g of acetic acid was added to the reaction mixture with stirring. The organic phase was evaporated to dryness. After drying, 32 g of the hygroscopic target product was obtained with a yield of 85.7%. Solubility in water: 500mg/ml; Elemental analysis: C ₂₁ H ₂₇ NO ₅ ; 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; ¹ H-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. Synthesis of 2-(3-phenoxyphenyl)propionic acid dimethylaminoethylthioester acetate

10.4 g (0.1 mol) of N,N-dimethylaminoethanethiol were dissolved in 200 ml of 10% sodium bicarbonate solution and 100 ml of acetone. 27.3 g (0.1 mol) of 2-(3-phenoxyphenyl)propionyl chloride were stirred into the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was suspended in 500 ml ethyl acetate. 200 ml of 5% aqueous sodium bicarbonate solution was added to the reaction mixture with stirring. The ethyl acetate layer was collected and washed three times with 500 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. The organic phase was evaporated to dryness. After drying, 34 g of the hygroscopic target product was obtained with a yield of 87.3%. Solubility in water: 400mg/ml; Elemental analysis: C ₂₁ H ₂₇ NO ₄ S; Molecular weight: 389.51. Theoretical value (%) C: 64.75; H: 6.99; N: 3.60; O: 16.43; S: 8.23. Measured value (%) C: 64.73; H: 6.98; N: 3.61; O: 16.46; S: 8.22. ¹ H-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 dimethylaminoethyl 2-(3-benzoylphenyl)propionamic acid acetate

8.8g (0.1mol) N, N-dimethylaminoethylamine was dissolved in 200ml 10% sodium bicarbonate solution and 100ml acetone, and 27.3g (0.1mol) 2-(3-benzoyl) was added with stirring in the reaction mixture phenyl) propionyl chloride. The reaction solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The residue was suspended in 500ml ethyl acetate. 200 ml of 5% aqueous sodium bicarbonate solution was added to the reaction mixture with stirring. The ethyl acetate layer was collected and washed three times with 500 ml of water. The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. The organic solvent was evaporated to dryness. After drying, 33 g of the hygroscopic target product was obtained with a yield of 85.9%. Solubility in water: 400mg/ml; Elemental analysis: C ₂₂ H ₂₈ N ₂ O ₅ ; 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 (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)propionamide acetate

25.7 g (0.1 mol) of 2-(3-benzoylphenyl)propionic acid were dissolved in 100 ml of acetonitrile. 32.1 g of O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate and 30 ml of triethylamine were added to the reaction mixture. To the reaction mixture was added 11.7 g of dimethylaminoethylamine. The mixture was stirred at room temperature for 3 hours. The reaction solvent was evaporated to dryness. 250 ml of ethyl acetate was added to the reaction mixture, and the mixture was washed with water 3 times, 100 ml each time. The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. 200ml of hexane was added. The solid product was collected by filtration. After drying, 32 g of the hygroscopic target product was obtained with a yield of 83.3%. Solubility in water: 400mg/ml; Elemental analysis: C ₂₂ H ₂₈ N ₂ O ₅ ; 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 (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. Synthesis of 2-(3-benzoylphenyl) diethylaminoethyl propionate acetate

Suspend 60 g of polymer-solidified triethylamine (3 mol/g, 100-200 mesh) in 180 ml of chloroform. 25.7 g (0.1 mol) of 2-(3-benzoylphenyl)propionic acid were added with stirring to the mixture. To the mixture was added 43 g (0.15 mol) of diethylaminoethyl bromide hydrogen bromide, 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 THF. 8.2 g (0.1 mol) of sodium acetate were stirred into the reaction mixture. The mixture was stirred for 2 hours. The solid was removed by filtration and washed three times with 50 mL of chloroform. The solution was concentrated in vacuo to 100ml. Then 300 ml of hexane was added to the solution. The solid product was collected by filtration and washed three times with 100 mL of hexane. After drying, 36 g of the hygroscopic target product were obtained with a yield of 87%. Solubility in water: 400mg/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 value (%) C: 69.69; H: 7.59; N: 3.36; O: 19.36. ¹ H-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 prodrug represented by general formula (1) "structural formula 1" is superior to ketoprofen and fenoprofen. They can be used in the treatment of any ketoprofen- and fenoprofen-treatable condition in humans and animals. They can be used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, reduce fever, and treat menstrual cramps. They are also used in diabetic neuropathy and acute migraine. Because these prodrugs penetrate biomembranes quickly, these prodrugs can also treat asthma by inhaling the host. Due to their anti-inflammatory properties, these prodrugs can be used in the treatment of acne. These prodrugs are water-soluble neutral salts and are well tolerated by the eye. They are useful in the treatment of inflammatory conditions of the eye, eye pain following corneal surgery, glaucoma, or inflammatory and/or painful conditions of the ear (otitis).

sequence listing text

Claims (9)

1. The compound represented by general formula (1) "structural formula 1":

Structural Formula 1 In structural formula ₁ , R represents H, any alkyl group with 1-12 carbon atoms, alkyl group with 1-12 carbon atoms, alkenyl group with 1-12 carbon atoms or alkynyl group with 1-12 carbon atoms, Or _aryl ; R represents H, any alkyl group with 1-12 carbon atoms, alkoxy group with 1-12 carbon atoms, alkenyl group with 1-12 carbon atoms or alkynyl group with 1-12 carbon atoms , or _aryl ; R 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 alkyne group of 1-12 carbon atoms Base, or aryl; R4 represents the following structure:

or

X stands for O, S or NH; A- stands for 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, can have single bond, double bond and triple bond; any _CH2 group can be substituted by O, S or NH. 2. The preparation method of the compound represented by the general formula (1) "structural formula 1" described in claim 1. 3. a compound represented by the general formula "structural formula 1" as claimed in claim 1 or a composition containing at least a compound represented by the general formula (1) "structural formula 1" as an active ingredient, which can be passed Oral or transdermal administration is used to treat any state that can be treated with ketoprofen and fenoprofen in humans or animals; the state that ketoprofen and fenoprofen can treat includes but is not limited to: toothache, headache, Arthritis, other inflammatory pains, fever, cancer, dysmenorrhea, vomiting from chemotherapy, diabetic neuropathy, migraine, hemophilic arthritis, bone loss, and sunburn. 4. the method for the treatable state of any ketoprofen and fenoprofen of people or animals, the method is by giving the general formula (1) as claimed in claim 1 in any part of the body with transdermal administration mode The compound represented by "structural formula 1" or a composition containing at least one compound represented by general formula (1) "structural formula 1" as an active ingredient, and achieve a therapeutically effective plasma concentration, wherein the transdermal administration methods include solution, spray Lotion, lotion, ointment, latex or gel. 5. The method for externally treating the pain of humans or animals, by administering a therapeutically effective dose of the compound represented by the general formula (1) "structural formula 1" as claimed in claim 1 in the inflammation area, or containing at least one general formula ( 1) A composition comprising a compound represented by "structural formula 1" as an active ingredient, wherein the pain includes headache, toothache, muscle pain, arthritis and other inflammatory pains. 6. The compound represented by the general formula (1) "structural formula 1" as claimed in claim 1 or the composition containing at least one compound represented by the general formula (1) "structural formula 1" as an active ingredient, which can pass through a solution, Sprays, lotions, ointments, latex, or gels are administered transdermally to treat acne, sunburn, or other skin conditions. 7. The compound represented by the general formula (1) "structural formula 1" as claimed in claim 1 or the composition containing at least one compound represented by the general formula (1) "structural formula 1" as an active ingredient, which can pass through the mouth Or nasal spray or other parts of the body to treat asthma. 8. The compound represented by the general formula (1) "structural formula 1" as claimed in claim 1 or the composition containing at least one compound represented by the general formula (1) "structural formula 1" as an active ingredient, which can treat human and Eye inflammatory diseases in animals, treatment of ocular pain after corneal surgery, treatment of glaucoma or inflammatory and/or painful conditions of the ear (otitis). 9. Transdermal therapeutic application system, containing the compound represented by the general formula (1) "structural formula 1" as claimed in claim 1 or the composition containing at least one compound represented by the general formula (1) "structural formula 1" as an active ingredient , can be used to treat any ketoprofen, fenoprofen treatable state in humans or animals; the above-mentioned system can be a bandage or a patch, which contains a matrix layer containing the active substance and an impermeable protective layer , the most preferred system is an active substance reservoir containing a permeable bottom facing the skin; by controlling the release rate, this system can stabilize ketoprofen and fenoprofen at optimal therapeutic blood levels to improve efficacy and reduce side effects.

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