HK1196284B - Positively-charged water-soluble aryl and heteroaryl propionic acid prodrug with rapid skin penetrating speed - Google Patents

Abstract

The invention discloses a drug composition comprising at least one compound shown as a structural formula 1 or a structural formula 2, a preparation method thereof and application thereof in preparation of drugs for treating states which can be treated by any non-steroid anti-inflammatory drugs and asthma of persons or animals. The invention also discloses a transdermal therapy application system comprising the drug composition.

Description

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

Statement of case division

The present application is a divisional application of chinese patent application entitled "positively charged water-soluble prodrugs of aryl and heteroarylpropionic acids with fast skin penetration rate" filed on 8/15 2006 under application number 200680055605.4.

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-benzoAzoleacetic acid (benoxaprofen), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid (alminoprofen), 5-benzoyl- α -methyl-2-thiopheneacetic acid (siloxanol)Fenamic acid), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylbenzeneacetic acid (pirfenin), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotrop-2-yl) propionic acid (zaltoprofen), 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxolanyl-2-yl) propionic acid (bermoprofen), 2- [4- (2-oxocyclopentylmethyl-methyl) phenyl ] propionic acid (loxoprofen), 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetic acid (indoprofen), α, 3-dichloro-4-cyclohexylphenylacetic acid (fenclorac), and related compounds are non-steroidal anti-inflammatory drugs belonging to the 2-aryl and heteroarylpropionic acids, 4, 5-diphenyl-2-oxazolepropanoic acid (oxaprool), 3- (4-biphenylcarbonyl) propionic acid (buclofenac), 5- (4-chlorophenyl) -3535- (5-chloro-phenyl) -2-dihydropyrrol-2-1-oxo-2H-isovalerolactonacic acid (indoprofen), and related compounds belonging to the 2H-acetyl-ketoprofen family of the non-phenyl, as anti-ketoprofen, as anti-inflammatory drugs, as well as the anti-inflammatory drugs, as the anti-inflammatory drugs of the non-ketoprofen, as the non-steroidal anti-inflammatory drugs of the non-ketoprofen, as the anti-inflammatory drugs of the patent, as the non-ketopyrrolidine, as the anti-keto.

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 [ susanvilosovich, 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 aryls having a positive chargeProdrugs of propionic acid and related compounds, 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-benzoOxazoacetic 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 -methylbenzeneacetic acid (pirifen), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotepen-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 -methylbenzeneacetic acid (indoprofen), α, 3-dichloro-4-cyclohexylphenylacetic acid (benzolofenac) and related anti-inflammatory compounds are all prodrugs of the general formula "aryl-propionic acid (heteroaryl-1, heteroaryl-propionic acid (heteroaryl-1, and non-aryl-propionic acid (heteroaryl-aryl-1, heteroaryl) and non-aryl-propionic acid (heteroaryl) are prodrugs of the general formula" general formula,

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 1-12 carbon atoms, alkoxy of 1-12 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 any other negative ion; n =0, 1, 2,3, 4,5, 6,7, 8, 9, 10 … …; aryl represents:

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-Oxazolepropanoic acid (oxaprozin), 3- (4-biphenylcarbonyl) propionic acid (fenbufen), 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionic acid (oxyphenoxin) and related compounds all belong to the class of 3-aryl and heteroaryl propionic acid NSAIDs.3-aryl and heteroaryl propionic acid prodrugs have the general formula (2) 'Structure 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, alkynyl of 1 to 12 carbon atoms, or aryl; r₂Represents H, any alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, alkenyl of 1-12 carbon atoms, alkynyl of 1-12 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 =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:

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:

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 object of the present invention is to avoid their side effects by increasing the solubility in gastric fluid and the rate of penetration through the biofilm and skin barrier 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 and by increasing the rate of penetration through the biofilm and skin barrier by transdermal administration (topical). these novel prodrugs share two structural features: they have a lipophilic portion (oil-soluble portion) and a primary, secondary, or tertiary acetate (water-soluble portion) in protonated form at physiological pH, which balance of water-soluble-oil is the condition necessary for the effective penetration of the biofilm [ saon osho, su ovin, sci, n, p-methylcarbamoyl) -5-methoxy-2-methylindole-methyl-3-methyl-ethyl acetate (7, p-chlorophenyl-ethyl-7-methyl-7-ethyl-7-chlorophenyl-methyl-ethyl-7-ethyl-7-ethyl-chlorophenyl-ethyl-7-ethyl-6-ethyl-2-chlorophenyl-ethyl-7-ethyl-7-ethyl-2-ethyl-chlorophenyl-ethyl-6-7-ethyl-7-ethyl-6-ethylAzole acetic acid diethylaminoethyl ester acetate, α -methyl-4- [ (2-methyl-2-propyl)Diethylaminoethyl acetate, diethylaminoethyl acetate 5-benzoyl- α -methyl-2-thiopheneacetate, diethylaminoethyl acetate 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylbenzeneacetate, diethylaminoethyl acetate 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotrop-2-yl) propionate, diethylaminoethyl acetate 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate, diethylaminoethyl acetate 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl acetate 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetate, diethylaminoethyl acetate α, diethylaminoethyl acetate 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl acetate 4, 5-diphenyl-2-oxazolinopropyl, diethylaminoethyl acetate 3- (4-carbonylbiphenyl) ethyl acetate, diethylaminoethyl propionate 5-chlorophenyl-2-indoprofen-1, indoxyl-2-propyl-phenyl-ethyl propionate, diethylaminoethyl propionate, diethylprofen acetate α, diethylfenoprofen acetate, diethylfenoprofen-2-p-chlorophenyl-ethyl benzoate, indoxyl-phenaprofen-2-one, diethylprofen-2-one-ethyl benzoate, diethylbenzoate, diethylfenoprofen-p-ethyl propionate, indoxyl-phenazinone-E, diethylbenzoate, diethylfenoprofen-1-ethyl benzoate, diethylfenoprofen-6-ethyl benzoate, diethylfenoprofen-1-5-ethyl benzoate, diethylfenoprofen-1-ethyl benzoate, diethylfenoprofen-ethyl benzoate, fenoprofen-5-p-ethyl benzoate, fenoprofen-p-ethyl benzoate, fenoprofen-ethyl acetate, fenoprofen-ethyl benzoate, feno>450mg，>400mg，>450mg，>450mg，>350mg，>450mg，>400mg，>450mg，>400mg，>450mg，>350mg，>400mg，>350mg，>400mg，>350mg，>400mg，>400mg，>350mg，>450mg，>350mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg，<0.1mg, 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, and,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 end group of the biological membrane is combined with H⁺And (4) bonding. 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.

The rate of penetration of aryl and heteroaryl propionic acids and their positively charged prodrugs and related compounds through human skin isolated from human skin tissue in front of or behind the thigh area (360-400 μ M thick.) the receiving solution consists of 10ml physiological saline containing 2% bovine serum globulin and stirred at 600 rpm the cumulative total amount of these prodrugs and their parent drugs penetrating the skin versus time was determined by specific HPLC the donor solution was 30% solutions of these prodrugs dissolved in 2ml phosphate buffer solution (0.2M) at pH7.4 respectively or 30% naproxen suspension, suprofen suspension, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid suspension, flurbiprofen suspension, carprofen suspension, and carprofen suspension in 2ml phosphate buffer solution (0.2M) at pH7.4 respectivelySuspension, pranoprofen suspension, benoxaprofen suspension, alminoprofen suspension, tiaprofenic acid suspension, pirprofen suspension, zaltoprofen suspension, bermoprofen suspension, loxoprofen suspension, indoprofen suspension, fenclorac suspension, oxaprozin suspension, fenbufen suspension, orpanoxin suspension, ketorolac suspension, clidanac suspension, as determined in fig. 1, fig. 2, fig. 3, and fig. 4, 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, diethylaminoethyl α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-amino-chlorophenyl-acetic acid-ethyl 2- (2-chlorophenyl) - α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-ethyl 3-chlorophenyl) -5-ethyl 3-chlorophenyl-acetateOxazole acetate, α -methyl-4- [ (2-methyl-2-propenyl) amino ] diacetin ethyl acetate, 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl acetate, 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylbenzeneacetic acid diethylaminoethyl acetate, 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiopin-2-yl) propionic acid diethylaminoethyl acetate, 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxoazepin-2-yl) propionic acid diethylaminoethyl acetate, 2- [4- (2-oxocyclopentylmethyl-methyl) phenyl ] propionic acid diethylaminoethyl acetate, 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetic acid diethylaminoethyl acetate, α, 3-dichloro-4-cyclohexylphenylacetic acid diethylaminoethyl acetate, 4-diphenyl-1-oxo-2H-isoindol-2-yl) - α -methylbenzeneacetic acid diethylaminoethyl acetate, 5-chloro-3-oxo-2H-isopropylphenyl-ethyl acetate, 5-3-chloro-3-1H-benzoylpropionic acid diethylaminoethyl acetate, β -chloro-1-chloro-3-1-oxo-1-ethyl acetate, 3-1-chloro-3-1-3-oxo-1-3-oxo-1-2-phenyl-ethyl acetate, 3-1The apparent penetration values of ethyl 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 through human skin are 3.5mg, 3.0mg, 4.0mg, 3.5mg, 4.0mg, 3.8mg, 4.0mg, 3.5mg, 4.2mg, 3.5mg, 3.7mg, 4.1mg, 3.4mg, 4.2mg, 3.8mg, 4.0mg, 3.6mg, 4.1mg, 3.8mg, 4.0mg, 0.03mg, 0.04mg, 0.03mg, 0.04mg, 0.0.0.0.0.0.04 mg, 0.04mg, 0.0.0.0.0.0.0.²The results of the experiments demonstrate that the prodrugs are diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate, diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate, diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate, diethylaminoethyl α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) - α -methyl-5-benzoOxazole acetate, α -methyl-4- [ (2-methyl-2-propenyl) amino ] diethylaminoethyl phenylacetate acetate, 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl acetate, 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylpheneacetic acid diethylaminoethyl acetate, 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionic acid diethylaminoethyl acetate, 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxpin-2-yl) propionic acid diethylaminoethyl acetate, 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionic acid diethylaminoethyl acetate, 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetic acid diethylaminoethyl acetate, α, 3-dichloro-4-cyclohexylphenylacetic acid diethylaminoethyl acetateDiethylaminoethyl acetate, diethylaminoethyl acetate 4, 5-diphenyl-2-oxazolepropionate, 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 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate penetrate the human skin at a rate that is very close to that of the transdermal prodrugs of the other transdermal prodrugs of the general formula "1-diethylaminoethyl acetate", 2-methoxy-2-methylindole-3-acetate, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclofenac acid, oxaprozin, bufen, oxyphendoxin, ketorolac, clidanac, indac, and the transdermal pro-drugs of the general formula "1-ethyl acetate" and the transdermal pro-drug "are very close to that the rate of the transdermal pro-dermal skin is very close to that of the biological pro-amino-ethyl-2- (4-fenprox-6-ethyl) and the transdermal pro-1-6-acetate.

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 mouse²The concentration 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, in plasma is determined by specific HPLC methods the results of the experiments (see, e.g., FIGS. 5, 6,7, and 8) show, after about 50 minutes from the use of the donor system, diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate, diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-methyl-diethylaminoethyl acetate, diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate acetate, 6-chloro- α -methyl-9H-carbazole-2-diethylaminoethyl acetate, α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-diethylaminoethyl acetate, 2- (4-chlorophenyl) - α -methyl-5-benzoDiethylaminoethyl carfencetate acetate, diethylaminoethyl carfenlacetate acetate α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl carfenlate- α -methyl-2-thiopheneacetate, diethylaminoethyl carfenlate- α -methylphenylacetate, diethylaminoethyl 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotephen-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) dipropionate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl carfenvalerate, diethylaminoethyl-5-2-indoloprofen-2H-isoindoloprofen-2-yl) - α -methylphenylacetate, diethylaminoethyl carfenprofen acetate, diethylaminoethyl-1-oxo-2H-isoindoprofen-2-isopropyl-2-phenyl-ethyl carfenprofen-2-ethyl acetate, diethylprofen-2-oxo-2H-isofenprofen-2-isopropyl-2-ethyl-2-phenyl-ethyl carfenprofen acetate, 3-oxo-4-1, 3-oxo-2-propyl-methyl-1-4-fenprofen-oxo-methyl-fenprofen-2-fenprofen-ethyl-2-fenprofen-2-ethyl carfenprofen-4, 2-oxo-ethyl-4-oxo-propyl-methyl-ethyl-oxo-2-oxaprofen-4, 2-oxaprofen-ethyl acetate, 2-oxaprofen, 2-ethyl-oxaprofen, 2-ethyl acetate, 2-oxaprofen, 2-oxaprofen-ethyl acetate, 2-oxaprofen, 2-oxaprofenBenoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, benclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and the peak drug concentration in the plasma is about 0.01mg/ml, while diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, α -methyl-4- (2-thenoyl) diethylaminoethyl phenylacetate acetate, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl acetate, diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate acetate, 6-chloro- α -methyl-9H-carbazole-2-acetic acid diethylaminoethyl ester, α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) - α -methyl-5-benzoin-5-acetic acidDiethylaminoethyl oxazole 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 ] thiotephen-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxodibenzo-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, diethylaminoethyl 5-diphenyl-1-oxo-2H-isoindol-2-yl) -propionate, diethylaminoethyl 1-5-hydroxy-phenyl-1-oxo-2H-isopropyl-2-ethyl-2-yl) -propionate, diethylaminoethyl 2-5-carbonyl-5 mg/1H-carbonyl-ethyl-5-oxo-2-ethyl-isopropyl-2-5-oxo-1, diethylaminoethyl-5-oxo-5-hydroxy-ethyl-5-phenyl-5-1-ethyl-5-oxo-5-ethyl-5-ethyl-1-oxo-ethyl-1-ethyl-oxo-1-oxo-2-ethyl-oxo-ethyl-1-phenyl-2-1-oxo-ethyl-1-5-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 up to 20-100 times higher than the plasma concentrations of analgesically and antiinflammatory agents. This is an exciting result. The naproxen, the suprofen, the ibuprofen and the pharmaceutical composition can be conveniently and quickly delivered in a prodrug form through transdermal administration,_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, 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 diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate, 50mg/kg of α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetate, 50mg/kg of diethylaminoethyl 2- (4-chlorophenyl) - α -methyl-5-benzoAzole acetic acid diethylaminoethyl ester acetate, 50mg/kg α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl50mg/kg of 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl acetate, 50mg/kg of 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl acetate, 50mg/kg of 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotephen-2-yl) propionic acid diethylaminoethyl acetate, 50mg/kg of 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionic acid diethylaminoethyl acetate, 50mg/kg of 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionic acid diethylaminoethyl acetate, 50mg/kg of 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetic acid diethylaminoethyl acetate, 50mg/kg of 3-dichloro-4-fenprofen-fenpropinoprofen-2-yl) propionate, 50mg/kg of fenpropinoprofen-6-feloprofen, 50mg/kg of felbinaphthrofen-2-fenprofen, 50mg/kg of felbinaphthol, 50mg/kg of felbinaphthrofen-2-fenprofen, 50mg/kg of fenaminofelbinaphthol, 50mg/kg of felbinaphthrofen-2-6-fenprofen, 50mg/kg of felbinaphthol, 50mg/kg, 3-fenprofen-6-fenpropiophenoprofen-6-fenpropiolazone, 50mg/kg, fenpropiophenoprofen-2-6-fenpropiolazone, 50mg/kg of felbinazone, fenpropiophenoprofen-6-2-6-ethyl acetate, 50mg/kg, fenpropiolazone, 50mg/kg of fenpropinoprofen-2-fenpropiolazone, 50mg/kg, fenpropiolazone, 50mg/kg of fenpropiolazone, 50mg/kg, fenpropiolazone, 50mg/kg of indole-6-fenpropiolazone, 50mg/kg of fenpropiolazone, 50mg/kg of fenpropiolazone, fenpropinoprofen-6-fenpropinopYl-2-naphthyl) propionic acid diethylaminoethyl ester acetate, α -methyl-4- (2-thenoyl) phenylacetic acid diethylaminoethyl ester acetate, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl ester acetate, 2- (2-fluoro-4-biphenyl 1) propionic acid diethylaminoethyl ester acetate, 6-chloro- α -methyl-9H-carbazole-2-acetic acid diethylaminoethyl ester acetate, α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate, 2- (4-chlorophenyl) - α -methyl-5-benzol-oneDiethylaminoethyl oxazole acetate, diethylaminoethyl 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 ] thioazepin-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxodibenzo-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4-diphenyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl 3-chloro-4- (3-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-chloro-3-2-oxo-2H-cyclohexylphenylacetate, diethylaminoethyl 5-oxazolinyl-2-ethyl-propionate, 3-1, diethylaminoethyl-2-chlorophenyl-2-yl-ethyl-propionate, and the like.

We also investigated the acute toxicity of the prodrug. Half Lethal Dose (LD) in rats₅₀) Is 2.2g/kg of 2- (6-methoxy-2-naphthyl) propionic acid diethylaminoethyl ester acetate, 0.8g/kg of 2- [4- (2-thenoyl) phenyl ] propionic acid diethylaminoethyl ester acetate, 6-chloro- α -methyl-9H-carbazole-2-acetic acid diethylaminoethyl ester acetate0.7g/kg, α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate 0.75g/kg, 2- (4-chlorophenyl) - α -methyl-5-benzoAzole acetic acid diethylaminoethyl ester acetate 1.3g/kg, 4- (1, 3-dihydro-1-oxo-2H-isoindolyl-2-ene) - α -methylbenzene acetic acid diethylaminoethyl ester acetate 3.5g/kg, α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate 1.1g/kg, α, 3-dichloro-4-cyclohexylbenzeneacetic acid diethylaminoethyl ester acetate 0.6g/kg, 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate 0.2 g/kg. results indicate that these prodrugs have lower toxicity LD than the parent drug naproxen (LD)₅₀=1.234g/kg), suprofen (LD)₅₀=0.59g/kg), carprofen (400mg/kg), pranoprofen (447mg/kg), benoxaprofen (LD)₅₀=0.8g/kg), alminoprofen (LD)₅₀=2400mg/kg), indoprofen (LD)₅₀=0.7mg/kg), benzoic acid (LD)₅₀=0.43g/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.

Analgesic Effect the prodrugs were each transdermally administered to mice at a dose of 50mg/kg, and the tails of the mice were exposed to thermal stimulation, and the pain threshold extension time was measured, as shown in FIG. 9, FIG. 10, FIG. 11, and FIG. 12. diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate, 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 acetate-2-diethylaminoethyl acetate, diethylaminoethyl α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7- (2-chlorophenyl) -539-2-methylamino-acetate, and diethylaminoethyl 6-chloro-9H-carbazole acetate, respectively, according to the method of D' Amour-Smith (J.Pharmac0l.Exp.Ther.,72, 74(1941))Diethylaminoethyl oxazole 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, 11-dihydro-11-oxodibenzo [ b, f ] oxodibenzo-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, diethylaminoethyl 5-diphenylamino-3- (3-oxazolylamino-2H-2-oxazolyl) -2-ethyl 3-oxazolinyl propionate, diethylaminoethyl β -3-1-oxo-1-oxo-2H-isoindol-2-yl-propionate, diethylaminoethyl 3625-3, diethylaminoethyl β -3-1, 3-oxazolyl-2-methyl-propionate, and diethylaminoethyl 3-methyl-1-oxazolyl-methyl-2The (E) -1H-pyrrolopyrrolidine-1-carboxylic acid diethylaminoethyl ester acetate and the 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate show good analgesic activity.

The number of writhing occurring after the abdominal cavity administration of the acetic acid solution was counted, and the inhibition rate of writhing was calculated based on the control group, diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (100mg/kg, B), diethylaminoethyl 2- [4- (2-thenoyl) phenyl ] propionate acetate (100mg/kg, C), α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl ester acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate acetate (100mg/kg, E), diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetic acid diethylaminoethyl ester acetate (100mg/kg, F), α -methyl-5H- [1] benzopyran [2,3-B ] pyridine-7-diethylaminoethyl acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5H-acetic acid diethylaminoethyl ester acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5H-benzoic acid diethylaminoethyl ester acetate (100mg/kg, G), and the like were transdermally administered to the mice 30 minutes before the administration of the acetic acidOxazole 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 -methylphenylacetic acid diethylaminoethyl ester acetate (100mg/kg, K), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propanoic acid diethylaminoethyl ester acetate (100mg/kg, L), 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propanoic acid diethylaminoethyl ester acetate (100mg/kg, M), 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propanoic acid diethylaminoethyl ester acetate (100mg/kg, N), 4- (1, 3-methyl-1-thiopheneacetic acid diethylaminoethyl ester acetate (100mg/kg, 3-oxazolyl) phenyl ] propanoic acid diethylaminoethyl ester acetate (100mg/kg, 3-2-oxazolyl) ethyl ester acetate (100mg/kg, 3-2-oxazolyl) phenyl-2-ethyl acetate (100mg/kg, 3 mg/g),5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate (100mg/kg, S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid diethylaminoethyl ester acetate (100mg/kg, T), 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate (100mg/kg, U). The 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 A group was blank control group, and 2 hours later, diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (100mg/kg, B), diethylaminoethyl 2- [4- (2-thenoyl) phenyl ] propionate acetate (100mg/kg, C), α -methyl- (p-chlorophenylacyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl ester acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate (100mg/kg, E), 6-chloro- α -methyl-9H-carbazole-2-acetic acid 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-benzoZoleacetic 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 -methylbenzeneacetic acid diethylaminoethyl ester acetate (100mg/kg, K), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiepin-2-yl) propionic acid diethylaminoethyl ester acetate (100mg/kg, L), 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionic acid diethylaminoethyl ester acetate (100mg/kg, M), 2- [4- (2-oxocyclopentylalkyl-methyl) benzeneDiethylaminoethyl propionate acetate (100mg/kg, N), diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate acetate (100mg/kg, O), diethylaminoethyl α, 3-dichloro-4-cyclohexylphenylacetate acetate (100mg/kg, P), 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), the results of the test compounds were given to rats at intervals of 100mg/kg, 90 minutes, 2 minutes.

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 of diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate group (100mg/kg, B), α -methyl-4- (2-thenoyl) phenylacetate diethylaminoethyl acetate (100mg/kg, C), α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl acetate (100mg/kg, D), diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate acetate (100mg/kg, E), 6-chloro- α -methyl-91H-carbazole-2-acetic acid diethylaminoethyl acetate (100mg/kg, F), α -methyl-5H- [1] benzopyran [2,3-B ] pyridine-7-acetic acid diethylaminoethyl acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5-benzoAzole acetic acidDiethylaminoethyl acetate (100mg/kg, H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl acetate (100mg/kg, I), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl acetate (100mg/kg, J), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl acetate (100mg/kg, K), 2- (10, 11-dihydro-10-oxodibenzo [ b, f ] thiotropin-2-yl) propionate acetate (100mg/kg, L), diethylaminoethyl acetate of 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxodibenzo-2-yl) propionate (100mg/kg, M), diethylaminoethyl acetate of 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate (100mg/kg, N), 4- (1-oxocyclopentylalkyl-phenyl) diethylaminoethyl propionate (100mg/kg, P-phenyl) acetate (100mg/kg, P-ethyl acetate, P-2-oxo-2-ethyl acetate, P-5-phenyl-ethyl acetate, P-ethyl acetate (100mg, P-5-ethyl-5-phenyl-ethyl-1-5-ethyl-5-ethyl-5-O-5-ethyl-O-5-O-ethyl acetate), as a prodrug, a compound, a after administration, a transdermal therapeutic effect, a similar to a, a test results showed a similar to a test results after administration of the formula shown in a rat 'S-ethyl acetate, a rat' S-ethyl acetate (100 mg-ethyl acetate, a test, a rat 'S-ethyl acetate, a test, a rat' S-ethyl acetate, a rat 'S-ethyl acetate, a test, a rat' S-ethyl acetate (100 mg-ethyl acetate, a test, a daily, a test.

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 preparation containing a prodrug represented by the general formula 'structural formula 1' or the 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',

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".

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; r4 represents H, any alkyl of 1-12 carbon atoms, alkoxy of 1-12 carbon atoms, alkenyl or alkynyl of 1-12 carbon atoms, or aryl; x represents O, S or NH; n =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'.

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 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; z represents halogen or p-toluenesulfonyl; a. the^-Represents C1^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; n =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'.

In the structural formula 7, P represents a crosslinked resin; aryl represents Aryl or heteroaryl in "structural formula 1" and "structural formula 2"; b represents any basic group, such as pyridyl, piperidyl, triethylamine or other basic groups.

Advantages of the invention

The prodrug molecules 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 are partially hydrophobic and partially hydrophilic (amino groups present in protonated form at physiological pH), the positively charged amino group has the advantage that, firstly, it greatly increases the solubility of the drug, when these new prodrugs are taken orally, such as tablets, capsules, solutions, or suspensions, they rapidly dissolve in gastric fluid, the positively charged amino group of these prodrugs can bond to the negative charge of the phosphate end of biological membranes, thus, the local concentration outside the membrane can be high, thus promoting the passage of these prodrugs from a high concentration region to a low concentration region where the prodrug molecules of these prodrugs enter the cytoplasmic, the depot of ibuprofen, loxoprofen-ibuprofen, the prodrug can be more effectively retained by the pro-loxoprofen, the same biological compounds, the depot, the pro-loxoprofen, the pro-ibuprofen, the pro-drugs can be absorbed in a less rapidly absorbed by the same time after the concentration of the depot, theThe data show diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl α -methyl-4- (2-thenoyl) phenylacetate, diethylaminoethyl α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate, diethylaminoethyl 2- (2-fluoro-4-biphenyl) propionate, diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate, diethylaminoethyl α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetate, diethylaminoethyl 2- (4-chlorophenyl) - α -methyl-5-benzoDiethylaminoethyl oxazole 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 ] thiotephen-2-yl) propionate, diethylaminoethyl 2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate, diethylaminoethyl 2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate, diethylaminoethyl 4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate, diethylaminoethyl α, diethylaminoethyl 3-dichloro-4-cyclohexylphenylacetate, diethylaminoethyl 4, diethylaminoethyl 5-diphenyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetate, diethylaminoethyl-propiolate-5-oxo-1H-indoprofen-2-yl) propionate, diethylaminoethyl 2-oxo-2H-isoindoprofen-2-yl) propionate, thioprofen acetate, thioteprofen-2-yl acetate, thioprofen acetate, thioteprofen acetate, thioprofen-4-oxo-methyl-1-4-oxo-methyl-1-ethyl 2-oxo-1-4-oxo-methyl-phenyl-ethyl 2-ethyl propionate, 3-oxo-4-one, 3-oxo-2-fenprofen-methyl-ethyl 2-one, thioprofen-ethyl propionate, thioprofen-2-one, thioprofen-ethyl benzoate, o-2-ethyl benzoate, o-one, o-ethyl benzoate, o-2-fenprofen, o-ethyl benzoate, o-fenprofen, o-methyl-fenproprofen-2-ethyl benzoate, o-2-fenprofen-ethyl benzoateIt is also known that the compounds are about 100-fold faster, 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, reach a peak plasma concentration 2-4 hours later when administered orally, whereas these prodrugs only reach a peak concentration 40-50 minutes later when administered orally, the prodrugs not only can be administered orally, but also can be used for any drug therapy in a transdermal manner, thereby avoiding the gastrointestinal toxicity associated with naproxen, suprofen, α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alfenprofen, tiaprofenic acid, pirprofen, indoprofen, fenflurbiprofen, fenprofen, indoprofen, and related compounds, especially the gastrointestinal toxicity associated with gastroprofen, ibuprofen, loxacinetoposide, loxacin, ibuprofen, loxacin, ibuprofen.

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 pH7.4 phosphate buffered saline (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-benzo, a derivative thereof, and a therapeutic agent for human skin tissue isolated in Franz cell (n =5)Diethylaminoethyl zoleacetate acetate (B, 30% solution), diethylaminoethyl α -methyl-4- [ (2-methyl-2-propenyl) amino ] benzeneacetate acetate (C, 30% solution), diethylaminoethyl 5-benzoyl- α -methyl-2-thiopheneacetate acetate (D, 30% solution), 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid 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) cumulative total.

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 pH7.4 phosphate buffered saline (0.2M) under each condition.

FIG. 4: diethylaminoethyl 4, 5-diphenyl-2-oxazole propionate 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 pH7.4 phosphate buffered saline (0.2M) under each condition.

FIG. 5: to the back of hairless mice (n =5) were topically applied 20% diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate (a), diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylacetate (B), diethylaminoethyl alpha-methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetate (C), diethylaminoethyl 2- (2-fluoro-4-biphenylyl) propionate acetate (D), diethylaminoethyl 6-chloro-alpha-methyl-9H-carbazole-2-acetate (E) solution and naproxen (F), sulbufen (G) in 1ml isopropanol, 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 dorsal topical application of 20% α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (A), 2- (4-chlorophenyl) - α -methyl-5-benzo in 1ml isopropanol to hairless mice (n =5)Total blood concentration of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid and pirprofen after a solution of glycal 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) isopropanol and a solution of pranoprofen (F), benoxaprofen (G), alminoprofen (H), tiaprofenic acid (I) or pirprofen (J).

FIG. 7: topical application to the back of hairless mice (n =5) of 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 topically applied a 20% solution of diethylaminoethyl 4, 5-diphenyl-2-oxazolpropionate 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 of 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 2- (6-methoxy-2-naphthyl) propionic acid diethylaminoethyl acetate (B), α -methyl-4- (2-thenoyl) phenylacetic acid diethylaminoethyl acetate (C), α -methyl- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid diethylaminoethyl acetate (D), 2- (2-fluoro-4-biphenyl) propionic acid diethylaminoethyl acetate (E) and 6-chloro- α -methyl-9H-carbazole-2-acetic acid diethylaminoethyl acetate (F) were transdermally administered, the pain threshold of the tail of the mouse was prolonged. A is a control group.

FIG. 10 transdermal administration of 50mg/kg α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (G), 2- (4-chlorophenyl) - α -methyl-5-benzoAfter zoleacetic acid diethylaminoethyl ester acetate (H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (I), 5-benzoyl- α -methyl-2-thiopheneacetic acid diethylaminoethyl ester acetate (J), and 3-chloro-4- (2, 5-dihydro-1H-pyrrol-1-yl) - α -methylphenylacetic acid diethylaminoethyl ester acetate (K), the pain threshold of the tail of the mouse was prolonged.

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

FIG. 12: after 50mg/kg of 4, 5-diphenyl-2-oxazolepropionic acid diethylaminoethyl ester acetate (Q), 3- (4-biphenylcarbonyl) propionic acid diethylaminoethyl ester acetate (R), 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionic acid diethylaminoethyl ester acetate (S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylic acid diethylaminoethyl ester acetate (T), 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylic acid diethylaminoethyl ester acetate (U) was transdermally administered, the pain threshold of 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 percent swelling after carrageenan injection (%) Carica gel 1 hour before carrageenan injection α -methyl-5H- [1] benzopyran [2,3-b ] pyridine-7-acetic acid diethylaminoethyl ester acetate (100mg/kg, G), 2- (4-chlorophenyl) - α -methyl-5-benzoAzoleacetic acid diethylaminoethyl ester acetate (100mg/kg, H), α -methyl-4- [ (2-methyl-2-propenyl) amino ] benzeneacetic 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 -methylbenzeneacetic acid diethylaminoethyl ester acetate (100mg/kg, K), a being a control group.

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/kg2- (8-methyl-10, 11-dihydro-11-oxodibenzo [ b, f ] oxepin-2-yl) propionate diethylaminoethyl acetate (100mg/kg, M), 100mg/kg2- [4- (2-oxocyclopentylalkyl-methyl) phenyl ] propionate diethylaminoethyl acetate (100mg/kg, N), 100mg/kg4- (1, 3-dihydro-1-oxo-2H-isoindol-2-yl) - α -methylphenylacetate diethylaminoethyl acetate (100mg/kg, O), 100mg/kg of α, 3-dichloro-4-cyclohexylphenylacetic acid diethylaminoethyl ester 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 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 =0, 1, 2,3, 4,5, 6,7, 8, 9, 10 … …; aryl 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, anyAn alkyl group of 1 to 12 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; x represents O, S, NH, OCH₂COO，OCH₂COS or OCH₂CONH；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; n =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 200m of 110% aqueous sodium hydrogencarbonate solution and 100ml of acetone, and 24.9g (0.1m0l) 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 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. The organic solvent was evaporated to dryness. 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): : 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) α -methyl-4- (2-thenoyl) phenylacetyl chloride is dissolved in 100ml chloroform, cooled to 0. C.the reaction solution is added with 15ml triethylamine and 11.7g (0.1mol) diethylaminoethanol, stirred at room temperature for 3 hours, the solvent is evaporated to dryness, the solid mixture evaporated to dryness is suspended in 300ml methanol, and 200ml 5% aqueous sodium bicarbonate solution is added with stirring, then stirred at room temperature for 3 hours, the mixture is evaporated to dryness, 300ml methanol is added to the evaporated mixture to dissolve, the solid is removed by filtration, the solution is washed by methanol, evaporated to dryness, 200ml chloroform is added to dissolve, 6g acetic acid is added to the reaction solution with stirring, a small amount of solid is removed by filtration, another 6g acetic acid is added to the filtrate with stirring, the organic solvent is evaporated to dryness, 35g of the target product with hygroscopic property is obtained after drying, the yield is 83.2%, the solubility in water is 400mg/ml, and the elemental analysis is that 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): : 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 10% aqueous sodium hydrogencarbonate solution and 100ml of acetone, and 26.3g (0.1mol) of 2- (2-fluoro-4-biphenylyl) 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 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): : 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 200m of 110% 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 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, 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): : 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).

N-dimethylaminoethyl 4, 5-diphenyl-2-Synthesis of azolopropionamide acetate

29.3g (0.1mol)4, 5-diphenyl-2-Azolopropionic acid was dissolved in 100ml of acetonitrile, and 32.1g of O-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate (HBTU) and 30ml of triethylamine were added under 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): : 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 polymer immobilized triethylamine (3mol/g, 100-mesh 200-mesh) was suspended in 180ml chloroform, 27.4g (0.1mol) 6-chloro- α -methyl-9H-carbazole-2-acetic acid was added to the mixture with stirring, 43g (0.15mol) diethylaminoethyl bromide hydrogen bromide was added to the mixture, the mixture was stirred at room temperature for 5 hours, the high molecular polymer was removed by filtration, the mixture was washed with tetrahydrofuran 3 times, 50ml each time, 8.2g (0.1mol) sodium acetate was added to the mixture with stirring, then stirring was continued for 2 hours, the solid was removed by filtration, washed with chloroform 3 times, 50ml each time, the solution was concentrated under reduced pressure to 50ml each time100 ml. 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; CI: 8.19, N: 6.47; o: 14.78; found value (%) C: 63.85; h: 6.78; CI: 8.17; n: 6.44; o: 14.76.¹H-NMR (400MHz, deuterated chloroform solvent): : 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.

Claims (21)

1. A compound represented by structural formula 1 or structural formula 2,

wherein 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 group of 1 to 12 carbon atomsAlkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H; x represents O, S, NH, OCH₂COO，OCH₂COS, or OCH₂CONH；A^-Represents a negative ion; n is 0,1, 2,3, 4,5, 6,7, 8, 9, or 10; w represents H, OH, Cl, F or Br; y represents H;

aryl represents the following structure:

z represents the following structure:

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

it is characterized in that the compound is selected from diethylaminoethyl 2- (6-methoxy-2-naphthyl) propionate acetate, diethylaminoethyl alpha-methyl-4- (2-thenoyl) phenylpropionate 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 acetate, and the like, 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, diethylaminoethyl 5- (4-chlorophenyl) - β -hydroxy-2-furanpropionate acetate, diethylaminoethyl 3- (4-biphenylcarbonyl) propionate, diethylaminoethyl 5- (2-furanpropionate, and mixtures thereof, Diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxylate acetate, diethylaminoethyl 6-chloro-5-cyclohexyl-2, 3-dihydro-1H-benzocyclopropene-1-carboxylate acetate, diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrolidine-1-carboxamide ester acetate, dimethylaminoethyl 4, 5-diphenyl-2-oxazole propionamide acetate, and diethylaminoethyl 6-chloro- α -methyl-9H-carbazole-2-acetate.

2. The method of synthesizing the compound according to claim 1, wherein the compound is prepared by reacting functional derivatives 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 compound represented by structural formula 5;

wherein R is₃Represents H, any 1-an alkyl group of 12 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; x represents O, S or NH; n is 0,1, 2,3, 4,5, 6,7, 8, 9, or 10.

3. A method of synthesizing a compound as claimed in claim 2 wherein the functionalized derivative comprises an acid halide or a mixed anhydride.

4. The method of synthesizing the compound according to claim 2, wherein the compound is 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 compound represented by structural formula 5, via coupling agents comprising: 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.

5. The method for synthesizing the compound according to claim 1, wherein the compound is prepared by reacting a metal salt, an organic base salt or a solid base salt 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 compound represented by 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 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; z represents halogen or p-toluenesulfonyl; a. the^-Represents a negative ion; n is 0,1, 2,3, 4,5, 6,7, 8, 9, or 10.

6. A pharmaceutical composition comprising at least one compound of claim 1.

7. An aqueous pharmaceutical composition comprising at least one compound of claim 1.

8. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 for the manufacture of a medicament, characterized in that the medicament manufactured is for the treatment of any non-steroidal anti-inflammatory drug-treatable condition 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.

9. The use of claim 8, wherein the arthritis is hemophilia arthritis.

10. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 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.

11. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 for the manufacture of a medicament for the treatment of pain in humans or animals by topical administration to an area of inflammation in a therapeutically effective dose, wherein pain includes headache, dental pain, muscular pain, arthritis and other inflammatory pain.

12. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 for the preparation of a medicament, characterized 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.

13. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 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.

14. Use of a compound according to claim 1 or a composition according to claim 6 or claim 7 for the preparation of a medicament, characterized in that the medicament prepared is useful for the treatment of inflammatory diseases of the eye, for the treatment of ocular pain after corneal surgery, for the treatment of glaucoma or for the treatment of ear inflammation and/or pain states in any human or animal.

15. Use according to one of claims 8 to 14, characterized in that the medicament is prepared in the form of a solution, spray, lotion, ointment, emulsion or gel.

16. Use according to any one of claims 8 to 14, wherein the medicament is prepared for transdermal administration at any site of the body.

17. Transdermal therapeutic application system comprising a compound according to claim 1 or a composition according to claim 6 or claim 7 or a composition comprising at least one compound according to claim 1 as active ingredient and being useful for the treatment of any non-steroidal anti-inflammatory drug treatable conditions in humans or animals.

18. The transdermal therapeutic application system of claim 17, wherein the system is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.

19. A transdermal therapeutic application system according to claim 17 comprising an active agent reservoir comprising a skin facing permeable base.

20. The transdermal therapeutic application system of claim 17, 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.

21. The transdermal therapeutic application system of claim 18, 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.