HK1200031B - Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate - Google Patents

Description

Positively charged, water-soluble prodrugs of oxicams and related compounds with rapid skin penetration

Division Statement

The present application is a divisional application of the Chinese patent application No. 200680056073.6 filed on October 11, 2006, entitled "Positively charged water-soluble prodrugs of oxicams and related compounds with rapid skin penetration rate".

Technical Field

The present invention relates to positively charged, water-soluble prodrugs of oxicams and related compounds and their use in treating any oxicam-treatable condition in humans or animals. Specifically, the present invention is intended to overcome the side effects associated with the use of oxicams and related compounds. These prodrugs can be administered orally or transdermally.

Background Art

Piroxicam, sudoxicam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinoxicam, meloxicam and related compounds are members of the enolic acid class of 4-hydroxy-1,2-benzothiazine-carboxamides, which have anti-inflammatory and analgesic effects. The first member of this class of compounds, piroxicam, was marketed in the United States in 1982 under the trade name Feldene (Pfizer). Oxicams are a very important class of analgesics and antipyretics. They can be used to alleviate the symptoms of rheumatoid arthritis, osteoarthritis and fever. Other oxicams are disclosed in U.S. Patent Nos. 3,787,324, 3,822,258, 4,180,662 and 4,376,768.

However, the use of oxicams and related compounds is associated with numerous side effects, most notably gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers, and gastritis. Fishman (Fishman; Robert, U.S. Patent No. 7,052,715) noted that oral administration presents an additional problem: to effectively treat pain or inflammation at distal sites, high circulating drug concentrations must be achieved. These concentrations are often far higher than would be practical if the drug were to be directly targeted to the site of pain or injury. Fishman and others (Van Engelen et al., U.S. Patent No. 6,416,772; Macrides et al., U.S. Patent No. 6,346,278; Kirby et al., U.S. Patent No. 6,444,234; Pearson et al., U.S. Patent No. 6,528,040; and Botknecht et al., U.S. Patent No. 5,885,597) have attempted to develop transdermal drug delivery systems through formulations. However, due to the slow rate of transdermal permeation, it is difficult to deliver these drugs into the host and achieve therapeutically effective plasma concentrations through formulations. Susan Milosovich et al. designed and synthesized 4-dimethylaminobutyrate testosterone hydrochloride (TSBH), a compound with a lipid-soluble moiety and a tertiary amine structure that exists in a protonated form at physiological pH. They found that this prodrug (TSBH) penetrates human skin nearly 60 times faster than the parent drug itself [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)].

Summary of the Invention

Technical issues

Piroxicam, sudoxicam, lornoxicam, tenoxicam, ampiroxicam, lomoxicam, isoxicam, cinoxicam, meloxicam, and related compounds can be used to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis, as well as to treat fever.

However, the use of oxacom and its related compounds is associated with a number of side effects, the most prominent of which are gastrointestinal discomfort such as indigestion, gastric and duodenal bleeding, gastric ulcers and gastritis.

Solution

The present invention relates to novel positively charged prodrugs of oxicams and related compounds and their application in medicine. These prodrugs of oxicams and related compounds have the structure of general formula (1) "Structural Formula 1".

or

Structural formula 1

In structural formula 1, R represents a branched or straight chain, -(CH ₂ ) _n -, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., an aryl group or a heteroaryl group; R ₁ represents H, any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; R ₂ represents H, any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; R ₃ represents H, any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; R ₄ represents H, CH ₃ , C ₂ H ₅ , CF ₃ , or C ₂ F ₅ ; 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 ...; R ₅ represents an aryl or heteroaryl system, which include, but are not limited to:

wherein X ₁ and X ₂ represent H, F, Cl, Br, I, CF ₃ , C ₂ F ₅ , SO ₂ CF ₃ , SO ₂ CH ₃ , NO ₂ , CN, or an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkenyl group having 1 to 8 carbon atoms, or an alkynyl group having 1 to 8 carbon atoms;

Representative aryl and heteroaryl groups include, but are not limited to:

Wherein, _X1 and _X2 represent H, _F , Cl, Br, I, _CF3 , _C2F5 , _SO2CF3 , _SO2CH3 , _{NO2 ,} or an alkyl _group of 1-8 carbon atoms, an alkoxy group of 1-8 carbon atoms, an alkenyl group of 1-8 carbon atoms, or an alkynyl group of 1-8 carbon atoms. All R, -( _CH2 ) _n- groups can be branched or straight chain, can include C, H, O, S or N atoms, and can contain single bonds, double bonds and triple bonds. Any _CH2 can be substituted by O, S or NH.

Whether absorbed through the gastrointestinal tract or other routes, drugs must cross the barrier membrane in molecular form. The drug must first dissolve, and if it possesses desirable biopharmaceutical properties, it will migrate from areas of high concentration to areas of low concentration, crossing the cell membrane and entering the bloodstream or systemic circulation. All biological membranes contain lipids as a primary component. The molecules that dominate the structure of biological membranes possess highly polar head structures containing phosphates and, in most cases, two highly hydrophobic hydrocarbon tails. Biological membranes have a double-layer structure, with the hydrophilic head structures facing the aqueous regions on either side. Highly hydrophilic drugs are unable to penetrate the hydrophobic layer of the biological membrane, while very hydrophobic drugs, due to similar compatibility, remain within the hydrophobic layer as part of the biological membrane, preventing them from effectively entering the cytoplasm within.

The present invention aims to improve the solubility of oxicams and related compounds in gastric juice and skin moisture and to improve their penetration rate through biological membranes and skin barriers, so that they can be administered transdermally (for external use), thereby avoiding the side effects of oxicams and related compounds. These novel prodrugs have two identical structural features: they have a lipophilic portion (oil-soluble portion) and a primary, secondary, or tertiary amine group (water-soluble portion) that exists in a protonated form under physiological pH conditions. Such a water-soluble-oil-soluble balance is necessary for the drug to effectively penetrate biological membranes [Susan Milosovich, et al., J. Pharm. Sci., 82, 227 (1993)]. The positively charged amino group greatly improves the solubility of the drug. 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl -2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2- Dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide The solubility of the oxide hydrochloride, piroxicam, sudoxicam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam in water is >300 mg, >300 mg, >300 mg, >300 mg, >300 mg, >300 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, and <0.1 mg, respectively. In most cases, drug dissolution is the slowest or rate-limiting step in the absorption process. Oxicam and its related compounds have very low solubility in gastric fluid or skin moisture. When these novel prodrugs are taken orally in dosage forms such as tablets, capsules, solutions, or suspensions, they dissolve rapidly in gastric fluid. The positive charge on the amino group in these prodrug molecules bonds with the negative charge on the phosphate end group of biological membranes. As a result, the local concentration of these prodrugs on the outer side of the biomembrane is high, facilitating their passage from high-concentration areas to lower-concentration areas. Once these prodrug molecules enter the biomembrane, their hydrophilic moieties propel them into the cytoplasm, a semi-liquid, concentrated aqueous solution or suspension. The pH in the stomach is 1-3, and the negatively charged phosphate groups on the gastric mucosal biomembrane will bond with protons (H ⁺ ). The positive charges on these prodrug molecules will not bond with the negatively charged phosphate groups on the gastric mucosa. Therefore, the prodrugs do not damage the stomach. 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3 -formamide-1,1-dioxide·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride, 4-N,N- The penetration rate of dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazol)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, piroxicam, sudoxicam, lornoxicam, tenoxicam, lomoxicam, isoxicam, meloxicam and related compounds through human skin was measured in vitro using a modified Franz cell using human skin tissue (360-400 μm thick) isolated from the anterior or posterior thigh area. The receptor solution consisted of 10 ml of physiological saline containing 2% bovine serum globulin and stirred at 600 rpm. The cumulative total amount of these prodrugs and their parent drugs permeating through the skin versus time was determined using a specific high performance liquid chromatography method. 2 ml of a 20% solution of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride dissolved in a phosphate buffer solution (0.2 M) at pH 7.4, 2 ml of a 20% solution of N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride dissolved in a phosphate buffer solution (0.2 M) at pH 7.4, and 2 ml of a 20% solution of N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride dissolved in a phosphate buffer solution (0.2 M) at pH 7.4 were added to the solution. 20% 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride solution dissolved in phosphate buffer solution (0.2M) at pH 7.4, 2 ml of 20% 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride solution dissolved in phosphate buffer solution (0.2M) at pH 7.4, 2 ml of 20% 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2- dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride solution, 2 ml of 20% 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride solution dissolved in phosphate buffer solution (0.2 M) at pH 7.4, 2 ml of 20% 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride solution dissolved in phosphate buffer solution (0.2 M) at pH 7.4, or 2 ml of 20% piroxicam suspension suspended in phosphate buffer solution (0.2 M) at pH 7.4, 2 ml of 20% piroxicam suspension suspended in phosphate buffer solution (0.2 M) at pH 7.4. 7.4 phosphate buffer solution (0.2 M) of sudoxicam suspension, 2 ml of lornoxicam suspension suspended in pH 7.4 phosphate buffer solution (0.2 M), 2 ml of tenoxicam suspension suspended in pH 7.4 phosphate buffer solution (0.2 M), 2 ml of lomoxicam suspension suspended in pH 7.4 phosphate buffer solution (0.2 M), 2 ml of isoxicam suspension suspended in pH 7.4 phosphate buffer solution (0.2 M), or 2 ml of meloxicam suspension suspended in pH 7.4 phosphate buffer solution (0.2 M) were used as donor solutions, and the results are shown in Figure 1. The calculated results were 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride, N-(2-thiazolyl)-4-N, N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride, 6- Chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide The apparent penetration values of methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, piroxicam, sudoxicam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam were 1.7 mg, 1.5 mg, 1.6 mg, 1.8 mg, 1.7 mg, 1.8 mg, 1.9 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, 0.001 mg, and 0.001 mg/ ^cm2 /h. The results suggest that the positive charge on the dialkylaminoethyl group is crucial for drug penetration through biological membranes or the skin barrier. Other prodrugs in Formula (1) (Structure 1) exhibited high transdermal penetration rates, similar to that of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride.

In vivo experiments compared 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide·hydrochloride, N-(2-thiazolyl)-4-N, N-dimethylaminobutyryloxy-2-methyl-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide·hydrochloride, 6-chloro-4-N, N-dimethylaminobutyryloxy Oxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy- The rate at which 2-(4-(2-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride, piroxicam, sudoxicam, lornoxicam, tenoxicam, lomoxicam, isoxicam, and meloxicam penetrate the skin of live, hairless, uninjured mice. The donor consisted of 1 ml of a 20% solution of these compounds in isopropyl alcohol, which was applied to a 10 cm ² area on the back of hairless mice. The drug concentration in plasma was determined by a specific high performance liquid chromatography method. The results (Figure 2) showed that after about 50 minutes of using the donor system, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride, N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2 -methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2- The concentrations of dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride reached peak values.

The plasma concentration of oxicams and their related compounds reaches a peak 1-2 hours after oral administration. The peak plasma concentration of piroxicam and sudoxicam is about 0.005 mg/ml, while 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, N-(2-thiazolyl)-4-N, N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine -3-carboxamide-1,1-dioxide hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-disulfide The peak plasma concentrations of hetero-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride were approximately 0.5 mg/ml (a difference of approximately 100 times). The plasma drug concentrations of 0.5 mg/ml of acetaminophen and acetaminophen are more than 50 times the concentrations required for effective analgesia and anti-inflammatory effects. This is an exciting result. Transdermal administration of these prodrugs allows for the rapid and easy delivery of therapeutically effective plasma concentrations of oxicams to the host. These results indicate that these prodrugs can be administered not only orally but also transdermally for various drug therapies. The other prodrugs in Formula 1 exhibited similar in vivo penetration rates to that of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride.

We also studied the acute toxicity of the prodrug. 4-N, N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, N-(2-thiazolyl)-4-N, N-dimethylaminobutyryloxy-2- Methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-yl)- The oral LD 50 of 4-amino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride and piroxicam in mice are ₅₅₀ mg/kg, 670 mg/kg, 580 mg/kg, 500 mg/kg, 610 mg/kg, 570 mg/kg, 590 mg/kg and 360 mg/kg. This suggests that the prodrug is less toxic than the parent drug.

A good prodrug should be able to revert to the parent drug in plasma. The prodrugs of this invention are rapidly cleaved in vitro by enzymes in human plasma. Over 90% of the prodrug reverts to the parent drug structure within minutes. Because the prodrug is absorbed more rapidly than the parent drug, it exhibits greater efficacy at the same dose. Oxicam has both analgesic and antipyretic effects. We tested the analgesic and antipyretic effects of these prodrugs and compared them with piroxicam.

Analgesic Effect: The prolongation of the pain threshold in the tail of mice was measured according to the D'Amour-Smith method (J. Pharmacol. Exp. Ther., 72, 74 (1941)). After transdermal administration of 20 mg/kg of these prodrugs, the tails of the mice were exposed to heat stimulation and the prolongation of the pain threshold was measured. The results are shown in Figure 3. These oxicams exhibited significant analgesic effects after transdermal administration.

The number of writhing events after intraperitoneal administration of acetic acid solution was counted, and the inhibition rate of writhing was calculated based on that of the control group. 60 minutes before administration of acetic acid solution, mice were transdermally administered with: 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (50 mg/kg, Group B), N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (50 mg/kg, Group C), 6-Chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (50 mg/kg, Group D), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide [2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride (50 mg/kg, Group E), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride (50 mg/kg, Group F), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride (50 mg/kg, Group G), and 4-N,N-dimethylaminobutyryloxy -2-Methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (50 mg/kg, Group H). Group A was a blank group. The results are shown in Table 1 below.

Table 1. Inhibition rate of writhing in mice by prodrugs of oxicams

Compound Dosage (mg/kg) Number of twists Inhibition rate (%) A 0 35.0 - B 50 15.6 55 C 50 15.7 55 D 50 16.5 53 E 50 16.9 53 F 50 17.5 50 G 50 15.8 55 H 50 18.2 48

The results showed that the prodrug had a good analgesic effect. Other compounds in the general formula "Structure 1" had similar analgesic effects.

Antipyretic effect: Rats received a suspension of inactivated Escherichia coli as a pyrogen. Group A served as the control group. Two hours later, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (25 mg/kg, Group B), N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (25 mg/kg, Group C), and 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (25 mg/kg, Group D) were transdermally administered. 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (25 mg/kg, Group E), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride (25 mg/kg, Group F), 4-N,N- Dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride (25 mg/kg, Group G) and 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazole)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (25 mg/kg, Group H). The rats' body temperatures were measured every 90 minutes before and after administration of the test compounds. The results are shown in Table 2 below.

Table 2: Antipyretic effect of prodrugs of oxicams

Compound t = 0 minutes t = 90 minutes t = 180 minutes t = 270 minutes A (control group) 37.54±0.05 37.66±0.07 37.67±0.05 37.64±0.08 B (25 mg/kg) 37.57±0.06 36.51±40.05 36.40±0.06 36.45±0.07 C (25 mg/kg) 37.50±0.07 36.61±0.04 36.50±0.07 36.60±0.05 D (25 mg/kg) 37.55±0.05 36.66±0.06 36.60±0.06 36.61±0.07 E (25 mg/kg) 37.54±0.06 36.61±0.06 36.58±0.08 36.55±0.05 F (25 mg/kg) 37.53±0.05 36.57±0.05 36.52±0.07 36.51±0.06 G (25mg/kg) 37.52±0.06 36.62±0.07 36.53±0.06 36.60±0.05 H (25 mg/kg) 37.57±0.07 36.53±0.08 36.52±0.08 36.50±0.07

The results showed that the prodrug exhibited a good antipyretic effect at a dose of 25 mg/kg. Other compounds in the general formula "Structure 1" had similar antipyretic effects.

When taken orally at high doses, NSAIDs can exhibit anti-reactive and anti-asthmatic effects by inhibiting cyclooxygenase activity. Because these prodrugs have rapid biomembrane penetration, they can be administered orally or nasally to treat asthma.

Because these prodrugs have high skin permeation rates and can inhibit the activity of cyclooxygenase, they can be used to treat psoriasis, acne, sunburn or other skin diseases. They can also be used to treat skin cancer, lung cancer, breast cancer and other cancers.

The present invention relates to pharmaceutical products containing the prodrug represented by the general formula "Structure 1" and its commonly used additives and adjuvants, such as tablets, capsules, or solutions for oral administration, or solutions, emulsions, ointments, latexes, or gels for transdermal administration. The novel active compound of the general formula "Structure 1" can be used in combination with vitamins such as vitamins A, B, C, E, beta-carotene, or other drugs such as beta-carotene, caffeine, pseudoephedrine, azaperone, folic acid, etc., to treat any oxicare-treatable condition in humans or animals.

Transdermal therapeutic application systems containing compounds of the general formula "Structure 1" or compositions containing at least one compound of the general formula "Structure 1" as an active ingredient can be used to treat any condition in humans or animals that can be treated with oxicams. These systems can be bandages or patches that contain a matrix layer containing the active substance and an impermeable protective layer. The most preferred system is an active substance reservoir with a permeable bottom facing the skin. By controlling the release rate, this system can stabilize the drug at an optimal therapeutic blood concentration, thereby improving efficacy and reducing side effects. These systems can be worn on the wrist, ankle, arm, leg, or anywhere else on the body.

The compound represented by the above-mentioned general formula (1) "Structure 1" can be prepared by reacting oxicams and related compounds with the compound represented by the general formula (2) "Structure 2" in the presence of a coupling agent, such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), and the like.

Structural Formula 2

In structural formula 2, R represents a branched or straight chain, -( _CH2 ) _n- , wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., an aryl group or a heteroaryl group; _R1 represents H, or any alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, alkenyl group having 1 to 12 carbon atoms, alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; _R2 represents H, or any alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, alkenyl group having 1 to 12 carbon atoms, alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group, wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.

The compound represented by the above general formula (1) "Structure 1" can be prepared by reacting oxicams and related compounds with the compound represented by the general formula (3) "Structure 3".

Structural formula 3

In structural formula 3, R represents a branched or straight chain, -( _CH2 ) _n- , wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., an aryl group or a heteroaryl group; _R1 represents H, or any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; _R2 represents H, or any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; _R3 represents H, or any alkyl group having 1 to 12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkenyl group having 1 to 12 carbon atoms, an alkynyl group having 1 to 12 carbon atoms, an aryl group or a heteroaryl group; X represents a halogen, or a p-toluenesulfonyl group; 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...

advantage

The prodrug structures of these oxicams and related compounds all have a lipid-soluble portion and a water-soluble portion (an amine group that exists in a protonated form at physiological pH). The positively charged amino group of these prodrugs offers two major advantages. First, it significantly enhances drug solubility; when these novel prodrugs are administered orally as tablets, capsules, solutions, or suspensions, they rapidly dissolve in gastric fluid. Second, the positive charge on the amino group of these prodrugs can bond with the negative charge on the phosphate head structure of biological membranes. This results in high local concentrations outside the membrane, facilitating the passage of these prodrugs from areas of high concentration to areas of low concentration. Once these prodrug molecules enter the biological membrane, the hydrophilic portion propels the drug into the cytoplasm, a concentrated, semi-liquid aqueous solution or suspension. Experimental studies have shown that over 90% of the prodrug is converted back to the parent drug within minutes. Because the prodrug has a higher absorption rate than the parent drug, it exhibits greater efficacy than oxicams and related compounds at equivalent doses. Experimental results show that oxicam prodrugs penetrate human skin nearly 100 times faster than oxicams. While oral administration of oxicams and related compounds reaches peak plasma concentrations approximately 1-2 hours after administration, prodrugs achieve peak plasma concentrations in just about 50 minutes. Most excitingly, prodrugs can be administered not only orally but also transdermally for any therapeutic application, avoiding most of the side effects of oxicams and related compounds, most notably gastrointestinal upset such as indigestion, gastroduodenal bleeding, gastric ulcers, and gastritis. Another major advantage of transdermal administration of these prodrugs is the ease of administration, particularly for children.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (A, 20% solution), N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (B, 20% solution) from human skin tissue separated by Franz cell (n=5). 6-Chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (C, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (D, 20% solution), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-disulfide Hetero-3-azabicyclo[4,3,0]nona-8,10-dien-5-one·hydrochloride (E, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride (F, 20% solution), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5- The cumulative total amount of 2-methyl-2-thiazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (G, 20% solution), piroxicam (H, 20% suspension), sudoxicam (I, 20% suspension), lornoxicam (J, 20% suspension), tenoxicam (K, 20% suspension), lomoxicam (L, 20% suspension), isoxicam (M, 20% suspension), and meloxicam (N, 20% suspension). In each case, the carrier solution was a phosphate buffer solution (0.2 M) at pH 7.4.

Figure 2: Hairless mice (n=5) were topically treated with 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, dissolved in 1 ml of isopropanol. 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride, 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, 4-N,N-dimethylaminobutyryloxy-2-methyl -N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride, piroxicam, sudoxicam solution, the total amount of drug in plasma.

Figure 3: Effects of transdermal administration of 20 mg/kg 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (B), N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (C), 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (D), Pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (D), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride (E), 8-chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-dithia-3-azabicyclo[4,3,0]nona-8,10-dien-5-one hydrochloride (F), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole] Prolongation of pain threshold of the tail of mice after administration of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride (G), 4-N,N-dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide hydrochloride (H). A is the blank group.

Figure 4: In structural formula 1, R represents a branched or straight chain, -( _CH2 ) _n- , wherein n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., an aryl or heteroaryl group; _R1 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, alkynyl group of 1-12 carbon atoms, aryl or heteroaryl group _{; R2 represents} H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, alkynyl group of 1-12 carbon atoms, aryl or heteroaryl group; R3 represents H, any alkyl group of 1-12 carbon atoms, alkoxy group of 1-12 carbon atoms, alkenyl group of 1-12 carbon atoms, alkynyl group of 1-12 carbon atoms, aryl or heteroaryl group; _R4 represents H, _CH3 , C ₂ H ₅ , CF ₃ , or C ₂ F ₅ ; R ₅ represents an aryl or heteroaromatic ring system as described in claim 1 . Ar represents an aromatic ring or a heteroaromatic ring as described in claim 1 . X represents a halogen or p-toluenesulfonyl group; 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 ...

Best Practice

Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride

Dissolve 33.1 g (0.1 mol) of 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 200 ml of acetone and 250 ml of 10% sodium bicarbonate solution. Add 22.3 g (0.12 mol) of N,N-dimethylaminobutyryl chloride hydrochloride with stirring. Stir at room temperature for 3 hours. Evaporate the solvent. Add 500 ml of ethyl acetate to the reaction mixture, wash once with 200 ml of 5% sodium bicarbonate solution and three times with 100 ml of water. Dry the organic solution over anhydrous sodium sulfate. Remove the sodium sulfate by filtration. Pass 4 g of hydrochloric acid gas _through the solution. Collect the solid product by filtration. After drying, 40 g of the hygroscopic product is obtained, with a yield of 83.2%. Solubility in water: 250 _mg /ml. Elemental analysis: _{C₂₁H₂₅ClN₄O₅S} ; molecular weight: _480.96 . Calculated % C: 52.44, H: 5.24, Cl: 7.37, N: 11.65, O: 16.63, S: 6.67; Found % C: 52.40, H: 5.27, Cl: 7.42, N: 11.60, O: 16.70, S: 6.61. ¹ H-NMR (400MHz, D ₂ O): δ: 2.00 (m, 2H), 2.23 (m, 2H), 2.46 (s, 3H), 2.85 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.20 (m, 1H), 7.40-7.44 (m, 2H), 7.56(m, 1H), 7.80(m, 1H), 8.10(m, 1H).

Implementation Plan

Preparation of N-(2-thiazolyl)-4-N,N-dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride

Dissolve 32.5 g (0.1 mol) of N-(2-thiazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and 16 g (0.1 mol) of diethylaminobutyric acid in 300 ml of dichloromethane. Cool the reaction mixture to 0°C in an ice bath. Add 20.6 g (0.1 mol) of N,N′-dicyclohexylcarbodiimide to the reaction mixture. Stir the mixture at 0°C for 1 hour and then at room temperature for 2 hours. Remove the solid by filtration. Wash the dichloromethane solution twice with 100 ml of 5% sodium bicarbonate solution and three times with 100 ml of water. Dry the organic layer over anhydrous sodium sulfate. Remove the sodium sulfate by filtration. Pass 4 g of hydrochloric acid gas through the solution. Collect the solid product by filtration. After drying, 37 g of the hygroscopic product is obtained, with a yield of 76%. Solubility in water: 250 mg/ml; Elemental analysis: C ₁₉ H ₂₃ ClN ₄ O ₅ S ₂ ; Molecular weight: 486.99. Calculated % C: 46.86, H: 4.76, Cl: 7.28, N: 11.50, O: 16.43, S: 13.17; Found % C: 46.83, H: 4.78, Cl: 7.31, N: 11.52, O: 16.41, S: 13.15. ¹ H-NMR (400MHz, D ₂ O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18(m, 2H), 6.50(m, 1H), 7.20(m, 1H), 7.40(m, 1H), 7.50(m, 1H), 7.58(m, 1H), 7.85(m, 1H).

Preparation of 6-chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride

Dissolve 36 g (0.1 mol) of 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide hydrochloride in 200 ml of acetone and 200 ml of 10% sodium bicarbonate solution. Add 22.3 g (0.12 mol) of dimethylaminobutyryl chloride hydrochloride to the mixture with stirring, and stir at room temperature for 3 hours. Evaporate the solvent. Add 500 ml of ethyl acetate to the reaction mixture, wash once with 500 ml of 10% sodium bicarbonate solution, and then wash three times with 100 ml of water each time. Dry the organic layer over anhydrous sodium sulfate, and remove the sodium sulfate solids by filtration. Bubble hydrochloric acid gas through the solution. Collect the solid product by filtration. After drying, 42 g of the hygroscopic product is obtained, with a yield of 80.5%. Solubility in water: 250 mg/ml, elemental analysis: C ₁₉ H ₂₂ Cl ₂ N ₄ O ₅ S ₂ ; molecular weight: 521.44. Calculated % C: 43.76, H: 4.25, Cl: 13.60, N: 10.74, O: 15.34, S: 12.30; found % C: 43.72, H: 4.27, Cl: 13.67, N: 10.70; O: 15.37, S: 12.27. ¹ H-NMR (400MHz, D ₂ O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18 (m, 2H), 6.60-6.70 (m, 2H), 7.10 (s, 1H), 7.44 (m, 1H), 8.10 (m, 1H).

Preparation of 4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride

32.5 g (0.1 mol) of 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethane. The reaction mixture was cooled to 0°C in an ice bath. 20.6 g (0.1 mol) of N,N′-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. The solid was removed by filtration. The dichloromethane solution was washed twice with 100 ml of 5% sodium bicarbonate solution and three times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 4 g of hydrochloric acid gas was passed through the solution. The solid product was collected by filtration. After drying, 39 g of hygroscopic product was obtained with a yield of 80.1%. Solubility in water: 250 mg/ml, elemental analysis: C ₁₉ H ₂₃ ClN ₄ O ₅ S ₂ ; molecular weight: 486.99. Calculated % C: 46.86, H: 4.76, Cl: 7.28, N: 11.50, O: 16.43, S: 13.17; found % C: 46.82, H: 4.77, Cl: 7.30, N: 11.47; O: 16.47, S: 13.15. ¹ H-NMR (400MHz, D ₂ O): δ: 2.02 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 2.86 (s, 6H), 3.18(m, 2H), 6.61-6.70(m, 2H), 7.30(d, 1H), 7.45(m, 1H), 7.60(d, 1H), 8.11(m, 1H).

Preparation of 4-N, N-dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide]·hydrochloride

32.5 g (0.1 mol) of 4-hydroxy-2-methyl-N-[5-methyl-3-isoxazole-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethane. The reaction mixture was cooled to 0°C in an ice bath. 20.6 g (0.1 mol) of N,N′-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. The solid was removed by filtration. The dichloromethane solution was washed twice with 100 ml of 5% sodium bicarbonate solution and three times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 4 g of hydrochloric acid gas was passed through the solution. The solid product was collected by filtration. After drying, 37 g of the hygroscopic product was obtained with a yield of 78.7%. Solubility in water: 250 mg/ml, elemental analysis: C ₁₉ H ₂₃ ClN ₄ O ₆ S, molecular weight: 470.93, calculated % C: 48.46, H: 4.92, Cl: 7.53, N: 11.90, O: 20.38, S: 6.81; found % C: 48.43, H: 4.94, Cl: 7.57, N: 11.86, O: 20.41, S: 6.79. ¹ H-NMR (400MHz, D ₂ O): δ: 2.01 (m, 2H), 2.22 (m, 2H), 2.44 (s, 3H), 2.85 (s, 6H), 3.18(m, 2H), 6.40(m, 1H), 7.20(m, 1H), 7.40(m, 1H), 7.52(m, 1H), 7.58(m, 1H), 7.85(m, 1H).

Industrial Applicability

These prodrugs of formula (1) "Structure 1" are superior to oxicams and their related compounds. They can be used to treat any condition in humans or animals that can be treated by oxicams and their related compounds. They can be used to alleviate the signs and symptoms of rheumatoid arthritis and osteoarthritis, treat fever, and treat menstrual pain. Because these prodrugs can penetrate biological membranes rapidly, they can be inhaled to treat asthma. They can also be used to treat breast cancer, colon cancer, pancreatic cancer, skin cancer, and any other cancer. Due to their anti-inflammatory activity, they can also be used to treat psoriasis, acne, sunburn, or other skin diseases.

Claims (19)

1. A compound represented by general formula (1) "structural formula 1", Where R represents the straight-chain -( _CH2 ) _n- , where n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R ₁ represents an alkyl group with 1-12 carbon atoms, an alkoxy group with 1-12 carbon atoms, an alkenyl group with 1-12 carbon atoms, or an alkynyl group with 1-12 carbon atoms; R ₂ represents any alkyl group with 1-12 carbon atoms, alkoxy group with 1-12 carbon atoms, alkenyl group with 1-12 carbon atoms, or alkynyl group with 1-12 carbon atoms; R ₃ represents H; _R4 represents _H , _CH3 , _C2H5 , _CF3 , or _{C2F5 ;} ^A- represents ^Cl- , ^Br- , ^F- , ^I- , ^AcO- , or citrate; R ₅ represents an aryl or heteroaryl system, selected from: _X1 and _X2 are independently selected from H _, F, Cl, Br, I, _CF3 , _C2F5 , _SO2CF3 , _SO2CH3 , _{NO2 ,} alkyl _with 1-8 carbon atoms, alkoxy with 1-8 carbon atoms, alkenyl with 1-8 carbon atoms, or alkynyl with 1-8 carbon atoms; Representative aryl and heteroaryl groups, selected from: Wherein, _X1 and _X2 are independently selected from H _, F, Cl, Br, I, _CF3 , _C2F5 , _SO2CF3 , _SO2CH3 , _NO2 , _alkyl , alkoxy, _alkenyl , or alkynyl groups with 1-8 carbon atoms; wherein, all R may include O, S, Cl, F, Br, I, or N atoms, and any _CH2 in R may be replaced by O, S, or NH; and Wherein, the alkenyl group does not include an alkenyl group with one carbon atom and the ynyl group does not include an ynyl group with one carbon atom. 2. A compound of general formula (1) "structural formula 1" as claimed in claim 1, or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient, wherein the compound or composition is administered orally or transdermally to treat an oxacron-treated condition in a human or animal, wherein the oxacron-treated condition is selected from: toothache, headache, inflammatory pain, fever, cancer, menstrual pain, nausea caused by radiation therapy, diabetic neuropathy, hemophilic arthritis, bone loss, and sunburn. 3. A compound represented by general formula (1) "Structural Formula 1" as claimed in claim 1, or a composition containing at least one compound represented by general formula (1) "Structural Formula 1" as an active ingredient, characterized in that the compound or the composition is administered transdermally to any part of the body via a solution, spray, emulsion, ointment, latex or gel formulation to achieve a therapeutically effective plasma concentration of the compound represented by general formula (1) "Structural Formula 1" to treat a human or animal with an oxacanthopanax-treated condition, wherein the oxacanthopanax-treated condition is selected from: toothache, headache, inflammatory pain, fever, cancer, menstrual pain, nausea caused by radiation therapy, diabetic neuropathy, hemophilic arthritis, bone loss and sunburn. 4. A compound represented by general formula (1) "Structural Formula 1" as claimed in claim 2 or 3, or a composition containing at least one compound represented by general formula (1) "Structural Formula 1" as an active ingredient, wherein the headache is an acute migraine. 5. The use of a compound of general formula (1) "structural formula 1" as claimed in claim 1, or a composition containing at least one compound of general formula (1) "structural formula 1" as its active ingredient, in the preparation of a medicament for topical treatment of pain in humans or animals by administering it to an inflamed area of a human or animal to achieve a therapeutically effective dose of the compound of general formula (1) "structural formula 1", wherein the pain is selected from headache, toothache, muscle pain, and inflammatory pain. 6. The use as described in claim 5, wherein the inflammatory pain is arthritis pain. 7. Use of a compound of general formula (1) "structural formula 1" as claimed in claim 1 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient in the preparation of a medicament for treating skin diseases, wherein the medicament is a solution, spray, emulsion, ointment, latex or gel dosage form. 8. The use as described in claim 7, wherein the skin disease is selected from psoriasis, acne, and sunburn. 9. Use of a compound of general formula (1) "structural formula 1" as claimed in claim 1 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient in the preparation of a medicament for treating asthma, wherein the medicament is administered by spraying onto the mouth or nose or other parts of the body to treat asthma. 10. Use of a compound of general formula (1) "structural formula 1" as claimed in claim 1 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient in the preparation of a medicament for treating ocular inflammation in humans or animals, treating ocular pain after corneal surgery, treating glaucoma, or treating ocular inflammation and/or ocular pain. 11. The use as claimed in claim 10, wherein the ear pain condition is otitis media. 12. Use of a compound of general formula (1) "structural formula 1" as claimed in claim 1 or a composition containing at least one compound of general formula (1) "structural formula 1" as an active ingredient in the preparation of a medicament for treating cancer, wherein the cancer is selected from breast cancer, colorectal cancer, pancreatic cancer and skin cancer. 13. A transdermal therapeutic application system comprising a compound represented by general formula (1) "Structural Formula 1" as claimed in claim 1, or a composition comprising at least one compound represented by general formula (1) "Structural Formula 1" as claimed in claim 1 as an active ingredient, for treating an oxacron-treated condition in a human or animal, wherein the oxacron-treated condition is selected from: toothache, headache, inflammatory pain, fever, cancer, menstrual pain, nausea caused by radiation therapy, diabetic neuropathy, hemophilic arthritis, bone loss, and sunburn. 14. The transdermal therapeutic application system of claim 13, wherein the system comprises a bandage or patch having a matrix layer containing an active substance and a non-permeable protective layer. 15. The transdermal therapeutic application system of claim 13 or 14, wherein the system comprises an active substance reservoir having a permeable, skin-facing base. 16. The transdermal therapeutic application system as claimed in claim 13 or 14, characterized in that, by controlling the release rate, the system is able to stabilize the compound represented by the general formula (1) "structural formula 1" at an optimal therapeutic blood concentration, thereby improving efficacy and reducing side effects. 17. The transdermal therapeutic application system of claim 15, characterized in that, by controlling the release rate, the system can stabilize the compound represented by the general formula (1) "structural formula 1" at an optimal therapeutic blood concentration, thereby improving efficacy and reducing side effects. 18. The transdermal therapeutic application system of claim 13 or 14, wherein the headache is an acute migraine. 19. A compound selected from: 4-N,N-Dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride N-(2-Thiazolyl)-4-N,N-Dimethylaminobutyryloxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride 6-Chloro-4-N,N-dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride 4-N,N-Dimethylaminobutyryloxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide·hydrochloride 8-Chloro-(4-N,N-dimethylaminobutyryloxy-pyridin-2-ylamino-methylene)-3-methyl-2,2-dioxo-2λ ^6,7 -dithia-3-azabicyclo[4,3,0]non-8,10-dien-5-one hydrochloride 4-N,N-Dimethylaminobutyryloxy-2-methyl-N-[5-methyl-3-isoxazolyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide] hydrochloride, 4-N,N-Dimethylaminobutyryloxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide·hydrochloride.