HK1137425A1 - Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate - Google Patents

Abstract

The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any NS AIAs-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 NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrugs enable naproxen, suprofen, a- methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description

Positively charged water-soluble prodrugs of aryl and heteroaryl propionic acids with fast skin penetration rate

Technical Field

The present invention relates to positively charged and water-soluble prodrugs of aryl and heteroarylpropionic acids and their use in the treatment of any non-steroidal anti-inflammatory drug (NSAIAs) treatable conditions in humans or animals. Specifically, the invention aims to overcome the side effects brought by the non-steroidal anti-inflammatory drugs. These prodrugs can be administered orally or transdermally.

Technical Field

Aryl and heteroaryl propionic acids include 2-aryl and heteroaryl propionic acids, 3-aryl and heteroaryl propionic acids, and cyclized aryl and heteroaryl propionic acids. 2- (6-methoxy-2-naphthyl) propionic acid (naproxen), α -methyl-4- (2-thenoyl) phenylacetic acid (suprofen); α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, 2- (2-fluoro-4-biphenylyl) propionic acid (flurbiprofen), 6-chloro- α -methyl-9H-carbazole-2-acetic acid (carprofen), α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetic acid (pranoprofen), 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetic acid (benoxaprofen), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid (alminoprofen), 5-benzoyl- α -methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid (pirifene), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiopin-2-yl) propionic acid (zaltoprofen), 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionic acid (bermoprofen), 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionic acid (loxoprofen), 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetic acid (indoprofen), alpha, 3-dichloro-4-cyclohexylphenylacetic acid (benzathine), and related compounds, are non-steroidal anti-inflammatory drugs belonging to the 2-aryl and heteroaryl propionic acids. 4, 5-diphenyl-2-oxazolepropionic acid (oxaprozin), 3- (4-biphenylcarbonyl) propionic acid (fenbufen), 5- (4-chlorophenyl) -beta-hydroxy-2-furanpropionic acid (oxyphenoxin) and related compounds are non-steroidal anti-inflammatory drugs belonging to the class of 3-aryl and heteroaryl propionic acids. 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid (clidanac), and related compounds are non-steroidal anti-inflammatory drugs belonging to the cyclized aryl and heteroaryl propionic acid series. They can be used for the treatment of rheumatic arthritis, osteoarthropathy, and dysmenorrhea. They can also treat acute gouty arthritis and ankylosing spondylitis. They can also be used to treat dementia (McGeer; Patrick L. et al, U.S. Pat. No. 5,192,753).

However, the use of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, also brings about many side effects, in particular side effects that cause gastrointestinal discomfort, such as dyspepsia, gastroduodenal bleeding, gastric ulcer, 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, 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 way 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) permeated through the skin nearly 60 times faster than the parent drug (TS) itself [ Susan Milosovich, et al, j.pharm. sci., 82, 227(1993) ].

Disclosure of Invention

Technical problem

Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds have been used medically for many years. It can be used for relieving signs and symptoms of rheumatoid arthritis and osteoarthritis, and treating dysmenorrhea.

However, the administration of non-steroidal anti-inflammatory drugs (NSAIAs) has many side effects, most notably gastrointestinal digestive tract disorders such as dyspepsia, gastroduodenal bleeding, and gastritis. They are insoluble in water or gastric juice and stay in the gastrointestinal tract for a long time, and thus may damage gastric mucosal cells.

Solution scheme

The present invention relates to novel positively charged prodrugs of aryl and heteroaryl propionic acids and related compounds, and their use in the medical field. 2- (6-methoxy-2-naphthyl) propionic acid (naproxen), α -methyl-4- (2-thenoyl) phenylacetic acid (suprofen), α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, 2- (2-fluoro-4-biphenylyl) propionic acid (flurbiprofen), 6-chloro- α -methyl-9H-carbazole-2-acetic acid (carprofen), α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetic acid (pranoprofen), 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetic acid (benoxaprofen), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid (alminoprofen), 5-benzoyl- α -methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid (pirifen), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiopin-2-yl) propionic acid (zaltoprofen), 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxpin-2-yl) propionic acid (bermoprofen), 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionic acid (loxoprofen), 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetic acid (indoprofen), α, 3-dichloro-4-cyclohexylphenylacetic acid (benzacric acid) and related compounds are among the 2-aryl and heteroaryl propionic acid nonsteroidal anti-inflammatory drugs. Prodrugs of 2-aryl and heteroarylpropionic acids have the general formula (1) 'Structure 1',

structural formula 1

In the structural formula 1, R represents CH₃OH, Cl, F or Br; r₁Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, 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, 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, alkynyl of 1 to 12 carbon atoms, or aryl; x represents O, S, NH, OCH₂COO，OCH₂COS, or OCH₂CONH；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Lemon (lemon)Acid radicals or any other negative ions; n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …; ary1 represents:

wherein X represents CH₃O，Cl，F，CH₃S，

Or CHF₂O

Wherein Y represents CH₃O，F，CH₃CO，(CH₃)₂N, wherein X represents F, Cl, H

CH₃Or CH₂＝CH-CH₂(ii) a X represents Cl, F, CF₃，

CH₃SO, or CH₃S; r represents CH₃，C₂H₅，C₃H₇

Wherein X represents Cl, Br, F, CH₃

Wherein X represents Cl, Br, F, CH₃

Wherein X represents Cl, Br, F

Wherein X represents CO or O, wherein X represents Cl, Br, F, or CH₃O

Wherein X represents O or S, Y represents CH₂，CO，

Z represents CO, CH₂R represents H, CH₃，C₂H₅.

All R groups may contain C, H, O, S or N atoms, and may have single, double and triple bonds. Any one CH₂The groups may be substituted with O, S or NH.

4, 5-diphenyl-2-oxazolepropionic acid (oxaprozin), 3- (4-biphenylcarbonyl) propionic acid (fenbufen), 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionic acid (oxyphenoxin) and related compounds are among the 3-aryl and heteroaryl propionic acid nonsteroidal anti-inflammatory drugs. The prodrugs of 3-aryl and heteroarylpropionic acids have the general formula (2) 'Structure 2',

structural formula 2

In the structural formula 2, W represents H, OH, Cl, F or Br; r₁Represents H, renWhich alkyl group of 1 to 12 carbon atoms, alkoxy group of 1 to 12 carbon atoms, alkenyl group of 1 to 12 carbon atoms, alkynyl group of 1 to 12 carbon atoms, or aryl group; r₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, 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, alkynyl of 1 to 12 carbon atoms, or aryl; x represents O, S, NH, OCH₂COO，OCH₂COS or OCH₂CONH；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate or other negative ions; n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …; w represents OH, Cl or F; y represents H, Cl, OH or CH₃(ii) a Z represents the following structure:

wherein X represents Cl, F, or Br

All of R, R₁，R₂，R₃And R₄The group may contain C, H, O, S or N atoms, and may have single, double and triple bonds. Any one CH₂The groups may be substituted with O, S or NH.

In the general formula (2) "Structure 2", when W is H, Y and Z together represent:

wherein X represents Cl, F, or Br

Cyclized aryl and heteroaryl propionic acids were also synthesized. They include 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid (clidanac), and related compounds.

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 purpose of the invention is: by increasing the solubility of naproxen, suprofen, alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds in gastric juice and increasing their rate of penetration through biological membranes and skin barriers, they can be administered transdermally (topically) to avoid their side effects. These novel prodrugs share two structural features: they have a lipophilic moiety (oil-soluble moiety) and a primary, secondary, or tertiary amine group (water-soluble moiety) that exists in protonated form at physiological pH. The balance of water-solubility to oil-solubility is the condition necessary for the drug to be able to effectively cross the biofilm [ Susan milovich, et al, j.pharm.sci., 82, 227(1993) ]. The positively charged amino groups greatly increase the solubility of the drug. Diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylpropionate acetate, diethylaminoethyl alpha-methyl- (p-chlorophenoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, diethylaminoethyl alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazolo-eacetate Diethylaminoethyl acetate, diethylaminoethyl acetate α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl acetate 5-benzoyl- α -methyl-2-thiopheneacetate, diethylaminoethyl acetate 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetate, diethylaminoethyl acetate 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate, diethylaminoethyl acetate 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxpin-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylmethyl-methyl) phenyl ] propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetate acetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylbenzeneacetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate, diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate, naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac have a solubility in water of > 450mg/ml, > 400mg/ml, > 450mg/ml, > 350mg/ml, > 450mg/ml, > 400mg/ml, more than 450mg/ml, < 400mg/ml, > 450mg/ml, > 350mg/ml, > 400mg/ml, > 350mg/ml, > 450mg/ml, > 350mg/ml, < 0.1mg/ml, and < 0.1 mg/ml. In most cases, dissolution of the drug is the slowest and rate-limiting step in the absorption process. Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds have very little solubility in gastric juice. They stay 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-drug into the cytoplasm, a semi-liquid concentrated aqueous solution or suspension. Due to the short residence time in the gastrointestinal tract, the prodrug does not cause damage to gastric mucosal cells. The pH of gastric juice is 1-3 and the negative charge on the phosphate head group on the biofilm will bond to H +. The positive charge on the prodrug cannot bond to the negative charge on the phosphate head group on the gastric mucosa. These prodrugs avoid the first (direct acid damage) and second (inhibition of prostaglandin synthesis) damage to the stomach.

Speed of penetration of aryl and heteroaryl propionic acids, and positively charged prodrugs and related compounds thereof, through human skinMeasurements were performed in vitro by means of a modified Franz cell in which human skin was isolated from human skin tissue (360-400 μm thick) in front of or behind the thigh region. The receiving solution consisted of 10ml of physiological saline containing 2% bovine serum globulin and was stirred at 600 rpm. The cumulative total amount of these pro-drugs and their parent drugs that cross the skin versus time was determined using specific high performance liquid chromatography. The donor solutions were 30% solutions of these prodrugs dissolved in 2ml of phosphate buffered solution at pH 7.4 (0.2M), respectively, or suspended in 30% of 2ml of phosphate buffered solution at pH 7.4 (0.2M), respectively: naproxen suspension, suprofen suspension, alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid suspension, flurbiprofen suspension, carprofen suspension, pranoprofen suspension, benoxaprofen suspension, alminoprofen suspension, tiaprofenic suspension, pirprofen suspension, zaltoprofen suspension, bermoprofen suspension, loxoprofen suspension, indoprofen suspension, fenclorac suspension, oxaprozin suspension, fenbufen suspension, oxyphenoxacin suspension, ketorolac suspension, clidanac suspension, and the determination results are shown in fig. 1, fig. 2, fig. 3 and fig. 4. Measuring diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, and alpha-methyl-5H- [1 [ -1 ]]Benzopyran [2, 3-b]Pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetate, α -methyl-4- [ (2-methyl-2-propenyl) amino]Diethylaminoethyl phenylacetate acetate, diethylaminoethyl 5-benzoyl-alpha-methyl-2-thiopheneacetate acetate, 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenylacetate, 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] acetate]Thiepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f)]Oxazepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- [4- (2-oxocyclopentylalkyl-methyl) benzeneBase of]Diethylaminoethyl propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate, naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, respectively, have an apparent penetration through human skin of 3.5mg/cm²/h、3.0mg/cm²/h、4.0mg/cm²/h、3.5mg/cm²/h、4.0mg/cm²/h、3.8mg/cm²/h、4.0mg/cm²/h、3.5mg/cm²/h、4.2mg/cm²/h、3.5mg/cm²/h、3.7mg/cm²/h、4.1mg/cm²/h、3.4mg/cm²/h、4.2mg/cm²/h、3.8mg/cm²/h、4.0mg/cm²/h、3.6mg/cm²/h、4.1mg/cm²/h、3.8mg/cm²/h、4.0mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.04mg/cm²/h、0.03mg/cm²/h、0.04mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.04mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²/h、0.04mg/cm²/h、0.03mg/cm²/h、0.04mg/cm²/h、0.03mg/cm²/h、0.03mg/cm²H and 0.04mg/cm²H is used as the reference value. The experimental results demonstrate that the prodrug: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, alpha-methylDiethylaminoethyl acetate-4- (2-thenoyl) phenylacetate, diethylaminoethyl acetate-5-methoxy-2-methylindole-3-acetate, diethylaminoethyl acetate-2- (2-fluoro-4-biphenyl) propionate, diethylaminoethyl acetate-6-chloro-alpha-methyl-9H-carbazole-2-acetate, alpha-methyl-5H- [1]Benzopyran [2, 3-b]Pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetate, α -methyl-4- [ (2-methyl-2-propenyl) amino]Diethylaminoethyl phenylacetate acetate, diethylaminoethyl 5-benzoyl-alpha-methyl-2-thiopheneacetate acetate, 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenylacetate, 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] acetate]Thiepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f)]Oxazepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl]Diethylaminoethyl propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, the speed of 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate penetrating the human skin is nearly 100-130 times faster than that of the parent drugs naproxen, suprofen, alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, oxyphenbutazone, ketorolac and clidanac. The results indicate that the positive charge on the diethylaminoethyl group is very important for the drug to permeate the biological membrane and skin barrier. Other prodrugs of the general formula "Structure 1" and the general formula "Structure 2" have high transdermal speed and are compatible with 2- (6-methoxy-2-naphthyl) propionic acidThe transdermal speed of diethylaminoethyl acetate was very close.

In vivo experiments compared the rate of penetration of aryl and heteroaryl propionic acids and their positively charged prodrugs and related compounds through the skin of live, hairless, intact mice. The donor consisted of a 20% solution of these compounds in 1ml of isopropanol. It is applied to 10cm back of hairless mouse²And (4) the part. The plasma concentrations of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac were determined by specific high performance liquid chromatography methods. The experimental results (as shown in fig. 5, fig. 6, fig. 7 and fig. 8) show that, after about 50 minutes using the donor system, diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate, α -methyl-5H- [1] acetate]Benzopyran [2, 3-b]Pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazole acetic acid diethylaminoethyl ester acetate, alpha-methyl-4- [ (2-methyl-2-propenyl) amino group]Diethylaminoethyl phenylacetate acetate, diethylaminoethyl 5-benzoyl-alpha-methyl-2-thiopheneacetate acetate, 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenylacetate, 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] acetate]Thiepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f)]Oxazepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl]Diethylaminoethyl propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate, 4, 5-bis (diethylamino) acetateDiethylaminoethyl acetate phenyl-2-oxazole propionate, diethylaminoethyl acetate 3- (4-biphenylcarbonyl) propionate, diethylaminoethyl acetate 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate, diethylaminoethyl acetate 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, and diethylaminoethyl acetate 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate, the drug concentration in plasma reached a peak. Naproxen, suprofen, alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, when taken orally, it took 2-4 hours for the drug concentration in the blood to reach its peak. Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and plasma peak concentrations of the drugs in the plasma are about 0.01mg/ml, while diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, alpha-methyl-5H- [1]Benzopyran [2, 3-b]Pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazole acetic acid diethylaminoethyl ester acetate, alpha-methyl-4- [ (2-methyl-2-propenyl) amino group]Diethylaminoethyl phenylacetate acetate, diethylaminoethyl 5-benzoyl-alpha-methyl-2-thiopheneacetate acetate, diethylaminoethyl 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenylacetate, and 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] acetate]Thiepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- (8-methyl-10, 11-dihydro-11-oxo dibenzo[b，f]Oxazepin-2-yl) propionic acid diethylaminoethyl ester acetate, 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl]Diethylaminoethyl propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, diethylaminoethyl acetate, diethylaminoethyl 4-5-biphenylcarbonyl-4-carbonyl-4-cyclohexylphenylacetate, diethylaminoethyl 5-chlorophenyl-2-furanpropionate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, and mixtures, The peak drug concentration in plasma of 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate was about 2mg/ml, with a difference of about 200-fold. About 2mg/ml of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac are in plasma concentrations that are 20-100 times higher than the plasma concentrations that are analgesic and anti-inflammatory. This is an exciting result. Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, oxyphenoxaxine, ketorolac, clidanac, and the like can be delivered readily and rapidly by transdermal administration in the form of a prodrug to achieve therapeutically 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 represented by the general formula "structural formula 1" or the general formula "structural formula 2" in vivo is close to that of diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate.

To examine the gastroduodenal bleeding caused by these drugs, we orally administered 50mg/kg of diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, 50mg/kg of diethylaminoethyl 2- [4- (2-thenoyl) phenyl ] propionate acetate, 50mg/kg of α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole, 50mg/kg of diethylaminoethyl 3-acetate, 50mg/kg of diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, 50mg/kg of 6-chloro- α -methyl-9H-carbazole-2-diethylaminoethyl acetate, 50mg/kg of a mixture of these drugs, 50mg/kg of diethylaminoethyl acetate α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate, 50mg/kg of diethylaminoethyl acetate 2- (4-chlorophenyl) - α -methyl-5-benzoxazolo-acetic acid, 50mg/kg of diethylaminoethyl acetate α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, 50mg/kg of diethylaminoethyl acetate 5-benzoyl- α -methyl-2-thiopheneacetate, 50mg/kg of diethylaminoethyl acetate 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylpheneacetate, and mixtures thereof, 50mg/kg of diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate acetate, 50mg/kg of diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxpin-2-yl) propionate acetate, 50mg/kg of diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate, 50mg/kg of diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate, 50mg/kg of α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate acetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate 50mg/kg, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate 50mg/kg, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate 50mg/kg, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate 50mg/kg, diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate 50mg/kg, 50mg/kg naproxen, 50mg/kg suprofen, 50mg/kg α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, 50mg/kg flurbiprofen, 50mg/kg carprofen, 50mg/kg pranoprofen, 50mg/kg benoxaprofen, 50mg/kg alminoprofen, 50mg/kg tiaprofenic acid, 50mg/kg pirprofen, 50mg/kg zaltoprofen, 50mg/kg bermoprofen, 50mg/kg loxoprofen, 50mg/kg indoprofen, 50mg/kg fenclorac, 50mg/kg oxaprozin, 50mg/kg fenbufen, 50mg/kg olpanosin, 50mg/kg ketorolac, 50mg/kg of clidanac, for 21 consecutive days. In the group of oral naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, we found 1-4 mg of hematochezia per gram of mouse feces; in the oral administration of diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl 1) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, diethylaminoethyl alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetate, diethylaminoethyl α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl 5-benzoyl- α -methyl-2-thiopheneacetate acetate, diethylaminoethyl 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetate, diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, diethylaminoethyl 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate acetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate, no hematochezia was found in the group of 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid diethylaminoethyl ester acetate, 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate.

We also investigated the acute toxicity of the prodrug. Half Lethal Dose (LD) in rats₅₀) Comprises the following steps: 2.2g/kg of 2- (6-methoxy-2-naphthyl) propionic acid diethylaminoethyl ester acetate, 2- [4- (2-thenoyl) phenyl]0.8g/kg of diethylaminoethyl propionate acetate, 0.7g/kg of 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid diethylaminoethyl acetate, alpha-methyl-5H- [1]Benzopyran [2, 3-b]0.75g/kg of diethylaminoethyl pyridine-7-acetate, 1.3g/kg of diethylaminoethyl 2- (4-chlorophenyl) - α -methyl-5-benzoxazolole-acetate, 3.5g/kg of diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindolyl-2-ene) - α -methylphenylacetate, and 3.5g/kg of α -methyl-4- [ (2-methyl-2-propenyl) amino]Diethylaminoethyl phenylacetate acetate 1.1g/kg, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate 0.6g/kg, and 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl acetate 0.2 g/kg. The results indicate that these prodrugs are less toxic than the parent naproxen (LD)₅₀1.234g/kg), suprofen (LD)₅₀0.59g/kg), carprofen (400mg/kg), pranoprofen (447mg/kg), benoxaprofen (LD)₅₀0.8g/kg), alminoprofen (LD)₅₀2400mg/kg), indoprofen (LD)₅₀0.7mg/kg), benzoic acid (LD)₅₀0.43g/kg), clidanac (LD)₅₀＝0.035g/kg)。

Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac have been shown to have anti-inflammatory, analgesic, antipyretic and antirheumatic effects. A good prodrug should return to the parent drug quickly in plasma. In vitro tests demonstrated that the N, N-diethylaminoethyl ester group in these prodrug molecules was rapidly cleaved by plasma enzymes in human plasma, and more than 90% of the prodrugs returned to the parent drug. Because of the higher absorption rate of the prodrug, the same dose of prodrug is more effective than the parent drug. The analgesic, antipyretic and anti-inflammatory effects of these prodrugs were tested separately and compared with naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, oxyphenoxacin, ketorolac or clidanac.

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)). These prodrugs were each administered transdermally to mice at a dose of 50mg/kg, and the tails of the mice were exposed to thermal stimuli to measure the time to increase pain threshold. The results are shown in fig. 9, 10, 11 and 12. Diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, diethylaminoethyl alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazole Diethylaminoethyl acetate, diethylaminoethyl acetate α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl 5-benzoyl- α -methyl-2-thiopheneacetate, diethylaminoethyl 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetate, diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate, and mixtures thereof, Diethylaminoethyl 2- [4- (2-oxocyclopentylmethyl-methyl) phenyl ] propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate acetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate, diethylaminoethyl acetate, diethylamino, 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-formic acid diethylaminoethyl ester acetate shows good analgesic activity.

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 minutes before administration of the acetic acid solution, the mice were administered transdermally: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (100mg/kg, B), diethylaminoethyl 2- [4- (2-thenoyl) phenyl ] propionate acetate (100mg/kg, C), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate (100mg/kg, E), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (100mg/kg, F), α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5-benzoxazolo-acetic acid acetate (100mg/kg, H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate acetate (100mg/kg, I), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (100mg/kg, J), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylpheneacetic acid diethylaminoethyl ester acetate (100mg/kg, K), diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate acetate (100mg/kg, L), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate (100mg/kg, M), diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (100mg/kg, N), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (100mg/kg, o), diethylaminoethyl acetate of α, 3-dichloro-4-cyclohexylphenylacetic acid (100mg/kg, P), diethylaminoethyl acetate of 4, 5-diphenyl-2-oxazolepropionic acid (100mg/kg, Q), diethylaminoethyl acetate of 3- (4-biphenylcarbonyl) propionic acid (100mg/kg, R), diethylaminoethyl acetate of 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (100mg/kg, S), diethylaminoethyl acetate of 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid (100mg/kg, T), diethylaminoethyl acetate of 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid ((S) 100mg/kg, U). Group A is a blank control group. The results are shown in Table 1 below.

TABLE 1 inhibition of writhing in mice by aryl and heteroaryl propionic acid prodrugs

Group of	Dosage (mg/kg)	Number of times of body twisting	Inhibition ratio (%)
				A	0	35.0	-
B	100	17.1	51
				C	100	15.7	55
D	100	13.8	61

E	100	15.6	55
				F	100	14.2	59
G	100	16.1	54
				H	100	17.1	51
I	100	15.6	55
				J	100	13.2	62
K	100	14.0	60
				L	100	14.2	59
M	100	13.8	61
				N	100	15.7	55
O	100	13.2	62
				P	100	15.2	57
Q	100	15.7	55
				R	100	14.2	59
S	100	15.6	55
				T	100	16.1	54
U	100	15.2	57

The results show that these prodrugs have remarkable analgesic effect. Other compounds in the general formula "Structure 1" or the general formula "Structure 2" also showed similar analgesic effects.

Antipyretic action: rats received inactivated E.coli suspension as pyrogen. Group A is a blank control group. After 2 hours, rats were administered transdermally: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (100mg/kg, B), diethylaminoethyl 2- [4- (2-thenoyl) phenyl ] propionate acetate (100mg/kg, C), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate (100mg/kg, E), 6-chloro- α -methyl-9H-carbazole-2-acetate (100mg/kg, F), α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5-benzoxazoloneamino acetic acid diethylaminoethyl ester acetate (100mg/kg, H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid acetate (100mg/kg, I), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (100mg/kg, J), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl ester acetate (100mg/kg, K) diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate acetate (100mg/kg, L), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate (100mg/kg, M), diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (100mg/kg, N), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (100mg/kg, o), diethylaminoethyl acetate of α, 3-dichloro-4-cyclohexylphenylacetic acid (100mg/kg, P), diethylaminoethyl acetate of 4, 5-diphenyl-2-oxazolepropionic acid (100mg/kg, Q), diethylaminoethyl acetate of 3- (4-biphenylcarbonyl) propionic acid (100mg/kg, R), diethylaminoethyl acetate of 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionic acid (100mg/kg, S), diethylaminoethyl acetate of 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid (100mg/kg, T), diethylaminoethyl acetate of 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid Ester acetate (100mg/kg, U). Rats were body temperature measured every 90 minutes before and after test compound administration. The results are shown in Table 2 below.

TABLE 2 antipyretic effect of aryl and heteroaryl propionic acid prodrugs

Compound (I)	t＝0min.	t＝90min.	t＝180min.	t＝270min.
					A (control group)	37.34±0.05	37.36±0.07	37.37±0.05	37.44±0.08
E(100mg/kg)	37.33±0.07	36.80±0.06	36.72±0.05	36.50±0.08
					F(100mg/kg)	37.28±0.06	36.65±0.06	36.58±0.08	36.45±0.07
B(100mg/kg)	37.35±0.06	36.71±0.05	36.60±0.08	36.59±0.07
					M(100mg/kg)	37.29±0.07	36.82±0.06	36.70±0.05	36.67±0.08
C(100mg/kg)	37.28±0.06	36.68±0.05	36.62±0.08	36.58±0.07
					D(100mg/kg)	37.27±0.06	36.76±0.05	36.65±0.08	36.49±0.07
E(100mg/kg)	37.25±0.07	36.82±0.06	36.70±0.05	36.50±0.08
					F(100mg/kg)	37.23±0.06	36.69±0.06	36.52±0.08	36.40±0.07
J(100mg/kg)	37.26±0.06	36.65±0.06	36.58±0.08	36.36±0.07
					G(100mg/kg)	37.27±0.06	36.68±0.05	36.62±0.08	36.58±0.07
H(100mg/kg)	37.25±0.06	36.71±0.05	36.65±0.08	36.64±0.07
					I(100mg/kg)	37.26±0.07	36.80±0.06	36.70±0.05	36.57±0.08
H(100mg/kg)	37.25±0.06	36.71±0.05	36.65±0.08	36.64±0.07
					J(100mg/kg)	37.28±0.06	36.65±0.06	36.58±0.08	36.56±0.07
K(100mg/kg)	37.25±0.06	36.75±0.05	36.62±0.08	36.58±0.07
					M(100mg/kg)	37.24±0.07	36.82±0.06	36.70±0.05	36.67±0.08
L(100mg/kg)	37.23±0.06	36.81±0.05	36.65±0.08	36.61±0.07
					M(100mg/kg)	37.29±0.07	36.82±0.06	36.60±0.05	36.67±0.08
J(100mg/kg)	37.22±0.06	36.65±0.06	36.58±0.08	36.51±0.07

The results show that the prodrug has strong antipyretic effect at the dosage of 100 mg/kg. The antipyretic effect of the other compounds represented by "structural formula 1" and "structural formula 2" is similar to that of the above-mentioned prodrugs.

Anti-inflammatory action: rats were dosed transdermally: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate group (100mg/kg, B), diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate acetate (100mg/kg, C), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate acetate (100mg/kg, E), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (100mg/kg, F), α -methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5-benzoxazoloneamino acetic acid diethylaminoethyl ester acetate (100mg/kg, H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (100mg/kg, I), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (100mg/kg, J), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl ester acetate (100mg/kg, K) acetate (100mg/kg, L), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate (100mg/kg, M), diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (100mg/kg, N), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (100mg/kg, O), diethylaminoethyl acetate α, 3-dichloro-4-cyclohexylphenylacetate (100mg/kg, P), diethylaminoethyl acetate 4, 5-diphenyl-2-oxazolepropionate (100mg/kg, Q), diethylaminoethyl acetate 3- (4-biphenylcarbonyl) propionate (100mg/kg, R), diethylaminoethyl acetate 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate (100mg/kg, S), diethylaminoethyl acetate 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate (100mg/kg, T), diethylaminoethyl acetate 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate (100mg/kg, U). 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 obtained results are shown in fig. 13, 14, 15 and 16. The results show that transdermal administration of these prodrugs shows strong anti-inflammatory effect. Other compounds represented by the general formula "Structure 1" or the general formula "Structure 2" also exhibited similar anti-inflammatory activity.

Certain non-steroidal anti-inflammatory drugs (NSAIAs) exhibit anti-reactive-anti-asthmatic effects by inhibiting cyclooxygenase activity when administered orally at high doses. Because these pro-drugs permeate biological membranes very rapidly, asthma can be treated by spraying into the mouth or nasal cavity.

Due to their anti-inflammatory action and their rapid transdermal speed, these prodrugs can be used to treat psoriasis, acne, sunburn or other skin disorders.

The invention relates to a pharmaceutical product containing a prodrug represented by a general formula 'structural formula 1' or a general formula 'structural formula 2' and common additives and auxiliary materials, such as 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" or the general formula "formula 2" can be used in combination with vitamins such as vitamin A, B, C, E, beta-carotene, etc., or other drugs such as folic acid, for the treatment of any human or animal condition for which non-steroidal anti-inflammatory drugs (NSAIAs) can be used.

Transdermal therapeutic application systems, compositions containing compounds of the general formula "formula 1" or the general formula "formula 2" or at least one compound of the general formula "formula 1" or the general formula "formula 2" as an active ingredient, are useful for treating conditions of humans and animals that can be treated by any non-steroidal anti-inflammatory drugs (NSAIAs). These systems may be bandages or patches comprising a matrix layer comprising the active substance and a non-permeable protective layer. The most preferred system is an active agent reservoir having a permeable bottom facing the skin. By controlling the release rate, the system can stabilize the non-steroidal anti-inflammatory drugs (NSAIAs) at the optimal therapeutic blood level, thereby improving the therapeutic effect and reducing the side effects of the non-steroidal anti-inflammatory drugs (NSAIAs). 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' and general formula (2) 'Structure 2' indicated above can be prepared by reacting aryl-and heteroarylpropionic acid-functionalized derivatives of the general formula (3) 'Structure 3' or general formula (4) 'Structure 4', such as acid halides or mixed anhydrides, for example, with compounds of the general formula (5) 'Structure 5',

structural formula 3 structural formula 4

In the structural formulae 3 and 4, X represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy, and aryl, R, Y, Z or W represents the same group as described in "structural formula 1" or "structural formula 2".

Structural formula 5

In the formula 5, 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 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; 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' or general formula (2) 'structure 2' indicated above can be prepared by reacting naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds with the compounds of the general formula (5) 'structure 5'. Coupling agents are: n, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate, O-benzotriazol-N, N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like.

When X represents O, the compounds of the general formula (1) 'structure 1' or the general formula (2) 'structure 2' indicated above can be obtained by reacting metal salts or organic bases of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds with the compounds of the general formula (6) 'structure 6'.

Structural formula 6

In the formula 6, 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 1-12An alkyl group of carbon 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; r₄Represents 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; z represents halogen or p-toluenesulfonyl; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; n is 0, 1, 2, 3, 4, 5 … …

When X represents O, the compounds of the general formula (1) 'structure 1' or the general formula (2) 'structure 2' indicated above can be prepared by reacting immobilized base salts of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, oxyphenbutazone, ketorolac, clidanac, and related compounds of the general formula (7) 'structure 7' with the compounds of the general formula (6) 'structure 6'.

Structural formula 7

In the structural formula 7, P represents a crosslinked resin; ary1 represents an aryl or heteroaryl group in "formula 1" and "formula 2";

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

Advantages of the invention

Naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds have a prodrug molecule that is hydrophobic in one part and hydrophilic in another part (an amino group that exists 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 are more readily absorbed and therefore more effective than naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds at the same dosage. The experimental data show that: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylacetate acetate, diethylaminoethyl alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate, diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate, diethylaminoethyl alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazoloacetate Diethylaminoethyl acetate, diethylaminoethyl acetate α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl acetate 5-benzoyl- α -methyl-2-thiopheneacetate, diethylaminoethyl acetate 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetate, diethylaminoethyl acetate 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate, diethylaminoethyl acetate 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxpin-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylmethyl-methyl) phenyl ] propionate acetate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetate acetate, diethylaminoethyl α, 3-dichloro-4-cyclohexylbenzeneacetate, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate, diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate exhibits a skin permeation rate that is about 100-fold faster than that of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds. Naproxen, suprofen, alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, when taken orally, reach their peak plasma levels after 2-4 hours, whereas they take 40-50 minutes to reach their peak levels when taken orally. The most exciting result is that the prodrugs can be used not only orally, but also transdermally for any kind of medical treatments and avoid the side effects of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, mainly gastrointestinal disorders such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, and renal toxicity. Another great benefit of transdermal administration is that it is more convenient to administer, especially to children.

Drawings

FIG. 1: diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (a, 30% solution), diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate acetate (B, 30% solution), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole 3-acetate (C, 30% solution), diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate (D, 30% solution), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (E, 30% solution), naproxen (F, 30% suspension), sulbufen (G, 30% suspension), the cumulative total amount of α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid (H, 30% suspension), flurbiprofen (I, 30% suspension) or carprofen (J, 30% suspension). The carrier solution was pH 7.4 phosphate buffered (0.2M) under each condition.

FIG. 2: α -methyl-5H- [1] benzopyran [2, 3-B ] pyridine-7-acetic acid diethylaminoethyl ester acetate (a, 30% solution), 2- (4-chlorophenyl) - α -methyl-5-benzoxazole acetic acid diethylaminoethyl ester acetate (B, 30% solution), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (C, 30% solution), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (D, 30% solution), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl ester acetate (D, 30% solution) of human skin tissue isolated by Franz cell (n ═ 5) Cumulative total amount of diethylaminoethyl acetate (E, 30% solution), pranoprofen (F, 30% suspension), benoxaprofen (G, 30% suspension), alminoprofen (H, 30% suspension), tiaprofenic acid (I, 30% suspension) or pirprofen (J, 30% suspension). The carrier solution was pH 7.4 phosphate buffered (0.2M) under each condition.

FIG. 3: diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ B, f ] thiepin-2-yl) propionate acetate (a, 30% solution), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ B, f ] oxepin-2-yl) propionate acetate (B, 30% solution), diethylaminoethyl 2- [4- (2-oxocyclopentylmethyl) phenyl ] propionate acetate (C, 30% solution), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (D, 30% solution), diethylaminoethyl acetate α, 3-dichloro-4-cyclohexylphenylacetate (E, 30% solution), zaltoprofen (F, 30% suspension), bermoprofen (G, 30% suspension), loxoprofen (H, 30% suspension), indoprofen (I, 30% suspension) or the cumulative total amount of benkeluoc acid (J, 30% suspension). The carrier solution was pH 7.4 phosphate buffered (0.2M) under each condition.

FIG. 4: diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate (a, 30% solution), diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate (B, 30% solution), diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (C, 30% solution), diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate (D, 30% solution), diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate (E, 30% solution), oxaprozin (F, 30% suspension), fenbufen (G, 30% suspension), orpanoxin (H, 30% suspension), ketorolac (I, 30% suspension) or clidanac (J, 30% suspension). The carrier solution was pH 7.4 phosphate buffered (0.2M) under each condition.

FIG. 5: to the back of hairless mice (n ═ 5) 20% diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (a), diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate (B), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (C), diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate (D), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (E) solution and naproxen (F), sulbufen (G) in 1ml isopropanol were topically applied, Total plasma concentrations of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen and carprofen following solutions of α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid (H), flurbiprofen (I) or carprofen (J).

FIG. 6: to the back of hairless mice (n ═ 5) 20% solution of α -methyl-5H- [1] benzopyran [2, 3-B ] pyridine-7-acetic acid diethylaminoethyl ester acetate (a), 2- (4-chlorophenyl) - α -methyl-5-benzoxazoloacetic acid diethylaminoethyl ester acetate (B), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (C), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (D), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl ester acetate (E) in isopropanol (n ═ 5) was applied topically And a solution of pranoprofen (F), benoxaprofen (G), alminoprofen (H), tiaprofenic acid (I), or pirprofen (J), the total plasma concentration of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, and pirprofen.

FIG. 7: topical application to the back of hairless mice (n ═ 5) 20% diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ B, f ] thiepin-2-yl) propionate acetate (A), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ B, f ] oxpin-2-yl) propionate acetate (B), diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (C), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (D) in 1ml isopropanol, (iii) diethylaminoethyl acetate (E), zaltoprofen (F), bermoprofen (G), loxoprofen (H), indoprofen (I) or benxololic acid (J), and the total plasma concentration of zaltoprofen, bermoprofen, loxoprofen, indoprofen and benxololic acid.

FIG. 8: to the back of hairless mice (n ═ 5) were applied topically a solution of 20% diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate (a), diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate (B), diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (C), diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate (D), diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate (E) in 1ml isopropanol with olprozin (F), Total blood concentration of oxaprozin, fenbufen, oxyphenoxin, ketorolac, or clidanac after solutions of fenbufen (G), oxyphenoxin (H), ketorolac (I), or clidanac (J).

FIG. 9: after 50mg/kg of diethylaminoethyl acetate-2- (6-methoxy-2-naphthyl) propionate (B), diethylaminoethyl acetate-4- (2-thenoyl) phenylacetate (C), diethylaminoethyl acetate-5-methoxy-2-methylindole-3-acetate (D), diethylaminoethyl acetate-2- (2-fluoro-4-biphenyl) propionate (E) and diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (F) were transdermally administered, the pain threshold of the tail of the mouse was prolonged. A is a control group.

FIG. 10: 50mg/kg of diethylaminoethyl alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate (G), diethylaminoethyl 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazole acetate (H), diethylaminoethyl alpha-methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate acetate (I), diethylaminoethyl 5-benzoyl-alpha-methyl-2-thiopheneacetate acetate (J), diethylaminoethyl 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenoacetate acetate (K) was transdermally administered, the pain threshold of the tail of the mouse is prolonged. A is a control group.

FIG. 11: 50mg/kg of diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate acetate (L), diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate (M), diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (N), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (O), diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate acetate (P) were transdermally administered, the pain threshold of the tail of the mouse is prolonged. A is a control group.

FIG. 12: after 50mg/kg of diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate (Q), diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate (R), diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (S), diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate (T), and diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate (U) were transdermally administered, the pain threshold in the tail of the mouse was prolonged. A is a control group.

FIG. 13-swelling ratio (%) after carrageenan injection. 1 hour before the injection of carrageenan, diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (100mg/kg, B), diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate (100mg/kg, C), diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate (100mg/kg, E), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate (100mg/kg, F) and A is a control group.

FIG. 14: swelling rate (%) after carrageenan injection. 1 hour before carrageenin injection, diethylaminoethyl acetate alpha-methyl-5H- [1] benzopyran [2, 3-b ] pyridine-7-acetate (100mg/kg, G), diethylaminoethyl acetate 2- (4-chlorophenyl) -alpha-methyl-5-benzoxazole acetate (100mg/kg, H), diethylaminoethyl acetate alpha-methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate (100mg/kg, I), diethylaminoethyl acetate 5-benzoyl-alpha-methyl-2-thiopheneacetate (100mg/kg, J), diethylaminoethyl 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) -alpha-methylphenylacetate Ethyl acetate (100mg/kg, K), a is control.

FIG. 15: swelling rate (%) after carrageenan injection. 1 hour before carrageenan injection diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionate acetate (100mg/kg, L), 100mg/kg diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate acetate (100mg/kg, M), 100mg/kg diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate acetate (100mg/kg, N), 100mg/kg diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate Ethyl acetate (100mg/kg, O), 100mg/kg of α, 3-dichloro-4-cyclohexylphenylacetic acid diethylaminoethyl acetate (100mg/kg, P) was transdermally administered, and A was a control group.

FIG. 16: swelling rate (%) after carrageenan injection. 1 hour before the carrageenan injection, diethylaminoethyl 4, 5-diphenyl-2-oxazolepropionate acetate (100mg/kg, Q), diethylaminoethyl 3- (4-biphenylcarbonyl) propionate acetate (100mg/kg, R), diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (100mg/kg, S), diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate (100mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate (100mg/kg, u), A is control group.

FIG. 17: in the structural formula 1, R represents CH₃OH, Cl, F or Br; 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 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, NH, OCH₂COO，OCH₂COS or OCH₂CONH；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …; ary1 represents aryl or heteroaryl.

FIG. 18: in the structural formula 2, W represents H, OH, Cl, F or Br; r₁Represents H, any alkyl, alkoxy, alkenyl or alkynyl group of 1 to 12 carbon atoms, or an aryl group; 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; x represents O, S, NH, OCH₂COO，OCH₂COS or OCH₂CONH；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …; y or Y and Z together represent aryl and heteroaryl.

Best mode for carrying out the invention

Synthesis of diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate

11.7g (0.1mol) of diethylaminoethanol were dissolved in 200ml of a 10% aqueous sodium hydrogencarbonate solution and 100ml of acetone, and 24.9g (0.1mol) of 2- (6-methoxy-2-naphthyl) propionyl chloride were added to the mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The evaporated mixture is suspended in 500ml of ethyl acetate and 200ml of a 5% aqueous sodium bicarbonate solution are added with stirring. The ethyl acetate 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. 6g of acetic acid was added to the reaction mixture with stirring. Is dried by distillation to obtainAn organic solvent. After drying, 36g of the hygroscopic target product were obtained, yield 89.8%. Solubility in water: 350 mg/ml; elemental analysis: c₂₂H₃₁NO₅(ii) a Molecular weight: 389.49. theoretical value (%) C: 67.84, respectively; h: 8.02; n: 3.60; o: 20.54 of; found value (%) C: 67.82, respectively; h: 8.04; n: 3.58 of; o: 20.56.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.36(t, 6H), 1.50(d, 3H), 2.11(s, 3H), 3.20(m, 4H), 3.47(m, 2H), 3.70(s, 3H), 3.78(m, 1H), 4.48(t, 2H), 6.88(b, 1H), 6.98(s, 1H), 7.03(d, 1H), 7.18(d, 1H), 7.43(s, 1H), 7.50(d, 1H), 7.54(d, 1H).

Detailed description of the preferred embodiments

Synthesis of alpha-methyl-4- (2-thenoyl) phenylacetic acid diethylaminoethyl ester acetate

28.1g (0.1mol) of α -methyl-4- (2-thenoyl) phenylacetyl chloride were dissolved in 100ml of chloroform and cooled to 0 ℃. To the reaction solution were added 15ml of triethylamine and 11.7g (0.1mol) of diethylaminoethanol. Stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The solid mixture which has been evaporated to dryness is suspended in 300ml of methanol and 200ml of a 5% aqueous sodium bicarbonate solution are added with stirring and then stirred at room temperature for 3 hours. The mixture was evaporated to dryness. The evaporated mixture was dissolved in 300ml of methanol. The solid was removed by filtration and washed with methanol. The solution was evaporated to dryness and 200ml of chloroform was added to dissolve it. 6g of acetic acid was added to the reaction solution with stirring. A small amount of solid formed was removed by filtration and an additional 6g of acetic acid was added to the filtrate with stirring. The organic solvent was evaporated to dryness. After drying, 35g of the hygroscopic target product were obtained in 83.2% yield. Solubility in water: 400 mg/ml; elemental analysis: c₂₂H₃₁NO₅S; molecular weight: 419.53. theoretical value (%) C: 62.68; h: 7.41; n: 3.32 of; o: 18.98 of the total weight of the powder; s: 7.61; found value (%) C: 62.63, respectively; h: 7.45 of; n: 3.31; o: 19.01, respectively; s: 7.60.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.36(t, 6H), 1.45(d, 3H), 2.11(s, 3H), 3.20(m, 4H), 3.47(m, 2H), 3.78(m, 1H), 4.48(t, 2H), 6.88(b, 1H), 6.98(s，1H)，7.31(d，2H)，7.05(m，1H)，7.43(m，2H)，7.70(d，2H)。

Synthesis of diethylaminoethyl thioester acetate 2- (2-fluoro-4-biphenyl) propionate

13.2g (0.1mol) of diethylaminoethanethiol were dissolved in 200ml of a 10% aqueous sodium hydrogencarbonate solution and 100ml of acetone, and 26.3g (0.1mol) of 2- (2-fluoro-4-biphenyl) propionyl chloride were added to the mixture with stirring. The reaction solution was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. The solid mixture which has been evaporated to dryness is suspended in 500ml of ethyl acetate and 200ml of a 5% aqueous sodium bicarbonate solution are added 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. 6g of acetic acid was added to the reaction mixture with stirring. The organic solvent was evaporated to dryness. After drying, 36g of the hygroscopic target product were obtained, yield 85.8%. Solubility in water: 400 mg/ml; elemental analysis: c₂₃H₃₀FNO₃S; molecular weight: 419.55. theoretical value (%) C: 65.84, respectively; h: 7.21; f: 4.53; n: 3.34; o: 11.44; s: 7.64. found value (%) C: 65.80, respectively; h: 7.23; f: 4.55; n: 3.32, O: 11.47; s: 7.63.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.35(t, 6H), 1.44(d, 3H), 2.11(s, 3H), 3.20(m, 4H), 3.30(t, 2H), 3.80(m, 1H), 3.88(t, 2H), 6.88(b, 1H), 6.88(m, 1H), 6.95(m, 1H), 7.22(m, 1H), 7.32(m, 2H), 7.41(m, 1H), 7.48(m, 2H).

Synthesis of N-diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxamide ester acetate

11.6g (0.1mol) of diethylaminoethylamine are dissolved in 200ml of 10% aqueous sodium hydrogencarbonate solution and 100ml of acetone, and 27.4g (0.1mol) of 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carbonyl chloride are added to the mixture with stirring. The reaction solution was stirred at room temperature for 3 hours. The reaction solvent was evaporated to dryness. The evaporated mixture is suspended in 500ml of ethyl acetate and 200ml of 5% aqueous sodium bicarbonate solution are added with stirring. The ethyl acetate layer was collected and washed with 500ml of water 3 times. The ethyl acetate solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 6g of acetic acid was added to the reaction mixture with stirring. The organic solvent was evaporated to dryness. After drying, 35g of the hygroscopic target product were obtained, yield 84.8%. Solubility in water: 400 mg/ml; elemental analysis: c₂₃H₃₁N₃O₄(ii) a Molecular weight 412.50. Theoretical value (%) C: 66.81, respectively; h: 7.56; n: 10.16; o: 15.48; found value (%) C: 66.90 of; h: 7.38; n: 10.18 of; o: 15.54.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.39(t, 6H), 2.10(s, 3H), 2.27(m, 2H), 3.22(m, 4H), 3.50(t, 2H), 3.60(t, 2H), 3.80(m, 2H), 3.71(m, 1H), 5.85(m, 1H), 6.70(m, 1H), 6.85(b, 1H), 7.32(b, 1H), 7.40(m, 1H), 7.45(m, 2H), 7.78(m, 2H).

Synthesis of N-dimethylaminoethyl 4, 5-diphenyl-2-oxazole propionamide acetate

29.3g (0.1mol)4, 5-diphenyl-2-oxazolepropionic acid are dissolved in 100ml acetonitrile and 32.1g O-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (HBTU) and 30ml triethylamine are added with stirring. 11.6g of diethylaminoethylamine were added to the mixture. The reaction solution was stirred at room temperature for 3 hours. The reaction solvent was evaporated to dryness. 250ml of ethyl acetate were added to the reaction mixture and 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. 6g of acetic acid was added to the reaction mixture with stirring. 200ml of hexane were added. The solid product was collected by filtration. After drying, 40g of the hygroscopic target product were obtained, yield 88.6%. Solubility in water: 400 mg/ml; elemental analysis: c₂₆H₃₃N₃O₄(ii) a Molecular weight: 451.56. theoretical value (%) C: 69.16; h: 7.37; n: 9.31, respectively; o: 14.17; found value (%) C: 69.11, respectively; h: 7.40; n: 9.30 of; o: 14.19.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.41(t, 6H), 2.10(s, 3H), 2.45(t, 2H), 2.76(t, 2H), 3.22(m, 4H), 3.49(t, 2H), 3.60(t, 2H), 6.87(b, 1H), 7.22(b, 1H), 7.22(m, 2H), 7.32(m, 4H), 7.47(m, 4H).

Synthesis of 6-chloro-alpha-methyl-9H-carbazole-2-acetic acid diethylaminoethyl ester acetate

60g of polymer-immobilized triethylamine (3mol/g, 100-mesh 200) were suspended in 180ml of chloroform. 27.4g (0.1mol) of 6-chloro-. alpha. -methyl-9H-carbazole-2-acetic acid were added to the mixture with stirring. 43g (0.15mol) of diethylaminoethyl bromide as the hydrogen bromide salt were added to the mixture, and the mixture was stirred at room temperature for 5 hours. The high molecular weight polymer was removed by filtration and washed with 50ml portions of tetrahydrofuran 3 times. To the mixture was added 8.2g (0.1mol) of sodium acetate with stirring. Stirring was then continued for 2 hours. The solid was removed by filtration and washed 3 times with 50ml portions of chloroform. The solution was concentrated to 100ml under reduced pressure. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed 3 times with 100ml of hexane each time. After drying, 38g of the hygroscopic end product are obtained, yield 87.8%. Solubility in water: 400 mg/ml; elemental analysis: c₂₃H₂₉ClN₂O₄(ii) a Molecular weight: 432.94, respectively; theoretical value (%): c: 63.81, respectively; h: 6.75; cl: 8.19, N: 6.47; o: 14.78; found value (%) C: 63.85; h: 6.78; cl: 8.17; n: 6.44; o: 14.76.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.39(t, 6H), 1.47(d, 3H), 2.11(s, 3H), 3.21(m, 4H), 3.49(m, 2H), 3.77(m, 1H), 4.48(t, 2H), 6.80(b, 1H), 6.85(m, 1H), 7.10(m, 1H), 7.05(m, 1H), 7.26(m, 1H), 7.34(m, 1H), 7.50(m, 1H), 7.52(m, 1H).

Industrial applicability

The prodrugs of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' are superior to naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and compounds thereof. They may be used to treat any of naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds useful in the treatment of diseases in humans and animals. They can relieve rheumatic arthritis and osteoarthropathy, relieve fever, and treat dysmenorrhea. These prodrugs are also useful in the treatment of diabetic neuropathy and acute migraine. Because these pro-drugs permeate biological membranes very rapidly, they can also be used in aerosol form to treat asthma by inhalation. Because these prodrugs have anti-inflammatory effects, they can also be used to treat psoriasis, acne, sunburn and other skin disorders.

Sequence Listing text

Claims (15)

1. A compound represented by the general formula (1) 'Structure 1',

structural formula 1

In the structural formula 1, R represents CH₃OH, Cl, F or Br; r₁Represents H, any alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, alkenyl of 1-12 carbon atoms, or C1-12An alkynyl group of atoms; 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; r₃Represents H; x represents O, S, OCH₂COO，OCH₂COS, or OCH₂CONH; a-represents an anion; n =0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; aryl represents the following structure:

wherein X represents CH₃O,Cl,F,CH₃S,

Or CHF₂O

Wherein Y represents CH₃O,F,CH₃CO,(CH₃)₂N, wherein X represents F, Cl, H

CH₃Or CH₂=CH-CH₂X represents Cl, F, CF₃,

CH₃SO, or CH₃S, R represents CH₃,C₂H₅,C₃H₇

Wherein X represents Cl, Br, F, CH₃

Wherein X represents Cl, Br, F, CH₃

Wherein X represents Cl, Br, F

Wherein X represents CO or O, wherein X represents Cl, Br, F, or CH₃O

Wherein X represents O or S, Y represents CH₂,CO,

Z represents CO, CH₂R represents H, CH₃,C₂H₅.

。

2. Compounds of the general formula (2) 'Structure 2',

structural formula 2

In the structural formula 2, W represents H, OH, Cl, F or Br; 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; 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; r₃Represents H; x represents O, S, OCH₂COO，OCH₂COS or OCH₂CONH; a-represents an anion; n =0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10; y represents H; z represents the following structure:

wherein X represents Cl, F, or Br

Or W represents H, Z and Y together represent the following structure:

wherein X represents Cl, F, or Br.

3. A method of synthesizing a compound according to claim 1 or claim 2, which comprises reacting naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, oxyphenoxacin, ketorolac, or clidanac with a compound represented by formula 5 via a coupling agent,

structural formula 5

In the formula 5, 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; r₄Represents 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; x represents O or S; n =0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10;

the coupling agent comprises: n, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate, benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazole-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate.

4. Use of a compound according to claim 1 or claim 2 for the manufacture of a medicament, characterised in that the medicament manufactured is for the treatment of any nonsteroidal anti-inflammatory drug treatable conditions in humans or animals by transdermal administration or oral administration; non-steroidal anti-inflammatory drug treatable conditions include: toothache, headache, arthritis and other inflammatory pain, fever, cancer, dysmenorrhea, emesis from radiation therapy, diabetic neuropathy and acute migraine, bone loss and sunburn.

5. The use of claim 4, wherein the arthritis is hemophilia arthritis.

6. Use of a compound according to claim 1 or claim 2 for the preparation of a medicament for the treatment of any non-steroidal anti-inflammatory drug treatable conditions in humans or animals by transdermal administration in any part of the body in the form of a solution, spray, emulsion, ointment, emulsion or gel formulation to achieve therapeutically effective plasma concentrations.

7. Use of a compound according to claim 1 or claim 2 for the manufacture of a medicament for the treatment of pain in humans or animals by topical administration to an area of inflammation in order to achieve a therapeutically effective dose, wherein pain includes headache, dental pain, muscular pain, arthritis and other inflammatory pain.

8. Use of a compound as claimed in claim 1 or claim 2 for the preparation of a medicament, characterised in that the medicament prepared is for transdermal administration in the form of a solution, spray, lotion, ointment, emulsion or gel for the treatment of psoriasis, acne, sunburn or other skin disorders.

9. Use of a compound as claimed in claim 1 or claim 2 for the manufacture of a medicament for the treatment of asthma by spray administration to the mouth or nose or other parts of the body.

10. Use of a compound according to claim 1 or claim 2 for the preparation of a medicament for the treatment of an eye inflammatory disease, for the treatment of ocular pain following corneal surgery, for the treatment of glaucoma or for the treatment of ear inflammation and/or pain states in any human or animal.

11. Transdermal therapeutic application system comprising a compound of the general formula (1) "structure 1" or the general formula (2) "structure 2" according to claims 1 and 2 or a composition comprising at least one compound of the general formula (1) "structure 1" or the general formula (2) "structure 2" as active ingredient and being useful for the treatment of any state treatable by a non-steroidal anti-inflammatory drug in a human or animal.

12. The transdermal therapeutic application system of claim 11, wherein the system is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.

13. A transdermal therapeutic application system according to claim 11 comprising an active agent reservoir comprising a skin facing permeable base.

14. The transdermal therapeutic application system of claim 11, wherein the nsaid is stabilized at an optimal therapeutic blood level by controlling the release rate, thereby increasing the therapeutic effect and reducing the side effects of the nsaid.

15. The transdermal therapeutic application system of claim 12, wherein the nsaid is stabilized at an optimal therapeutic blood level by controlling the release rate, thereby increasing the therapeutic effect and reducing the side effects of the nsaid.