HK1136815A - Positively charged water-soluble prodrugs of diclofenac with very fast skin penetration rate - Google Patents

Description

Positively charged water-soluble diclofenac prodrugs with fast skin penetration rate

Technical Field

The present invention relates to positively charged water-soluble prodrugs of 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid (diclofenac) and their medical use in the medical treatment of any diclofenac-treatable condition in humans or animals. In particular, the invention aims to overcome the side effect caused by using diclofenac. These prodrugs can be administered orally or transdermally.

Technical Field

Diclofenac is a non-steroidal anti-inflammatory drug of aryl and heterocyclic aryl acetic acids. Diclofenac was first synthesized in 1969 (a. salman and r. pfister, ger. patent No.1,815,802). Diclofenac is available in 120 different countries and is probably the most commonly used non-steroidal anti-inflammatory drug in the world. Diclofenac has aryl alkanoic acid and anthranilic acid structure of anti-inflammatory drugs, and has anti-inflammatory, analgesic and antipyretic effects. In the aspect of analgesia, the curative effect of diclofenac is 6 times that of indometacin and 40 times that of aspirin; in the aspect of defervescence, the curative effect of diclofenac is 2 times that of indometacin and 350 times that of aspirin. "PDR genetics" (PDR genetics, 1996, second edition, Medical Economics, Montvale, New Jersey, pg243) recites a number of Medical uses for diclofenac. Diclofenac can be used to relieve signs and symptoms of rheumatoid arthritis and osteoarthritis, osteoarthritis and ankylosing spondylitis. The potassium salt can be used for treating dysmenorrhea. Diclofenac can be used alone or as an adjuvant for the treatment of biliary colic, fever and pain due to perineotomy. It can also be used for the treatment of gout, acute migraine, renal colic, and for the treatment of post-operative inflammation in patients after cataract extraction.

However, diclofenac administration produces many side effects, most notably gastrointestinal disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations and gastritis. Fishman (Fishman; Robert, u.s.pat. No.7,052,715) states that another problem associated with oral administration is that the concentration of the drug in the blood circulation must be very high in order to effectively treat the pain or inflammation that occurs at a remote 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 Botknecht et al, U.S. Pat. No. 5,885,597) have attempted to develop drug delivery systems for transdermal administration by way of formulation. Song et al developed a transdermal delivery system containing an anti-inflammatory analgesic such as diclofenac diethylammonium salt (Song et al, U.S. Pat. No. 6,723,337). A topical ointment containing heparin and diclofenac was developed by Donati et al (Donati et al, U.S. Pat. No. 6,592,891). Kawaji et al developed an external ointment patch containing diclofenac sodium (Kawaji et al, U.S. Pat. No. 6,262,121). Effing et al developed a device for transdermal delivery of diclofenac (Effing et al, U.S. Pat. No. 6,193,996). However, it is difficult to administer therapeutically effective plasma concentrations of diclofenac in a host by means of a formulation. Susan Miloovich et al designed and synthesized testosterone 4-dimethylaminobutyrate ester hydrochloride (TSBH) having a lipophilic portion and a tertiary amine structure that exists in protonated form at physiological pH. They found that the pro-drug (TSBH) penetrated the skin approximately 60 times faster than the parent drug (TS) itself. [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993) ].

Disclosure of Invention

Technical problem

Diclofenac has been used as a pharmaceutical for over 30 years, and is superior to aspirin in its anti-inflammatory and prostaglandin biosynthesis inhibitory effects. Diclofenac can be used for relieving symptoms of rheumatoid arthritis and osteoarthritis, relieving mild and moderate pain, relieving fever, and treating dysmenorrhea. Diclofenac is available in 120 different countries and is probably the most commonly used non-steroidal anti-inflammatory drug in the world.

However, diclofenac administration produces a number of side effects, most notably gastrointestinal upset such as dyspepsia, heartburn, vomiting, gastroduodenal bleeding, gastric ulcerations and gastritis. Diclofenac-induced gastroduodenal bleeding is usually painless, but causes stool bleeding and leads to persistent iron deficiency anemia.

Solution scheme

The invention relates to the preparation of novel diclofenac prodrugs with positive charge and their medical use. These prodrugs have the general formula (1) 'Structure 1'.

Structural formula 1

In the formula 1, R₁Represents H, any alkyl 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 or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate or other negative ions; all R groups, where n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …, may contain C, H, O, S, N atoms, and may have single, double or triple bonds; any CH₂The group may be substituted with O, S or NH.

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

The purpose of the invention is to avoid the side effects of diclofenac by increasing its solubility in gastric juice and increasing its speed of penetration through biological membranes and skin barriers, so that it can be administered transdermally (for external use). These novel prodrugs of diclofenac have two identical structural features: they have a lipophilic moiety and a primary, secondary, or tertiary amine group in the protonated form at physiological pH. Such a water-oil balance is necessary for the drug to effectively cross the barrier membrane [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]. The positively charged amino groups greatly increase the solubility of the drug. 2- [ (2, 6-dichlorophenyl) amino group]Diethylaminoethyl phenylacetate acetate and 2- [ (2, 6-dichlorophenyl) amino group]The solubility of phenylacetic acid (diclofenac) in water is respectively>400mg/ml and 0.1 mg/ml. In most cases, dissolution of the drug is the slowest and rate-limiting step in the absorption process. Diclofenac has very low solubility in gastric juice. It stays in the gastrointestinal tract for a long time and thus may cause damage to gastric mucosal cells. 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 combine with the negative charge on the phosphate head group of the membrane. Thus, local concentration of the drug outside the biofilmThe concentration is so high as to facilitate passage of these prodrugs 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. Due to the short residence time in the gastrointestinal tract, the prodrug does not cause damage to gastric mucosal cells. 2- [ (2, 6-dichlorophenyl) amino group]Diethylaminoethyl phenylacetate acetate and 2- [ (2, 6-dichlorophenyl) amino]The rate of permeation of phenylacetic acid (diclofenac) through human skin isolated from human skin tissue (360-400 μm thick) in front of or behind the thigh region was measured in vitro by a modified Franz cell. The receiving solution consisted of 10ml of physiological saline containing 2% bovine serum globulin and was stirred at 600 rpm. 2- [ (2, 6-dichlorophenyl) amino group]Diethylaminoethyl phenylacetate acetate and 2- [ (2, 6-dichlorophenyl) amino]The cumulative amount of phenylacetic acid (diclofenac) that permeates through the skin versus time is determined by specific high performance liquid chromatography. With 30% 2- [ (2, 6-dichlorophenyl) amino group in 2ml of phosphate buffered saline (0.2M) pH7.4]A suspension of phenylacetic acid (diclofenac) or a solution containing 30% 2- [ (2, 6-dichlorophenyl) amino group dissolved in 2ml of phosphate buffered saline (0.2M) pH7.4]Suspension of phenethyl ester, or 30% 2- [ (2, 6-dichlorophenyl) amino group dissolved in 2ml of phosphate buffered saline (0.2M) pH7.4]The result of using a solution of diethylaminoethyl phenylacetate acetate as a donor solution is shown in FIG. 1. P-2- [ (2, 6-dichlorophenyl) amino]Phenylacetic acid (diclofenac), 2- [ (2, 6-dichlorophenyl) amino]Phenylacetic acid ethyl ester (without positive charge, common diclofenac ethyl ester) and 2- [ (2, 6-dichlorophenyl) amino]The calculated apparent penetration values of diethylaminoethyl phenylacetate acetate are 0.2mg, 0.2mg and 50mg/cm²H is used as the reference value. The results indicate that the prodrug, 2- [ (2, 6-dichlorophenyl) amino]Diethylaminoethyl phenylacetate acetate, which has a diffusion rate in human skin higher than that of 2- [ (2, 6-dichlorophenyl) amino]Phenylacetic acid (diclofenac) and 2- [ (2, 6-dichlorophenyl) amino]Ethyl phenylacetate was nearly 250 times faster. Common ester, 2- [ (2, 6-dichlorophenyl) amino]The transdermal speed of phenylacetate and diclofenac themselves are not very different. The results indicate that the positive charge on the dialkylaminoethyl group passes through the drugThe biofilm and skin barrier are very important. Other prodrugs of the general formula "Structure 1" have very high transdermal speed and are conjugated with 2- [ (2, 6-dichlorophenyl) amino group]The transdermal speed of the diethylaminoethyl phenylacetate acetate is very close.

2- [ (2, 6-dichlorophenyl) amino group was compared in vivo]Diethylaminoethyl phenylacetate acetate and 2- [ (2, 6-dichlorophenyl) amino group]The rate of penetration of phenylacetic acid (diclofenac) through the skin of live hairless, non-lesioned mice. The donor was prepared from 20% 2- [ (2, 6-dichlorophenyl) amino group dissolved in 1ml isopropanol]Diethylaminoethyl phenylacetate solution or 20% 2- [ (2, 6-dichlorophenyl) amino dissolved in 1ml isopropanol]Phenylacetic acid solution. It is applied to the back of hairless mouse by 1cm²And (4) the part. The results (fig. 2) show that the concentration of diclofenac reaches a peak after about 40 minutes using the donor system. It takes 1-2 hours for diclofenac to reach its peak concentration when taken orally. Diclofenac having a peak value of about 0.001mg/ml, 2- [ (2, 6-dichlorophenyl) amino group]The peak value of diethylaminoethyl phenylacetate acetate was about 2.1mg/ml (about 2100-fold difference). Diclofenac at about 2.1mg/ml in plasma is up to 1000 times higher than diclofenac plasma concentration (about 0.002mg/ml) which is both analgesic and anti-inflammatory effective. This is an exciting result. By these prodrugs, diclofenac can be easily and rapidly administered to a host at 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 of the general formula "Structure 1" with 2- [ (2, 6-dichlorophenyl) amino]The acetate of the diethylaminoethyl phenylacetate is close to that of the diethylaminoethyl phenylacetate.

To examine the gastroduodenal bleeding caused by these drugs, we orally administered 25mg/kg diclofenac or diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate to rats (two groups of 10 rats) daily for 21 days. We found an average of 3mg of blood per gram of rat feces in the diclofenac group, while no fecal blood was found in the [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl acetate group.

We also carried out acute toxicity of the prodrugThe study was conducted. Oral LD in rats₅₀Comprises the following steps: [ (2, 6-dichlorophenyl) amino]Diethylaminoethyl phenylacetate acetate and [ (2, 6-dichlorophenyl) amino group]The acetic acid dimethylaminoethyl ester acetate was 0.75g/kg and 0.7 g. The results indicate that the toxicity of the prodrug is lower than that of diclofenac (LD)₅₀＝0.45g/kg)。

Diclofenac has been shown to have anti-inflammatory, analgesic, antipyretic, and antirheumatic effects. A good prodrug should return to the parent drug in the blood. The diethylaminoethyl ester group of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate is rapidly cleaved in vitro by enzymes in human plasma, with over 90% of the prodrug returning to the parent diclofenac. Due to the higher absorption rate of the prodrug, the same dose of prodrug is more effective than diclofenac itself. We tested the analgesic, antipyretic and anti-inflammatory effects of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate and compared diclofenac. Other compounds of the general formula "formula 1" were also tested in the same manner and gave results very similar to those of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate.

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)). Mice were orally administered 25mg/kg diclofenac, and after oral and transdermal administration of 25mg/kg of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate, the tails of the mice were exposed to thermal stimulation, and the pain threshold extension time was measured. The results are shown in FIG. 3. The groups administered orally (C) and transdermally (D) with 25mg/kg of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate showed stronger analgesic activity than the group administered with 25mg/kg of diclofenac.

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. 42 mice were divided into 7 groups (6 per group). Mice in groups B1 and B2 were dosed with diclofenac (10mg and 20mg/kg), while groups C1 and C2 were dosed orally with diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate (10mg and 20 mg/kg). Groups D1 and D2 were transdermally administered [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (10mg and 20 mg/kg). A is a control group. The test compound was administered to the mice 30 minutes before the acetic acid solution was administered. The results are shown in Table 1.

Table 1: inhibition rate of diclofenac and prodrug thereof on writhing of mice

Group of	A	B1	B2	C1	C2	D1	D2
								Dosage (mg/kg)	0	10	20	10	20	10	20
Number of times of body twisting	34.2	14.2	10.1	12.1	9.2	10.3	8.8
								％	-	58.5	70.5	64.6	73.1	69.9	74.3

The results show that the analgesic effect of the diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate is stronger than that of diclofenac. Other compounds in the general formula "Structure 1" show similar analgesic activity.

Antipyretic action: rats received inactivated E.coli suspension as pyrogen. 56 rats were divided into 7 groups. Group A is a control group. After 2 hours diclofenac was administered orally (10mg/kg for group B1 and 20mg/kg for group B2), diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate (10mg/kg for group C1 and 20mg/kg for group C2) and transdermally [ (2, 6-dichlorophenyl) amino ] phenylacetate diethylaminoethyl acetate (10mg/kg for group D1 and 20mg/kg for group D2)

mg/kg). Rats were body temperature measured every 90 minutes before and after test compound administration. The results are shown in Table 2 below.

TABLE 2 antipyretic effect of diclofenac and its prodrugs

Group of	t＝0min.	t＝90min.	t＝180min.	t＝270min.
					Blank group (A)	37.56±0.05	37.55±0.07	37.53±0.05	37.52±0.08
(10mg/kg，B1)	37.56±0.06	36.90±0.05	36.91±0.08	36.92±0.07
					(20mg/kg，B2)	37.55±0.09	36.60±0.07	36.53±0.06	36.55±0.05
(10mg/kg, C1, oral)	37.52±0.07	36.50±0.06	36.60±0.05	36.55±0.08
					(20mg/kg, C2, oral)	37.54±0.08	36.30±0.05	36.35±0.07	36.38±0.08
(10mg/kg, D1, transdermal administration)	37.58±0.06	36.30±0.06	36.35±0.08	36.31±0.07
					(20mg/kg, D2, transdermal administration)	37.59±0.05	36.25±0.05	36.30±0.07	36.20±0.05

The results show that the antipyretic activity of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate at a dose of 10mg/kg and 20mg/kg is better than that of diclofenac at the same dose. The results show that the transdermal administration of the diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate is better than the oral administration. Other compounds in the general formula "Structure 1" show similar antipyretic activity.

Anti-inflammatory action: 10mg/kg of [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate and 10mg/kg of diclofenac were administered orally or transdermally to rats. After 60 minutes the carrageenan solution was administered subcutaneously under the flesh pad of the rat paw. The volume of the hind paw of the rat was measured every 1 hour after the administration of carrageenan, and the rate of increase in the volume of the hind paw was calculated and used as the swelling rate (%). The results obtained are shown in FIG. 4. The results show that oral and transdermal administration of 10mg/kg of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate has a better anti-inflammatory effect than oral administration of the same dose of diclofenac. The anti-inflammatory effects of the other compounds represented by the general formula "structural formula 1" are similar.

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

Structural formula 2

In the structural formula 2, Y represents halogen, alkoxycarbonyl or substituted aryloxycarbonyloxy, and Z represents halogen or other negative ions.

Structural formula 3

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

The compounds of the general formula 1 "structure 1" indicated above can be prepared by reacting diclofenac with the compounds of the general formula (3) "structure 3" indicated above via coupling agents, for example: n, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (HBTU), benzotriazol-N, N' -tetramethyluronium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate, and the like.

When X represents O, the compound represented by the general formula (1) 'structure 1' described above can be obtained by reacting a metal salt or an organic base salt of diclofenac with the compound represented by the general formula (4) 'structure 4'.

Structural formula 4

In the formula 4, R₁Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; r₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; z represents halogen, or p-toluenesulfonyl; a. the^-Represents Cl^-，Br^-，F^-，AcO^-Citrate, or other negative ions; n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …

When X represents O, the compound represented by the general formula (1) 'Structure 1' described above can be obtained by reacting an immobilized base salt of diclofenac represented by the general formula (5) 'Structure 5' with a compound represented by the general formula (4) 'Structure 4'.

Structural formula 5

In the structural formula 5, R represents a crosslinked resin; b represents any basic group, such as pyridyl, piperidyl, triethylamine, or other basic groups.

The present invention relates to a pharmaceutical preparation comprising a prodrug of diclofenac represented by the general formula "formula 1" and usual additives and adjuvants, for example, tablets, capsules or solutions for oral administration, or solutions, emulsions, ointments, emulsions or gels for transdermal administration, etc. The novel active compounds of the general formula "formula 1" 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 diclofenac treatable conditions in humans or animals.

Diclofenac can exhibit an anti-reactive-anti-asthmatic effect by inhibiting the activity of cyclooxygenase. Due to their high membrane penetration rate, these prodrugs can be used to treat asthma by spraying into the mouth or nasal cavity of the host.

Because of their anti-inflammatory effects, these prodrugs can also be used to treat acne and other skin disorders. They are also useful in the treatment and prevention of endothelial dysfunction.

These prodrugs are water-soluble neutral salts and are well tolerated by the eye. They are useful for the treatment of ocular inflammation, for the treatment of ocular pain following corneal surgery, for the treatment of glaucoma or for the treatment of otic inflammation and/or pain states (otitis).

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

Advantages of the invention

Some of these diclofenac prodrugs are hydrophobic and others are hydrophilic (amine groups present in protonated form at physiological pH). These prodrugs have two major advantages with positively charged amino groups. First, it greatly improves the solubility of the drug; when these novel prodrugs are administered orally, e.g., as tablets, capsules, solutions or suspensions, they dissolve rapidly in gastric fluid. Second, the positively charged amino groups of these prodrugs can bond to the negatively charged phosphate head structure of the biofilm. Thus, the local concentration outside the membrane may be high, thereby facilitating the permeation of the drug from the high concentration region through the low concentration region. When these pro-drugs enter the membrane, the hydrophilic part will push the drug into the cytoplasm, which is a concentrated semi-liquid aqueous solution or suspension. Since these prodrugs stay in the gastrointestinal tract for a short period of time, they do not cause damage to the gastric mucosa. The results of the experiment show that 90% of the prodrug can be converted back to the parent drug. These prodrugs have a better absorption rate, so that the prodrug has a better therapeutic effect than diclofenac at the same dose. Experiments prove that the speed of penetrating the prodrug, [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate through human skin is approximately 250 times faster than that of diclofenac and [ (2, 6-dichlorophenyl) amino ] phenylacetic acid ethyl ester. The rate of penetration of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate through the skin of living hairless mice in vivo is very high. The blood concentration of the diclofenac reaches the peak value after 1 to 2 hours of oral administration of the diclofenac tablet, but the diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate can reach the peak value of the blood concentration of the diclofenac within only 30 minutes. The most exciting result is that the prodrug can be administered not only orally, but also transdermally for any kind of medical treatment and avoids most of the side effects of diclofenac, most notably gastrointestinal disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, etc. Another great advantage of transdermal administration of these prodrugs resides in the greater ease of administration, particularly to children.

Drawings

FIG. 1: cumulative total amount of [ (2, 6-dichlorophenyl) amino ] phenylacetic acid (diclofenac, a), [ (2, 6-dichlorophenyl) amino ] phenylacetic acid ethyl ester (common ester of diclofenac with no positive charge, B) and [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate (C) of human skin tissue isolated by Franz cell (n ═ 5). Diclofenac and ethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate are administered as a 30% suspension; a30% solution of diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate was administered. The carrier solution was in each case pH7.4 phosphate buffer (0.2M).

FIG. 2: total blood concentration of diclofenac after topical application of 1ml of 20% [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl acetate solution and [ (2, 6-dichlorophenyl) amino ] phenylacetic acid (diclofenac) solution in isopropanol to the back of hairless mice (n ═ 5).

FIG. 3: after oral administration of 25mg/kg diclofenac (B), oral administration of (C) and transdermal administration of (D)25mg/kg diethylaminoethyl [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate, the pain threshold of the tail of the mice was prolonged. A is the control curve.

FIG. 4: swelling rate (%) after carrageenan injection. The carrageenin is orally taken for 1 hour before injection with 10mg/kg of diclofenac (B), orally taken (C) and transdermally administered (D) with 10mg/kg of [ (2, 6-dichlorophenyl) amino ] phenylacetic acid diethylaminoethyl ester acetate. A is a control group.

Structural formula 1: in the formula 1, R₁Represents H, an alkyl group of 1 to 12 carbon atoms, an alkenyl group of 1 to 12 carbon atoms, an alkynyl group of 1 to 12 carbon atoms, or an aryl group; r₂Represents H, alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; r₃Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, or aryl; x represents O, S or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or other negative ions; all R groups, where N is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …, may include C, H, O, S, N atoms, and may contain single, double, and triple bonds. Any CH₂The groups may all be substituted with O, S, or NH.

Best mode for carrying out the invention

Preparation of diethylaminoethyl 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate

35.1g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino group]Phenylacetyl chloride hydrochloride was dissolved in 100ml of chloroform. The mixture was cooled to 0 ℃.30 ml (0.1mol) of triethylamine and 11.7g of diethylaminoethanol were added to the reaction mixture with stirring. The reaction solution was stirred at room temperature for 3 hours. The solid by-product was removed by filtration and washed 3 times with 30ml portions of chloroform. 6g of acetic acid was added to the reaction solution with stirring. The organic solvent was evaporated to dryness. After drying, 39g of the target product, which is hygroscopic, was obtained with a yield of 85.6%. Solubility in water: 400 mg/ml; elemental analysis: c₂₂H₂₈Cl₂N₂O₄(ii) a Molecular weight: 455.37. theoretical value (%) C: 58.03, respectively; h: 6.20; cl: 15.57; n: 6.15; o: 14.05; found value (%) C: 58.01; h: 6.22; cl: 15.55, N: 6.14; o: 14.09.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 1.56(t, 6H), 2.21(s, 3H), 3.28(m, 4H), 3.50(s, 2H), 3.52(m, 2H), 3.81(b, 1H), 4.51(t, 2H), 6.32(d, 1H), 6.50(m, 2H), 6.78(b, 1H), 6.82(m, 2H), 6.91(d, 2H).

Detailed description of the preferred embodiments

Preparation of dimethylaminoethyl 2- [ (2, 6-dichlorophenyl) amino ] phenylacetate acetate

35.1g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino group]Phenylacetyl chloride hydrochloride was dissolved in 100ml of acetone. The mixture was cooled to 0 ℃. 8.9g (0.1mol) of N, N-dimethylaminoethanol was added to the reaction mixture. To the mixture was added 20g of sodium bicarbonate and 100ml of water. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. 100ml of acetone was added to the reaction mixture. The solid by-product was removed by filtration and washed 3 times with 30ml portions of acetone. 6g of acetic acid was added to the mixture with stirring. The organic solvent was evaporated to dryness. After drying, 38g of the target product, which is hygroscopic, were obtained with a yield of 88.9%. Dissolving in waterAnd (3) resolution: 410 mg/ml; elemental analysis: c₂₀H₂₄Cl₂N₂O₄(ii) a Molecular weight: 427.32. theoretical value (%) C: 56.21; h: 5.66; cl: 16.59, N: 6.56; o: 14.98 of the total weight of the mixture; found value (%) C: 56.18 parts; h: 5.68; cl: 16.56, N: 6.55; o: 15.03.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 2.21(s, 3H), 2.91(s, 6H), 3.50(s, 2H), 3.52(m, 2H), 3.81(b, 1H), 4.51(t, 2H), 6.32(d, 1H), 6.50(m, 2H), 6.78(b, 1H), 6.82(m, 2H), 6.91(d, 2H).

Preparation of 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid dimethylaminoethylthioester acetate

35.1g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino group]Phenylacetyl chloride hydrochloride was dissolved in 100ml acetone. The mixture was cooled to 0. DEG C. 9.3g of N, N-dimethylaminoethanethiol (0.1mol) was added to the reaction mixture. To the mixture was added 20g of sodium bicarbonate and 100ml of water. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. To the residue was added 100ml of acetone. The solid by-product was removed by filtration and washed 3 times with 30ml portions of acetone. 6g of acetic acid was added to the reaction mixture with stirring. The organic solvent was evaporated to dryness. After drying, 40g of the target product, which is hygroscopic, was obtained with a yield of 90.2%. Solubility in water: 410 mg/ml; elemental analysis: c₂₀H₂₄Cl₂N₂O₃S; molecular weight: 443.39. theoretical value (%) C: 54.18, respectively; h: 5.46; cl: 15.99, N: 6.32; o: 10.83, S: 7.22; found value (%) C: 54.16, respectively; h: 5.48; cl: 15.97, N: 6.31; o: 10.86, S: 7.23.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 2.21(s, 3H), 2.91(s, 6H), 3.31(t, 2H), 3.66(s, 2H), 3.91(m, 2H), 3.93(b, 1H), 6.32(d, 1H), 6.50(m, 2H), 6.78(b, 1H), 6.82(m, 2H), 6.91(d, 2H).

Preparation of N-dimethylaminoethyl 2- [ (2, 6-dichlorophenyl) amino ] phenylacetylaminoacetate

35.1g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino group]Phenylacetyl chloride hydrochloride was dissolved in 100ml acetone. The mixture was cooled to 0 ℃. Mixing 8.9g N, N-bisMethylaminoethylamine is added to the reaction mixture. 20g of sodium bicarbonate and 100ml of water were added to the mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. To the residue was added 100ml of acetone. The solid by-product was removed by filtration and washed 3 times with 30ml portions of acetone. To the reaction mixture was added 6g of acetic acid with stirring. The organic solvent was evaporated to dryness. After drying, 40g of the target product, which is hygroscopic, were obtained with a yield of 93.8%. Solubility in water: 450 mg/ml; elemental analysis: c₂₀H₂₅Cl₂N₂O₃(ii) a Molecular weight: 426.34. theoretical value (%) C: 56.34; h: 5.91; cl: 16.63, N: 9.86 of the total weight of the steel; o: 11.26; found value (%) C: 56.31; h: 5.5.94, respectively; cl: 16.61, N: 9.84; o: 11.30.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 2.21(s, 3H), 2.91(s, 6H), 3.44(s, 2H), 3.51(t, 2H), 3.64(t, 2H), 3.93(b, 1H), 6.32(d, 1H), 6.50(m, 2H), 6.78(b, 1H), 6.82(m, 2H), 6.91(d, 2H), 8.0(b, 1H).

Preparation of dipropylaminoethyl acetate salt of 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid

31.8g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino]Sodium phenylacetate was suspended in 180ml chloroform. 28.8g (0.1mol) of dipropylaminoethyl bromide hydrogen bromide was added to the mixture, and the mixture was stirred at room temperature for 5 hours. 8.2g (0.1mol) of sodium acetate are added with stirring to the reaction solution. The mixture was stirred for 2 hours. The solid was removed by filtration and washed 3 times with 50ml of chloroform. The solution was concentrated to 100ml in vacuo. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed three times with 100ml of hexane each. After drying, 41g of the target product, which is hygroscopic, were obtained with a yield of 87%. Solubility in water: 300 mg/ml; elemental analysis: c₂₄H₃₂Cl₂N₂O₄(ii) a Molecular weight: 483.43. theoretical value (%) C: 59.63, respectively; h: 6.67; cl: 14.67; n: 5.79; o: 13.24; theoretical value (%) C: 59.60, respectively; h: 6.70; cl: 14.65, N: 5.78; o: 13.27.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 0.97(t, 6H), 1.78(m, 4H), 2.21(s, 3H), 3.24(t, 4H), 3.50(s, 2H), 352(m, 2H), 3.81(H, 1H), 4.51(t, 2H), 6.34 (d)，1H)，6.50(m，2H)，6.78(b，1H)，6.82(m，2H)，6.91(d，2H)。

Preparation of dipropylaminoethyl acetate of 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid

60g of polymer-solidified triethylamine (3mmol/g, 100-mesh 200) were suspended in 180ml of chloroform. To the mixture was added 31.8g (0.1mol) of 2- [ (2, 6-dichlorophenyl) amino group with stirring]Phenylacetic acid. 43g (0.15mol) of dipropylaminoethylbromide hydrobromide was added to the reaction solution, and the reaction solution was stirred at room temperature for 5 hours. The polymer was removed by filtration and washed three times with 50ml of tetrahydrofuran each time. 8.2g (0.1mol) of sodium acetate was added to the filtrate with stirring, and the mixed solution was stirred for 2 hours. The solid was removed by filtration and washed three times with 50ml of chloroform each time. The solution was concentrated to 100ml in vacuo. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed three times with 100ml of hexane each. After drying, 45g of the target product, which is hygroscopic, were obtained with a yield of 93.2%. Solubility in water: 300 mg/ml; elemental analysis: c₂₄H₃₂Cl₂N₂O₄(ii) a Molecular weight: 483.43. theoretical value (%) C: 59.63, respectively; h: 6.67; cl: 14.67; n: 5.79; o: 13.24; found value (%) C: 59.60, respectively; h: 6.70; cl: 14.65, N: 5.78; o: 13.27.¹H-NMR (400MHz, deuterated chloroform solvent): δ: 0.97(t, 6H), 1.78(m, 4H), 2.21(s, 3H), 3.24(t, 4H), 3.50(s, 2H), 3.52(m, 2H), 3.81(b, 1H), 4.51(t, 2H), 6.34(d, 1H), 6.50(m, 2H), 6.78(b, 1H), 6.82(m, 2H), 6.91(d, 2H).

Industrial applicability

The prodrugs of the general formula (1) 'Structure 1' are superior to diclofenac. They can be used to treat any diclofenac-treatable conditions in humans and animals. They can be used for relieving signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and for treating dysmenorrhea. They can be used alone or as adjuvant drugs for treating biliary colic, fever, and pain due to perineotomy. They are also useful in the treatment of gout, acute migraine, renal colic, and in the treatment of post-operative inflammation in patients after cataract extraction. They are also useful in the prevention of cancer. Due to their high membrane permeability, these prodrugs can also be used to treat asthma by inhalation into the host. Because these prodrugs have anti-inflammatory effects, they may also be used to treat acne. These prodrugs are water-soluble neutral salts and are well tolerated by the eye. They may also be used for the treatment of ocular inflammation, for the treatment of ocular pain after corneal surgery, for the treatment of glaucoma or for the treatment of inflammation of the ear and/or states of ear pain (otitis).

Claims (9)

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

structural formula 1

Wherein R is₁Represents 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 group of 1-12 carbon atoms, 1-12Alkoxy of 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 or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Acetylsalicylate, citrate or other negative ions; all R groups, where n is 0, 1, 2, 3, 4, 5, 6,7, 8, 9, 10 … …, may include C, H, O, S, N atoms and may contain single, double or triple bonds; any CH₂The group may be substituted with O, S or NH.

2. A method for synthesizing a compound represented by the general formula (1) 'structure 1' described in claim 1.

3. The compounds of the general formula "structure 1" or a composition containing at least one compound of the general formula (1) "structure 1" as active ingredient can be used for treating any diclofenac-treatable conditions in humans or animals by oral or transdermal administration; diclofenac treatable conditions include, but are not limited to: toothache, headache, arthritis and other inflammatory pain, fever, cancer, dysmenorrhea, acute migraine.

4. A method for treating any diclofenac-treatable conditions in humans or animals by administering a compound of the general formula (1) "structure 1" or a composition containing at least one compound of the general formula (1) "structure 1" as an active ingredient according to claim 1 in a transdermal administration manner to any part of the body, wherein the transdermal administration manner comprises a solution, spray, emulsion, ointment, latex or gel, and achieves a therapeutically effective plasma concentration.

5. A method for the topical treatment of pain in humans or animals, by administering a therapeutically effective dose of a compound of the general formula (1) 'structure 1' or a composition comprising at least one compound of the general formula (1) 'structure 1' as claimed in claim 1 as an active ingredient to an area of inflammation, wherein the pain includes headache, toothache, muscle pain, arthritis and other inflammatory pain.

6. The compound of the general formula (1) 'structure 1' or the composition containing at least one compound of the general formula (1) 'structure 1' as an active ingredient according to claim 1, which can be transdermally administered in the form of a solution, spray, lotion, ointment, emulsion or gel, for the treatment of acne, sunburn or other skin disorders.

7. The compound represented by the general formula (1) 'structure 1' or the composition containing at least one compound represented by the general formula (1) 'structure 1' as an active ingredient according to claim 1, which can treat asthma by spray administration to the mouth or nose or other parts of the body.

8. The compound of the general formula (1) 'structure 1' or the composition comprising at least one compound of the general formula (1) 'structure 1' as claimed in claim 1 as an active ingredient, which can treat any ocular inflammatory disorders in humans and animals.

9. Transdermal therapeutic application systems containing a compound of the general formula (1) 'structure 1' according to claim 1 or a composition containing at least one compound of the general formula (1) 'structure 1' as active ingredient, which can be used for the treatment of any diclofenac-treatable conditions in humans or animals; the system described above may be a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer, most preferably the system is an active substance reservoir comprising a permeable skin-facing base; by controlling the release rate, the system can stabilize diclofenac at optimal therapeutic blood levels to improve therapeutic efficacy and reduce the side effects of diclofenac.