HK1190388A - Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate - Google Patents

Description

Positively charged water-soluble prodrugs of acetaminophen and related compounds with fast skin penetration rate

Statement of case division

The application is a divisional application of Chinese patent application with application number 200680055747.0 filed on 9/3/2006 and invented as 'prodrug of water-soluble acetaminophen with positive charge and related compound having rapid skin penetration rate'.

Technical Field

The present invention relates to positively charged, water-soluble prodrugs of acetaminophen, acetaminosalol, and related compounds and their use in treating any acetaminophen and acetaminosalol treatable conditions in humans or animals. In particular, the present invention is directed to overcoming the side effects associated with the use of acetaminophen and related compounds. These prodrugs can be administered orally or transdermally.

Background

N-acetyl-p-aminophenol (acetaminophen), 4-acetamidophenylsalicylic acid (acetaminosalol) and related compounds belong to the class of 4-aminophenol nonsteroidal anti-inflammatory drugs. N-acetyl-p-aminophenol (acetaminophen) is a major antipyretic analgesic. Acetaminophen is well tolerated, does not have many of the side effects of aspirin, and is available without prescription. They are useful for alleviating the signs and symptoms of rheumatoid arthritis and osteoarthritis, and for reducing fever.

However, the administration of acetaminophen and related compounds has many side effects, most notably hepatotoxicity, and in rare cases nephrotoxicity in humans and experimental animals. Acute overdosing of acetaminophen can cause dose-dependent and potentially fatal hepatic necrosis, and in rare cases renal tubular necrosis and hypoglycemia. 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 and many others (Van Engelen et al, U.S. Pat. No. 6,416,772; Macrides et al, U.S. Pat. No. 6,346,278; Kirby et al, U.S. Pat. No. 6,444,234, Pearson et al, U.S. Pat. No. 6,528,040, and Botknecht et al, U.S. Pat. No. 5,885,597) have attempted to develop drug delivery systems for transdermal administration by means of formulations. 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 lipid soluble portion and a tertiary amine structure that exists in protonated form at physiological pH. They found that this prodrug (TSBH) penetrated the human skin 60 times faster than the parent drug (TS) [ Susan milovich, et al, j.pharm.sci., 82, 227(1993) ].

Disclosure of Invention

Technical problem

N-acetyl-p-aminophenol (acetaminophen), 4-acetamidophenylsalicylic acid (acetaminosalol) and related compounds belong to the class of 4-aminophenol nonsteroidal anti-inflammatory drugs. N-acetyl-p-aminophenol (acetaminophen) is a major antipyretic analgesic. They are useful for alleviating the signs and symptoms of rheumatoid arthritis and osteoarthritis, and for reducing fever.

However, the administration of acetaminophen and related compounds has many side effects, most notably hepatotoxicity, and in rare cases nephrotoxicity in humans and experimental animals. Acute overdosing of acetaminophen can cause dose-dependent and potentially fatal hepatic necrosis, and in rare cases renal tubular necrosis and hypoglycemia.

Solution scheme

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

Structural formula 1

In the formula 1, R₁Represents H, any one of 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 one of 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 one of 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, or 2-OCO-C₆H₄-O；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 … …; all R groups may include C, H, O, S, or N atoms, and may contain single, double, and triple bonds; any CH₂The groups may be substituted with O, S, or NH.

Drug absorption, whether through the gastrointestinal tract or other routes, requires the passage of molecules across the barrier membrane. The drug must first be dissolved 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 cell 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 phosphate-containing highly polar head structure and, in most cases, two highly hydrophobic hydrocarbon tail chains. The biofilm has a bilayer structure with a hydrophilic head structure facing the aqueous phase regions on both 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 aim of the invention is to avoid the need for paracetamol by increasing its solubility in gastric juice and its related compounds and increasing its penetration rate through the biological membrane and skin barrier, so that it can be administered transdermally (topically)Side effects of aminophenols and related compounds. These novel prodrugs have two structural features in common: 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. Such a water-oil balance is necessary for the drug to effectively cross the biological membrane [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]. The positively charged amino groups greatly increase the solubility of the drug. N-acetyl-4-aminophenyldimethylaminobutyrate ester hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride, N-acetyl-4-aminophenol (acetaminophen), 4-acetamidophenylsalicylic acid (acetaminosalol) have solubilities in water of respectively>400mg，>400mg，<0.2mg，<0.1 mg/ml. In most cases, dissolution of the drug is the slowest and rate-limiting step in the absorption process. Acetaminophen, acetaminosalol, and related compounds have very little solubility in gastric juice. When these novel prodrugs are administered orally in dosage forms such as tablets, capsules, solutions and suspensions, 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 to facilitate passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part pushes the pro-drug into the cytoplasm, a semi-liquid concentrated aqueous solution or suspension. The pH in the stomach is 1-3, so the negative charge of the phosphate head group on the cell membrane of the gastric mucosa will be coupled with protons (H)⁺) And (4) bonding. The positive charge in these pro-drugs does not bond to the phosphate head group of the gastric mucosa. These prodrugs do not cause damage to the stomach.

The rate of permeation of N-acetyl-p-aminophenyldimethylaminobutyrate ester hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride, N-acetyl-p-aminophenol (acetaminophen), 4-acetamidophenylsalicylic acid (acetaminosalol), and related compounds through human skin was measured in vitro by a modified Franz cell. Wherein the human skinSkin was isolated from the skin tissue at the anterior or posterior thigh sites (360-. 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. As donor solutions, 2ml of 30% N-acetyl-p-aminophenyldimethylaminobutyrate hydrochloride solution, 2ml of 30% 4-acetamidophenylsalicylic acid dimethylaminobutyrate hydrochloride solution, 2ml of 30% acetaminophen suspension, or 2ml of 30% acetaminosalol suspension were used, and all solvents were phosphate buffered at pH =7.4 (0.2M), and the results are shown in FIG. 1. The calculated apparent penetration values of N-acetyl-p-aminophenyldimethylaminobutyrate ester hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride, acetaminophen, acetaminosalol were 1.5mg, 1.8mg, 0.01mg and 0.01mg/cm²H is used as the reference value. The results indicate that the positive charge on the dialkylaminoethyl group is important for the drug to cross biological membranes and skin barriers. The transdermal speed of other prodrugs in the general formula "structure 1" is very high and very close to that of N-acetyl-4-aminophenyldimethylamino butyrate hydrochloride.

In vivo experiments compared the rate of permeation of N-acetyl-4-aminophenyldimethylaminobutyrate hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate hydrochloride, acetaminophen, acetaminosalol through the skin of live hairless, atraumatic 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. Plasma concentrations of acetaminophen and 4-acetamidophenylsalicylic acid were determined by specific high performance liquid chromatography methods. The results (FIG. 2) show that plasma concentrations of N-acetyl-p-aminophenyldimethylaminobutyrate ester hydrochloride and 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride peaked after about 50 minutes of use of the donor system. The peak plasma drug concentration is only reached about 1-2 hours after oral administration of acetaminophen, acetaminosalol, and related compounds. The peak plasma drug concentration of acetaminophen and acetaminosalol was about 0.01mg/ml, while the N-acetyl-p-aminophenyldimethylaminobutylamineThe peak plasma drug concentration of the acid ester hydrochloride and 4-acetamidophenylsalicylic acid dimethylaminobutyrate hydrochloride was about 1.2mg/ml (about 120-fold difference). Acetaminophen and acetaminosalol, at about 1.2mg/ml in plasma, are more than 50 times higher than plasma concentrations that are both analgesic and anti-inflammatory effective. This is an exciting result. Paracetamol and acetaminosalol can be conveniently and rapidly delivered to a host in a prodrug form by transdermal administration and 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 the other prodrugs of the general formula (1) 'Structure 1' in vivo is comparable to that of N-acetyl-p-aminophenyldimethylaminobutyrate hydrochloride.

The acute toxicity of these prodrugs was experimentally determined. Oral half-Lethal Dose (LD) in mice₅₀) The following were used: LD of N-acetyl-p-aminophenyldimethylaminobutyrate ester hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride, acetaminophen and acetaminosalol₅₀550mg/kg, 670mg/kg, 338mg/kg, 550mg/kg, respectively.

Acetaminophen and acetaminosalol have been shown to have analgesic and antipyretic 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 enzymes in plasma in human plasma. More than 90% of the prodrug returns to the parent drug. Because of the better absorption rate of the prodrug, the prodrug has stronger curative effect than the parent drug at the same dosage. The analgesic and antipyretic effects of these prodrugs were tested separately and compared with acetaminophen and acetaminosalol.

The analgesic effect is as follows: the extension 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. 3. N-acetyl-4-aminophenyl dimethyl amino butyrate hydrochloride and 4-acetamidophenyl salicylic acid dimethyl amino butyrate hydrochloride have 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. The mice were given a transdermal dose of acetic acid solution 60 minutes before each administration: n-acetyl-4-aminophenyldimethylaminobutyrate hydrochloride (100 mg/kg, B) and 4-acetamidophenylsalicylic acid dimethylaminobutyrate hydrochloride (100 mg/kg, C). A is blank control. The results are shown in Table 1.

TABLE 1 inhibition of writhing in mice by acetaminophen and acetaminosalol prodrug

Group of	Dosage (mg/kg)	Number of times of body twisting	Inhibition ratio%
				A	0	35.0	-
B	100	15.6	55
				C	100	15.7	55

The results show that the prodrug has good analgesic activity. Other compounds in the general formula "Structure 1" also show similar analgesic activity.

Antipyretic action: rats received inactivated E.coli suspension as pyrogen. Group A is blank. After 2 hours, rats were administered transdermally: n-acetyl-4-aminophenyldimethylaminobutyrate hydrochloride (100 mg/kg, B); 4-Acetaminophenylsalicylate dimethylaminobutyrate hydrochloride (100 mg/kg, C). Rats were subjected to body temperature measurements every 90 minutes before and after dosing, and the results are shown in table 2.

TABLE 2 antipyretic effect of acetaminophen and acetaminosalol prodrug

Compound (I)	t =0 min	t =90 minutes	t =180 minutes	t =270 minutes
					A (control group)	37.34±0.05	37.36±0.07	37.37±0.05	37.44±0.08
B(100mg/kg)	37.32±0.06	36.61±0.05	36.50±0.08	36.50±0.07
					C(100mg/kg)	37.27±0.06	36.63±0.05	36.52±0.08	36.50±0.07

The results show that the prodrug shows stronger antipyretic activity when being administered at a dose of 100 mg/kg. Other compounds in the general formula "Structure 1" show similar antipyretic activity.

Certain non-steroidal anti-inflammatory drugs exhibit anti-reactive-anti-asthmatic effects by inhibiting cyclooxygenase activity when administered orally at high doses. Because of the high membrane penetration rate of these pro-drugs, asthma can be treated by spraying into the mouth or nasal cavity.

These prodrugs are useful for treating psoriasis, acne, sunburn or other skin disorders because they inhibit cyclooxygenase activity and are transdermally permeable. They are also useful in the treatment of skin cancer, lung cancer, breast cancer and other cancers.

The invention relates to a pharmaceutical preparation containing the prodrug represented by the general formula 'structural formula 1' and common additives and auxiliary agents thereof, 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" can be used in combination with vitamins such as vitamin A, B, C, E or beta-carotene, or other drugs such as beta-carotene, N-acetylcysteine, caffeine, pseudoephedrine, azaperone, folic acid, etc., for the treatment of any acetaminophen and acetaminosalol-treatable conditions in humans or animals.

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

The compounds of the general formula (1) 'Structure 1' indicated above can be prepared by reacting acetaminophen, acetaminosalol and related compounds thereof with the compounds of the general formula (2) 'Structure 2' under the action of a coupling agent. Coupling agents are: n, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazol-N, N' -tetramethyluronium Hexafluoro Borate (HBTU), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), and the like.

Structural formula 2

In the formula 2, R₁Represents H, any one of 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 one of alkyl with 1 to 12 carbon atoms, alkoxy with 1 to 12 carbon atoms and alkene with 1 to 12 carbon atomsA radical, an alkynyl radical of 1 to 12 carbon atoms, or an aryl radical; n =0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …

The compounds of the general formula (1) 'Structure 1' indicated above can be prepared by reacting acetaminophen, acetaminosalol and related compounds thereof with the compounds of the general formula (3) 'Structure 3'.

Structural formula 3

In the formula 3, R₁Represents H, any one of 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, or any one of 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, or any one of 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 halogen, or p-toluenesulfonyl; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or any other negative ion; n =0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …

Advantages of the invention

These pro-drug structures of acetaminophen, acetaminosalol, and related compounds all have a lipid soluble portion and a water soluble portion (the amine group, which exists in protonated form at physiological pH). The positively charged amino groups of these prodrugs have two major advantages: first, it greatly enhances the solubility of the prodrug, which dissolves rapidly in gastric fluid when administered orally as a tablet, capsule, solution or suspension. Second, the positively charged amino groups of these prodrugs can bond to the negatively charged phosphate head group on the cell membrane. Thus, the local concentration of the prodrug outside the membrane will be high, facilitating the permeation of these prodrugs 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, a concentrated semi-liquid aqueous solution or suspension. Experiments have shown that more than 90% of the pro-drugs can be quickly returned to the parent drug. These prodrugs have better absorption rates, and therefore, the therapeutic effect of the prodrugs is better than that of acetaminophen, acetaminosalol and related compounds at the same dosage. The results show that the pro-drugs, N-acetyl-4-aminophenyldimethylaminobutyrate hydrochloride and 4-acetamidophenylsalicylic acid dimethylaminobutyrate hydrochloride, permeate human skin approximately 150-fold faster than acetaminophen and acetaminosalol. Acetaminophen, acetaminosalol, and related compounds peak in plasma drug concentration after about 1-2 hours of oral administration, whereas prodrugs only took about 50 minutes to reach their peak in plasma drug concentration. The most exciting result is that the prodrug can be used not only orally, but also transdermally for any kind of treatment, avoiding most of the side effects of acetaminophen, acetaminosalol, and related compounds, most notably hepatotoxicity and nephrotoxicity. Another great benefit of transdermal administration is the ease of administration, especially to children.

Drawings

FIG. 1: n-acetyl-4-aminophenyldimethylaminobutyrate ester hydrochloride (a, 30% solution), 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride (a, 30% solution), N-acetaminophen (a, 30% suspension), and 4-acetamidophenylsalicylic acid (D, 30% suspension) of human skin tissue isolated by Franz cells (N = 5). The carrier solution under each condition was a phosphate buffered solution (0.2M) at pH 7.4.

FIG. 2: the total amount of paracetamol and acetaminosalol in plasma after topical application of N-acetyl-4-aminophenyldimethylaminobutyrate ester hydrochloride, 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride, paracetamol and acetaminosalol in 1ml isopropanol to the backs of hairless mice (N = 5).

FIG. 3: after 50mg/kg of N-acetyl-4-aminophenyldimethylaminobutyrate ester hydrochloride and 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride are transdermally administered, the pain threshold of the tail of the mouse is prolonged. A is a control group.

FIG. 4: in the formula 1, R₁Represents H, any one of 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 one of 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 one of 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, or 2-OCO-C₆H₄-O；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 … …; all R groups may include C, H, O, S, or N atoms, and may contain single, double, and triple bonds. Any CH₂The groups may be substituted with O, S, or NH.

Best mode for carrying out the invention

Preparation of N-acetyl-4-aminophenyldimethylaminobutyrate hydrochloride

15.1g (0.1 mol) of paracetamol are dissolved in 200ml of acetone and 200ml of 10% sodium bicarbonate solution. 18.6g (0.1 mol) of dimethylaminobutyryl chloride hydrochloride was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated. 500ml of ethyl acetate are added and the mixture is washed 1 time with 200ml of 5% sodium bicarbonate solution and 3 times with 100ml of water. The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. Hydrogen chloride gas is introduced into the filtrate. The solid product was collected by filtration. Drying to obtain 26g of target product which is easy to absorb moisture, wherein the yield is 86.4%. Solubility in water: 400 mg/ml; elemental analysis: c₁₄H₂₁ClN₂O₃(ii) a Molecular weight: 300.78. theoretical value (%) C: 55.90 of; h: 7.04; cl: 11.79, respectively; n: 9.31, respectively; o: 15.96 parts; found value (%) C: 55.96, respectively; h: 7.06; cl: 11.76; n: 9.29; o: 15.93.¹H-NMR（400MHz，D₂O）：δ：1.98（s，3H），2.01（m，2H），2.21（m，2H），2.90（s，6H），3.24（m，2H），7.05（m，2H），7.60（m，2H），7.80（b，1H）。

detailed description of the preferred embodiments

Preparation of N-acetyl-4-aminophenyldiethylaminobutyrate hydrochloride

15.1g (0.1 mol) of acetaminophen and 16g (0.1 mol) of diethylaminobutyric acid were dissolved in 300ml of dichloromethane. The reaction was cooled to 0 ℃ with an ice bath. 20.6g (0.1 mol) of N, N' -dicyclohexylcarbodiimide were added. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for 2 hours. The solid was removed by filtration. The dichloromethane solution was washed 2 times with 100ml of 5% sodium bicarbonate solution and 3 times with 100ml of water. 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. The solid product was collected by filtration. After drying, 27g of the hygroscopic target product were obtained, yield 82.1%. Solubility in water: 400 mg/ml; elemental analysis: c₁₆H₂₅ClN₂O₃(ii) a Molecular weight: 328.83. theoretical value (%) C: 58.44; h: 7.66; cl: 10.78; n: 8.52; o: 14.60 of; found value (%) C: 58.40, respectively; h: 7.68; cl: 10.76; n: 8.55; o: 14.61.¹H-NMR（400MHz，D₂O）：δ：1.50（t，6H），2.00（m，2H），2.02（s，3H），2.21（m，2H），3.24（m，2H），3.27（m，4H），7.05（m，2H），7.60（m，2H），7.80（b，1H）。

preparation of 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride

27.1g (0.1 mol) of acetaminosalol are dissolved in 200ml of acetone and 200ml of 10% sodium bicarbonate solutionIn (1). 18.6g (0.1 mol) of dimethylaminobutyryl chloride hydrochloride was added thereto, and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. To the reaction mixture was added 500ml of ethyl acetate, and the mixture was washed 1 time with 200ml of 5% sodium bicarbonate solution and 3 times with 100ml of water. The organic layer was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. Hydrogen chloride gas is introduced into the filtrate. The solid product was collected by filtration. Drying to obtain 36g of target product which is easy to absorb moisture, wherein the yield is 85.5%. Solubility in water: 400 mg/ml; elemental analysis: c₂₁H₂₅ClN₂O₅(ii) a Molecular weight: 420.89. theoretical value (%) C: 59.93; h: 5.99; cl: 8.42; n: 6.66; o: 19.01, respectively; found value (%) C: 59.96, respectively; h: 6.02; cl: 8.40; n: 6.64 of; o: 18.98.¹H-NMR（400MHz，D₂O）：δ：1.99（s，3H），2.01（m，2H），2.21（m，2H），2.90（s，6H），3.24（m，2H），7.13（m，2H），7.22（m，2H），7.47（m，1H），7.60（m，2H），7.80（b，1H），8.10（m，1H）。

preparation of 4-acetamidophenylsalicylic acid dimethylaminobutyrate ester hydrochloride

27.1g (0.1 mol) of acetaminosalol and 16g (0.1 mol) of diethylaminobutyric acid were dissolved in 300ml of dichloromethane. The reaction mixture was cooled to 0 ℃ with an ice bath. 20.6g (0.1 mol) of N, N' -dicyclohexylcarbodiimide were added. The mixture was stirred at 0 ℃ for 1 hour and at room temperature for 2 hours. The solid was removed by filtration. The dichloromethane solution was washed 2 times with 100ml of 5% sodium bicarbonate solution and 3 times with 100ml of water. The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. The solid product was collected by filtration. After drying, 39g of the target product which is easy to absorb moisture is obtained, and the yield is 86.9%. Solubility in water: 400 mg/ml; elemental analysis: c₂₃H₂₉ClN₂O₅(ii) a Molecular weight: 448.94. theoretical value (%) C: 61.53, respectively; h: 6.51; cl: 7.90 of; n: 6.24; o: 17.82; found value (%) C: 61.50; h: 6.56; cl: 7.85; n: 6.22; o: 17.87.¹H-NMR（400MHz，D₂O）：δ：1.50（t，6H），2.00（m，2H），2.02（s，3H），2.21（m，2H），3.24（m，2H），3.27（m，4H），7.11（m，2H），7.21（m，2H），7.47（m，1H），7.65（m，2H），7.80（b，1H），8.10（m，1H）。

industrial applicability

These prodrugs in the general formula (1) 'Structure 1' are superior to acetaminophen, acetaminosalol, and related compounds. They may be used to treat any acetaminophen, acetaminosalol, and related compounds-treatable conditions in humans or animals. They are useful for relieving signs and symptoms of rheumatoid arthritis and osteoarthritis, for reducing fever and for treating dysmenorrhea. Asthma can be treated by inhalation because of the rapid rate of membrane penetration of these pro-drugs. Due to their anti-inflammatory effects, these prodrugs can be used for the treatment of psoriasis, acne, sunburn or other skin disorders. They are also useful in the treatment of skin cancer, lung cancer, breast cancer and other cancers.

Claims (26)

1. A compound represented by "structural formula 1",

   structural formula 1

   Wherein the content of the first and second substances,

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

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

   R₃represents H, any alkyl group of 1 to 12 carbon atoms, alkoxy group of 1 to 12 carbon atoms, alkenyl group of 1 to 12 carbon atoms, or alkynyl group of 1 to 12 carbon atoms;

   x represents 2-OCO-C₆H₄-O；A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ion capable of balancing the positive charge of the protonated amine group; and

   n =0, 1, 2, 3, 4, 5, 6,7, 8, 9 or 10.
2. 2. The compound of claim 1, wherein R₃Represents H.
3. 3. The compound of claim 1 or 2, wherein a^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Or citrate.
4. 4. A composition comprising as its active ingredient at least one compound as claimed in claim 1, 2 or 3.
5. 5. The composition of claim 4, further comprising water.
6. 6. Formulation comprising a composition according to claim 4 or 5, and/or an additive and/or adjuvant.
7. 7. The formulation of claim 6, which is an orally administrable dosage form selected from the group consisting of tablets, capsules, solutions, and suspensions.
8. 8. The formulation of claim 6, which is a transdermal administration form selected from the group consisting of a solution, a spray, a lotion, an ointment, a latex, and a gel form.
9. 9. A system for transdermal therapeutic application comprising at least one active agent, wherein the active agent is a compound according to claim 1, 2 or 3, a composition according to claim 4 or 5, or a formulation according to claim 6,7 or 8.
10. 10. The transdermal therapeutic application system of claim 9, wherein the system is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.
11. 11. A transdermal therapeutic application system according to claim 9 or 10 comprising an active substance reservoir comprising a permeable skin-facing base.
12. 12. A transdermal therapeutic application system according to claim 9, 10 or 11 wherein the rate of release is controlled such that the system provides a stable optimal therapeutic blood level of the non-steroidal anti-inflammatory drug thereby increasing the therapeutic efficacy and reducing the side effects of the non-steroidal anti-inflammatory drug.
13. 13. A transdermal therapeutic application system according to claim 9, 10 or 11, characterized in that the release rate can be controlled and the system can stabilize the active substance or its metabolite at the optimum therapeutic blood level to increase the therapeutic effect and reduce the side effects.
14. 14. Use of a compound according to claim 1, 2 or 3, a composition according to claim 4 or 5, or a formulation according to claim 6,7 or 8 for the manufacture of a medicament for the treatment of asthma in a human or animal, wherein the medicament is for administration by spray to the mouth or nose or other parts of the body.
15. 15. Use of a compound according to claim 1, 2 or 3, a composition according to claim 4 or 5, or a formulation according to claim 6,7 or 8 for the manufacture of a medicament for the treatment of a non-steroidal anti-inflammatory drug treatable condition in a human or animal.
16. 16. The use of claim 15, wherein the non-steroidal anti-inflammatory drug treatable condition is selected from the group consisting of: pain, fever, cancer, emesis from radiation therapy, diabetic neuropathy, hemophiliac arthritis, bone loss, glaucoma, skin disorders, and sunburn.
17. 17. The use of claim 16, wherein the pain is selected from the group consisting of headache, dental pain, muscle pain, dysmenorrhea, acute migraine, post-corneal surgery ocular pain, ear pain, and arthritic pain.
18. 18. The use according to claim 15, wherein the non-steroidal anti-inflammatory drug is capable of treating a condition selected from the group consisting of psoriasis and acne.
19. 19. The use according to claim 15, wherein the condition treatable by the nsaid is selected from the group consisting of ocular inflammation and otic inflammation.
20. 20. The use of claim 15, wherein the pain state is inflammatory pain.
21. 21. The use of claim 15, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, and skin cancer.
22. 22. The use according to any one of claims 15 to 21, wherein the medicament is for treatment by oral or transdermal administration.
23. 23. The use of any one of claims 15 to 21, wherein the medicament is treatable by transdermal administration of a solution, spray, lotion, ointment, emulsion or gel formulation to a site on the body to achieve a therapeutically effective plasma concentration.
24. 24. The use of any one of claims 15 to 21, wherein the medicament is an oral dosage form or a transdermal dosage form.
25. 25. The use according to any one of claims 15 to 21, wherein the medicament is in a transdermal dosage form.
26. 26. Use according to any one of claims 15 to 21, wherein the medicament is for treatment by administration via a transdermal therapeutic application system according to any one of claims 9 to 12.