CN103705496A

CN103705496A - Positively charged water-soluble prodrugs of aryl and heteroaryl propionic acids with fast skin penetration rate

Info

Publication number: CN103705496A
Application number: CN201310470404.2A
Authority: CN
Inventors: 于崇曦; 徐丽娜
Original assignee: Techfields Biochem Co Ltd
Current assignee: Taifeier Biomedical Suzhou Co ltd; Yu Chongxi
Priority date: 2006-08-15
Filing date: 2006-08-15
Publication date: 2014-04-09
Anticipated expiration: 2026-08-15
Also published as: CN103705496B

Abstract

The present application discloses a pharmaceutical composition comprising at least one compound of formula 1 or formula 2, as well as a process for the preparation of the pharmaceutical composition and its use in the manufacture of a medicament for the treatment of any non-steroidal anti-inflammatory drug treatable conditions and asthma in a human or animal. Also disclosed are transdermal therapeutic application systems comprising the pharmaceutical compositions.

Description

Positively charged water miscible aryl and the heteroaryl phenoxy propionic acid prodrug with rapid skin penetration speed

Division statement

The application is dividing an application of the application number submitted on August 15th, 2006 is 200680055605.4, denomination of invention is " positively charged water miscible aryl and the heteroaryl phenoxy propionic acid prodrug with rapid skin penetration speed " Chinese patent application.

Technical field

The present invention relates to aryl and heteroaryl phenoxy propionic acid with positive charge and water miscible prodrug and the application on any nonsteroidal antiinflammatory drug (NSAIAs) for the treatment of human or animal can therapeutic state thereof.Specifically, the present invention is the side effect bringing in order to overcome nonsteroidal antiinflammatory drug.These prodrugs can oral or transdermal administration.

Technical background

Aryl and heteroaryl phenoxy propionic acid comprise 2-aryl and heteroaryl propanoic acid, the aryl of 3-aryl and heteroaryl propanoic acid and cyclisation and heteroaryl propanoic acid.2-(6-methoxyl group-2-how base) propanoic acid (naproxen), Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid (suprofen), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, 2-(the fluoro-4-xenyl of 2-) propanoic acid (flurbiprofen), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid (carprofen), Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid (pranoprofen), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid (Benoxaprofen), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid (alminoprofen), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid (tiaprofenic acid), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid (pyrroles is fragrant), 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid (zaltoprofen), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid (bermoprofen), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid (loxoprofen), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid (indoprofen), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-(fenclorac), and related compound is the nonsteroidal antiinflammatory drug that belongs to 2-aryl and heteroaryl phenoxy propionic acid.4,5-diphenyl-2-isoxazolepropionic acid (oxaprozin), 3-(4-biphenylyl carbonyl) propanoic acid (fenbufen), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid (orpanoxin) and related compound is the NSAID (non-steroidal anti-inflammatory drug) that belongs to 3-aryl and heteroaryl phenoxy propionic acid.5-benzoyl-2; 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid (ketorolac); the chloro-5-of 6-cyclohexyl-2,3-dihydro-1H-benzo ring propylene-1-formic acid (clidanac), and related compound is to belong to the aryl of cyclisation and the NSAID (non-steroidal anti-inflammatory drug) of heteroaryl propanoic acid system.They can treat rheumatic arthritis and osteoarthritis and dysmenorrhea.They also can treat acute gouty arthritis and ankylosing spondylitis.They can also treat dementia (McGeer; PatrickL. etc., U.S. Patent number 5,192,753).

Yet; the use of naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and related compound also brings a lot of side effect; particularly can cause the side effect of gastrointestinal upset, as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer and gastritis.Fishman (Fishman; Robert, U.S. Patent number 7,052,715) point out that another problem of following oral medication to produce is, the pain or the inflammation that in order effectively to treat remote location, produce, the concentration of medicine in blood circulation must be very high.These concentration are often required far above the reality of the direct targeting pain of hypothesis medicine energy or injury.

The people such as Fishman (Van Engelen etc., U.S. Patent number 6,416,772; Macrides etc., U.S. Patent number 6,346,278; Kirby etc., U.S. Patent number 6,444,234, Pearson etc., U.S. Patent number 6,528,040, and Botknech etc., U.S. Patent number 5,885,597) attempted being used for transdermal administration by the mode developing drugs transmission system of preparation.Yet because the skin penetration speed of these medicines is very slow, the mode by preparation is difficult to make its plasma concentration to reach effective treatment level.Susan Milosovich etc. has designed and synthesized 4-dimethylaminobutyricacid acid testosterone hydrochlorate (TSBH), and it has a lipophilic portion and a tertiary amine structure existing with protonated form under physiological pH.They find that the transdermal speed of this prodrug (TSBH) is nearly 60 times ［ SusanMilosovich, et al., J.Pharm.Sci., 82,227 (1993) ］ of female medicine (TS) itself.

Summary of the invention

Technical problem

Naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and related compound are medically being used for many years.It can be used for sign and the symptom of rheumatoid arthritis, osteoarthritis, and treatment dysmenorrhea.

Yet taking NSAID (non-steroidal anti-inflammatory drug) (NSAIAs) has many side effect, main is not just as dyspepsia, stomach and duodenal hemorrhage and gastritis of gastro-intestinal digestion road.Their water insoluble or gastric juice, can rest in gastrointestinal tract for a long time, so may damage gastric mucosal cell.

Solution

The present invention relates to the novel aryl of positive charge and the prodrug of heteroaryl propanoic acid and related compound, and in the application of field of medicaments.2-(6-methoxyl group-2-how base) propanoic acid (naproxen), Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid (suprofen), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, 2-(the fluoro-4-xenyl of 2-) propanoic acid (flurbiprofen), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid (carprofen), Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid (pranoprofen), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid (Benoxaprofen), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid (alminoprofen), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid (tiaprofenic acid), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid (pyrroles is fragrant), 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid (zaltoprofen), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid (bermoprofen), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid (loxoprofen), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid (indoprofen), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-(fenclorac) and relevant compound are all to belong to 2-aryl and heteroaryl propionic non-steroid antiphlogistic.The prodrug of 2-aryl and heteroaryl propanoic acid has the structure of general formula (1) " structural formula 1 ",

In structural formula 1, R represents CH ₃, OH, Cl, F or Br; R ₁represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R ₂represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R ₃represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; X represents O, S, NH, OCH ₂cOO, OCH ₂cOS, or OCH ₂cONH; A ^-represent Cl ^-, Br ^-, F ^-, I ^-, AcO ^-, citrate or other any anion; N=0,1,2,3,4,5,6,7,8,9,10 Aryl representative:

All R bases can comprise C, H, and O, S or N atom, can have singly-bound, two key and triple bond.Any one CH ₂group can be by O, and S or NH replace.

4,5-diphenyl-2-

azoles propanoic acid (oxaprozin), 3-(4-biphenylyl carbonyl) propanoic acid (fenbufen), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid (orpanoxin) and related compound all belong to 3-aryl and heteroaryl propionic non-steroid antiphlogistic.3-aryl and heteroaryl phenoxy propionic acid prodrug have the structure of general formula (2) " structural formula 2 ",

In structural formula 2, W represents H, OH, Cl, F or Br; R ₁represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R ₂represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; R ₃represent H, the alkynyl of the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom, a 1-12 carbon atom, or aryl; X represents O, S, NH, OCH ₂cOO, OCH ₂cOS or OCH ₂cONH; A ^-represent Cl ^-, Br ^-, F ^-, I ^-, AcO ^-, citrate or other anion; N=0,1,2,3,4,5,6,7,8,9,10 W represents OH, Cl or F; Y represents H, Cl, OH or CH ₃; Z represents following structure:

All R, R ₁, R ₂, R ₃and R ₄group can comprise C, H, and O, S or N atom, can have singly-bound, two key and triple bond.Any one CH ₂group can be by O, and S or NH replace.

General formula (2) " structural formula 2 " and in, when W is H, Y represents together with Z:

The aryl of cyclisation and heteroaryl propanoic acid are also synthesized.They comprise 5-benzoyl-2,3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid (ketorolac), the chloro-5-of 6-cyclohexyl-2,3-dihydro-1H-benzo ring propylene-1-formic acid (clidanac) and related compound thereof.

Medicine no matter is through intestines and stomach digestive system or other approach absorb, and all need to pass barrier film with the form of molecule.First medicine need dissolve, and if medicine there is desirable biopharmacy characteristic, the region that its can be from the regional diffusion of high concentration to low concentration, strides across biomembrane and enters blood or systemic circulation system.All biomembranes all contain lipid as Main Ingredients and Appearance.In biofilm structure active molecule all have the head construction that contains phosphatic high polarity and, in most of the cases, two highly hydrophobic hydrocarbon tail chains.Biomembrane has double-decker, and hydrophilic head structure is towards the water region of both sides.Very hydrophilic medicine cannot be by through biomembranous lipid layer, very hydrophobic medicine stops wherein as a biomembranous part because of the reason of similar compatibility, thereby can not effectively enter inner Cytoplasm.

The object of the invention is: by improving naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, dissolubility in gastric juice of clidanac and its related compound and improve the speed that it sees through biomembrane and skin barrier, make it can avoid by the mode of transdermal administration (external) their side effect.These novel prodrugs have two construction featuress: they have a lipophilic part (oil-soluble part) and an one-level existing with protonated form under physiological pH condition, secondary, or tertiary amine group (water-soluble portion).Water-soluble-molten balance of oil is that medicine can effectively pass the essential condition ［ Susan Milosovich, et al., J.Pharm.Sci., 82,227 (1993) ］ of biomembrane.With the amino of positive charge, greatly increased the dissolubility of medicine.2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) benzenpropanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate, naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the dissolubility of clidanac in water is respectively >450mg, >400mg, >450mg, >450mg, >350mg, >450mg, >400mg, >450mg, >400mg, >450mg, >350mg, >400mg, >350mg, >400mg, >350mg, >400mg, >400mg, >350mg, >450mg, >350mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, <0.1mg, and <0.1mg/ml.In most cases, the dissolving of medicine is the step of the slowest in absorption process and maximum speed limit.Naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and the dissolubility of related compound in gastric juice thereof are very little.They rest on for a long time in intestines and stomach and may cause gastric mucosal cell damage.When these novel prodrugs are oral with the dosage form such as tablet, capsule, solution or suspensoid, they can be dissolved in gastric juice rapidly.Positive charge in these prodrugs on amino can with the negative charge bonding of the phosphate end group of cell membrane.Therefore, thus medicine very high these prodrugs that contribute to of local concentration in biomembrane outside arrive the region of low concentration by area with high mercury.After these prodrugs enter into biomembrane, hydrophilic parts can promote prodrug and enter Cytoplasm, a kind of concentrated aqueous solution or suspension of semi liquid state.Because the time of staying in gastrointestinal tract is short, prodrug can not cause damage to gastric mucosal cell.The pH value of gastric juice is 1-3, the negative charge on the phosphate end group on biomembrane will with H ⁺bonding.Positive charge on prodrug can not with gastric mucosa on phosphate end group negative charge bonding.These prodrugs have been avoided first order injury (directly acid damage) and the second level injury (suppressing the synthetic of prostaglandin) to stomach.

Aryl and heteroaryl propanoic acid with and the prodrug of positively charged and the related compound speed that sees through human body skin by improved Franz pond, measure in vitro, human body skin separation human skin tissue (360-400 μ m is thick) before huckle position or below wherein.Accept that solution contains 2% bovine serum globulin normal saline by 10ml forms and stir with the speed of 600 revs/min.These prodrugs and female medicine thereof are to measure by specific high performance liquid chromatography through the accumulation total amount of skin to the relation of time.Donor solution is for being dissolved in respectively 30% solution of these prodrugs of the phosphate buffered solution (0.2M) of 2ml pH7.4, or be suspended in respectively 2ml pH7.4 phosphate buffered solution (0.2M) 30%: naproxen suspension, suprofen suspension, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid suspension, flurbiprofen suspension, carprofen suspension, pranoprofen suspension, Benoxaprofen suspension, alminoprofen suspension, tiaprofenic acid suspension, pirprofen suspension, zaltoprofen suspension, bermoprofen suspension, loxoprofen's suspension, indoprofen suspension, fenclorac suspension, oxaprozin suspension, fenbufen suspension, orpanoxin suspension, ketorolac suspension, clidanac suspension, measurement result is shown in Fig. 1, Fig. 2, Fig. 3 and Fig. 4.Record 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate, naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the apparent penetrating value that sees through human body skin of clidanac is respectively 3.5mg, 3.0mg, 4.0mg, 3.5mg, 4.0mg, 3.8mg, 4.0mg, 3.5mg, 4.2mg, 3.5mg, 3.7mg, 4.1mg, 3.4mg, 4.2mg, 3.8mg, 4.0mg, 3.6mg, 4.1mg, 3.8mg, 4.0mg, 0.03mg, 0.03mg, 0.03mg, 0.03mg, 0.04mg, 0.03mg, 0.04mg, 0.03mg, 0.03mg, 0.03mg, 0.03mg, 0.04mg, 0.03mg, 0.03mg, 0.04mg, 0.03mg, 0.04mg, 0.03mg, 0.03mg and 0.04mg/cm ²/ h.The results show prodrug: 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo zole acetic acid ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate sees through the speed of human body skin than female medicine naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac is fast nearly 100～130 times.Positive charge on presentation of results diethylin ethyl is extremely important through biomembrane and skin barrier to medicine.The transdermal speed of other prodrug of general formula " structural formula 1 " and general formula " structural formula 2 " is very high, and very approaching with the transdermal speed of 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate.

In body experiment compared aryl and heteroaryl propanoic acid and positively charged prodrug and related compound thereof see through live without hair without the speed of hindering the skin of mice.Donor is by 20% the solution composition that is dissolved in these compounds of 1ml isopropyl alcohol.Be applied to hairless mouse back 10cm ²position.In blood plasma, the concentration of naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac is to measure with specific efficient liquid-phase chromatography method.Experimental result is (as Fig. 5, Fig. 6, Fig. 7 and Fig. 8) show, using for system after approximately 50 minutes, 2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, the drug level of 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate in blood plasma reaches peak value.Oral naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, need 2-4 the drug level in hour blood just can reach peak value.Naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the about 0.01mg/ml of peak value of the drug level in the blood plasma of clidanac, and 2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2,3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, the about 2mg/ml of drug level peak value in the blood plasma of 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate, differ approximately 200 times.The naproxen of about 2mg/ml in blood plasma, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac than can effectively ease pain and the plasma concentration of effective antiinflammatory exceeded 20-100 doubly more than.This is stem-winding result.With the form of prodrug by transdermal administration can easily send rapidly naproxen, suprofen, _α-methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac reach the effective plasma concentration for the treatment of.These results show that prodrug not only can be oral, and can be used for various treatments by transdermal administration.The transdermal speed of transdermal speed in vivo of represented other prodrug of general formula " structural formula 1 " or general formula " structural formula 2 " and 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate approaches.

For stomach and the duodenal hemorrhage that checks that these guiding drugs rise, we to the 2-of Oral Administration in Rats 50mg/kg (6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate every day, the 2-of 50mg/kg ［ 4-(2-Thenoyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, the Alpha-Methyl of 50mg/kg-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole, the 3-acetic acid lignocaine ethyl ester acetate of 50mg/kg, the 2-of 50mg/kg (the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate of 50mg/kg, Alpha-Methyl-5H-of 50mg/kg ［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, the 2-of 50mg/kg (4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-of 50mg/kg ［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate of 50mg/kg, the chloro-4-of 3-of 50mg/kg (2,5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, the 2-of 50mg/kg (10,11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, the 2-of 50mg/kg (8-methyl isophthalic acid 0,11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, the 2-of 50mg/kg ［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, the 4-of 50mg/kg (1,3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, the α of 50mg/kg, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4 of 50mg/kg, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, the 3-of 50mg/kg (4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, the 5-of 50mg/kg (4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2 of 50mg/kg, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2 of 50mg/kg, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate, the naproxen of 50mg/kg, the suprofen of 50mg/kg, the Alpha-Methyl of 50mg/kg-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, the flurbiprofen of 50mg/kg, the carprofen of 50mg/kg, the pranoprofen of 50mg/kg, the Benoxaprofen of 50mg/kg, the alminoprofen of 50mg/kg, the tiaprofenic acid of 50mg/kg, the pirprofen of 50mg/kg, the zaltoprofen of 50mg/kg, the bermoprofen of 50mg/kg, the loxoprofen of 50mg/kg, the indoprofen of 50mg/kg, the fenclorac of 50mg/kg, the oxaprozin of 50mg/kg, the fenbufen of 50mg/kg, the orpanoxin of 50mg/kg, the ketorolac of 50mg/kg, the clidanac of 50mg/kg, continuous oral 21 days.In the group of oral naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, we have 1～4mg to have blood in stool in finding every gram of Oletum Ratti norvegici, and at oral 2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl 1 of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, in the group of 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate, do not find to have blood in stool.

We are also studied the acute toxicity of prodrug.Half lethal dose (LD in rat ₅₀) be: 2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester acetate 2.2g/kg; 2-［ 4-(2-Thenoyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate 0.8g/kg; 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate 0.7g/kg; Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2; 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate 0.75g/kg, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate 1.3g/kg, 4-(1,3-dihydro-1-oxygen-2H-isoindolyl-2-alkene)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate 3.5g/kg, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate 1.1g/kg, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate 0.6g/kg, the chloro-5-of 6-cyclohexyl-2,3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate 0.2g/kg.The toxicity of these prodrugs of presentation of results is lower than female medicine naproxen (LD ₅₀=1.234g/kg), suprofen (LD ₅₀=0.59g/kg), carprofen (400mg/kg), pranoprofen (447mg/kg), Benoxaprofen (LD ₅₀=0.8g/kg), alminoprofen (LD ₅₀=2400mg/kg), indoprofen (LD ₅₀=0.7mg/kg), fenclorac (LD ₅₀=0.43g/kg), clidanac (LD ₅₀=0.035g/kg).

Naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac have been proved to be antiinflammatory, have eased pain, bring down a fever and antiheumatic effect.A good prodrug should be able to very quick return to female medicine in blood plasma.Testing in vitro proves, the N in people's blood plasma in these prodrugs, and N-lignocaine ethyl ester base can be sheared rapidly by the enzyme in blood plasma, over 90% prodrug, can get back to female medicine.Because the absorbance of prodrug is higher, the prodrug curative effect of same dose is better than its female medicine.Experiment tested respectively these prodrugs analgesia, bring down a fever and antiinflammatory action, and compare with naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac or clidanac.

Analgesic activity: according to the method for D ' Amour-Smith (J.Pharmac0l.Exp.Ther., 72,74 (1941)). measure the time expand of the mouse tail threshold of pain.By these prodrugs respectively with the dosage of 50mg/kg to mice transdermal administration, the tail of mice is exposed in thermostimulation, measure threshold of pain time expand.Result is as shown in Fig. 9, Figure 10, Figure 11 and Figure 12.2-(6-methoxyl group-2-naphthyl) propanoic acid lignocaine ethyl ester ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2,3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-of 3-(2,5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10,11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0,11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1,3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4,5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2,3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2,3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate has shown good analgesic activities.

The writhing number of times occurring after mouse peritoneal administration acetum is counted, and based on matched group, calculated the suppression ratio of writhing.At administration acetum before 30 minutes, respectively to mice transdermal administration: 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate (100mg/kg, B), 2-［ 4-(2-Thenoyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, C), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (100mg/kg, D), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (100mg/kg, E), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate (100mg/kg, F), Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (100mg/kg, G), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid acetate (100mg/kg, H), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetate. acetate (100mg/kg, I), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (100mg/kg, J), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, K), 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, L), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, M), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, N), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, O), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (100mg/kg, P), 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (100mg/kg, Q), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, R), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propionic ester. acetate (100mg/kg, S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (100mg/kg, T), the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (100mg/kg, U).A group is blank group.The results are shown in following table 1.

Table 1. aryl and the suppression ratio of heteroaryl propanoic acid prodrug to mouse writhing

Group	Dosage (mg/kg)	Writhing number of times	Suppression ratio (%)
				A	0	35.0	-
B	100	17.1	51
				C	100	15.7	55
D	100	13.8	61
				E	100	15.6	55
F	100	14.2	59
				G	100	16.1	54
H	100	17.1	51
				I	100	15.6	55
J	100	13.2	62
				K	100	14.0	60
L	100	14.2	59
				M	100	13.8	61
N	100	15.7	55
				O	100	13.2	62
P	100	15.2	57
				Q	100	15.7	55
R	100	14.2	59
				S	100	15.6	55
T	100	16.1	54
				U	100	15.2	57

Result shows that these prodrugs have outstanding analgesic effect.In general formula " structural formula 1 " or general formula " structural formula 2 ", other compound has also shown similar analgesic activity.

Antipyretic effect: rat is accepted colibacillus deactivating suspension as pyrogen.A group is blank group.After 2 hours, respectively to rat transdermal administration: 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate (100mg/kg, B), 2-［ 4-(2-Thenoyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, C), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (100mg/kg, D), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (100mg/kg, E), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid salt (100mg/kg, F), Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (100mg/kg, G), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate (100mg/kg, H), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid acetate (100mg/kg, I), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (100mg/kg, J), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, K), 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, L), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, M), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, N), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, O), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (100mg/kg, P), 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (100mg/kg, Q), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, R), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (100mg/kg, S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (100mg/kg, T), the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (100mg/kg, U).Before and after test compounds administration, every 90 minutes, to rat, survey body temperature.The results are shown in following table 2.

The antipyretic effect of table 2. aryl and heteroaryl phenoxy propionic acid prodrug

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

[0041]?

K(100mg/kg)	37.25±0.06	36.75±0.05	36.62±0.08	36.58±0.07
					M(100mg/kg)	37.24±0.07	36.82±0.06	36.70±0.05	36.67±0.08
L(100mg/kg)	37.23±0.06	36.81±0.05	36.65±0.08	36.61±0.07
					M(100mg/kg)	37.29±0.07	36.82±0.06	36.60±0.05	36.67±0.08
J(100mg/kg)	37.22±0.06	36.65±0.06	36.58±0.08	36.51±0.07

Result shows that the aforementioned prodrugs of 100mg/kg dosage has very strong antipyretic effect.The antipyretic effect of other compounds that " structural formula 1 " and " structural formula 2 " is represented is very close with above-mentioned these prodrugs.

Antiinflammatory action: to rat transdermal administration: 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate group (100mg/kg respectively, B), Alpha-Methyl-4-(2-Thenoyl) phenylacetate lignocaine ethyl ester acetate (100mg/kg, C), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (100mg/kg, D), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (100mg/kg, E), 6-chloro-Alpha-Methyl-91H-carbazole-2-acetic acid lignocaine ethyl ester acetate (100mg/kg, F), Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (100mg/kg, G), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate (100mg/kg, H), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, I), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (100mg/kg, J), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, K), 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propionic ester. acetate (100mg/kg, L), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, M), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, N), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, O), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (100mg/kg, P), 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (100mg/kg, Q), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, R), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (100mg/kg, S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (100mg/kg, T), the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (100mg/kg, U).After 60 minutes, angle dish sol solution subcutaneous administration is arrived under the meat pad of rat claw.Within after the dish glue of administration angle every 1 hour, measure the volume of a rat hind paw, calculate rear solid end volume rate of increase and as swelling rate (%).The result obtaining is as shown in Figure 13, Figure 14, Figure 15 and Figure 16.Result shows that above-mentioned these prodrugs of transdermal administration demonstrate very strong antiinflammatory action.General formula " structural formula 1 " or other represented compound of general formula " structural formula 2 " also show similar anti-inflammatory activity.

When some nonsteroidal antiinflammatory drug (NSAIAs) of oral high dose, it can show anti-reactivity-antasthmatic effect by suppressing the activity of Cycloxygenase.Because these prodrugs are very fast through biomembrane, thereby can treat asthma by spraying into the mode of mouth or nasal cavity.

Owing to having antiinflammatory action and transdermal speed faster, these prodrugs can be treated psoriasis, acne, sunburn or other dermatosis.

The present invention relates to contain the pharmaceutical preparation of the represented prodrug of general formula " structural formula 1 " or general formula " structural formula 2 " and typical additives, adjuvant, for example, for oral tablet, capsule or solution etc., or for solution, emulsion, ointment, latex or the gel etc. of transdermal administration.The novel active compound of general formula " structural formula 1 " or general formula " structural formula 2 " can be with vitamin as vitamin A, B, C, E, beta-carotene etc., or other medicines, as folic acid, in conjunction with the state that is used for the treatment of the treatable any human body of nonsteroidal antiinflammatory drug (NSAIAs) or animal.

Skin-penetrating therapeutic application system, containing the compound shown in general formula " structural formula 1 " or general formula " structural formula 2 " at least contain a kind of general formula " structural formula 1 " or general formula " structural formula 2 " shown in compound as the compositions of active component, the state that can be used for treating the treatable human body of any nonsteroidal antiinflammatory drug (NSAIAs) and animal.These systems can be binder or paster, the protective layer that it contains a kind of hypothallus that comprises active substance and a non-infiltration.Most preferred system is a kind of active substance reservoir, and it has the permeable bottom towards skin.By controlling rate of release, this system can make nonsteroidal antiinflammatory drug (NSAIAs) be stabilized in optimal treatment blood drug level, thereby improves curative effect, and reduces NSAID (non-steroidal anti-inflammatory drug) (NSAIAs) side effect.These systems can be worn over any position of wrist, ankle joint, arm, lower limb or health.

Compound in above-mentioned general formula (1) " structural formula 1 " and general formula (2) " structural formula 2 " can be in general formula (3) " structural formula 3 " or general formula (4) " structural formula 4 " aryl and heteroaryl propanoic acid functional derivative, as etheride or mixed acid anhydride etc., react to make with the compound in general formula (5) " structural formula 5 "

In

structural formula

3 and 4, X represents halogen, the aryloxy group carbonyl acyloxy of alkoxy carbonyl group or replacement, and aryl, R, Y, Z or W represent and group identical described in " structural formula 1 " or " structural formula 2 ".

In structural formula 5, R ₃represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R4 represents H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; X represents O, S or NH; N=0,1,2,3,4,5,6,7,8,9,10

Above-mentioned general formula (1) " structural formula 1 " or the represented compound of general formula (2) " structural formula 2 " can be by naproxens, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and the related compound compound represented with general formula (5) " structural formula 5 " reacts and makes.Coupling agent has: N, N '-dicyclohexylcarbodiimide, N, N '-DIC, O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester, O-BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, BTA-1-base-oxygen base-tri-(dimethyl amido) phosphorus-hexafluorophosphate etc.

When X represents O, above-mentioned general formula (1) " structural formula 1 " or the represented compound of general formula (2) " structural formula 2 " can be by naproxens, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the slaine of clidanac and related compound thereof or the salt of organic base, the compound represented with general formula (6) " structural formula 6 " reacts and obtains.

In structural formula 6, R ₂represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R ₃represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R ₄represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; Z represents halogen or p-toluenesulfonyl; A ^-represent C1 ^-, Br ^-, F ^-, I ^-, AcO ^-, citrate, or other anion; N=0,1,2,3,4,5

When X represents O, the represented compound of above-mentioned general formula (1) " structural formula 1 " or general formula (2) " structural formula 2 " can be by the represented naproxen of general formula (7) " structural formula 7 ", suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the immobilization alkali salt of clidanac and related compound thereof, the compound represented with general formula (6) " structural formula 6 " reacts and makes.

In structural formula 7, P represents the resin of interlinkage; Aryl or heteroaryl in Aryl representative " structural formula 1 " and " structural formula 2 "; B represents any basic group, as pyridine radicals, piperidyl, triethyamino or other basic group.

Advantage

Naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid; flurbiprofen; carprofen, pranoprofen, Benoxaprofen; alminoprofen; tiaprofenic acid, pirprofen, zaltoprofen; bermoprofen; loxoprofen, indoprofen, fenclorac; oxaprozin; fenbufen, orpanoxin, ketorolac; some is hydrophobicity for the prodrugs of clidanac and related compound thereof, and another part is hydrophilic (amino existing with protonated form under physiology pH value).The amino of positively charged has two large advantages: first, it has greatly improved the dissolubility of medicine; When these new prodrugs with such as tablet, capsule, solution or suspensoid when oral, it can be dissolved in gastric juice rapidly.The second, the amino of these prodrug positively chargeds can with the negative charge bonding of biomembranous phosphate end group.Therefore, the local concentration outside film can be very high, thus promote these prodrugs from area with high mercury thoroughly to low concentration region.When these prodrugs enter into after biomembrane, hydrophilic parts enters promotion medicine in Cytoplasm, and Cytoplasm is concentrated semi liquid state aqueous solution or suspension.Because the time that these prodrugs stop in gastric juice is very short, therefore can not damage gastric mucosa.Experimental result shows that 90% prodrug can become female medicine again.These prodrugs have better absorbance; so under same dose, the curative effect of prodrug is better than naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and related compound.Experimental data shows: 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate, 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate, 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2, 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate, 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate, Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate, 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate, the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate, 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate, 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate, α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate, 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate, 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate, 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate, 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate, the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate sees through the velocity ratio naproxen of human body skin, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and related compound thereof are fast about 100-130 doubly.When oral naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and related compound thereof, after 2-4 hour, blood drug level just reaches peak value, and oral these prodrugs only need 40-50 minute just can reach peak value.The most exciting result is, prodrug not only can be oral, and can be used for any Drug therapy in the mode of transdermal administration, thereby avoided naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, the side effect of clidanac and related compound, mainly that gastrointestinal upset is as dyspepsia, stomach and duodenal hemorrhage, gastric ulcer, gastritis and Toxicity of Kidney.Another large benefit of transdermal administration is that administration is convenient, particularly to child's administration.

Accompanying drawing explanation

Fig. 1: by 2-(6-methoxyl group-2-naphthyl) the propanoic acid lignocaine ethyl ester acetate (A of human skin tissue separated in Franz pond (n=5), 30% solution), Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate (B, 30% solution), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole 3-acetic acid lignocaine ethyl ester acetate (C, 30% solution), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (D, 30% solution), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate (E, 30% solution), naproxen (F, 30% suspension), Shu Bufen (G, 30% suspension), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid (H, 30% suspension), flurbiprofen (I, 30% suspension) or carprofen (J, 30% suspension) accumulation total amount.Carrier solution under various conditions is pH7.4 phosphate buffer solution (0.2M).

Fig. 2: by Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2 of human skin tissue separated in Franz pond (n=5), 3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (A, 30% solution), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate (B, 30% solution), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate (C, 30% solution), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (D, 30% solution), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (E, 30% solution), pranoprofen (F, 30% suspension), Benoxaprofen (G, 30% suspension), alminoprofen (H, 30% suspension), tiaprofenic acid (I, 30% suspension) or pirprofen (J, 30% suspension) accumulation total amount.Carrier solution under various conditions is pH7.4 phosphate buffer solution (0.2M).

Fig. 3: by the 2-(10 of human skin tissue separated in Franz pond (n=5), 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (A, 30% solution), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (B, 30% solution), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (C, 30% solution), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (D, 30% solution), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (E, 30% solution), zaltoprofen (F, 30% suspension), bermoprofen (G, 30% suspension), loxoprofen (H, 30% suspension), indoprofen (I, 30% suspension) or fenclorac (J, 30% suspension) accumulation total amount.Carrier solution under various conditions is pH7.4 phosphate buffer solution (0.2M).

Fig. 4: by 4 of human skin tissue separated in Franz pond (n=5), 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (A, 30% solution), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (B, 30% solution), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (C, 30% solution), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (D, 30% solution), the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (E, 30% solution), oxaprozin (F, 30% suspension), fenbufen (G, 30% suspension), orpanoxin (H, 30% suspension), ketorolac (I, 30% suspension) or clidanac (J, 30% suspension) accumulation total amount.Carrier solution under various conditions is pH7.4 phosphate buffer solution (0.2M).

Fig. 5: to local 20% 2-(6-methoxyl group-2-how base) the propanoic acid lignocaine ethyl ester acetate (A) that is dissolved in 1ml isopropyl alcohol that uses in hairless mouse (n=5) back, Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate (B), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (C), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (D), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate (E) solution and naproxen (F), Shu Bufen (G), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid (H), after the solution of flurbiprofen (I) or carprofen (J), naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, total blood drug level of flurbiprofen and carprofen.

Fig. 6: to local 20% Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2,3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (A), 2-(the 4-chlorphenyl)-Alpha-Methyl-5-benzo that is dissolved in 1ml isopropyl alcohol that use in hairless mouse (n=5) back

zole acetic acid lignocaine ethyl ester acetate (B), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate (C), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (D), the chloro-4-(2 of 3-, 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (E) aqueous isopropanol and pranoprofen (F), Benoxaprofen (G), alminoprofen (H), after the solution of tiaprofenic acid (I) or pirprofen (J), pranoprofen, Benoxaprofen, alminoprofen, total blood drug level of tiaprofenic acid and pirprofen.

Fig. 7: to local 20% the 2-(10 that is dissolved in 1ml isopropyl alcohol that uses in hairless mouse (n=5) back, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (A), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (B), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (C), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (D), α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (E), zaltoprofen (F), bermoprofen (G), loxoprofen (H), after the solution of indoprofen (I) or fenclorac (J), zaltoprofen, bermoprofen, loxoprofen, total blood drug level of indoprofen and fenclorac.

Fig. 8: to hairless mouse (n=5) back local use be dissolved in 1ml isopropyl alcohol 20% 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (A), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (B), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (C), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (D), the chloro-5-of 6-cyclohexyl-2, the aqueous isopropanol of 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (E) and oxaprozin (F), fenbufen (G), orpanoxin (H), after the solution of ketorolac (I) or clidanac (J), oxaprozin, fenbufen, orpanoxin, total blood drug level of ketorolac or clidanac.

Fig. 9: after transdermal administration 50mg/kg2-(6-methoxyl group-2-how base) propanoic acid vinegar lignocaine ethyl ester hydrochlorate (B), Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate (C), Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (D), 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (E), 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate (F), mouse tail threshold of pain time expand.A is matched group.

Figure 10: transdermal administration 50mg/kg Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2,3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (G), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo

zole acetic acid lignocaine ethyl ester acetate (H), Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate (I), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (J), the chloro-4-(2 of 3-; 5-dihydro-1H-pyrroles-1-yl) after-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (K), mouse tail threshold of pain time expand.A is matched group.

Figure 11: transdermal administration 50mg/kg2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (L), 2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (M), 2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (N), 4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (O), α, after the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (P), mouse tail threshold of pain time expand.A is matched group.

Figure 12: transdermal administration 50mg/kg4; 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (Q), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (R), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (S), 5-benzoyl-2; 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (T), the chloro-5-of 6-cyclohexyl-2; after 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (U), mouse tail threshold of pain time expand.A is matched group.

Figure 13. the swelling rate (%) after the dish glue of injection angle.Angle dish glue is injected first 1 hour transdermal administration 2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate (100mg/kg; B); Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate (100mg/kg; C); Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid lignocaine ethyl ester acetate (100mg/kg; D); 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine ethyl ester acetate (100mg/kg; E); 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate (100mg/kg; F), A is matched group.

Figure 14: the swelling rate (%) after the dish glue of injection angle.Angle dish glue is injected first 1 hour transdermal administration Alpha-Methyl-5H-［ 1 ］ .alpha.-5:6-benzopyran ［ 2,3-b ］ pyridine-7-acetic acid lignocaine ethyl ester acetate (100mg/kg, G), 2-(4-chlorphenyl)-Alpha-Methyl-5-benzo zole acetic acid lignocaine ethyl ester acetate (100mg/kg; H); Alpha-Methyl-4-［ (2-methyl-2-acrylic) amino ］ phenylacetic acid lignocaine ethyl ester acetate (100mg/kg; I), 5-benzoyl group-alpha-methyl-2-thiophene acetic acid lignocaine ethyl ester acetate (100mg/kg, J); the chloro-4-(2 of 3-; 5-dihydro-1H-pyrroles-1-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, K), A is matched group.

Figure 15: the swelling rate (%) after the dish glue of injection angle.Angle dish glue is injected first 1 hour transdermal administration 2-(10, 11-dihydro-10-oxo dibenzo ［ b, f ］ sulfur Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, L), transdermal administration 100mg/kg2-(8-methyl isophthalic acid 0, 11-dihydro-11-oxo dibenzo ［ b, f ］ oxygen Zhuo-2-yl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, M), transdermal administration 100mg/kg2-［ 4-(2-oxo-cyclopentane base-methyl) phenyl ］ propanoic acid lignocaine ethyl ester acetate (100mg/kg, N), transdermal administration 100mg/kg4-(1, 3-dihydro-1-oxo-2H-iso-indoles-2-yl)-Alpha-Methyl phenylacetic acid lignocaine ethyl ester acetate (100mg/kg, O), transdermal administration 100mg/kg α, the chloro-4-cyclohexylphenylacetic acid of 3-bis-lignocaine ethyl ester acetate (100mg/kg, P), A is matched group.

Figure 16: the swelling rate (%) after the dish glue of injection angle.Angle dish glue is injected first 1 hour transdermal administration 4, 5-diphenyl-2-isoxazolepropionic acid lignocaine ethyl ester acetate (100mg/kg, Q), 3-(4-biphenylyl carbonyl) propanoic acid lignocaine ethyl ester acetate (100mg/kg, R), 5-(4-chlorphenyl)-beta-hydroxy-2-furan propanoic acid lignocaine ethyl ester acetate (100mg/kg, S), 5-benzoyl-2, 3-dihydro-1H-pyrrolopyrrole alkane-1-formic acid lignocaine ethyl ester acetate (100mg/kg, T), the chloro-5-of 6-cyclohexyl-2, 3-dihydro-1H-benzo ring propylene-1-formic acid lignocaine ethyl ester acetate (100mg/kg, U), A is matched group.

Figure 17: in structural formula 1, R represents CH ₃, OH, Cl, F or Br; R ₁represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R ₂represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R ₃represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; X represents O, S, NH, OCH ₂cOO, OCH ₂cOS or OCH ₂cONH; A ^-represent Cl ^-, Br ^-, F ^-, I ^-, AcO ^-, citrate, or other anion; N=0,1,2,3,4,5,6,7,8,9,10 Aryl represents aryl or heteroaryl.

Figure 18: in structural formula 2, W represents H, OH, Cl, F or Br; R ₁represent H, any 1-12 carbon atom alkyl, alkoxyl, alkenyl or alkynyl, or aryl; R ₂represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; R ₃represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom, or aryl; X represents O, S, NH, OCH ₂cOO, OCH ₂cOS or OCH ₂cONH; A ^-represent Cl ^-, Br ^-, F ^-, I ^-, AcO ^-, citrate, or other anion; N=0,1,2,3,4,5,6,7,8,9,10 Y or Y represent aryl and heteroaryl together with Z.

Preferred forms

2-(6-methoxyl group-2-how base) propanoic acid lignocaine ethyl ester acetate synthetic

11.7g (0.1mol) diethylaminoethanol is dissolved in the sodium bicarbonate aqueous solution and 100ml acetone of 200m110%, and 24.9g (0.1m0l) 2-(6-methoxyl group-2-how base) propionyl chloride is added in mixed liquor.Mixed liquor at room temperature stirs 3 hours.By solvent evaporate to dryness.The mixture of evaporate to dryness is suspended in 500ml ethyl acetate, and stirs the sodium bicarbonate aqueous solution that adds 200ml5%.Collect ethyl acetate, and wash with water 3 times, each 500ml.Ethyl acetate solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Under agitation add 6g acetic acid in reaction mixture.Evaporate to dryness organic solvent.After dry, obtain the easy hygroscopic target product of 36g, productive rate 89.8%.Dissolubility in water: 350mg/ml; Elementary analysis: C ₂₂h ₃₁nO ₅; Molecular weight: 389.49.Theoretical value (%) C:67.84; H:8.02; N:3.60; O:20.54; Measured value (%) C:67.82; H:8.04; N:3.58; O:20.56. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.36 (t, 6H), 1.50 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47 (m, 2H), 3.70 (s, 3H), 3.78 (m, 1H), 4.48 (t, 2H), 6.88 (b, 1H), 6.98 (s, 1H), 7.03 (d, 1H), 7.18 (d, 1H), 7.43 (s, 1H), 7.50 (d, 1H), 7.54 (d, 1H).

Embodiment

Synthesizing of Alpha-Methyl-4-(2-Thenoyl) phenylacetic acid lignocaine ethyl ester acetate

28.1g (0.1mol) Alpha-Methyl-4-(2-Thenoyl) phenyllacetyl chloride is dissolved in 100ml chloroform, is cooled to 0.C。In reaction solution, add 15ml triethylamine and 11.7g (0.1mol) diethylaminoethanol.Stirring at room 3 hours.By solvent evaporate to dryness.The solid mixture of evaporate to dryness is suspended in 300ml methanol, and stirs the sodium bicarbonate aqueous solution that adds 200ml5%, and then stirring at room is 3 hours.By mixture evaporate to dryness.In the mixture of evaporate to dryness, add 300ml dissolve with methanol.Solids removed by filtration, and wash with methanol.By solution evaporate to dryness, then add 200ml chloroform to dissolve.In reaction solution, stir and add 6g acetic acid.Remove by filter and generate a small amount of solid, filtrate stirring adds other 6g acetic acid.Evaporate to dryness organic solvent.After dry, obtain the easy hygroscopic target product of 35g, productive rate 83.2%.Dissolubility in water: 400mg/ml; Elementary analysis: C ₂₂h ₃₁nO ₅s; Molecular weight: 419.53.Theoretical value (%) C:62.68; H:7.41; N:3.32; O:18.98; S:7.61; Measured value (%) C:62.63; H:7.45; N:3.31; O:19.01; S:7.60. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.36 (t, 6H), 1.45 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.47 (m, 2H), 3.78 (m, 1H), 4.48 (t, 2H), 6.88 (b, 1H), 6.98 (s, 1H), 7.31 (d, 2H), 7.05 (m, 1H), 7.43 (m, 2H), 7.70 (d, 2H).

Synthesizing of 2-(the fluoro-4-xenyl of 2-) propanoic acid lignocaine second thioesters acetate

13.2g (0.1mol) diethylamino ethanethiol is dissolved in the sodium bicarbonate aqueous solution and 100ml acetone of 200ml10%, under agitation 26.3g (0.1mol) 2-(the fluoro-4-xenyl of 2-) propionyl chloride is added in mixed liquor.Reaction solution at room temperature stirs 3 hours.By solvent evaporate to dryness.The solid mixture of evaporate to dryness is suspended in 500ml ethyl acetate, and stirs the sodium bicarbonate aqueous solution that adds 200ml5%.Collect ethyl acetate layer, and wash with water 3 times, each 500ml.Ethyl acetate solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Under agitation add 6g acetic acid in reaction mixture.Evaporate to dryness organic solvent.After dry, obtain the easy hygroscopic target product of 36g, productive rate 85.8%.Dissolubility in water: 400mg/ml; Elementary analysis: C ₂₃h ₃₀fNO ₃s; Molecular weight: 419.55.Theoretical value (%) C:65.84; H:7.21; F:4.53; N:3.34; O:11.44; S:7.64.Measured value (%) C:65.80; H:7.23; F:4.55; N:3.32, O:11.47; S:7.63. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.35 (t, 6H), 1.44 (d, 3H), 2.11 (s, 3H), 3.20 (m, 4H), 3.30 (t, 2H), 3.80 (m, 1H), 3.88 (t, 2H), 6.88 (b, 1H), 6.88 (m, 1H), 6.95 (m, 1H), 7.22 (m, 1H), 7.32 (m, 2H), 7.41 (m, 1H), 7.48 (m, 2H).

N-diethyllaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolopyrrole alkane-1-Methanamide ester acetate synthetic

11.6g (0.1mol) diethylamino-ethylamine is dissolved in 200m110% sodium bicarbonate aqueous solution and 100ml acetone; under agitation, by 27.4g (0.1mol) 5-benzoyl-2,3-dihydro-1H-pyrrolopyrrole alkane-1-formyl chloride is added to mixed liquor.Reaction solution at room temperature stirs 3 hours.By reaction dissolvent evaporate to dryness.The mixture of evaporate to dryness is suspended in 500ml ethyl acetate, and stirring adds 200ml5% sodium bicarbonate aqueous solution.Collect ethyl acetate layer, and wash with water 3 times, each 500ml.Ethyl acetate solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Under agitation add 6g acetic acid in reaction mixture.Evaporate to dryness organic solvent.Dried to the easy hygroscopic target product of 35g, productive rate 84.8%.Dissolubility in water: 400mg/ml; Elementary analysis: C ₂₃h ₃₁n ₃o ₄; Molecular weight 412.50.Theoretical value (%) C:66.81; H:7.56; N:10.16; O:15.48; Measured value (%) C:66.90; H:7.38; N:10.18; O:15.54. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.39 (t, 6H), 2.10 (s, 3H), 2.27 (m, 2H), 3.22 (m, 4H), 3.50 (t, 2H), 3.60 (t, 2H), 3.80 (m, 2H), 3.71 (m, 1H), 5.85 (m, 1H), 6.70 (m, 1H), 6.85 (b, 1H), 7.32 (b, 1H), 7.40 (m, 1H), 7.45 (m, 2H), 7.78 (m, 2H).

N-dimethylaminoethyl 4,5-diphenyl-2- synthesizing of azoles propionic acid amide. acetate

29.3g (0.1mol) 4,5-diphenyl-2-

azoles propanoic acid is dissolved in 100ml acetonitrile, under agitation by 32.1g O-BTA-1-yl)-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester (HBTU) and 30ml triethylamine.11.6g diethylamino-ethylamine joins in mixed liquor.Reaction solution was stirring at room 3 hours.By reaction dissolvent evaporate to dryness.In reactant mixture, add 250ml ethyl acetate, and wash with water 3 times, each 100ml.Organic solution anhydrous sodium sulfate drying.Remove by filter sodium sulfate.Under agitation add 6g acetic acid in reaction mixture.Add 200ml hexane.Solid collected by filtration product.After dry, obtain the easy hygroscopic target product of 40g, productive rate 88.6%.Dissolubility in water: 400mg/ml; Elementary analysis: C ₂₆h ₃₃n ₃o ₄; Molecular weight: 451.56.Theoretical value (%) C:69.16; H:7.37; N:9.31; O:14.17; Measured value (%) C:69.11; H:7.40; N:9.30; O:14.19. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.41 (t, 6H), 2.10 (s, 3H), 2.45 (t, 2H), 2.76 (t, 2H), 3.22 (m, 4H), 3.49 (t, 2H), 3.60 (t, 2H), 6.87 (b, 1H), 7.22 (b, 1H), 7.22 (m, 2H), 7.32 (m, 4H), 7.47 (m, 4H).

Synthesizing of 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid lignocaine ethyl ester acetate

The immobilized triethylamine of 60g polymer (3mol/g, 100-200 order) is suspended in 180ml chloroform.Under being stirred, 27.4g (0.1mol) 6-chloro-Alpha-Methyl-9H-carbazole-2-acetic acid adds in mixed liquor.The hydrogen bromide salt of 43g (0.15mol) diethyllaminoethyl bromide adds in mixture, and mixture at room temperature stirs 5 hours.Filter and remove high molecular polymer, with oxolane, wash 3 times, each 50ml.In mixed liquor, stir and add 8.2g (0.1mol) sodium acetate.Then continue to stir 2 hours.Filter and remove solid, with chloroform, wash 3 times, each 50ml.By solution through being evaporated to 100ml.Then in solution, add 300ml hexane.Solid collected by filtration product, and with hexane, wash 3 times each 100ml.After dry, obtain the easy hygroscopic target product of 38g, productive rate 87.8%.Dissolubility in water: 400mg/ml; Elementary analysis: C ₂₃h ₂₉clN ₂o ₄; Molecular weight: 432.94; Theoretical value (%): C:63.81; H:6.75; CI:8.19, N:6.47; O:14.78; Measured value (%) C:63.85; H:6.78; CI:8.17; N:6.44; O:14.76. ¹h-NMR (400MHz, deuterochloroform solvent): δ: 1.39 (t, 6H), 1.47 (d, 3H), 2.11 (s, 3H), 3.21 (m, 4H), 3.49 (m, 2H), 3.77 (m, 1H), 4.48 (t, 2H), 6.80 (b, 1H), 6.85 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 7.26 (m, 1H), 7.34 (m, 1H), 7.50 (m, 1H), 7.52 (m, 1H).

Industrial applicability

General formula (1) " structural formula 1 " and the represented prodrug of general formula (2) " structural formula 2 " are better than naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and compound thereof.They can be used for the treatment of any naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen; carprofen, pranoprofen, Benoxaprofen, alminoprofen; tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen; loxoprofen, indoprofen, fenclorac; oxaprozin, fenbufen, orpanoxin; ketorolac, clidanac, and related compound can be treated the disease of humans and animals.They can slow down rheumatic arthritis and osteoarthritis symptom, bring down a fever, and treatment dysmenorrhea.These prodrugs also can be used for treating diabetic neuropathy and acute migraine.Because it is very fast that these prodrugs see through biomembranous speed, they can also treat asthma by the mode sucking with spray-type.Because these prodrugs have antiinflammation, they can also treat psoriasis, acne, sunburn and other dermatosis.

Claims

1. a pharmaceutical composition, it comprises at least one by the compound shown in structural formula 1 or structural formula 2, wherein,

In structural formula 1, R represents CH ₃, OH, Cl, F or Br; R ₁represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; R ₂represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; R ₃represent H; X represents O, S, OCH ₂cOO, OCH ₂cOS, or OCH ₂cONH; A-represents anion;

N=0,1,2,3,4,5,6,7,8,9, or 10; Aryl represents following structure:

In structural formula 2, W represents H, OH, Cl, F or Br; R ₁represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; R ₂represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; R ₃represent H; X represents O, S, OCH ₂cOO, OCH ₂cOS or OCH ₂cONH; A ^-represent anion;

N=0,1,2,3,4,5,6,7,8,9, or 10; Y represents H; Z represents following structure:

Or W represents H, Z represents following structure together with Y:

2. compositions as claimed in claim 1, wherein said in the compound shown in structural formula 1 or structural formula 2 or

residue is partly to obtain by being selected from least one compound deriving in naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac and clidanac.

3. the preparation method of compositions as claimed in claim 1 or 2, it comprises naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac represented with structural formula 5 compound by coupling agent, react " to is " comprising by naproxen, suprofen, Alpha-Methyl-(to chlorobenzene acyl group)-5-methoxyl group-2 methyl indole-3-acetic acid, flurbiprofen, carprofen, pranoprofen, Benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac or more than the etheride of compound or mixed acid anhydride and structural formula5 represented compounds react by coupling agent,

Wherein,

In structural formula 5, R ₃represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; R ₄represent H, the alkoxyl of the alkyl of any 1-12 carbon atom, a 1-12 carbon atom, the thiazolinyl of a 1-12 carbon atom or the alkynyl of 1-12 carbon atom; X represents O or S; N=0,1,2,3,4,5,6,7,8,9,10; With

Described coupling agent comprises: N, N '-dicyclohexyl carbimide, N, N '-diisopropyl carbimide, O-BTA-N, N, N ', N '-tetramethylurea Tetrafluoroboric acid ester, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, BTA-1-base-oxygen base-tri-(dimethyl amido) phosphorus-hexafluorophosphate.

4. skin-penetrating therapeutic application system, it contains pharmaceutical composition as claimed in claim 1 or 2.

5. skin-penetrating therapeutic application system as claimed in claim 4, is characterized in that described system is binder or paster, the protective layer that it contains a hypothallus that comprises active substance and a non-infiltration.

6. skin-penetrating therapeutic application system as claimed in claim 4, is characterized in that containing an active substance reservoir, and it contains a permeable bottom towards skin.

7. skin-penetrating therapeutic application system as claimed in claim 4, is characterized in that making nonsteroidal antiinflammatory drug be stabilized in optimal treatment blood drug level by controlling rate of release, thereby improves curative effect, and reduce NSAID side effect.

8. skin-penetrating therapeutic application system as claimed in claim 5, is characterized in that making nonsteroidal antiinflammatory drug be stabilized in optimal treatment blood drug level by controlling rate of release, thereby improves curative effect, and reduce NSAID side effect.

9. the purposes of pharmaceutical composition as claimed in claim 1 or 2 in the medicine of state of the available NSAIDs in Treatment for the preparation for the treatment of human or animal.

10. purposes as claimed in claim 9, wherein said medicine is solution, suspension, spray, emulsion, ointment, latex or gel dosage form.

11. purposes as claimed in claim 9, the state of wherein said available NSAIDs in Treatment is selected from: the vomiting that pain, fever, cancer, radiotherapy cause, diabetic neuropathy, glaucoma, dermatosis, bone loss, sunburn, arthritis and other inflammation.

12. purposes as claimed in claim 11, wherein said arthritis is hemophilic arthritis.

13. purposes as claimed in claim 11, wherein said pain is selected from ocular pain, arthritis pain and other inflammatory pain after headache, toothache, dysmenorrhea, acute migraine, myalgia, operation on cornea.

14. purposes as claimed in claim 11, wherein said dermatosis is selected from psoriasis, acne or other dermatosis.

15. purposes as claimed in claim 11, wherein said inflammation is selected from eye inflammation and ear's inflammation.

16. purposes as claimed in claim 9, wherein said medicine is treated by the mode of oral or transdermal administration.

17. purposes as claimed in claim 9, wherein said medicine is treated by the skin-penetrating therapeutic application system as described in any one in claim 3 to 7.

18. the purposes of pharmaceutical composition as claimed in claim 1 or 2 in the medicine of the asthma for the preparation for the treatment of human or animal.

19. purposes as claimed in claim 18, wherein said medicine is treated by the mode of lip-syncing or nose or other position spray deliveries of health.